Almost half of pediatric third-year residents surveyed in 2000 had never led a resuscitation event. With increasing restrictions on residency work hours and a decline in patient volume in some hospitals, there is potential for fewer opportunities.Our primary purpose was to test the hypothesis that an unannounced mock resuscitation in a high-fidelity in-situ simulation training program would improve both residents’ self-confidence and observed performance of adopted best practices in neonatal resuscitation.Each pediatric and medicine–pediatric resident in one pediatric residency program responded to an unannounced scenario that required resuscitation of the high fidelity infant simulator. Structured debriefing followed in the same setting, and a second cycle of scenario response and debriefing occurred before ending the 1-hour training experience. Measures included pre- and post-program confidence questionnaires and trained observer assessments of live and videotaped performances.Statistically significant pre–post gains for self-confidence were observed for 8 of the 14 NRP critical behaviors (p=0.00–0.03) reflecting knowledge, technical, and non-technical (teamwork) skills. The pre–post gain in overall confidence score was statistically significant (p=0.00). With a maximum possible assessment score of 41, the average pre–post gain was 8.28 and statistically significant (p<0.001). Results of the video-based assessments revealed statistically significant performance gains (p<0.0001). Correlation between live and video-based assessments were strong for pre–post training scenario performances .Results revealed high receptivity to in-situ, simulation-based training and significant positive gains in confidence and observed competency-related abilities. Results support the potential for other applications in residency and continuing education. Four million babies are born in the United States per year. Approximately 10% of all neonates require some level of resuscitation by health care providers at the time of birth, and less than 1% will require advanced resuscitative measures . The firBecoming proficient in the NRP usually requires routine participation in real-life events. The Accreditation Council for Graduate Medical Education (ACGME) and the Residency Review Committee (RRC) allow a maximum of 6 months of intensive care in a pediatric training program . Based oHow feasible is it to engage all pediatric and medicine–pediatric residents at all training levels in a NRP in-situ simulation-based training program using unannounced mock codes and a high-fidelity infant simulator (HFIS), the Laerdal SimNewB™?To what extent do residents’ self-confidence for performing critical NRP behaviors change from pre- to post-simulation training assessments, as measured by residents’ responses on pre- and post-training questionnaires?How do residents’ performances change from pre- to post-simulation training, as measured by direct observation conducted by trained assessors using an assessment instrument for critical NRP performance behaviors?To what extent do direct observation-based assessment data correlate with residents’ self-confidence to perform critical NRP behaviors?To what extent do data from video-based assessments correlate with those from direct observation-based assessments of residents’ live NRP performances?In the last decade, simulation-based training has been increasingly adopted for clinical training across the medical education continuum. Such training often immerses trainees in realistic scenarios. These scenarios replicate real-life situations with sufficient fidelity to achieve ‘suspended disbelief’ . Such trPrior to initiation of the program, approval was obtained by the LSU Health-New Orleans Institutional Review Board. The sample was comprised of all 2009–10 Pediatric and Medicine–Pediatric residents at LSUHNO who rotated through Children's Hospital of New Orleans, Louisiana (CHNOLA) during the study period (January–June 2010). Subjects were included if they participated in the unannounced HFIS resuscitation training and voluntarily completed the study questionnaires. Residents were informed about the project prior to initiation, that each would participate in only one session, but they would not know when they would be called to a training session; thus, creating the unannounced mock code feature.An area of the neonatal intensive care unit (NICU) was set up to support the training environment. Upon arrival to an unannounced mock code, the resident encountered and responded to HFIS resuscitation scenario that required him/her to perform both bag and mask positive pressure ventilation (PPV) and chest compressions in an infant delivered by emergent cesarean section for non-reassuring fetal heart tones. A staff nurse participated as an actor in the scenario to reflect a real-life situation. Resuscitation proceeded up to 10 min followed immediately by a structured debriefing session in the same setting between the resident and faculty trainer, lasting 10–15 min . The sceIn the focused debriefings, the faculty trainer/facilitator prompted the resident to reflect on what went well and what could be improved. The trainer also provided specific feedback and coaching, targeting specific improvement strategies to focus practice on enhancing targeted knowledge and behaviors/skills. Closure was achieved by summarizing the scenario-based experiences, reinforcing strengths, and targeting specific strategies for further improvement. Because debriefing occurred in the simulation setting, video recordings were not necessary to achieve accurate recall. Residents were asked to honor the confidentiality of the session and scenarios by not discussing these with anyone outside of the session.Kirkpatrick's four levels of training effectiveness provided a model for program evaluation . ResidenThe pre- and post-training questionnaire contained several demographic items  and 14 specific behaviors reflecting adopted NRP best practices derived from literature review and input from content experts experienced with resident education . Residents responded to the 14 NRP items using a four-point Likert-type scale  that yielded a maximum possible total score of 56. Residents responded to the same 14 NRP items on the post-training questionnaire and also to 10 items pertaining to session effectiveness . Three open-ended questions provided additional opportunities for residents to comment on their desire for future training, input on increasing realism of scenarios, and other feedback for improving training sessions. The direct observation assessment instrument used for both live and video-recorded resident performances included the specific behaviors reflected in 14 NRP critical behaviors and additional performance quality and time measurements defined for specific NRP behaviors, yielding 23 discrete assessment judgments. The overall structure of the instrument was an adaptation of an assessment protocol developed and used previously for evaluating simulation-based training in pediatric resuscitation using unannounced mock codes in which the instrument demonstrated good psychometric qualities. Scoring of the observation-based assessments yielded a maximum possible total score of 41.Residents completed the pre-program questionnaire at the start of the project period before any training was initiated. Residents completed the post-training session questionnaire immediately upon completion of their respective training event. For each questionnaire, residents followed directions to generate a record identification code for matching individual responses across measures, while maintaining anonymity. At each training session, one trained observer only recorded the directly observed behaviors and did not assign any numerical scores. A senior member of the team representing an expert clinician (‘gold standard’) completed a separate and independent observation-based assessment of each video-recorded resident performance using the same instrument that was used in the live session. All observation-based assessments were subsequently scored by two members of the research team using a standard ‘grading’ rubric reflecting the critical NRP behavior standards. Three trained assessors were neonatology Fellows, of which one was a senior neonatology faculty member who served as the ‘Gold standard’ content expert.t-test for observation-based assessment data. To examine relationships between residents’ self-confidence and actual observed performance and between observation data for live and video-based assessments, correlational analyses were conducted.After data compilation and initial screening, descriptive statistics were calculated. Data for the pre- and post-self-confidence questionnaire responses were examined using the Wilcoxon Signed Rank Test. Content analysis was used to examine narrative responses to open-ended questions for common perspectives. Comparison of residents’ performances in scenarios 1 and 2 was accomplished using the paired Results are reported by the research questions set forth at the beginning of this article.in situ unannounced mock code training sessions per training day. No narrative feedback from residents or feedback from faculty and staff participants indicated any significant interruption or inconvenience with other typical responsibilities.Each of the 32 residents rotating through CHNOLA during the study period completed one training session and participated voluntarily in the study . One faculty member was able to conduct one or more Pre-training data were not available for five residents due to a logistical glitch, so the analysis included matched pre/post data for 27 residents. t-test, n=32, p<0.0001). Results of the observation-based assessments using a video recording also revealed statistically significant performance gains (p<0.0001). Results showed an improvement in response time and quality of actions from the first simulation scenario to the second. The greatest improvement was found in first-year trainees (PGY-1). The average performance scores for each of the two scenarios, represented per year of training, are shown in With a maximum possible total score of 41, the average pre–post gain was 8.28 and statistically significant .Correlation between the live and video-based observations was strong for both pre- and post-training scenario performances . The differences in total scale scores between live and video-based observations were greater for pre than post-training performances . Pre- to post-training gains were noted for both live and video-based observations, and item ratings were generally higher for video-based than live assessments.Several limitations of this study are worthy of mention. First, the study occurred in one setting at one institution with pediatric residents. Second, the study did not include a control group, but used residents as their own control through pre–post training measures. Given the existing structure of residents’ educational program and limited hands-on NRP experience, and faculty agreement that NRP knowledge and skill was limited, priority was given to providing training to all currently enrolled residents. Third, training evaluation included measures addressing Kirkpatrick's Levels 1–3 , but Level 4 measurement of actual practice outcomes in the real-life setting was not possible because of logistical constraints. The extent to which the results generalize to other pediatric residency programs will depend on the similarity of contexts and residents’ prior experiences in neonatal resuscitation. Also, replication of the curriculum and training with an intervention and control group and the inclusion of Level 4 outcomes measurement would contribute to strengthening the program evaluation design and resulting evidence from conclusions could be generalized to other pediatric residency settings.in situ NRP simulation-based training program was logistically feasible. Training fit well within the context of the existing curriculum and clinical care requirements. Using an unannounced/unscheduled format provided the flexibility necessary to complete activities within the context of the residents’ schedule and the requirements of a typical work day within a reasonable study time frame. Most residents responded positively to the unannounced mock NRP simulation training.Regarding Question 1, results demonstrated that the in situ, for learning and assessing clinical skills when real-life experiences are either insufficient or inappropriate for teaching, learning, and assessment. In the context of developing future physicians, self-confidence is an important measure at certain points within a curriculum and for certain learning experiences . Consequently, from an educational and practical perspective, the statistically significant gains in self-confidence for 8 of 14 NRP critical performance behaviors are considered an important contribution of this study.Results pertaining to Question 2 (self-reported self-confidence) provided strong evidence of the efficacy of simulation-based training for NRP. While self-confidence is not entirely a proxy for actual performance in real-life settings, its contribution should not be under-estimated. According to Bandura's construct of self-efficacy and the work on developing expertise by Ericsson et al., self-confidence is a significant influence on individuals’ motivation and self-regulation of behavior , 32–35. The results pertaining to Question 3  reiterate the caution previously communicated about using self-confidence as an overall proxy measure for actual performance or behavior change. However, as mentioned in the previous paragraph, there are other valid reasons for attending to and measuring self-confidence in the teaching and learning process. Upon closer examination of the data, we observed that third-year residents’ self-confidence ratings were higher than those of less experienced residents, perhaps simply reflecting a higher level of motivation and persistence to strive toward achievement and expertise, given their closer proximity to graduation and entry into professional practice. Similarly, we observed that three of the first-year residents reported less self-confidence on post-training than pre-training, possibly an indication of their inflated espoused abilities prior to having hands-on experiences in real-life and simulation scenarios. Their post-training responses may be indicative of achieving a more accurate self-appraisal that resulted from the simulation-based training. This may be an important consideration for the use of simulation-based training as a strategy for enhancing both individual motivation and self-regulation in professional learning and for improving safety in patient care for the future.Question 4 was important to consider the feasibility of using video-based observation as an accurate alternative to conducting assessment during the live simulation-based training sessions. We recognize that seeing and hearing performances is easier and more accurate in the live observations, as the placement and fidelity of video cameras cannot substitute for the incredible abilities of the human senses. The positive and statistically significant correlation between live and video-based assessments was encouraging. The higher correlation between live and video assessments for observations of post-training performances may have been due the residents’ more explicit or enhanced demonstration of specific behaviors in post-training performances or it may have been due to the influence of practice on assessors’ abilities in observing and recording judgments on the assessment instrument. With increased demands and time constraints, the use of a video-based approach for performance-based assessment appears to be a practical option, at least for low-stakes, informal assessments used for coaching and providing formative feedback.In summary, we are encouraged by the study results regarding the development of a sustainable, standardized curriculum to enhance NRP competency in pediatric residents. While self-confidence and demonstration of improved abilities in a realistic, simulated scenario is important, there is still the need to include examination of the transfer of learning and abilities to real-life practice and to relevant outcomes . Furthermore, the NRP simulation-based training model may be a viable option for maintaining adequate levels of competency for specific clinical knowledge, technical, and non-technical skills reflected in low frequency, high stakes situations or when learning and training in procedural skills is not feasible or appropriate in the context of real patient care. In addition to residency training, such use of in-situ and center-based simulation could be highly relevant for physicians in practice, particularly in certain types of communities where frequency and consequence may be even more critical  , 39, 40.


