International rates of breast cancer for females aged 40-44 years (the “early” rate) and for females aged 65-69 years (the “late” rate) were positively correlated with sugar and fat intakes. The correlation explained three-quarters of the variation in the late rate, for 22 countries, but only half of the variation in the early rate. The late rate was, further, positively correlated with estimates of the percentage of nulliparous women (9 populations) and, together with terms for sugar and fat intakes, the multiple regression explained 90% of the variation. Early registration rates (13 populations) were positively correlated with blood group A which appeared, from the multiple regression equation, to contribute more than twice the amount to the early rate than did sugar and fat intakes. The contribution of blood group A to the late rate appeared to be only one-third of that for sugar and fat intakes.


Photodynamic therapy (PDT) is a promising technique for the treatment of small tumours in organs where it is essential to minimise damage to immediately adjacent normal tissue as PDT damage to many tissues heals by regeneration rather than scarring. As preservation of function is one of the main aims of treating laryngeal tumours, this project studied the effects of PDT on the normal rabbit larynx with two photosensitisers, endogenous protoporphyrin IX (PPIX) induced by the administration of 5-aminolaevulinic acid (ALA) and disulphonated aluminium phthalocyanine (AIS2Pc). The main aims of the study were to examine the distribution of protoporphyrin IX and AIS2Pc by fluorescence microscopy in the different regions of the larnyx and to assess the nature and subsequent healing of PDT damage. Peak levels of PPIX were found 0.5-4 h after administration of ALA (depending on dose) with highest levels in the epithelium of the mucosa. With 100 mg kg-1, PDT necrosis was limited to the mucosa, whereas with 200 mg kg-1 necrosis extended to the muscle. With 1 mg kg-1 AIS2Pc, 1 h after administration, the drug was mainly in the submucosa and muscle, whereas after 24 h, it was predominantly in the mucosa. PDT at 1 h caused deep necrosis whereas at 24 h it was limited to the mucosa. All mucosal necrosis healed by regeneration whereas deeper effects left some fibrosis. No damage to cartilage was seen in any of the animals studied. The results of this study have shown that both photosensitisers are suitable for treating mucosal lesions of the larynx, but that for both it is important to optimise the drug dose and time interval between drug and light to avoid unacceptable changes in normal areas.


The survival of clonogenic cells in the B16 melanoma has been studied simultaneously by 3 methods: an in vitro assay in soft agar, a lung-colony assay, and the end-point dilution technique. Details of the first 2 methods have previously been reported, but those of the third are described here. The 3 methods have agreed well in investigations of the response of the B16 melanoma to cyclophosphamide.


One hundred and one pre-treatment primary central primitive neuroectodermal tumours were analysed for the expression of p53 protein by immunohistochemistry using the monoclonal antibody DO-7. The staining intensity was classified into four groups: strong, medium, weak and negative and strong staining intensity was associated with the poorest survival. DNA sequencing of the p53 gene was performed in 28 cases representing all four staining groups. Mutations were found in only three of the strong staining tumours suggesting that DNA mutations were not common events and that in the majority of the tumours with over-expressed p53, the protein was likely to be wild-type. Results of immunohistochemistry showed a significantly positive relationship between the expression of p53 and Bax and Bcl-2 proteins, but not Waf-1. Multivariate analyses supported the prognostic value of p53 immunostaining in central primitive neuroectodermal tumours and also of age and gender of patients.British Journal of Cancer (2002) 86, 1117–1123. DOI: 10.1038/sj/bjc/6600151www.bjcancer.comCancer Research UK© 2002  Primitive neuroectodermal tumours of the central nervous system (cPNETs) account for 6–8% of all brain tumours and for 12–25% of paediatric brain tumours . HoweverA wide range of clinical and biological factors have been studied for their effects on patient survival in the hope of identifying high risk and low risk groups in order to tailor aggressive treatment regimens according to patient prognosis. Among clinical factors studied are patients' age and gender extent of tumour resection and presence of metastasis at diagnosis . The p53Our group has previously reported the prognostic value of the immunohistochemical staining intensity of p53 protein in a series of 88 cPNETs  not distOne hundred and one patients presenting with cPNETs (including 80 medulloblastomas) in the Northern region between 1963 and 1997 were studied, including 85 from the previous study mentioned above  contents in the PCR mixture, to maintain the dATP concentration within adequate limits for reaction efficiency and fidelity during PCR.This method was applied to all samples to detect the presence of an 18 bp deletion in exon 5 which was identified in one sample during sequencing. A radiolabelled nucleotide α-The Kaplan–Meier method (Graphpad Prism) was used to estimate survival probability as a function of time, and the log-rank test to examine differences in survival between subgroups. Multivariate analysis for p53 SI and LI, age, sex and year of diagnosis (YOD), was performed by Cox's regression using the forward stepwise selection method .p53 and Waf-1 were not detectable in normal cerebellar tissues present in 10 tumour sections  was 35% at 5 years. The accumulation of p53 protein, which in the majority of cases was wild-type, has significant prognostic value . No significant difference in survival was observed between groups categorised for Waf-1, Bax and Bcl-2 staining. The categories and corresponding P-values for the survival analysis for each protein are shown in Table 3The prognostic value of the accumulation of p53, Waf-1, Bax and Bcl-2 proteins was assessed by both univariate and multivariate analyses, using the Kaplan–Meier method and Cox's regression, respectively. The overall survival of the patients studied  had high staining intensity. The level of staining of p53 in the present study, which employed microwaving for antigen retrieval in the immunohistochemistry was consistent with that of a previous study  and coulThe low incidence of p53 gene mutations in these cPNETs suggested that the p53 protein in these tumours was likely to be wild-type and functional. This was consistent with the significantly positive relationship between the expression of p53 and Bax (Table 5activity . The experbB2, a member of the epidermal growth factor receptor or EGFR family (Contrary to p53 and Bax, the positive relationship between the expression of p53 and Bcl-2 proteins in the cPNETs  was unexR family .In conclusion, the present study has shown that a high level of p53 protein in cPNETs measured by immunostaining intensity was associated with poor patient survival, supporting the findings of a previous study, and appeared to reflect the aggressiveness of the tumours. Sequencing results and the overall positive relationship between the expression of p53 and Bax pointed to the possibility that the p53 protein in the current series of cPNETs was wild-type and functional, except in the subset of tumours which expressed high levels of Bcl-2. In addition, maleness, young age at diagnosis and diagnosis before 1979 were all independent indicators of poor prognosis. Further research work, including functional assays involving reporter systems in cell lines and studies investigating the mechanisms underlying the expression of Bcl-2 in cPNETs, will clarify the functional status of p53 in central primitive neuroectodermal tumours.


Near term infants are a main part of preterms. They are at higher risk for mortality and morbidity than term infants and could show a quite different development of tone and reflexes from them. The aim of the present study was to describe longitudinally, in a large sample of healthy near term infants, the development of the forward parachute reaction (FPR) and its correlation with the age of acquisition of independent walking.The assessment of FPR  was performed at 3, 6, 9, 12 months of corrected age in 484 infants, with a gestational age between 35.0 and 36.9 weeks. The age of acquisition of independent walking was monitored until its appearance. A correlation analysis was done between the age of walking and the acquisition of a complete or incomplete FPR, using the Spearman Rank correlation. The Mann-Withney U test was used to identify significant gestational age differences for the age of FPR appearance.Most of infants had a two-step development pattern. In fact, they showed at first an incomplete and then a complete FPR, which was observed more frequently at 9 months. An incomplete FPR only, without a successive maturation to a complete FPR, was present in the 21% of the whole sample. Infants with a complete FPR walked at a median age of 13 months, whereas those with an incomplete FPR only walked at a median age of 14 months.We identified two groups within our sample of near term infants. The first group showed a progressive maturation of FPR, whereas the second one was characterised by the inability to get a complete pattern, within the one year observation's period. Furthermore, we observed a trend toward a delayed acquisition of independent walking in the latter group of infants. During the last two decades, the population of near term infants (34 weeks through 36 weeks of gestation) is increased progressively and it is actually the 70% of the whole population of preterms -3. ImproThe forward parachute reaction (FPR) is a milestone "key" for the neuromotor development of infants. In fact, several authors showed that infants need a previous acquisition of this reaction before standing and walking ,8. In clth percentile), major congenital malformations, severe postnatal infectious diseases, metabolic or haematological complications and variable follow-up program. The study protocol was previously approved by the Ethics Committee of our Institution and a signed informed consent was obtained from parents.The infants described in this study are a part of a large cohort admitted to the Neonatal Unit of the Department of Paediatrics of the University of Catania between January 2001 – December 2005. They were consecutively enrolled in a follow-up research program until the age of 2 years. Although the near term well babies are not likely to stay at hospital longer than a few days, our follow-up research program included one assessment for cranial ultrasound (US) during the first week, one after 14 days and one at term age. The last two US scans were done after discharge from the hospital. As a part of the follow up program, neurological development was systematically followed with a structured neurological assessment, performed at 3, 6, 9 and 12 months of corrected age (CA) , and a nThe FPR was assessed at 3, 6, 9, 12 months CA in all infants included in the present study.FPR was evoked by holding the infant by the hips in a prone position  and by dropping him suddenly downwards at 45 degrees with the head directed towards a surface with the eyes open. The manoeuvre was applied when the infant was in the most appropriate behavioural state, corresponding to state 4 of Brazelton  . It was The age of onset of independent walking was defined as the time when the infant took the first five successive steps without support . The parValues are reported as median, minimum-maximum and 25°–75° percentiles. For analysis purposes, infants were divided in two groups. A first group (group A) was composed by infants who gained a complete FPR within the observation's period; in this group are enclosed those infants showing an incomplete FPR followed by a complete FPR too. A second group (group B) was represented by those who had an incomplete FPR only. A third group of infants contemplate those infants with no FPR (both incomplete or complete) within the first year of life; because of the limited number of this group, it was not enclosed in the statistical analysis. The number of infants who had a complete or incomplete FPR at 3, 6, 9, 12 months were calculated. A correlation analysis was done between the age of walking and the acquisition of a complete or incomplete FPR, using the Spearman Rank correlation. The Mann-Withney U test was used to identify significant GA differences for the age of FPR appearance. The level of significance was set at p < 0.05.During the study period, 648 consecutive newborns with a GA between 35,0 and 36,9 weeks were discharged from our Neonatal Unit; from this population 164 babies were excluded because of major lesions at US scanning (n = 86) or an incomplete follow-up program (n = 78); 484 infants fulfilled the inclusion criteria; 228 were born at 35 weeks and 256 at 36 weeks GA. A Normal cranial US was found in 415 infants, whereas transient flares or IVH 1 were respectively observed in 59 and 10 infants. The 51% of this sample was male. No significant differences (p > 0.05) between infants born at 35 and those born at 36 weeks were found for the age of acquisition of FPR. Infants with minor lesions on US showed similar findings to those observed in the group with normal US. The results of neuromotor assessments performed during the first year of life are reported in a previous paper [In Fig. Fig. All infants showed an independent walking within 17 months of age, with a median of 13 months. Infants with a complete FPR at 3 months developed precociously an independent walking at a median age of 10 months, whereas those who had a complete FPR at 6, 9 and 12 months walked respectively at a median age of 12, 13 and 14 months .The correlation analysis (r) between the age of acquisition of an independent walking and the age of a complete FPR by 12 month was 0.32 (p < 0.0001) whereas for those with an incomplete FPR only, Our study investigated the development of FPR in a large sample of near term infants, during the first year of life. We found that most of infants showed a complete FPR as previously shown both in term  and pretThe possible physiological background of FPR was proposed by Touwen , who sugThe incomplete FPR is characterised by an incomplete extension and/or by an asymmetric extension of the upper limbs and/or of closed hands ,10. Its An interesting result of our study is the presence of a small subgroup of infants who develop an early incomplete reaction (at 3 months) showing an independent walking around 12 months. These infants were not able to gain a complete FPR within the first year of life and, in the same line of evidence reported by other authors ,8, it seThe systematic observation of the sensory-motor development of infants has shown that it occurs according to a timed calendar. In fact, a normal infant acquires the sitting position at about 6 months, on all-fours at 9 months, supported walking at 12 months and independent walking between 12–15 months ,8,17,18.Then, our study shows for the first time not only the features and the development of FPR in near term infants, but also the temporal relationships between the development of an incomplete FPR and an independent walking.A peculiar characteristic of our sample is represented by the high number of infants who were recruited for the study. In fact, it seems to be sufficiently consistent, from a statistical point of view, to follow the development of FPR during the first year of age. Since, the infants enrolled for this investigation were near term babies only, it is not possible to extend our observations to healthy infants born at term age. However, we can conclude by indicating that, in our near term sample, a milestone "key", as a complete FPR, follows a development quite overlapping to that of term infants and similarly correlated to the acquisition of independent walking. On the other hand, we should consider two main limitations of this study. Firstly, the fact that our observation's period was limited to the first year of age and secondly that the interval between each evaluation was of 3 months. Consequently, we cannot indicate the exact time of acquisition and maturation of FPR.In conclusion, by this study we point out the role played by the FPR in the process of near term infant's maturation and its correlation with the acquisition of functional abilities as independent walking. The knowledge of the maturation of these patterns could be useful for clinicians to identify those infants with motor delay. Future studies could be needed to enrol large samples of infants at low and high risk to identify the predictive value of FPR maturation in relation to the development of posture and movement.FPR: Forward Parachute Reaction; US: Ultrasound; CA: Corrected Age; CAT-CLAMS: Clinical Adaptive Test/Clinical, Linguistic and Auditory Milestone Scale; GA: Gestational Age; IVH 1: Germinal layer haemorrhages grade 1; r: Correlation analysis.The authors declare that they have no competing interests.DMMR participated in the design of the study, performed the clinical neurological assessments and helped to draft the manuscript. MC participated in the design of the study and drafted the manuscript. MS performed the clinical neurological assessments. FP performed the statistical analysis. AP and AS participated in the design of the study. MGR conceived the study, participated in its design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The value of apparent molar absorptivity of the complex in terms of iron is(2.00) x 104 l mole-1 cm-1 at an absorption maximum of 490 nm. The detection limit of the method is 8 ppb Fe. The sample throughput is 90 samples/h at a flow rate of 4.0 ml/min. The reaction mechanism, optimization of FIA variables, and effect of various types of surfactant are described. None of the tested anions and cations interfered with the determination of iron. The method was used for the quantification and flux determination of iron in rain water.This paper explains a new procedure for flow injection analysis (FIA) determination of iron in rain water based on the colour reaction of Fe


In mice given a single dose of diethylnitrosamine, a hepatonecrotic dose of carbon tetrachloride, 5 weeks after dosing with DEN and repeated 6 times at 4-weekly intervals, augmented the tumour yield in the livers. A single hepatonecrotic dose of CCl4 24 h before a single dose of DEN also increased the number of tumours produced. The effect of the repeated administration of CCl4 after the dose of DEN occurred in addition to, and was therefore independent of, the enhancing effect of a single dose of CCl4 before DEN. These results may be interpreted as implying (1) that the liver in the regenerative phase after a hepatonecrotic dose of CCl4 is more susceptible to an initiating action of DEN, i.e. produces more potential foci of tumour growth than in the normal liver and (2) that the repeated doses of CCl4 leading to repeated phases of regeneration, after the dose of DEN, provide a promoting stimulus.