Colorectal cancer (CRC) is the third most common cancer in the world. In 75% CRC develops sporadically, in 25% hereditary or as a consequence of inflammatory bowel disease. CRC carcinogenesis develops over many years. The cause of CRC in 85% is chromosomal instability (CIN) and in 15% microsatellite instability (MSI-H), where hereditary nonpolyposis colorectal cancer (HNPCC) represents 10–20%. Microsatellite sequences (MS) are repeated sequences of short stretches of DNA all over the genome. Microsatellite stability (MSS) means MS are the same in each cell of an individual, whereas microsatellite instability (MSI-H) means MS differ in normal and cancer cells of an individual. The cause of MSI-H is a damaged mismatch repair mechanism (MMR), with the most important MMR proteins being MSH2, MLH1 and MSH6.MSI-H seems to be an important prognostic factor in CRC and an important predictive factor of CRC chemotherapeutic treatment efficacy. Clinical trials conducted until now have shown contradictory findings in different chemotherapeutic settings, adjuvant and palliative; therefore MSI-H is going to be the object of the future research. The future of cancer treatment is in the individualized therapy based on molecular characteristics of the tumour, such as MSI-H in CRC. Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer related deaths in the world.520 years ago Fearon and Vogelstein developed a theory about CRC carcinogenesis on the genetical level they called multistep carcinogenesis.11CRC develops because of the genomic instability as a consequence of mutations in gatekeeper and caretaker genes.189 base pairs the rate of mutation would be more than thousand errors with each cell replication.26CRC developing because of MSI has smaller genomic abnormalities, CRC is diploid without major chromosomal abnormalities.In cells with MMR genes mutation replication errors occur, MS develop mutations and in some cells MSI-H occurs. MSI-L CRC does not appear to differ clinically or pathologically from MSS CRC.32The functions of MMR proteins are recognition of mis-incorporated base pairs, the recognition of mother and daughter DNA strand and repairing mis-incorporated base pairs with the base excision. In bacteria MMR mechanism is comprised out of three MMR proteins: MutS, MutL and MutH .3333MutS protein forms a dimmer and recognizes mismatched base pairs on the daughter strand or nucleotides not being paired. MutL protein binds to the MutS - the daughter DNA strand complex and enables binding of MutH protein. MutH recognizes the daughter DNA strand that is not methylated. The daughter strand is split at the nearest GATC sites in 5′ and 3′ direction. MutH also has an endonuclease activity; it excises the daughter DNA strand between the both restriction sites. DNA polymerase and ligase complete the missing daughter strand and enzyme methylase finishes the process of replication by methylating it.36In hereditary form of CRC HNPCC most commonly mutated genes are hMSH2, hMSH6 in hMLH1. In the sporadic form of CRC the most commonly present mutation is an epigenetic alteration, hMLH1 promotor hypermethylation, and its subsequent lower expression.37CRC is defined as MSI-CRC because of mutations present in the MS of CRC cancer cells. MSI-H and MSI-L are further characterized by the number of positive Bethesda markers as noted earlier in this article. CRC is defined as being MSS if there are no mutations in the MS of CRC cancer cells. Apart from its genetic origin MSI-H CRC differs from MSS CRC in many other features.48The chemotherapeutic treatment carries with its adverse effects that are more or less expressed in an individual.In vitro cell line trials concerning MSI-H cells have shown the resistance to the treatment with 5-FU.59Three classes of chemotherapeutic agents are used in CRC treatment: antimetabolites, alkylating agents and topoisomerase inhibitors.In vitro cell line trials concerning MSI-H cells have shown higher sensitivity to irinotecan.61Chemotherapeutic irinotecan causes with inhibition of enzyme topoisomerase I brakes of DNA strand and apoptosis of cancer cell. Chemotherapeutic oxaliplatin is an alkylating agent and is a platinum analog. Platinum analogs form covalent bonds with DNA strand stopping the cell cycle and causing apoptosis.47et al. have conducted the first metaanalysis of clinical trials about MSI-H as a prognostic factor in CRC.et al. have conducted a metaanalysis of 7 clinical trials of MSI-H as a predictive factor in adjuvant chemotherapeutical setting in stage II and III of the disease after the surgical treatment.et al. have also conducted a metaanalysis of 6 clinical trials of MSI-H as a predictive factor in palliative chemotherapeutical setting in stage IV of the disease.et al. have conducted a metaanalysis of 31 clinical trials with 12872 patients, 1972 of them were MSI-H, representing 15.4% of all patients in all stages of the disease.In the recent 5 years several metaanalyses concerning MSI-H as a prognostic and predictive factor of CRC chemotherapeutic treatment were performed . In 2005et al. have conducted a trial where they developed a prognostic model of determining probability of MSI-H in CRC regarding the clinical and pathological characteristics of patients diagnosed with CRC.CRC develops through MSI-H pathway in 15%. It, therefore, would not be cost efficient to determine the MSI-H status in each CRC patient. In 2010 Sinicrope Cancer patients nowadays have more and more diagnostic and therapeutic possibilities. The future of their treatment is an individualized therapy determined by patient characteristics and by tumour molecular characteristics that influence survival, chemotherapeutic treatment efficacy and incidence of adverse effects. MSI status is one of those prognostic and predictive factors in CRC.