About 130 million people are infected with the hepatitis C virus (HCV) worldwide, but effective treatment options are not yet available. One of the most promising targets for antiviral therapy is nonstructural protein 3 (NS3). To identify possible changes in the structure of NS3 associated with virological sustained response or non-response of patients, a model was constructed for each helicase NS3 protein coding sequence. From this, the goal was to verify the interaction between helicases variants and their ligands.Evidence was found that the NS3 helicase portion of non-responder patients contained substitutions in its ATP and RNA binding sites. K210E substitution can cause an imbalance in the distribution of loads, leading to a decrease in the number of ligations between the essential amino acids required for the hydrolysis of ATP. W501R substitution causes an imbalance in the distribution of loads, leading and forcing the RNA to interact with the amino acid Thr269, but not preventing binding of ribavirin inhibitor.Useful information is provided on the genetic profiling of the HCV genotype 3, specifically the coding region of the NS3 protein, improving our understanding of the viral genome and the regions of its protein catalytic site. Hepatitis C virus (HCV) is the main causative agent of non-A and non-B hepatitis. The clinical manifestations of infection include acute and chronic forms of hepatitis C, liver cirrhosis and hepatocellular carcinoma . The oveThe HCV genome contains a positive single-stranded RNA of ~9.6 kb. It encodes a single precursor polyprotein containing ~3000 amino acids -6, whichThe NS3 protein of the hepatitis C virus (HCV) is a target for development of antiviral agents. It is a hydrophobic protein of ~69 kDa, with its serine-protease function encoded in its N-terminal portion accounting for one-third of the entire protein . The C-tTo identify possible changes in the structure of the NS3 protein associated with virologically sustained responder and non-responder patients, a model was constructed for each helicase NS3 protein coding sequence.The study material consisted of the serum samples of the 16 patients infected with hepatitis C virus genotype 3. After confirming the positive diagnosis of infection, defined by positivity for the virus antibody by ELISA and qualitative PCR for RNA, the patients were given 24 weeks of treatment with interferon-alpha and ribavirin, and were followed-up for up to 6 months after medication. Serum collections were made at 12 and 24 weeks during treatment, and 7, 14, 21 and 28 days after the treatment had been completed, then monthly for up to 6 months. Co-infection with the human immunodeficiency virus (HIV) and/or with the hepatitis B virus (HBV) was taken as an exclusion criterion. The project was approved by the research ethics committee of the São José do Rio Preto School of Medicine .For the modeling of NS3, the restrain-based modeling approach was used as implemented in the MODELLER program . A totalThe stereochemical evaluation quality of the final model was assessed by PROCHECK , X-PLOR The Molegro Virtual Docker program (version 2.0) was used to generate an ensemble of docked conformations for each variant helicase protein and ATP, RNA and Ribavirin compounds .A total of 16 patients were treated and followed until 6 months after the end of the treatment. Seven patients (43.7%) presented a virological sustained response (VSR), of whom 6 were male and 1 was female. Nine patients (56.3%) presented non-response (NR), 6 being male and 3 female. Thirteen patients were infected with HCV genotype 3a and 3 with HCV genotype 3e. The patients' average age was 47.7 years  normally bind to a helicase in the cleft that separates two adjacent RecA-like domains. The most critical residues for ATP binding arise from the Walker A and B motifs. The Walker A motif of HCV helicase forms a phosphate binding loop (P-loop) with the conserved Lys210, thereby probably contacting the γ phosphate of ATP [To verify that the consequences the K210E substitution led to interaction with ATP, docking simulations were performed between helicase variant and the compost. The exchange of charges due to the substitution produced an imbalance in the distribution of loads, leading to a decrease in the number of ligations between the essential amino acids for the exercise of hydrolysis of ATP Figures . ATP ande of ATP . With thKim et al.  through The substitution (W501R; see Table et al. [et al. [Based on the observation that the oligonucleotide appears to be locked in the binding cleft because a residue in domain 3, Trp501, is stacked against the 3'-terminal base, Kim et al. , propose [et al. .Since interferon-alpha did not act as a protease inhibitor, we also performed docking simulations between the variant protein W501R and the compound Ribavirin to find a correlation between the substitutions found in Helicase and the response of patients to treatment. This inhibitor connects to altered Helicase the same way that as in Helicase wild type, independent of the substitution of tryptophan by arginine at position 501, and thereby maintaining its function Figures . From thNatural occurrence of amino acids substitution in non-responder HCV patients has been explored for important sites in relation to the perfect excise of helicase function. Correlations of the variants L210E and W501R with patients' responses to the treatment may not be valid at this time because other forms of viruses that have the helicase in their wild types are predominant in the patient, thus ensuring viral replication. It is important to find these variants so that future enzymatic studies can be carried out on them. Individual analysis of treatment with future inhibitors can be important to treatment response.The authors declare that they have no competing interests.PJSP carried out the experiments, acquisition of data, analysis and interpretation of data and drafting the manuscript; HAA and MSP carried out the molecular modeling and suggestions in this manuscript; IMVGCM participated in the study and made suggestions to the manuscript; JRRP and MLN participated in the study; PR conceived the study, participated in its analysis and coordination and suggestions in this manuscript. All authors read and approved the final manuscript.Methods, Figure S1 and S2Click here for file


The hypothesis is explored that CRPS I (the "new" RSD) persists due to undiagnosed injured joint afferents, and/or cutaneous neuromas, and/or nerve compressions, and is, therefore, a misdiagnosed form of CRPS II . An IRB-approved, retrospective chart review on a series of 100 consecutive patients with "RSD" identified 40 upper and 30 lower extremity patients for surgery based upon their history, physical examination, neurosensory testing, and nerve blocks. Based upon decreased pain medication usage and recovery of function, outcome in the upper extremity, at a mean of 27.9 months follow-up (range of 9 to 81 months), gave results that were excellent in 40% (16 of 40 patients), good in 40% (16 of 40 patients) and failure 20% (8 of 40 patients). In the lower extremity, at a mean of 23.0 months follow-up (range of 9 to 69 months) the results were excellent in 47% (14 of 30 patients), good in 33% (10 of 30 patients) and failure 20% (6 of 30 patients). It is concluded that most patients referred with a diagnosis of CRPS I have continuing pain input from injured joint or cutaneous afferents, and/or nerve compressions, and, therefore, similar to a patient with CRPS II, they can be treated successfully with an appropriate peripheral nerve surgical strategy. For the patient given the traditional diagnosis of "Reflex Sympathetic Dystrophy" (RSD) who fails to recover from sympathetic blocks, anti-inflammatory medication and physical therapy, current treatment options largely consign the patient to a Pain Management center for life.,2 ChangiPeripheral nerve surgery has been considered an option in the upper extremity for the diagnosis of co-existing carpal tunnel syndrome once the patient has passed the acute phase of pain and associated swelling.,14-16 ReWith the hypothesis that chronic pain input to the dorsal spinal columns can be the source of CRPS II, misdiagnosed as CRPS I, and with the hypothesis that injured joint and/or cutaneous afferents as well as chronic nerve compression can be the source of these painful dorsal column inputs, an approach was taken to re-evaluate patients with CRPS I of the upper or lower extremity. The results of this approach are now reported.Absolute: pain extending outside the area of trauma, impaired extremity function, and either cold or warm perceptions or temperature changes in the affected extremity; Relative: swelling, increased hair or nail growth, hyperalgesia, allodynia, abnormal skin coloring.An IRB-approved, retrospective chart review was carried out on a series of 100 consecutive patients with the diagnosis of "RSD" from a computer database from 01-01-2000 through 04-30-2006. Diagnosis was made based upon the International Association for Study of Pain criteria:[Inclusion into the surgery group required 1) failure to have the chronic pain resolve despite more than 6 months of therapy, edema control, anti-inflammatory medication, and opiates under the control of a pain management