Patients are at risk of developing pressure injuries in the peri-operative setting. Studies evaluating the impact of educational interventions on peri-operative nurses’ knowledge and reported practice are scarce. The purpose of this study was to evaluate the effect of a multifaceted intervention on peri-operative nurses’ (a) knowledge of pressure injury risks, risk assessment and prevention strategies for patients in the operating suite; and (b) reported practice relating to risk assessment practices and implementation of prevention strategies for patients in the operating suite.A before-after research design was used. A convenience sample of all registered and enrolled nurses employed in two hospitals’ operating suites was recruited. A multifaceted intervention was delivered which comprised a short presentation, educational materials and reminder posters. A 48-item survey tool was completed pre-and post-intervention to measure self-reported knowledge and practice.70 eligible peri-operative nurses completed both surveys. Post-intervention, statistically significant improvements were seen in knowledge of correct descriptions of pressure injury stages (p=0.001); appropriate reassessment for patients with a new pressure injury (p=0.05); appropriate actions for patients with an existing stage 1 (p=0.02) and stage 2 pressure injury (p=0.04). Statistical improvements were also seen in reported practice relating to an increase in the use of a risk assessment tool in conjunction with clinical judgement (p=0.0008); verbal handover of patients’ pressure injury risk status from the operating room nurse to the recovery room (p=0.023) and from the recovery room nurse to the postoperative ward nurse (p=0.045). The number of participants reporting use of non-recommended and recommended pressure-relieving strategies was unchanged.A multi-faceted educational intervention can improve some aspects of perioperative nurses’ knowledge and reported practice such as risk assessment practices but not others such as use of recommended pressure-relieving devices. Further research is required to ascertain effective interventions which improve all areas of practice and knowledge, particularly in the use of appropriate pressure-relieving devices in order to prevent pressure injuries in surgical patients. Pressure injuries  are painful injuries of the skin or the underlying tissues, which form most often over a bony prominence as a result of unrelieved pressure, either in isolation or in combination with shearing forces . PressurReported pressure injury prevalence rates for acute care settings in Canada, Europe, Australia and North American range from 10–28% -14. In rTo address these evidence-practice gaps, a number of studies have evaluated the impact of different strategies on nurses’ knowledge and practice, although no studies were found that had specifically targeted peri-operative nurses. For example, following a 40-minute education session (didactic presentation of slides with question and answer) the knowledge of nurses working in an acute hospital setting in the United States improved when tested immediately after the education . HoweverConsidering that a number of studies and systematic reviews have found that multi-faceted interventions are effective in changing practice for a number of areas of clinical care ,41, thisThe aims of the study were twofold: to determine the effect of an educational intervention on(a) peri-operative nurses’ knowledge of pressure injury risk assessment and prevention strategies for patients in the operating suite; and (b) peri-operative nurses’ reported practice regarding pressure injury risk assessment and prevention strategies for patients in the operating suite.This research was designed as a pre-post intervention study.The study was conducted in the operating suites of two large metropolitan hospitals in Sydney, between April 2009 and February 2010. Hospital 1 is a 305-bed tertiary-referral facility in the public sector and Hospital 2 is a 195-bed private facility.A convenience sample of all eligible registered and enrolled nurses employed in the participating operating suites was recruited for the survey. Nurses working in direct-patient care roles in the operating theatre setting and employed on a full-time or part-time basis were eligible for inclusion (part-time was defined as minimum of two shifts per fortnight and the expected duration of the study was nine months). Nurses employed for short clinical placements to the operating suites; on a casual basis or employed for specific surgeons’ lists were not eligible as they would not be present for the entire study period. An invitation letter and a pre-intervention questionnaire was attached to all eligible nurses’ payslips six weeks before the educational intervention. Completion of the questionnaire was considered implied consent to participate in the study.The multifaceted intervention, Pressure Ulcer Prevention Program (PuPP), was developed by the first author, who is a registered nurse with 30 years experience in the peri-operative setting. Core content was derived from the latest national pressure injury prevention guidelines at the time of the study  and fromPuPP comprised three elements: i) a 30 minute presentation by the first author on pressure injury risks and prevention strategies for the peri-operative setting; ii) a companion folder of educational materials, additional reference material and policy documents; and iii) a series of reminder posters on the key points from the presentation. The latter two resources were placed in the peri-operative workplace and all nurses would have been exposed to these resources in the course of the working day. The intervention was implemented from August to December 2009, approximately six weeks after distribution of the pre-intervention survey.The pre-intervention survey was conducted April–July 2009 and the post-intervention survey was conducted October 2009–February 2010. Secure survey collection boxes were provided for anonymous return of completed questionnaires and consent forms in both operating suites. The same process was repeated for the post-intervention survey six weeks after the educational sessions were held. There were three prompts at each time period to remind non-responders to complete their questionnaires.The self-administered standardised questionnaire was developed for the study by the first author, with reference to content in similar questionnaires that have assessed nurses’ pressure injury knowledge and practice ,47,48 anThe questionnaire comprised 48 items (closed and open-ended questions). Demographic data was collected on employment details, practice areas and peri-operative roles and year of first nursing qualification. Reported knowledge was measured at both time points by questions on: a) pressure injury staging; b) definitions of pressure injury stages according to the NPUAP (2007) stages and local policy; and c) post-operative nursing actions to manage a patient with a new stage 1 heel pressure injury and a new stage 2 pressure injury on the buttocks.Reported practice was measured at both time points by questions on: a) methods  used for pressure injury risk assessment; b) selection of positioning and pressure relieving devices most frequently used for pressure prevention in the peri-operative setting from a list which included recommended devices, non-recommended devices and devices for which there is no evidence of effectiveness, and c) the use of pressure injury risk assessment scores during clinical handover.Five case scenarios were used as a basis for questions related to reported practice Table . In CaseThe protocol for this research project was approved by the Human Research Ethics Committee of the Australian Catholic University and hospital sites. Consent was implied by return of questionnaire.t-test to analyse any changes in mean scores relating to knowledge and practice post-intervention that was measured using Likert scales.Analysis was undertaken on those who had completed both the pre and post-intervention questionnaires. Sample characteristics and paired data were analysed using SPSS (Version 17.0). Frequencies were obtained for all variables. Significance tests were conducted using McNemar’s test for analyses of paired categorical data and the paired Questionnaires were distributed to all eligible nurses at both operating suites  and we received a total of 90 surveys back from the pre-intervention mail out (response rate 62%) and 90 surveys from the post-intervention mail out (response rate 63%).Seventy nurses participated in both surveys, and these comprised the sample for analysis. The majority of these nurses were registered nurses . The number of years since first nursing qualification ranged from 2 to 44 years with the mean number of years being 16 (sd 11). The majority of nurses qualified from 1986 when nursing education in Australia was transferred from the hospital to the university sector . More than two-thirds of nurses were employed full-time. Table X2(3)=30.12, p=0.001). For a patient with a new stage 1 PI on the heel, a significantly higher proportion of participants post-intervention reported that they would re-assess the patient’s PI Risk Assessment score, increasing from 41% to 57% (X2(1)=4.71, p=0.05) (Table X2(1)=0.40, p=0.02) or a new stage 2 pressure injuries on the buttocks =8.08, p=0.04). All other results were non-significant =3.26, p=0.0001), and would use both a PI risk assessment tool and clinical judgement =0.01, p=0.008). Pillows, gel pads and gel overlays were the three most frequently reported devices used for pressure prevention in the peri-operative setting both pre-and post-intervention (ranging from 61% to 96%). The numbers of those using non-recommended devices or devices with no evidence to support their use did not change. There was a statistically significant mean increase in the likelihood that the patient’s PI risk assessment score would be verbally reported during clinical handover from the operating room nurse to the recovery room  and significantly higher mean increase in participants reporting that it was likely that the PI score would be verbally reported from the recovery room nurse to the postoperative ward nurse . There were no other significant results . In addition, significantly fewer nurses reported post-intervention they would use the non-recommended action of rubbing or massaging the affected area for a patient with a new pressure injury. There were, however, no improvements in knowledge regarding notification of the nurse at handover of new pressure injuries (stage 1 or 2); completion of an incident report and repositioning the patient onto their side (recommended practice). It is of concern from a patient safety perspective that a multifaceted and comprehensive evidence-based intervention, specifically targeted at nurses who are involved at all stages of the patient peri-operative journey, did not increase their knowledge on these factors.Encouragingly, two measures of nurses’ reported practice showed improvement following the intervention. Significantly more nurses post-intervention reported using a tool in combination with clinical judgement in line with best practice . This isThere were no changes in relation to knowledge or practice of use of non-recommended pressure prevention devices. Ongoing use of non-recommended actions for pressure injuries such as the use of donut air-pillows, which have been long discredited, has also been reported by other researchers ,26,52. TIn addition, there was no reported increase in terms of perioperative nurses use of recommended pressure-relieving devices. However, for some recommended devices use was high at both time points (90% for one recommended device and nearly 80% for another). It is likely too that surgeons’ and anaesthetists’ preferences for particular pressure-relieving devices may be an influential factor in use of particular devices. This suggests that future interventions focused on disseminating evidence-based recommendations should target the entire peri-operative team.Our results indicated that there are reported practices and areas of knowledge that are harder to shift in the desired direction in line with the evidence, a situation that has been reported in nursing implementation research . StudiesDeficiencies in knowledge and practice of aspects of pressure injury prevention in the peri-operative setting despite a multi-faceted intervention is concerning because surgical patients are at high risk of postoperative pressure injuries. Further research is therefore warranted to investigate the factors that influence peri-operative nurses and other peri-operative team members decision-making in respect of evidence-based care, in order to better inform the development of future targeted interventions.The strengths of this study include the survey size, which was multi-site, with peri-operative nurses participating from two large metropolitan hospitals, and the good response rate of 62% pre-intervention and 63% post-intervention which is comparable with other surveys of hospital clinicians . We calcOur study found that educational interventions can improve some aspects of nurses’ knowledge and reported practice in peri-operative settings. Practices relating to the use of non-recommended pressure-relieving support surfaces may be more difficult to change and require additional intervention strategies such as audit and feedback and simultaneous introduction of guidelines and recommended pressure-relieving devices. Education on pressure injury risks, risk assessment and prevention strategies should be included in orientation programs and with ongoing education in the peri-operative setting. Where practice is influenced by team-based decisions, such as in the operating room, interventions should consider targeting all members of the peri-operative team. Further research is needed to investigate whether improvements in peri-operative nurses’ knowledge and reported practice are associated with improvements in nurses’ actual practice and whether this in turn affects pressure injury incidence in the post-operative period.PI: pressure injury.The authors declare that they have no competing interests.SS-F conceived the study topic. SS-F and SM finalised the study design. EM and SM advised on protocol details including recruitment. SS-F, EM and EMaher prepared the framework of this manuscript. SS-F and EMaher collected and inputted data. SS-F, EMaher and EM analysed the data. SS-F and EM led revisions of the paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6955/11/25/prepub


In sub-Saharan Africa, malnutrition and malaria remain major causes of morbidity and mortality in young children. There are conflicting data as to whether malnutrition is associated with an increased or decreased risk of malaria. In addition, data are limited on the potential interaction between HIV infection and the association between malnutrition and the risk of malaria.A cohort of 100 HIV-unexposed, 203 HIV-exposed (HIV negative children born to HIV-infected mothers) and 48 HIV-infected children aged 6 weeks to 1 year were recruited from an area of high malaria transmission intensity in rural Uganda and followed until the age of 2.5 years. All children were provided with insecticide-treated bed nets at enrolment and daily trimethoprim-sulphamethoxazole prophylaxis (TS) was prescribed for HIV-exposed breastfeeding and HIV-infected children. Monthly routine assessments, including measurement of height and weight, were conducted at the study clinic. Nutritional outcomes including stunting (low height-for-age) and underweight (low weight-for-age), classified as mild (mean z-scores between -1 and -2 during follow-up) and moderate-severe (mean z-scores < -2 during follow-up) were considered. Malaria was diagnosed when a child presented with fever and a positive blood smear. The incidence of malaria was compared using negative binomial regression controlling for potential confounders with measures of association expressed as an incidence rate ratio (IRR).The overall incidence of malaria was 3.64 cases per person year. Mild stunting  and moderate-severe stunting  were associated with a similarly increased incidence of malaria compared to non-stunted children. Being mildly underweight  and moderate-severe underweight  were not associated with a significant difference in the incidence of malaria compared to children who were not underweight. There were no significant interactions between HIV-infected, HIV-exposed children taking TS and the associations between malnutrition and the incidence of malaria.Stunting, indicative of chronic malnutrition, was associated with an increased incidence of malaria among a cohort of HIV-infected and -uninfected young children living in an area of high malaria transmission intensity. However, caution should be made when making causal inferences given the observational study design and inability to disentangle the temporal relationship between malnutrition and the incidence of malaria.NCT00527800.ClinicalTrials.gov:  Malaria is a leading cause of childhood morbidity and mortality in sub-Saharan Africa . AccordiFindings from studies evaluating associations between various measures of malnutrition and malaria have been contradictory. Some studies suggest a protective effect against malaria for wasted children  and chilThe role that HIV exposure and infection may have on potential associations between malnutrition and malaria in children has not yet been reported. This is a critical gap because HIV infection has been associated with an increased risk of both malnutrition ,16 and mTo assess associations between paediatric malnutrition and the incidence of malaria by HIV status, prospective data were collected from a cohort of HIV-unexposed, HIV-exposed and HIV-infected children living in Tororo, a rural area in Uganda with high malaria transmission intensity .This study was conducted in the district of Tororo, a rural area in south-eastern Uganda. Malaria transmission in Tororo is holo-endemic, occurring perennially with an entomologic inoculation rate estimated to be 562 infective bites per person-year . Data weSubjects were followed for all medical problems at a dedicated study clinic open seven days a week from 8 am to 5 pm. Parents (or guardians) were encouraged to bring their children to the study clinic whenever they were ill. After-hours care was available through the Tororo District Hospital. Children who presented with new medical problems underwent a standardized medical evaluation using algorithms to guide therapy for common illnesses that were developed locally by the study investigators. Medications with anti-malarial activity were avoided for the treatment of non-malarial illnesses. Monthly routine assessments were performed in the study clinic to ensure adherence with the study protocol. HIV-exposed children were re-tested for HIV by DNA PCR six to eight weeks after breastfeeding cessation. Those children who remained HIV-uninfected after breastfeeding cessation were then randomized to continue or discontinue TS prophylaxis as has been described elsewhere . HIV-infWeight and length/height measurements were taken at every visit to the study clinic at least once a month by trained study nurses in accordance with internationally recommended procedures . ParticiSubjects who presented to the study clinic with a documented fever (tympanic temperature ≥ 38.0°C) or history of fever in the previous 24 hours, had blood obtained by finger prick for a thick smear. If the thick smear was positive, the patient was diagnosed with malaria regardless of parasite density. Study participants ≥ 4 months and ≥ 5 kg were randomly assigned to receive either open label artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) at the time their first episode of uncomplicated malaria was diagnosed. Study participants received the same treatment regimen for all subsequent episodes of uncomplicated malaria. Episodes of uncomplicated malaria in children < 4 months of age or weighing < 5 kg, as well as episodes of complicated malaria and treatment failures occurring within 14 days of initiating treatment were treated with quinine.Thick and thin blood smears were stained with 2% Giemsa for 30 minutes. A thick smear was considered negative if no parasites were seen after review of 100 high-powered fields. Speciation of parasites was based on readings of thin smears by a trained microscopist. A final diagnosis of malaria used in the analysis was based on a rigorous quality-control system that included re-reading of all blood smears by a second microscopist and resolution of any discrepancies between the first and second readings by a third microscopist within 24 hours of the initial smear reading.Assessment of infants HIV status prior to enrolment and at six to eight weeks after cessation of breastfeeding involved collecting a heel, toe or finger-prick blood sample on filter paper which was sent to a reference laboratory for HIV DNA PCR using Roche Amplicor HIV-1 DNA PCR test v1.5 kits .Data were double entered in Access , and statistical analysis was performed using STATA, version 10 . The observation period for each study participant began the day after enrolment and ended when a study participant was either prematurely withdrawn from the study or reached 2.5 years of age.Nutritional status was assessed using the following standardized anthropometric z-scores as per WHO guidelines ,28: heigMalaria incidence was defined as the number of new episodes of malaria per time at risk. Episodes of malaria occurring within 14 days of a previous episode were not considered incident events. Longitudinal associations between variables of interest and malaria incidence were estimated as an incidence rate ratio using generalized estimating equations with exchangeable correlation, negative binomial distribution, and adjusted for repeated measures. For longitudinal associations, measures of malnutrition were categorized into none, mild, and moderate-severe based on the cut-offs above for mean z-scores during observation periods of interest. Interaction among potential confounders was also examined by including interaction terms into the multivariate models. A p-value < 0.05 was considered statistically significant for all analyses.A total of 100 HIV-unexposed children, 203 HIV-exposed children, and 48 HIV-infected children were enrolled between August 2007 and April 2008  and then rose slightly to 30 months of age  and being prescribed TS chemoprophylaxis  were associated with a lower risk of stunting of any severity  of the study participants had experienced at least one episode of malaria. A total of 2,414 new episodes of malaria were diagnosed, resulting in an overall incidence of 3.64 episodes per person year. In multi-variate analysis, children with mild stunting  and moderate-severe stunting  had a similarly higher incidence of malaria compared to children without stunting (Table % of the This study was conducted in a cohort of young children living in an area of high malaria transmission intensity, where the incidence of malaria was over 3.6 episodes per person-year despite the use of long-lasting ITNs by all study participants and TS prophylaxis in majority of the study participants. Malnutrition was also very common, with 70% of study participants meeting criteria for mild stunting, and 38% of study participants being mildly underweight. HIV infection was associated with an increased risk of both stunting and being underweight, while breastfeeding and the use of TS prophylaxis were protective against stunting, but not being underweight.The main objective of the study was to evaluate associations between paediatric malnutrition and the incidence of malaria by HIV status. Stunting was associated with a modest 24% increase in the incidence of malaria after controlling for potential confounding factors, but the degree of stunting did not modulate this association. In addition, the association between stunting and an increased incidence of malaria was consistent between HIV-infected and uninfected children. In contrast, there was no statistically significant association between being underweight and the incidence of malaria.Interactions between malnutrition and HIV infection are complex and have been suggested to have negative feedback loops. Malnutrition is a significant risk factor for AIDS-related mortality and HIV-associated wasting often persists even with use of ART ,30. The Another novel finding of this study was that children taking TS prophylaxis had a significantly lower risk of stunting. A similar finding was reported in a randomized control trial of TS prophylaxis among HIV-infected adults in Côte d'Ivoire, suggesting that TS prophylaxis may improve nutritional status by the prevention of morbidity-related malnutrition or by other indirect mechanisms .Associations between measures of malnutrition and the risk of malaria appear to be complex as previous studies have reported a wide range of findings. One source of this complexity is due to differences in the indicators commonly used for malnutrition. Stunting is generally considered an indicator of chronic malnutrition, wasting generally reflects a recent and severe process, and underweight a reflection of a combination of factors. Earlier studies provide some evidence of a protective effect of stunting against malaria ,35 and tThere are several hypotheses as to why chronic malnutrition may increase the risk of malaria. It is now widely known that nutrition plays an important role in modulation of anti-pathogen immunity and most studies have demonstrated a deleterious effect of malnutrition on the appropriate immune response to infection ,38. In aStrengths of this study include the prospective, longitudinal study design and the assessment of HIV status. The mean of anthropometric measures of malnutrition taken over an extended period of follow-up were obtained and therefore better reflect the long-term nutritional status of a child compared to studies which rely on single measurements. In addition, malaria morbidity was analysed using an incidence measure of clinical disease, which best reflects the repeated nature of malaria in children residing in high transmission areas. Another strength is the inclusion of HIV-exposed and infected children, which has not been previously reported in studies evaluating associations between malnutrition and malaria. Limitations of this study include the lack of assessment of the temporal relationship between malnutrition and malaria. A number of studies have indicated a deleterious effect of malaria on nutritional status ,42. TherIn this study of young children living in a high transmission area, stunting was associated with an increased risk of malaria regardless of HIV status. Of note, the incidence of malaria was high in this cohort despite the use of ITNs and TS prophylaxis in a substantial number of children. Intervention studies aimed at improving nutritional status as a means of reducing the incidence of malaria in similar epidemiological settings deserve exploration.The authors declare that they have no competing interests.EA, TGS, JH, HW, AK, JT, MRK and GD contributed to the study design and oversight. EA, AG, WV, SY and GD contributed to the methodology, data analysis, interpretation of the results and drafting of the manuscript. All authors read and reviewed the final manuscript. All authors read and approved the final manuscript.