physician, 2) documentation of a pain input source by nerve blocks of joint and/or cutaneous afferents, with a ≥ 5 point reduction in pre-block pain on a Visual Analog Scale , and 3) documentation of chronic nerve compression by abnormal neurosensory testing and the presence of a positive Tinel sign at the known site of anatomic narrowing . Based upon these inclusion criteria, seventy patients from the 100 were selected for surgery, 40 patients had upper extremity and 30 patients had lower extremity CRPS.The nerve block was done using a 50:50 mixture of 1% xylocaine and 0.5% bupivicaine, each without epinephrine. Sterile technique was used. For each nerve block, 5 cc of this mixture was infiltrated into the region of the known joint afferent or suspected cutaneous neuroma. The joint itself was not infiltrated. The nerve itself was not knowingly injected. Sites of suspected nerve compressions were not injected to avoid increasing the pressure on the compressed nerve. Failure of the nerve block to relieve pain could imply that the block was not done properly, and therefore "failure" meant that while loss of sensation did occur in the distribution of the sensory nerve that was blocked, there was insufficient pain relief to deem that block successful. When this occurred, it was still possible that another nerve contributed to the pain mechanism and that the two sensory territories overlapped, e.g., the radial sensory nerve and lateral antebrachial cutaneous nerve, or the sural and superficial peroneal nerve territories. This anatomic possibility was investigated by a new block of the suspected adjacent nerve. If the pain remained after nerve block of all possible sensory nerve territories, then failure to obtain pain relief was interpreted to mean that there was a fixed central mechanism  for the pain and that peripheral nerve surgery would not be of benefit.Patient demographics are given in Table The distribution of the mechanisms of injury in each group is given in Table In patients with either 1) a history of repeated swelling or acute exacerbations of pain after extremity use, 2) evidence of persistent sympathetic over-activity, or 3) pre-emptive anesthesia was requested by the patient's Pain Management doctor, the surgery was done using indwelling brachial plexus or epiduThe distribution of surgical procedures done is given in Table Outcomes included measurement of pain, level of drug use, improved function as determined by activities of daily living and return to work. An excellent result required the pain level to be from 0 to 2, a cessation of opiate use, the ability to use the upper or lower extremity for normal activities of daily living, and the return to work (if previously employed) or school. A good result required the pain level to be from 3 to 4, an occasional use of a non-opiate, a slight restriction of activity of daily living, and the return to work (if previously employed) or school. All impairments greater than the above criteria were considered a failure. Descriptive statistics were used for the demographics.In order to evaluate whether there was a difference in outcomes between patients with a relatively short length of follow-up and those with a longer length of follow-up, the patient population was grouped into those whose follow up was ≥ 9 but ≤ 24 months, and those whose follow-up was > 24 months.In the upper extremity the results were excellent in 40% (16 of 40 patients), good in 40% (16 of 40 patients) and failure 20% (8 of 40 patients).In the lower extremity the results were excellent in 47% (14 of 30 patients), good in 33% (10 of 30 patients) and failure 20% (6 of 30 patients).In the upper extremity the results were excellent in 35% (9 of 26 patients), good in 38% (10 of 26 patients) and a failure in 27% (7 of 26 patients).In the lower extremity the results were excellent in 41% (7 of 17 patients), good in 35% (6 of 17 patients) and a failure in 24% (4 of 17 patients).In the upper extremity the results were excellent in 50% (7 of 14 patients), good in 43% (6 of 14 patients) and a failure in 7% (1 of 14 patients).In the lower extremity the results were excellent in 55% (7 of 13 patients), good in 30% (4 of 13 patients) and a failure in 15% (2 of 13 patients).There was no statistically significant difference between results in the upper versus the lower extremity or between any of the three time-frame groupings.This study demonstrated that more than 80% patients with a diagnosis of "CRPS I" of the upper or the lower extremity have one or more injured and/or compressed peripheral nerve(s) as the source of their continuing dorsal column painful neural input. This means that perhaps as many as 80% of patients with the current diagnosis of "CRPS I" should actually have a diagnosis of "CRPS II", and provides optimism that a peripheral nerve source for their pain can be identified and successfully treated using an appropriate peripheral nerve strategy.This study demonstrates that the accepted principles of upper extremity peripheral nerve surgery apply to the lower extremity. If nerve decompression of the median nerve in the carpal tunnel can be accomplished safely for the patient with CRPS I, then nerPainful dorsal column input can arise from injured joint afferents caused by wrist or ankle sprain/dislocation, arthroscopy, or total joint replacement. This source of pain can be determined by nerve block of the appropriate nerve(s). If the nerve block reduces the pain level by ≥ 5 on the Visual Analog Scale, partial joint denervation should be considered. For the wrist, partial denervation can be achieved by resecting the anterior and the posterior interosseous nerves.,26 For tPainful dorsal column input can arise from neuromas of cutaneous nerves, which can also be determined by nerve block of the appropriate nerve, taking care not to place the anesthetic where two nerves will be blocked simultaneously. If the nerve block reduces the pain level by ≥ 5 on the Visual Analog Scale, resection of the nerve(s) should be considered with implantation of the proximal end into a muscle with minimal excursion.Patients with "RSD" of the Knee -5 shouldThe group of patients with a poor result from this surgical approach, and those in the initial cohort identified by our computer search who were not selected for this peripheral nerve surgical approach, may be concluded to have CRPS I. It is possible that those in our failure group have a fixed central nervous system site for their pain generator, making them unresponsive to peripheral nerve surgery, even if they obtained some relief from a peripheral nerve block.While there is no doubt that patients with CRPS have impairment in their daily life, documenting this degree of disability is difficult. One approach is to use validated "instruments", or questionnaires to do this. A limitation of the present study is that it did not use a validated outcome instrument to measure the patients before and after their surgical treatment. The outcomes used to assess the results of the surgical interventions in this small group of upper and lower extremity patients with CRPS II do suggest that the appropriate surgical intervention can impact each patient's quality of life, and do this with a low risk of increasing their impairment. The results of the present study suggest that it would be appropriate for a prospective study to utilize both a generalized health-related quality of life instrument as well as one uniquely related to upper extremity function and lower extremity function. The first paper to study quality of life issues in patients with CRPS compared the Nottingham Health Profile, the European Quality of Life 5D, and the Sickness Impact Profile 68 to 100 patients with RSD, 33 in the upper and 21 in the lower extremity. RegardleIt is concluded that most patients referred with a diagnosis of CRPS I have continuing pain input from injured joint and/or cutaneous afferents, and/or chronic nerve compression(s), and therefore, similar to a patient with CRPS II, they can be treated successfully with an appropriate peripheral nerve surgical strategy. Using nerve blocks to identify patients whose pain is from a peripheral nerve source is critical to decision making with regard to which nerve(s) should be resected.ALD has a proprietary interest in the Pressure-Specified Sensory Device™ and owns Sensory Management Services, LLC.ALD originated the concept of the study, and the surgical procedures, wrote the first and final drafts of the manuscript. EA did the chart data review and analysis, and edited the Manuscript. GDR participated in the surgery, helped conceive the research design and IRB approval, reviewed the data and the manuscript.


A line of human leukaemia-derived cells is described that kills a wide range of human and animal cell lines, whether normal or malignant, even at a ratio of 1:1. During exposure to the target cells, the killer cells released a factor into the culture medium which destroyed target cells in the absence of the killer cells. This phenomenon occurs without exogenous complement and requires no pre-treatment of target or killer cells. The humoral factor is a protein precipitable by 60% saturation of ammonium sulphate and has a mol. wt. of approximately 70,000; It prevented the growth of a fibrosarcoma in mice.


The 7-valent pneumococcal conjugate vaccine has been introduced in national immunisation programmes of most industrialised countries and recently in two African GAVI eligible countries (Rwanda and The Gambia). However the long term effects of PCV are still unclear, as beneficial direct and herd immunity effects might be countered by serotype replacement.Streptococcus pneumoniae transmission was developed to predict the potential impact of PCV7 on the incidence of invasive disease accounting for both herd immunity and serotype replacement effects. The model was parameterised using epidemiological data from England and Wales and pre and post-vaccination surveillance data from the US.A dynamic, age-structured, compartmental model of Model projections showed that serotype replacement plays a crucial role in determining the overall effect of a PCV7 vaccination programme and could reduce, negate or outweigh its beneficial impact. However, using the estimate of the competition parameter derived from the US post-vaccination experience, an infant vaccination programme would prevent 39,000 IPD cases in the 20 years after PCV7 introduction in the UK. Adding a catch-up campaign for under 2 or under 5 year olds would provide a further reduction of 1,200 or 3,300 IPD cases respectively, mostly in the first few years of the programme.This analysis suggests that a PCV vaccination programme would eradicate vaccine serotypes from circulation. However, the increase in carriage of non-vaccine serotypes, and the consequent increase in invasive disease, could reduce, negate or outweigh the benefit. These results are sensitive to changes in the protective effect of the vaccine, and, most importantly, to the level of competition between vaccine and non-vaccine types. The techniques developed here can be used to assess the introduction of vaccination programmes in developing countries and provide the basis for cost-effectiveness analyses. Streptococcus pneumoniae infection in developing countries, the available 7-valent pneumococcal conjugate vaccine (PCV7) introduced in 2000 in the US and included in a number of European countries routine immunisation schedules [Despite the considerable burden of disease caused by chedules , has yetchedules -8, the cchedules -12. An ichedules -16.While surveillance systems can and should closely monitor country-specific trends in the post vaccination era, there is the need to investigate the potential scenarios that the longer term effects of these interventions might produce and to evaluate the economic acceptability of such interventions considering medium to longer term consequences such as herd immunity and serotype replacement.S. pneumoniae infection, by using pre and post invasive disease surveillance data from, respectively, Australia and the US [http://www.hpa.org.uk and it is having major implications for the overall impact of the programme.Transmission dynamic models have now been extensively used to describe the dynamics of infectious diseases  and to pd the US ,30. NeitThe model presented here generates projections for England and Wales and evaluates the policies that were under consideration at the Department of Health for the UK at the time of introduction of PCV7. However, future changes to the vaccine formulations and/or schedule can be considered with the current model and it can also be adapted to look at other countries programs. Mathematical models can provide insights on the overall impacts produced by alternative public health interventions and should be used by policy makers as an additional tool to inform their decision.The following three distinctive datasets were used to parameterise the model:• pneumococcal carriage prevalence data from England and Wales  to estimcase:carrier ratio (i.e. the proportion of infection that progress into a disease state)• the national enhanced surveillance of IPD in England and Wales  to deriv• the Active Bacterial Core Surveillance data (ABC)  which, bIn the following a brief description of the three datasets is given.A longitudinal study was carried out by collecting nasopharyngeal swabs every month from 489 individuals including 121 pre-school children (<3 yrs.) for a period of 10 months, from October 2001 to July 2002 in England and Wales ,34. SwabS. pneumoniae infection and on the isolated serotypes  is an active laboratory and population-based surveillance system for invasive bacterial pathogens of public health importance. From the ABCs system, IPD cases were identified from 8 counties in the US . The total population is estimated at 18,041,585  and the total number of IPD cases was 22,365 for the period 1998-2004 . As the c = 0.01), with a total stable population  which adds up to 1 [i moving up to become age group i+1. Each age cohort goes through the transmission cycles according to the infection process outlined in the following paragraph.The model consists of 100 cohorts of individuals  each corresponding to one year of age and each of equal size  and non-vaccine type (λNi) pneumococci. Individuals carrying VT become co-colonised at a rate cNλNi where cN is the relative susceptibility of an individual colonised with VT to acquiring NVT compared with an uncolonised individual. Similarly NVT carriers become co-infected at a rate cVλVi. Once infected, individuals can recover from carriage and go back to a susceptible state (V→S or N→S) or, if they were co-colonised, to carriage of a unique type (B→V or B→N). This happens at an age-dependent rate ri which is the same whether or not the individual was in the colonised state (V or N) or in the co-colonised state (B).Uninfected, unprotected individuals (S) become infected according to the age-specific force of infection of vaccine type (λγi) where γi is the degree of protection. The force of infection for NVT among vaccine-protected individuals is the same as among unprotected individuals. Vaccine-protected individuals may lose their protection and go back to the equivalent unprotected compartment at a waning rate w  that is constant throughout all ages and across all compartments. Vaccination is assumed not to affect infectiousness: vaccinated VT carriers are assumed to be as infectious as unvaccinated VT carriers.Following vaccination, all vaccinated individuals move into the equivalent vaccine-protected compartment according to their carriage status, and gain partial protection against VT acquisition. The force of infection of VT pneumococci, among vaccine-protected individuals, is reduced by a factor .We assume that the risk of disease occurs at the time of carriage acquisition. The proportions of those infected who develop IPD, Vi = rNi) [The average duration of carriage was estimated using a previously developed modelling framework ,42 and ci = rNi) ,43, and j and the rate of effective contacts between individuals in the age class i and those in age class j (βij), as follows:The forces of infection for VT and NVT were age- and time-dependent, varying as a function of the number of vaccinated and unvaccinated carriers in each age class ij and the underlying assumptions on the mixing patterns adopted in the model are described in Appendix 2 and follow the techniques originally developed for sexually-transmitted infections [The derivation of the transmission rates βfections . In brieN (how much VT carriage protects against acquisition of NVT). As there is little information in this data set on cV, we used the value, cV = 0.5, as a baseline value, and analysed the sensitivity using the values of 0 and 1. We optimised ε and cN by fitting to the incidence of IPD in each age group from the US data by minimizing the Poisson deviance. The reported annual coverage level for 1+ doses in children between 19 and 35 months in 2003 of 86%  was assumed as the baseline annual vaccine coverage of routine vaccination from 2001 onward. Vaccination coverage in the first year of the program was set at 43% for 0 (routine) and 1 (catch-up) year olds as the vaccine was introduced around the middle of the year (July 2000). As the vaccine coverage levels varied each year, the coverage assumed in the model was varied as well, from 80% to 90% with an increment of 2% for the sensitivity analysis.The introduction of PCV7 for routine use in children aged <5 years in the United States yields valuable information about the impact of vaccination at a population level. We used national surveillance data on the number of cases of invasive disease caused by VT and NVT before and in the four years after the vaccine introduction  to estimThe age-specific proportions of VT and NVT pneumococcal infections that lead to IPD (case: carrier ratio) were estimated by fitting a model to the age-specific incidence of these diseases attributable to pneumococci as reported from the national enhanced surveillance of pneumococcal disease in the pre-vaccination years . A totalWe assume that all individuals who received PCV7 move to the vaccine protected group. The average duration and degree of vaccine-induced protection were estimated by fitting the model to the ABCs data from the pre- and post- vaccination US experience. The sensitivity of the model results to these parameter estimates was assessed.The alternative vaccination strategies investigated here are the ones that were relevant for the UK routine immunisation schedule:Strategy 1: routine vaccination at 2 and 4 months of age, plus a booster dose at 12 m;◦ Strategy 2: Strategy 1 plus catch-up campaign targeting all those under the age of 24 m;◦ Strategy 3: Strategy 1 plus catch-up campaign targeting all those under the age of 60 m.