Reports on the sexual behavior of people on antiretroviral therapy (ART) are inconsistent. We selected 14 articles that compared the sexual behavior of people with and without ART for this analysis.We included both cross-sectional studies that compared different ART-naïve and ART-experienced participants and longitudinal studies examining the behavior of the same individuals pre- and post-ART start. Meta-analyses were performed both stratified by type of study and combined. Outcome variables assessed for association with ART experience were any sexual activity, unprotected sex and having multiple sexual partners. Random-effect models were applied to determine the overall odds ratios. Sub-group analyses and meta-regression analyses were performed to examine sources of heterogeneity among the studies. Sensitivity analysis was also conducted to evaluate the stability of the overall odds ratio in the presence of outliers.The meta-analysis failed to show a statistically significant association of any sexual activity with ART experience. It did, however, show an overall statistically significant reduction of any unprotected sex, having multiple sexual partners and unprotected sex with HIV negative or unknown HIV status with ART experience. Meta-regression showed no interaction between duration of ART use or recall period of sexual behavior with the sexual activity variables. However, there was an association between the percentage of married or cohabiting participants included in a study and reductions in the practice of unprotected sex with ART.In general, this meta-analysis demonstrated a significant reduction in risky sexual behavior among people on ART in sub-Saharan Africa. Future studies should investigate the reproducibility and continuity of the observed positive behavioural changes as the duration of ART lasts a decade or more. Across the globe, the introduction of antiretroviral therapy (ART) has saved millions of life since it was widely introduced in developed countries in 1996 and in sub-Saharan Africa in 2002 .As severely ill HIV patients recover on ART, they feel general wellbeing and their sexual desire is likely to resume. Is the sexual behavior of HIV patients on ART safe or risky? Reports on sexual behaviors of people on ART have been inconsistent; six studies African and non-African countries have shown that patients on ART are more likely to engage in unprotected sex -10; howeIn a systematic review of three articles, Kennedy et al found a significant reduction in sexual risk-taking behaviour among patients on ART in developing countries . One verNo previous meta-analysis has been published on the sexual behaviors of people on ART in Sub-Saharan Africa. This meta-analysis and meta-regression was conducted based on studies comparing the sexual behavior of people on ART with HIV-infected people not on ART. We hope this analysis sheds more light on the gradient of risky sexual behaviours among people on ART in Sub-Saharan Africa.We conducted a computer search of PubMed, Google Scholar, WHO (HINARI) for articles on risky sexual behavior in relation to ART in sub-Saharan Africa published from January 2000 to October 2011. We obtained article texts either free on-line or from HINARI , sample size, sexual history , recall period for sexual activities, duration on ART and proportion of married participants.In this article, we use the terms “ART-naïve” and “ART-experienced” only with respect to studies comparing behavior among different individuals. We use the terms “pre-ART” and “post-ART” only with respect to studies comparing behavior within the same individuals. We did not attempt to standardize definitions of these terms; we used them as used in each of the articles selected. We use the term “unprotected sex” to mean either sexual activity without the use of a condom or inconsistent condom use with any partner irrespective of HIV serostatus. We use the term “multiple sexual partners” to mean sexual activity with two or more sex partners during the study period. In this analysis, all the study participants were HIV positive. All articles selected for this meta-analysis have got ethical clearance from their respective institution.2, Chi-square (Q), I2 and P-value. For this analysis, when the value of I2 exceeded 50%, we considered the total variation across the studies to be large and to be due to heterogeneity rather than to chance [We used Meta Analyst (Beta 3.13) software  and Compo chance .In the presence of significant heterogeneity, summary estimates from meta-analyses are believed to be difficult to interpret; and Lijmer et al recommends investigating heterogeneity using subgroup (stratified) analysis and meta-regression analysis  ThereforSensitivity analysis was also conducted to see the stability of the overall odds ratio to inclusion of individual studies. For all statistical tests, P-value ≤ 0.05 was considered as statistically significant.The studies making comparisons among individuals included 5129 participants (1911 ART-naïve participants and 3218 ART–experienced participants). The studies making within-individual comparisons included 1024 participants were included. The participants’ duration on ART ranged from 3–36 months (median six months and interquartile range 6–12 months). Figure The within-individual studies were more inconsistent than studies that made comparisons between individuals. Two studies ,27 found2 = 87.9%), signifying that the variation was due to heterogeneity rather than chance. The impact of duration on ART and recall time on the overall odds ratio was assessed by the random effect meta-regression model. As shown in Table Sensitivity analysis attested to the stability of the overall odds ratio; it oscillated in the range of 1.07 to 1.21 . The test of heterogeneity showed a significant variation among the included studies . Meta-regression found no statistically significant interaction between unprotected sex and duration on ART  or between unprotected sex and recall time . But the meta-regression incorporating six studies [The studies included in the meta-analysis of unprotected sex also found to have significant variation due to heterogeneity rather than to chance , recall time  nor percentage of married participants  were significantly associated with having multiple sexual partners.Of the 14 studies included, only four ,25,26,28Because of several contradictory reports, the issue of sexual behaviour of people on ART in sub-Saharan Africa still continues to be debatable. This meta-analysis is the first to provide a pooled quantitative estimate of the sexual behavior of people on ART by categorizing and analyzing the studies by type. In other words, the strength of this analysis is that it examined the sexual behavioral change with ART within individuals (pre-ART vs. post-ART study type) and among different individuals (ART-naïve vs. ART-experienced study type), and finally, combining the two study types (HIV-infected people not on ART vs. HIV-infected people on ART). We would expect the within-individual studies to be less affected by confounding variables due to variations between the individuals included than the studies that compared different ART-naïve and ART-experienced individuals. Our analysis also permitted exploration of different dimensions of the sexual behavior of HIV infected patients. Although we found no statistically significant difference in sexual activity among HIV-infected people on ART, six of the 10 studies -24,26-28In addition, one may argue that the dramatic improvement in their health after beginning ART may have given HIV patients the hope of living long. Their previous sufferings had been an extremely bad experience; and professionals probably counseled them not to put themselves and their partners at risk of infection with new HIV strains, with HIV strains resistant to antiretroviral drugs and with other sexually transmitted infections. In support of this hypothesis, a qualitative study from Uganda reported that many ART patients were worried about risking their improving health through HIV super-infection and about the risk of resuming sexual practice . The posA meta-analysis on adherence to ART in Sub-Saharan Africa and North America found better adherence among Sub-Saharan Africans . The obsThere are some studies from Sub-Saharan Africa which report the association of higher rates of unprotected sex with shorter duration of ART therapy  ,38,43. HOur meta-regression also found no significant relationship between sexual activity and the time period over which participants were asked to recall such activity. However, the meta-regression of rates of unprotected sex in relation with the percentage of participants who were married found a significant interaction. The higher the percentage of married participants in a study, the lower the rates of unprotected sex found. This finding would be expected and may explain why the majority of studies included in this analysis found a reduction in unprotected sex, but other reports have not .One limitation of our analysis is that all the primary studies analyzed used interviews to collect data on sexual behavior; this is open to recall bias and social desirability bias . First, In conclusion, the significant reduction in risk taking sexual behavior among people on ART regardless of duration on ART is consistent with several individual studies and a systematic review from developing countries ,45. HoweAuthors would like to declare that there was no competing interest associated with this manuscript.Both authors (AB and YB) actively involved in designing, articles search, articles selection, and manuscript writing. The contribution of AB was immense in doing the meta-analysis and meta-regression. Both authors read and approved the final manuscript.


Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons. Sc) form of the endogenous cellular prion protein (PrPC) in the brain and in the lymphoid tissues Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of progressive, invariably fatal, neurodegenerative diseases, affecting both animals and humans. The common underlying feature associated with development of the neuropathology is the presence of an abnormally folded, protease resistant , reduced Purkinje cell density, atrophy of the molecular and granular cell layer Using the mouse-adapted 22L prion strain we have studied the progression of synaptic degeneration in the hippocampus and cerebellum. This approach allows us to address region-selective degenerative processes involving distinct neuronal types. Our findings show that in the pathogenesis of a single prion strain pre-synaptic compartments within the hippocampus are more susceptible to chronic neurodegenerative changes than other compartments, while in the cerebellum Purkinje cell dendrites are first to exhibit hallmarks of degeneration. Notably, this occurs without obvious changes in biochemical and ultrastructural properties of the major pre-synaptic elements such as observed previously in hippocampal CA1 neurons We have previously described the specific pathology of glutamatergic synapses induced by the ME7 strain in detail The differential dendritic and synaptic degeneration in the cerebellum was first identified by immunolabeling of the Purkinje cells and the parallel fibres. Calcium-binding protein calbindin D-28k  is expressed abundantly not only in Purkinje cells but also in climbing fibres In control, normal brain homogenate-injected (NBH)-animals, at 18 weeks (LS) p.i. calbindin immunoreactivity was specifically present within cell bodies of Purkinje cells and continuously filled dendritic arborizations in the molecular layer . In 22L-We next explored the distribution of parallel fiber boutons that form the majority of excitatory synaptic connections in this layer. Different isoforms of a vesicular glutamate transporter can mediate glutamate uptake into the synaptic vesicles of excitatory neurons; however, parallel fibers in the molecular layer of the cerebellum have only VGLUT1 Similar to the previous reports describing the ME7 strain In the electron microscope the synaptic alterations in the stratum radiatum of the 22L–infected hippocampus, were virtually identical to those that we have described in the hippocampus of animals injected with the ME7 prion strain In the cerebellum we saw no evidence of dark, electron-dense pre-synaptic profiles or abnormally shaped post-synaptic PSDs . The parThe cerebellum has a well-described organization, with clearly defined cell types, afferent and efferent pathways, and intrinsic cortical circuits. Axons of granule cells are unmyelinated, like the Schaffer collaterals innervating CA1 pyramidal neurons in the hippocampus; they ascend from the granular to the molecular layer, which is relatively sparsely populated with cells. In the molecular layer, they branch into parallel fibers that run perpendicular to the Purkinje cells arborization and contact their dendrites via dendritic spines . ParalleIt was immediately apparent that the dendritic segments in the superficial molecular layer  of 22L-aIn previous studies the ultrastructure of neuronal mitochondria appeared sensitive to disease progression. Mitochondria that are present in abundance and uniformly distributed in control Purkinje dendrites, were abnormally clustered under the plasma membrane in 22L-animals. This redistribution of mitochondria is indicative of an ongoing degenerative process apparent at ES . This obDespite the significant pathology of the Purkinje cell dendrites, there were no identifiable concomitant ultrastructural alterations of the innervating parallel fibre.The light microscopy and electron microscopy described above suggest that the degeneration of the post-synaptic Purkinje cells is initiated prior to, or even in the absence of, degeneration of the pre-synaptic terminals and contrasts with the early synaptic pathology in the hippocampus in the same animals.In a number of chronic neurodegenerative diseases such as AD Our present findings show that synaptic pathology in the stratum radiatum of the hippocampus of 22L-animals, exhibits all features that were previously observed in ME7-animals. We have detected numerous, degenerating pre-synaptic terminals of Type I synapses that were progressively engulfed by PSD membranes of post-synaptic dendritic spines as they curved around the degenerating pre-synaptic element. Despite ongoing pre-synaptic deterioration, there was little or no evidence of dendritic pathology of CA1 dendrites at early stage. In agreement with our previous findings in the ME7 model, activated glial cells were not directly involved in phagocytosis of the degenerating synapses Sc present throughout the cerebellum The 22L prion strain has been reported to predominantly affect cerebellar function and thus motor coordination tasks Several possibilities could explain why the glutamatergic synapses of the molecular layer in the cerebellum are relatively resistant to the degenerative process. A distinct feature of Type I synapses in the molecular layer is the degree of their glial ensheathment. Bergmann glia, unlike the astrocytes in the stratum radiatum, tightly enclose individual synaptic boutons in the molecular layer and express high levels of glutamate transporters that limit diffusion of glutamate during its release from synaptic terminals. It is also thought that Bergmann glia cells consist of independent compartments capable of autonomous interactions tuned to the particular state of synapses they ensheath Taken together, it appears that Bergmann glia cells exert a powerful control over the function of Purkinje cells in a disease situation. We suggest that Bergmann glia cells could provide a protection by creating relatively self-sufficient compartmentalized microdomains, tightly ensheathing synapses in the molecular layer. We did not observe any morphological evidence to suggest that the function of Bergmann glia cells was adversely affected during neurodegeneration, thereby compromising their protective capacity.Atg7Autophagy is a regulated lysosomal degradation process responsible for the turnover of long-lived proteins or organelles; in mammals, it is required for normal neuronal function and conditional inactivation of autophagy-related genes in the central nervous system leads to neurodegeneration In summary our study demonstrates that within a brain undergoing a chronic neurodegenerative process the first stages of degeneration may involve distinct neuronal compartments, either pre- or post-synaptic elements. The molecular events that predispose a neuron to undergo a particular type of degeneration when exposed to a toxic misfolded protein, in this case prion protein, pose an interesting and important challenge.C57BL/6J (Harlan) female mice aged 8–10 weeks were obtained from Harlan Laboratories  and were group-housed within the animal care facilities at the University Southampton as previously described All animals were housed under specific pathogen-free conditions and experiments were performed according to the guidelines approved by the UK Home Office regulations. Every effort was made to minimize any suffering to the animals.All operations were performed under the UK Home Office licence, as previously described NBH- and 22L-animals were terminally anaesthetized with sodium pentobarbital and killed by perfusion fixation for transmission electron microscopy (TEM) at 12  and 18  weeks post injection (p.i.), to study the early and later stages of synaptic loss. A slow cardiac perfusion (20–30 min) was performed with fixative containing 3.4% paraformaldehyde, 1.25% glutaraldehyde, 0.2% picric acid in 0.1 M sodium phosphate buffer  immediately after short (<1.5 min) perfusion with heparinised saline, to minimise synaptic and glial ultrastructural changes that could be caused by brain hypoxia Coronal sections passing though the dorsal hippocampus and the cerebellum (10 µm) were cut from formalin fixed paraffin wax-embedded brains at 12  and 18  weeks post injection (p.i.). Following dewaxing and rehydration of the tissue, citrate buffer-microwaving and trypsin  antigen retrieval was performed; after blocking  in phosphate buffered saline (PBS) for 30 min), sections were incubated in a humid chamber overnight at 4°C with one of the following primary antibodies: anti-calbindin –D-28K  or anti-vesicular glutamate transporter 1 (VGLUT1)  and subsequently with Alexa Flour 488  or 546 (anti-VGLUT1) conjugated secondary antibodies . All antibodies were diluted in 0.25% BSA/PBS and washed off using PBS/Tween. The sections were covered with Vector-shield mounting medium containing DAPI, coversliped and imaged. Control sections were covered with the appropriate blocking serum followed by the secondary antibody while other sections were covered with the primary antibody diluted as above without addition of secondary antibody.2 of the molecular layer have been obtained from at least three cerebellar sections per animal and normalized to the pixel density of the background for each section using ImageJ software . The identities of the coded blocks and tissue sections were only revealed to the observer after the data analysis was complete. One-way analysis of variance (ANOVA) with Tukey’s multiple comparison tests were performed to compare final data between NBH (N = 4) and 22L-animals (N = 4) at each of ES and LS using GraphPad Prism software .VGLUT1 immunoreactivity was also analyzed at ES and LS p.i. following challenge with 22L-brain homogenate and at 18 weeks with NBH. Pixel density values of 100 µm


Acupuncture is currently gaining popularity worldwide as a “complementary” or “alternative therapy.” The underlying mechanisms of acupuncture in general require further investigation to be delineated, although acupuncture therapy has been demonstrated to be effective in several clinical areas. Recently, there is a growing focus on the critical role of the brain and a need to explain how acupuncture affects endocrine function through the CNS . This special issue was developed to stimulate the continuing efforts in defining and promoting the neuroendocrine mechanism of acupuncture.This special issue contains thirteen papers, of which five are related to analgesic effect of acupuncture, and two cover opiate addiction. There are single papers focusing on cardiac, Parkinson's disease, hot flashes, and hypertension. Another deals with brain-modulated effect of auricular acupressure. Finally, one explores the impairments of spatial memory.“Effects of electroacupuncture on N-methyl-D-aspartate receptor-related signaling pathway in the spinal cord of normal rats” by H.-N. Kim provides evidence that calcium influx by N-methyl-D-aspartate receptor activation may play an important role in EA analgesia of normal rats through modulation of the phosphorylation of spinal phosphatidylinositol 3-kinase (PI3K) and cAMP response element-binding protein (CREB). “Changes in cytokine expression after electroacupuncture in neuropathic rats” by M. H. Cha revealed that EA reduced the levels of proinflammtory cytokines elevated after nerve injury in peripheral nerves and dorsal root ganglia (DRG). “Effects of electroacupuncture at BL60 on formalin-induced pain in rats” by K.