◦ For each vaccination strategy the model predicted the number of cases of IPD caused by VT and NVT in each age group over time. The coverage of routine and catch-up vaccinations for PCV7 in the UK was assumed to be the same as for the meningococcal serogroup C conjugate vaccine pre-school catch-up  . Catch-uThere were three stages to the analysis. First, a steady state pre-vaccination model estimated age-stratified values for the forces of infection and case:carrier ratios for VT and NVT. Second, a dynamic post-vaccination model estimated key vaccine parameters, interaction between VT and NVT and the level of assortativeness of mixing pattern from US surveillance data. Third, the dynamic model was used to assess the impact of alternative vaccination strategies in England and Wales.N). The fully assortative and fully proportionate mixing matrices between the six age-groups were also generated and later used as two extremes in the transmission model. Age-specific case:carrier ratios were then derived fitting the model to the age distribution of IPD cases caused by, respectively, vaccine and non-vaccine serotypes in the pre-vaccination era. The procedure, which required the minimisation of a Poisson deviance using the SOLVER in Excel, was run for both England and Wales and the US to calculate the risk of developing disease when colonised.The pre-vaccination model was programmed in Excel to estimate forces of infection for VT and NVT and for the following age groups: 0-1, 2-4, 5-9, 10-19, 20-39 and 40-99 using the carriage prevalence data available for England and Wales and a given value for the competition parameter (cN). The forces of infection, case:carrier ratios and extreme mixing matrices were updated for each value of cN. The estimate of cN was derived by finding the value that minimised the deviance.The transmission dynamic model was programmed in Berkeley Madonna  and fitted to the pre- and post- vaccination IPD data from the US to estimate degree and duration of protection of the vaccine against invasive disease, and the mixing parameter (ε) for different values of the competition parameter .N = 85%, 15% protection), and that population mixing was closer to assortative than proportionate (ε = 0.87) in line with a recent European contact study [Graphical comparison between the observed and predicted VT and NVT IPD cases by age group from 1998 to 2004 in the 8 counties covered by the Active Bacterial Core Surveillance is presented in Figure ct study . The conSeven pairs of the degree and duration of PCV7 vaccine protection were chosen within the 95% confidence area (including the best fitted pair with the baseline US PCV7 coverage) and showed that the UK transmission model predictions of IPD changes are insensitive to the assumptions. The fitting results indicated that the higher the degree is the shorter the duration of protection. The baseline parameters used for the following simulations of England and Wales predictions are the ones estimated when fixing the coverage level to 86% Table . Age-speIn the long term, the model predicted that all three strategies had a similar impact and eliminated transmission of VT. Strategy 3, which has the largest catch-up, has the most rapid impact on carriage and IPD, while Strategy 1 with no catch-up was the slowest Figure . The modIn the long term, the model predicts a 63% reduction of all IPD cases in children aged less than 5 years old and 35% reduction in the rest of the population, which amounts to the prevention of 2,300 cases of IPD annually after 20 years of the PCV7 introduction with all three vaccine programme strategies. Following the results for the impact on carriage, Strategy 1 is the least effective in terms of disease prevented. The routine vaccination and booster for one year old (Strategy 1) reduces 6000 IPD cases within the first five years of the programme, and an additional catch-up for children up to 23 months of age (Strategy 2) prevents extra 1,200 IPD cases. Extending the catch-up to age 59 month (Strategy 3) prevents further 3,300 IPD cases. The impact of vaccination on the long term incidence of VT and NVT disease by age group and vaccine programme strategies is illustrated in Figure N (lower protection from VT carriage) would result in lower replacement of VT by NVT after PCV7 introduction and thus in a small number of IPD cases while a lower competition parameter (i.e. higher protection from VT carriage) would result in more IPD cases than in the pre-vaccination period. Thirdly, lower values of ε (less assortative mixing pattern) would facilitate and hasten elimination of VT transmission with more IPD case reductions. On the contrary, higher values of ε would result in VT continuing to be carried due to less herd immunity effects of the vaccine.If the vaccine was less protective than assumed here, (i.e. lower duration or degree of protection), the program achieved lower coverage, or the population was less assortative, then transmission of vaccine types may not be eliminated. Extensive sensitivity analysis was conducted and the results are presented in Table S. pneumoniae infection presented in this paper enables investigation of the potential effects of infant PCV7 vaccination. It builds on previous S. pneumoniae models [The transmission model of e models ,28 and, Simulation results indicated that all of the vaccination strategies considered in this paper were sufficient to eliminate VT transmission in England and Wales with base case values for vaccination coverage and other parameters. Although the model predicts some replacement of VT with NVT, the annual total of IPD cases was reduced from 6,184 to 3,765 (38% reduction) in the long-term (20 years after the PCV7 introduction) and reduction of 39,000 IPD cases accumulated over the period. Catch-up campaigns for children aged under 2 and 5 prevent additional 1,600 and 4,100 IPD cases respectively compared to routine vaccination alone during the first twenty years of the PCV7 program . However, this conclusion is sensitive to vaccine and other model parameters. Small reductions in vaccine coverage, in the duration or degree of protection, from their base case values are sufficient to prevent elimination of VT being achieved. We cannot therefore exclude the possibility that PCV7 vaccination fails to eliminate VT transmission in the UK. On the other hand, NVT dynamics post vaccination are extremely sensitive to the level of competition between VT and NVT, and the model predicted an overall increase of the number of IPD cases pre to post vaccination if the level of protection of VT from NVT acquisition were almost complete.V , was assumed to be 50% since there is little information from post-vaccination surveillance on the protective effect of NVT carriage on VT acquisition. Sensitivity analysis suggested that the reduction in annual IPD cases after 10 years of PCV7 introduction is not sensitive to this parameter, with a maximum difference of 1% between scenarios (cV = 0 or = 100%). On the other hand, the degree of serotype replacement is sensitive to cN , which was estimated by fitting to the US post vaccination surveillance data. The sensitivity analysis indicated that the lower this value, the more replacement of VT by NVT will occur after the introduction of PCV7 in the community. Based on the UK surveillance after the PCV7 introduction, the replacement appears greater than the replacement in the US http://www.hpa.org.uk and the cause of this difference is currently being investigated. Potential contributing factors include differences in secular trends in prevalence and antimicrobial sensitivity of specific serotypes at the time of introduction [The competition parameter, coduction , differeThe mechanism of competition incorporated in the model may influence the projected outcomes . Here, tThe mixing pattern determines herd immunity effects of PCV7 vaccination among the unvaccinated age groups. From the impact observed in the US experience, we estimated that the mixing between individuals is more assortative than proportionate. Thus, similarly to other infections , contactThe relationship between acquisition of carriage and onset of invasive and non-invasive disease is not well understood. Here we assume that the risk of pneumococcal disease occurs at the time of acquisition of carriage, with age- and type-specific proportions developing IPD. An alternative assumption is that this risk is spread over the entire duration of carriage. We do not envisage that adopting this latter mechanism would markedly affect our results, especially as we have assumed that the duration of carriage is the same for both vaccine and non-vaccine types.One critical aspect of the current work is that the model categorises pneumococcal serotypes as either vaccine-type (including 6A) or non-vaccine type and assumes that the characteristics are homogeneous within each of these two categories. Firstly, the inclusion of serotype 6A in the vaccine group was implemented due to existing evidence that the 7-valent pneumococcal conjugate vaccine induces cross-protection against 6A ,57. HoweThe impact of pneumococcal vaccination on non-invasive diseases such as Acute Otitis Media (AOM) and Community Acquired Pneumonia (CAP) is not considered in this paper although some level of protection has been reported against these conditions in both developed ,70 and dThe outputs of any model are limited by the validity of the model assumptions and accuracy of the parameter estimates. In this study, considerable attention was paid to estimating appropriate parameter values and to assessing the sensitivity of the results to these values. Data from the longitudinal study in UK families were used to derive the initial prevalence of carriage, recovery rates and the forces of infection. Surveillance data on IPD cases pre- and post- PCV7 introduction in the US were used to estimate vaccine parameters, mixing patterns and to infer the degree of competition between VT and NVT. Moreover, the model developed here may also be useful for other countries considering the introduction of the pneumococcal conjugate vaccine and to estimate effects of alternative vaccine strategies. In future, these models will be improved by refining parameter estimates using the observed effects of the UK programme. The UK experience with the Hib and MenC vaccines -75 showeThe effect of PCV7 introduction on the burden of IPD is assessed using an age structured dynamic model which was parameterised with UK and US data. Model projections show the