-H. Chang showed the effect of EA in relieving inflammatory pain and the possible involved mechanism. Furthermore, “Effect of electroacupuncture on activation of p38MAPK in spinal dorsal horn in rats with complete Freund's adjuvant-induced inflammatory pain” by Y. Liang indicated that anti-inflammatory and analgesic effect of EA might be associated with its inhibition of spinal p38 MAPK activation and thereby provide a potential mechanism for the treatment of inflammatory pain by EA. On the other hand, “Does acupuncture needling induce analgesic effects comparable to diffuse noxious inhibitory controls?” by J. Schliessbach showed that acupuncture at low pain stimulus intensity did not produce a DNIC-like effect comparable to a classical, painful DNIC-test, indicating that the penetration of an acupuncture needle seems not to induce an analgesic effect mainly mediated by DNIC.“Acupuncture for the treatment of opiate addiction” by J. G. Lin is a systematic review of randomized clinical trials which applied acupuncture for treating opiate addiction and analysed the possible mechanism underlying the effect of acupuncture. “Electroacupuncture suppresses discrete cue-evoked heroin-seeking and Fos protein expression in the nucleus accumbens core in rats” by S. Liu highlights the therapeutic benefit of EA in preventing relapse to drug addiction, through the results that EA stimulation reduced active responses elicited by discrete cues and attenuated Fos expression in the core but not the shell of the nucleus accumbens. “Electroacupuncture at PC6 (Neiguan) improves extracellular signal-regulated kinase signaling pathways through the regulation of neuroendocrine cytokines in myocardial hypertrophic rats” by J. Li revealed that EA could improve cardiac function in rats with myocardial hypertrophy by modulating upstream neuroendocrine cytokines that regulate extracellular signal-regulated kinase (ERK) signaling. This proposes a mechanism underlying EA's effect in treating cardiac diseases.Acupuncture as treatment of hot flashes and the possible role of calcitonin gene-related peptide” by A.-C. S. Holm discussed the role of CGRP involved in acupuncture as an alternative treatment for hot flashes, based on the evidence for connections between the opioid system and the release of CGRP. “Neuroendocrine mechanisms of acupuncture in the treatment of hypertension” by W. Zhou discussed current knowledge of acupuncture effects on central nervous system and how they contribute to regulation of acupuncture on the endocrine system. This approach provides a perspective on treating of hypertension. “Brain-modulated effects of auricular acupressure on the regulation of autonomic function in healthy volunteers” by X. Gao investigated the acute effect of ear acupressure on autonomic function, indicating that this approach of auricular acupressure was based on intensification of the related mechanism of blood pressure regulation. “Acupuncture stimulation alleviates corticosterone-induced impairments of spatial memory and cholinergic neurons in rats” by B. Lee demonstrated that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction by immune responses and gene expression.The cortical and striatal gene expression profile of 100 Hz electro-acupuncture treatment in 6-hydroxydopamine-induced Parkinson's disease model by Li-Rong Huo applied high-throughput microarray analysis to analyze gene expressions. This study suggested that EA may induce recovery of homeostasis in the transcript network and many regulated functional clusters in the cortex and striatum; this characteristic underlies the mechanism of EA's effect in improving behavioral characteristics of PD rats. “Due to recent development not only in invasive methodology such as PET in human and animals and optogenetic technique, but also in molecular biology, the research of acupuncture at the whole organismic level and an in-depth analysis becomes more available. It is essential to focus on some critical factors which impact the effect of acupuncture, such as biophysical action of acupoints, combination of acupoints, and acupuncture method. A recent study proposed a neurophysiological mechanism to explain the beneficial effects of acupuncture based on the stimulated purinergic signalling by acupuncture. This potential provokes some scientists interested in acupuncture to investigate further in this rapidly expanding field. Finally, we should never forget the need for careful consideration of the role of placebo in this and other CAM analyses.Of course, the selected topics and papers are not a comprehensive representation of the area of this special issue. Nonetheless, they represent the rich and many-faceted knowledge that we have the pleasure of sharing with the readers.


Treatment of psoriasis in the setting of chronic hepatitis C virus (HCV) infection is difficult, because standard therapies like methotrexate are associated with increased hepatic toxicity. Due to the HCV suppressive effect. Cyclosporine may represent a valid systemic alternative for psoriatic-HCV patients.In this study, we report the successful usage of intermittent cycles of cyclosporine in the setting of chronic HCV infection and we try to call the attention once again in a very effective and forgotten therapeutic option for severe chronic plaque psoriasis.We describe a 48 years - old patient who has a 20 year history of severe chronic plaque psoriasis and HCV infection . Five courses (range of duration of three to six months) of oral cyclosporine (5 mg/kg/day) were followed during a 38 month period. The viral load and the transaminases’ levels diminished during the 38 months of intermittent cyclosporine therapy to the lowest level measured at 36th month. The good psoriatic response was associated to a slight improvement of the liver condition, even though the HCV-RNA was reduced by less than 1 log10 without normalization of aminotransferase’ levels.The reduced liver toxicity, the potential anti-HCV properties and the well-known systemic anti-inflammatory effect, make cyclosporine a good alternative for recalcitrant psoriatic patients with HCV-liver disease Treatment of psoriasis in the setting of chronic hepatitis C virus (HCV) infection is demanding, because standard treatments like methotrexate are associated with increased hepatical toxicity . Due to Nowadays Cyclosporine is one of the most effective systemic therapies for chronic plaque psoriasis, and it is considered as second-line treatment after phototherapy for high needed psoriasis patients where no contraindications are present. Unfortunately the scarce literature evidence regarding the use of cyclosporine in the setting of chronic HCV infection and the increasing enthusiasm on biological therapies and mainly anti-TNF-α agents, have been made that recently published guidelines proposed the use of cyclosporine only as third line-therapy after the use of adalimumab, etanercept and/or infliximab. This report describes the successful usage of intermittent cycles of cyclosporine in the setting of chronic HCV infection.A 48 years-old white man was followed for a 20-years history of severe chronic plaque psoriasis. In 1990 HCV infection was demonstrated with raised liver enzymes and ongoing viral replication. The patient presented to us with persistently elevated aminotransferase levels , HCV infection with genotype 2a-2c (Simmonds Classification) and HCV-RNA titer  of 2,050,000 IU/mL . A liverTreatment of recalcitrant psoriasis in the setting of chronic HCV infection is difficult and guidelines from the medical board of the national psoriasis foundation recommend the use of cyclosporine only as third-line therapy after a second-line therapy with etanercept, adalimumab, infliximab and/or etanercept 5]6]. A[6]. A5][. A[6]. A


The present study aimed to evaluate the long-term follow-up results of patients with intraductal papillary mucinous neoplasm (IPMN) and to estimate the degree of IPMN malignancy based on pathological and molecular features of resected specimens. The detection rate of IPMN has increased over the last decade; however, the management of this neoplasm remains controversial. This is particularly so for branch duct-type IPMN, which carries a high potential for malignancy and risk of recurrence. We retrospectively reviewed a single institution’s prospective pancreatic resection database to identify IPMN patients who underwent pancreatectomy with curative intent. The clinicopathological variables of 100 patients resected for IPMN were analyzed with a detailed review of histopathological results  to determine the grade of IPMN malignancy based on transforming growth factor (TGF)-β/SMAD4 signaling. The incidence of malignant change was significantly higher in patients with main duct-type IPMN (69.7%) compared with branch duct-type IPMN cases (17.9%). However, patients with an invasive carcinoma had a significantly worse outcome if it was derived from branch duct-type IPMN compared with those derived from main duct-type IPMN, and TGF-β mRNA expression was significantly increased in the former patient group. Immunohistochemistry also showed higher numbers of SMAD4-positive cells in patients with carcinoma derived from branch duct-type IPMN. Our results demonstrated that invasive carcinoma derived from branch duct-type IPMN is more aggressive than that derived from main duct-type IPMN, once invasive morphological change takes place. Determining TGF-β and/or SMAD4 status at initial diagnosis may be useful for stratifying IPMN patients into treatment regimens. Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a relatively new entity that is being diagnosed with increasing frequency . IPMN isIn 2004, an international conference defined the International Consensus Guidelines (ICG) for selecting patients for immediate surgery or a surveillance strategy . Main paEarly studies of IPMN suggested that patients resected for branch duct-type IPMN had a more benign neoplasm compared with those with main duct-type IPMN -14. ShorThe purpose of this study was to characterize the clinicopathological features of patients with branch duct-type IPMN resected at our institution with detailed examination of histopathological and molecular investigations, and to compare the outcomes of these patients with those with main duct-type IPMN. Furthermore, we discuss the malignant potential of invasive intraductal papillary mucinous carcinoma (IPMC) derived from branch duct-type IPMN based on our analysis of the TGF-β/SMAD4 pathway.This is a study of prospectively collected, retrospectively analyzed data. The diagnosis of IPMN was suspected following imaging and endoscopic analysis and was confirmed by pathological analysis. We retrospectively reviewed the surgical pathology database of Kochi Medical School to identify patients who underwent resection for IPMN. Case selection was restricted to patients who underwent resection in or after 2000, as since then all clinical diagnoses of IPMN of the pancreas were evaluated using standardized diagnostic modalities, including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP) and in particular endoscopic ultrasonography (EUS). All IPMN patients who had undergone a pancreatic resection in the Department of Surgery at Kochi Medical School between January 2000 and December 2011 were included in this study.a posteriori for all patients in accordance with the ICG (The indication for resection or surveillance was verified  the ICG . All pat the ICG .in situ (non-invasive IPMC) and invasive carcinoma (invasive IPMC). When more than one pathological type was present, the tumor was classified according to the worst lesion present.The diagnosis was validated on the basis of the histological findings in a surgical specimen, or the outcome of surveillance. The lesions were classified into three categories according to the World Health Organization classification: slight dysplasia and intraductal papillary mucinous adenoma, moderate dysplasia or borderline malignancy (borderline IPMN), severe dysplasia or IMPC The study was approved by the ethics committee of Kochi Medical School. Written informed consent was obtained from the patients.2). A self-administered questionnaire was used to determine the smoking and drinking habits of all IPMN patients. Data of patient outcomes were obtained through retrospective review of a prospectively maintained pancreatic resection database, electronic hospital charts and medical records.Medical records were reviewed retrospectively for the following information: patient characteristics, clinical history, physical examination, laboratory investigations, surgical management, pathology examinations and post-operative course. Any history of a previous extra-pancreatic neoplasm or ordinary pancreatic carcinoma was investigated thoroughly. Body mass index (BMI) was calculated as weight (kg) divided by height squared  according to the manufacturer’s instructions. We measured the expression of TGF-β with normalization as previously described  sections of all IPMN tumors were collected from the surgical pathology archives. In the present study, we extracted RNA from the samples of both main and branch duct-type IPMN of the pancreas using the RNeasy FFPE Kit  . Total Rescribed . Real-tiescribed . PrimersThe streptavidin-biotin-peroxidase method with the Dako kit  was used to detect SMAD4 protein expression on three serially cut representative sections. Following inactivation of endogenous peroxidase and blocking of nonspecific antibody binding, the specimens were treated with biotinylated antibodies specific for SMAD4  at 4°C overnight. Subsequently, sections were incubated with the streptavidin-biotin-peroxidase complex reagent for 30 min at room temperature. Diaminobenzidine tetrahydrochloride was used as the chromogen and hematoxylin was used for counterstaining.2 test (two-tailed) or Fisher’s exact test (two-tailed) by a biostatistics specialist, as appropriate. Survival probabilities were determined using the Kaplan-Meier method and compared using the log-rank test. Survival analysis excluded patients who died in the 30-day postoperative period. Cause of mortality was not available for all patients, so only overall survival was calculated. P<0.05 was considered to indicate a statistically significant result. All analyses were performed using SPSS® .Continuous variables are presented as mean ± SD. Dichotomous variables are presented as both number and percentage values. Data were analyzed using Student’s t-test (two-tailed), with dichotomous variables analyzed by the χOf the 100 patients enrolled in the present study, 33 (33.0%) were found to have main duct-type IPMN  and 67 (67.0%) had branch duct-type IPMN  after excluding patients who died in the 30-day post-operative period  and those suffering from ordinary pancreatic carcinoma . Patient follow-up as of December 2011 ranged from 4 to 196 months, with a median of 54 months . In general, patients with an invasive IPMC had a significantly worse outcome compared with those with borderline or non-invasive IPMC . The cumThe overall survival in patients with an invasive adenocarcinoma derived from branch duct-type IPMN was significantly worse than in those patients with invasive adenocarcinoma derived from main duct-type IPMN. We therefore examined TGF-β/SMAD4 signaling in all patients. In this retrospective study, we found that invasive carcinoma derived from branch duct-type IPMN was more aggressive than that derived from main duct-type IPMN, once invasive morphological change was apparent. This study also clarified the progression pattern of TGF-β/SMAD4 signaling in IPMNs.As observed in previous studies, 55 (82.1%) of the 67 patients in this study with branch duct-type IPMN had a benign neoplasm at the time of initial pre-operative surgical indication –14. The TGF-β is a potent inhibitor of epithelial cell growth and survival through modulating the expression of cell cycle regulators and activating apoptosis, although these effects are highly dependent on cellular context . HoweverPancreatic surgery is burdened by significant morbidity and mortality, even at specialized centers . ResectiThe prognosis and recurrence rate of IPMN depend mainly on tumor invasiveness and the type of duct involved. The recurrence rate is higher for invasive lesions of the branch duct, and such lesions must therefore be treated surgically as soon as feasibly possible, similar to classic pancreatic adenocarcinoma. Advances in imaging technologies have increased the number of diagnoses of asymptomatic lesions, thus more stringent and careful criteria should be included in the ICG to increase their specificity and define malignancy risk pre-operatively. As it stands, the ICG definition of differential clinical diagnosis for IPMN of the pancreas is unsatisfactory with regard to malignant status. Indeed, patients with IPMN, invasive or not, should be submitted for lifetime follow-up checking for recurrence in the remnant pancreas and for associated cancers.


Posterior epidural migration of thoracic disc herniation is extremely rare but may occur in the same manner as in the lumbar spine.A 53-year-old Japanese man experienced sudden onset of incomplete paraplegia after lifting a heavy object. Magnetic resonance imaging revealed a posterior epidural mass compressing the spinal cord at the T9-T10 level. The patient underwent emergency surgery consisting of laminectomy at T9-T10 with right medial facetectomy, removal of the mass lesion, and posterior instrumented fusion. Histological examination of the mass lesion yielded findings consistent with sequestered disc material. His symptoms resolved, and he was able to resume walking without a cane 4 weeks after surgery.Pre-operative diagnosis of posterior epidural migration of herniated thoracic disc based on magnetic resonance imaging alone may be overlooked, given the rarity of this pathology. However, this entity should be considered among the differential diagnoses for an enhancing posterior thoracic extradural mass. Posterior epidural migration of a herniated thoracic disc is extremely rare but may occur in the same manner as it does in the lumbar spine. To the best of our knowledge, only five cases of posteriorly migrated thoracic disc herniation have been reported in the English-language literature-5. We prA healthy 53-year-old Japanese man experienced sudden onset of incomplete paraplegia after lifting a heavy object. The physical examination revealed that his motor strength was grade 0/5 in the right lower extremity and 0–2/5 in the left lower extremity. Sensory loss was observed below the level of the umbilicus. Urinary incontinence was also present. Magnetic resonance imaging (MRI) revealed a posterior epidural mass compressing the spinal cord at the T9-T10 level  with posteriorly migrated thoracic disc herniation presented with sudden onset of severe motor weakness-5. GenerHerein we report the case of a patient with an extremely rare presentation of posteriorly migrated thoracic disc herniation. The patient experienced sudden onset of incomplete paraplegia, and surgical treatment relieved the symptoms. Pre-operative diagnosis of posterior epidural migration of a herniated thoracic disc based on MRI alone may be difficult, given the rarity of this pathology. However, this entity should be considered among the differential diagnoses for an enhancing posterior thoracic extradural mass.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.The operation was performed by NM. All authors were involved in the writing of the manuscript and the patient’s clinical care. All authors read and approved the final manuscript.


Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed. Parkinson's disease (PD) is a common chronic neurodegenerative disorder characterized by the clinical presentation of motor  and nonmotor  symptoms. Although the aetiology and pathogenetic mechanisms that cause PD remain unknown, classical descriptions of PD pathology mainly focus on the progressive degeneration of the nigrostriatal dopamine (DA) pathway and the pathology in other brainstem, cortical and subcortical structures . PD patiGIDs have been suggested to develop as a result of fiber outgrowth from the graft, causing increased DA release , or as tOther theories have included observations from animal models of PD and suggested that failure of the grafts to restore DA synaptic contacts with the host striatal neurons could result in abnormal signaling and abnormal synaptic plasticity in the transplanted striatum and therefore dyskinesia . FurtherRecent work from our lab  has focu1A agonist, buspirone, which activates the inhibitory 5-HT autoreceptors and attenuates transmitter release from serotonergic neurons, resulted in significant attenuation of GIDs [Two patients with PD showing remarkable improvement of their motor symptoms more than a decade after striatal transplantation with fetal VM tissue, who received no DA drugs but developed disabling GIDs, were studied clinically and with positron emission tomography (PET) and radioligands tagging markers of presynaptic DA and 5-HT neurons. The results indicated excessive striatal 5-HT innervation in all grafted sites. Systemic administration of a 5-HT of GIDs .1A agonist  interferes with this 'dialog' and by activating the inhibitory 5-HT autoreceptors attenuates the transmitter release from the 5-HT neurons, thus leaving most of the synaptic DA to be normally regulated from the DA terminals. The clinical correspondence of such interference is the significant attenuation of GIDs.The results suggested that the occurrence of GIDs in these patients is caused by a 'dialog' between the graft-derived excess of 5-HT neurons and the normally functioning DA neurons Figure . The hyp1A or 5-HT1B agonists resulted in attenuation of LIDs [1A agonists [Animal models of PD have recently demonstrated that removal of striatal 5-HT afferents or the dampening of 5-HT activity with 5-HT of LIDs . However of LIDs . In patiagonists , while Lagonists .1A agonists, but the benefit could be greater and more practical by developing 5-HT1A agonists with sustained release.The occurrence of GIDs is a serious adverse reaction of striatal transplantation with fetal VM tissue in patients with PD hindering the development of future cell replacement therapies. The 5-HT hypothesis underlying the development of GIDs is the first hypothesis with experimental verification . These rHowever, more data are needed to fully establish the 'terms' of 5-HT/DA neuron 'dialog'. These data should come from transplanted PD patients with different degree of 5-HT/DA striatal reinnervation and should include those with incomplete DA reinnervation and those who do not experience GIDs.The verification of the 5-HT hypothesis in the development of GIDs alongside the intense animal and human research of the past decade since the abandonment of fetal cell therapy in PD, indicates that we have come closer to designing new optimized protocols for the safer and more effective application of fetal cell transplantation in patients with PD.DA: dopamine; DAT: dopamine transporter; GID: graft-induced dyskinesia; 5-HT: serotonin; LID: L-DOPA-induced dyskinesia; PD: Parkinson's disease; PET: positron emission tomography; SERT: serotonin transporters; VM: ventral mesencephalic.The authors declare that they have no competing interests.MP is entirely responsible for the content of this article.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/8/80/prepub