importance of considering the existence of competition between serotypes contained and not contained in the vaccine formulation in order to being able to realistically predict possible scenarios. The current model will be extended to incorporate non invasive pneumococcal disease and will form the basis for cost-effectiveness analysis for alternative vaccination programmes, especially in developing countries where the burden of pneumococcal disease is extremely high and the financial resources are limited.The authors declare that they have no competing interests.AM conceived the work, developed the programme and produced the initial draft of the manuscript. NJG contributed to the implementation of the model. YHC extended the programme, contributed to the drafting of the manuscript and performed final simulations. WJE and EM contributed to the interpretation of the results. RG provided the carriage data and contributed to the interpretation of the results. All the authors have read and agreed on the final manuscript.i represents the vaccine coverage in age group i, πi(t) is a function, describing the vaccination program in cohort i to occur at certain time as scheduled, rVi and rNi are, respectively, the proportion that recover from VT and NVT infection, ω is the rate of waning of vaccine-induced protection, cN (cV) represent the relative susceptibility of VT (NVT) carriers, compared with uncolonised individuals, to acquiring NVT (VT) carriage (i.e. competition parameters), γ is the vaccine efficacy against VT carriage, λVi(t) and λNi(t) represent the age-specific force of infection for, respectively, VT and NVT pneumococci at time t.Where i is the age group, νV and cN), the effective transmission coefficients (βVij and βNij) were calculated by fitting a model to the number of VT and NVT carriers in each age group at steady state  and proportionate (βp) mixing between the six age groups. A parameter ε, the assortativeness of mixing, is introduced to define the weight that is given to each of these matrices [Given values of the pneumococcal transmission parameters (in particular the competition parameters ce Figure . Matricematrices :Hence, if ε = 1, then full weight is given to the fully assortative matrices and mixing patterns is totally assortative whereas if ε = 0 full weight is given to the proportionate matrix. A value of ε is estimated when fitting to the pre and post vaccination disease incidence data for the US.Observed and fitted prevalence of carriage of pneumococcal vaccine and non-vaccine serotypes by age group in England and Wales are presented in Figure The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/10/90/prepub


Perceived milk intolerance is a common complaint, and tests for lactose malabsorption (LM) are unreliable. This study assesses the agreement between diagnostic tests for LM and describes the diagnostic properties of the tests.Patients above 18 years of age with suspected LM were included. After oral intake of 25 g lactose, a combined test with measurement of serum glucose (s-glucose) and hydrogen (H2) and methane (CH4) in expired air was performed and symptoms were recorded. In patients with discrepancies between the results, the combined test was repeated and a gene test for lactose non-persistence was added. The diagnosis of LM was based on an evaluation of all tests. The following tests were compared: Increase in H2, CH4, H2+CH4 and H2+CH4x2 in expired air, increase in s-glucose, and symptoms. The agreement was calculated and the diagnostic properties described.Sixty patients were included, seven (12%) had LM. The agreement  between the methods varied from 0.25 to 0.91. The best test was the lactose breath test with measurement of the increase in H2 + CH4x2 in expired air. With a cut-off level < 18 ppm, the area under the ROC-curve was 0.967 and sensitivity was 100%. This shows that measurement of CH4 in addition to H2 improves the diagnostic properties of the breath test.The agreement between commonly used methods for the diagnosis of LM was unsatisfactory. A lactose breath test with measurement of H2 + CH4x2 in expired air had the best diagnostic properties. The population based prevalence of lactose malabsorption (LM) in Scandinavia is 2-8% -3. The pLactose is an unabsorbable disaccharide hydrolysed by lactase (lactase-phlorizin hydrolase) in the intestinal brush border into galactose and glucose that are absorbed. LM is a failure to hydrolyse lactose. In adults the most common cause is a genetic defect with lack of intestinal lactase. The unabsorbed lactose is metabolised by colonic bacteria to produce gas (hydrogen H2) and methane (CH4)) and short chain fatty acids. Clinical manifestations of LM are abdominal pain/discomfort, borborygmi, bloating, flatulence and diarrhoea  and meth. In subjCommonly used tests for the diagnosis of LM are based on an exaggerated increase in H2 and/or CH4 in the expired air after intake of lactose, or an inappropriate increase in serum glucose (s-glucose). Other tests are assessment of lactase activity in jejunal biopsies, a test for genetic defects ,13, and The aims of this study were to assess the agreement between commonly used diagnostic methods for LM , describe the diagnostic properties of the methods and establish the best method and cut-off levels for clinical use.Patients with intolerance to milk or dairy products and/or unexplained abdominal discomfort consistent with LM seen in one outpatient gastroenterological unit were invited to participate in the study. Exclusion criteria were age below 18 years, insufficient understanding of written instructions, intake of antibiotics the last two weeks and a previous diagnosis of LM. Age, sex, Body Mass Index (BMI), ethnicity, smoking habits, the patients' reaction to milk and dairy products, and current and past diseases were noted.The initial diagnostic test for LM was a combined breath- and s-glucose test after intake of 25 g lactose. The test was performed at the hospital in the morning. Prior to the test the patients were on a low fibre diet for 48 hours, and they were not allowed to eat, drink or smoke the last 12 hours before the test. Physical activity, except for the limited activity necessary to reach the hospital, was prohibited in the morning before the test. H2 and CH4 were measured in the expiratory air before, and 30, 60, 120, and 180 minutes after intake of lactose with a stationary gas chromatograph . Alveolar air was collected using a Y-piece device (QuinTron AlveoSampler) after 10 seconds' expiration, analysed immediately after the collection and corrected for alveolar CO2. Samples for s-glucose were taken before, and 15, 30, 60, and 90 minutes after intake of lactose. An increase in H2 ≥20 ppm (parts per million) compared to the lowest measured value, an increase in CH4 ≥12 ppm compared to the value measured before the intake of lactose, or an increase in the sum of H2 and CH4 ≥15 ppm was considered as a diagnostic test for LM, as was increase in s-glucose < 1.1 mmol/L from baseline. If the s-glucose test and the breath test had concurrent outcomes , the patient was classified as not having LM or having LM.Twenty-four hours after the first combined breath- and s-glucose tests the patients filled in a questionnaire which was returned to the hospital. They were asked about the presence of abdominal symptoms during and for 24 hours after the combined test. If abdominal symptoms were present, they answered three additional questions: 1) When did the symptoms start?  2) What type of symptoms have you experienced?  and 3) How long did the symptoms last? . In accordance with a previous study, symptoms starting within 5 h after intake of lactose and lasting for more than 2 h were classified as "Early and Long Lasting" (ELL) [In cases of discrepancies between the initial breath test and the s- glucose test, the combined test was repeated without registration of symptoms, and a diagnostic gene test  was added ,13. The Because the synthesis of CH4 consumes large amounts of H2, an increase in CH4 in the expiratory air reduces the production of H2. Therefore, the diagnostic properties of the increase in H2 + CH4x2 were studied in addition to the conventional variables . The diagnostic properties of the gene test are not reported because of the limited number of analyses. The results of all tests (the first and the repeated ones) were used for evaluation of the diagnostic properties of the test variables.In search of optimal cut-off levels for screening purposes, high sensitivity and therefore a lower specificity, was preferred, with further diagnostic examinations in subjects with positive tests.Comparisons between the groups were analysed with Mann-Whitney test and Fisher's exact test, and agreement with kappa statistics. Receiver Operating Characteristic (ROC) curves describe the diagnostic properties of the variables. SPSS version 14.0 with exact tests was used for the analyses. P-values < 0.05 were considered statistically significant, and 95% confidence intervals (CI) were calculated for the main variables.The study was conducted according to the Declaration of Helsinki, and approved by the Regional Committee for Medical Research Ethics, Trondheim, Norway and Norwegian Social Science Data Services. Written informed consent was given by all participants before inclusion.Sixty patients were included. Five patients had LM and 45 had not after the first combined breath- and s-glucose test (both tests were clearly positive or negative). In ten patients with discrepancies between the blood- and breath tests, the combined test was repeated and the gene test performed. Two of these ten patients were classified as having LM (they had three positive and two negative tests) and eight were normal . The gene test was positive in one of the two patients with LM, and negative in eight patients without LM. In total, seven patients (12%) were classified as having LM.Table One patient did not fill in the symptom questionnaire after the lactose test, and one patient did not report exact indication of time, which made evaluation of ELL impossible. Table Table Table This study clearly demonstrates the unsatisfactory agreement between commonly used diagnostic tests for LM. The major methodological problem is the lack of a "gold standard" for the diagnosis of LM. Jejunal biopsies for assessment of lactase activity is an unreliable method due to the irregular dissemination of lactase in the intestine, the available genetic test does not detect all genetic disorders related to LM and does not diagnose secondary LM, breaths tests are highly dependent on the microflora throughout the gut, and serum glucose depends on the glucose absorption and metabolism . TherefoLactose breath test with measurement of H2+CH4x2 was judged as the best test. It was superior to H2+CH4 because of better sensitivity and a somewhat higher area under the ROC-curve tables  and 5. TBreath tests with measurement of only H2 have been judged as reliable tests for LM ,17. The S-glucose is an alternative to breath test. The agreement with the breath test was modest and clinically unsatisfactory, but the diagnostic properties  were identical with that of H2 table . The pooRegistration of symptoms after intake of lactose has been used as a simple test for LM . EvaluatIn this study the genetic test was performed in only ten subjects with discrepancies at the first combined test and the results therefore give limited information about the usability of the test. The test is probably highly indicative of lactase non-persistence in adults ,13. But The selection criteria were pragmatic and based on perceived milk intolerance or symptoms judged as possible LM by the doctor. The selection was not strictly scientific, but according to everyday practice. The prevalence of LM was rather low despite the fact that most patients had symptoms related to intake of milk or lactose and were referred with suspected LM. This is in accordance with other studies in Scandinavia showing a low prevalence of LM both in the general population and in patients with FGID ,3. A somPerformance of the breath tests varies. In this study, the tests were performed according to recently published guidelines concerning devices for breath sampling, stationary and immediate analyses, prolonged expiration and correction for alveolar CO2, use of antibiotics, diet, cigarette smoking and physical exercise . HoweverPractical and correct dietary advice to patients with FGID and food intolerance is impossible without valid and reliable tests for food intolerance. Such tests are by and large missing. Patients with food intolerance often make unnecessary changes in the diet which for some result in malnutrition ,26. FurtThis trial shows unsatisfactory agreement between commonly used diagnostic tests for LM. The test with the best diagnostic properties was lactose breath test with 25 g lactose and measurement of the increase in the sum of H2 and CH4x2. The area under the ROC-curve was 0.976, sensitivity was 100% with a cut-off level < 18 ppm, and specificity was 100% with a cut-off level < 53 ppm. Results in the range from 18 ppm to 52 ppm render further tests necessary to obtain a conclusive diagnosis.The authors declare that they have no competing interests.ØH participated in the design of the study, took part in the acquisition of data, did most of the analyses and interpretation of the data and wrote the draft manuscript.PGF was the main contributor to the concept and design of the study, took part in the acquisition of data, was responsible for analyses and interpretation of the data, and has written the final manuscript.Both authors approved the published version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/9/82/prepub


This study was designed to investigate leukaemia mortality in the population under the age of 25 residing around the 13 French nuclear sites operating in 1985. In four geographical zones defined according to the distance from the site, 503 exposed communes were identified and followed up between 1968 and 1989. A total of 4,132,000 person-years of observation were accumulated. The number of leukaemia deaths observed (69) did not differ from the expected number (86.15) estimated according to national mortality statistics. There was no difference in the risks of leukaemia mortality according to sex, age, type of installation and no trend with an increasing distance from installations.


We wanted to investigate acetabular labral tears and their correlation with femoroacetabular impingement in patients with sports injury.Among 111 patients who were diagnosed with the acetabular labral tears after arthroscopic treatment from January 2004 to December 2007, we selected 41 patients with sports injury. There were 12 cases of Taekwondo injury, 5 of golf injury, 4 of soccer injury, 3 of gymnastics injury, 2 of Hapkido injury, 2 of aerobics injury, 2 of rock-climbing injury, 2 of fitness training injury and 9 of other sports injuries. We checked the subtypes of acetabular labral tears and the accompanying femoroacetabular impingement. For the cases with accompanying femoroacetabular impingement, we investigated the subtypes according to the types of sports, gender and age. At last follow-up, we checked the Harris Hip Score (HHS), the Hip Outcome Score (HOS) sports scale and the percentage of patients who returned to their sports activity.The average age of symptomatic onset was 26 years . The ratio of males to females was 29 : 12. An average duration of the hip pain was 17 months . The degenerative type of acetabular labral tears was the most prevalent with 32 cases (78%), and there were 9 cases (22%) of the partial tear type. Thirty cases (73%) were accompanied by femoroacetabular impingement. The average age of the 23 cases (56%) of the cam-type was 23 years , and it was more likely to occur in men (87%) and for people practicing martial arts such as Taekwondo or Hapkido. An average age of the 5 cases (12%) of the pincer-type was 26 , it usually occurred in women (60%) and for non-martial arts such as golf and gymnastics. There were 2 cases of the mixed type (cam + pincer-type). At 27 months follow-up, the HHS was 61 to 92 points, the HOS sports scale increased 43 to 75%, and the rate of returning to sports was 71%.In spite of the early expression of symptoms and the short duration of the acetabular labral tears, the high rate of degenerative acetabular labral tears in sports patients is likely associated with repetitive injury after the expression of symptoms. Femoroacetabular impingement in sports patients is seemed to be a cause of the early occurrence of acetabular labral tears. Because the possibility of acetabular labral tears is high in femoroacetabular impingement, sports patients may need to undergo early screening for the diagnosis and care of femoroacetabular impingement. Acetabular labral tears (ALT) have been the subject of many studies regarding their pathophysiology, diagnosis and treatment, and their rehabilitation and prognosis.5)The advancement in the diagnostic methods and hip arthroscopy have allowed the lesions of the acetabular labrum that are caused by sports injuries to be diagnosed at an increasing rate and this has promoted discussion concerning the treatment.In addition, ALT has been identified as a cause of hip pain in patients with FAI,14)In this study, we investigated the different types of ALT in athletic patients. We explored the associations between ALT and FAI and we assessed the outcomes of arthroscopic treatment.From January 2004 to December 2007 at our institution, ALT was the definite diagnosis for 111 patients who had undergone arthroscopic treatment under the provisional diagnosis of either ALT or ALT accompanied by FAI, and they were diagnosed using MR-arthrograms and 3D-CT. The patients had complained of acute or chronic pain and they had positive impingement test results. Of these 111 patients, 41 athletic patients were retrospectively reviewed for this study.The mean age of the enrolled patients at the onset of symptoms was 26 years . There were 29 males and 12 females. The mean duration of illness was 17 months .In this study, an athlete was defined as one who participated in a particular sport more than 4 hours a day and 5 days per week for more than 1 year until hip pain developed, and this was regardless of the patient having a professional or amateur status. Twelve patients were involved in Taekwondo, 5 in golf, 4 in soccer, 3 in gymnastics, 2 in Hapgido, 2 in aerobics, 2 in rock climbing, 2 in fitness training, 1 in baseball, 1 in swimming, 1 in inline skating, 1 in cycling, 1 in tennis, 1 in basketball, 1 in yoga, 1 in badminton and 1 in another athletic sport.The patients who complained of hip pain underwent history taking, physical examinations, blood tests and radiography  at the time of the visit.The data obtained during history taking is as follows: the age at the time of the onset of hip pain, the age at the time of initial sports participation, the types of sports, the daily time spent on sports activities, the frequency of participation in sports in a week and the positions that aggravate the hip pain. For making the differential diagnosis, the patients were also asked about their past history of trauma and systemic diseases. The level of pain was rated according to the JOA pain scoring system set by the Japanese Orthopaedic Association: intermittent or continuous severe pain = 0 points, intermittent mild pain or occasional severe pain = 1 point, occasional mild pain = 2 points and no pain = 3 points.1)On the physical examination, if passive flexion, adduction and internal rotation of the hip (impingement test)14)Pain caused by systemic inflammatory disorders such as rheumatoid arthritis and ankylosing spondylitis was ruled out according to the diagnostic criteria.17)For the patients with 0 or 1 point (the JOA pain score), a positive impingement test and suspected FAI based on the plain radiographs despite conservative treatment, an MR-arthrogram was performed for those patients with nonspecific plain radiographic findings, but with suspected ALT on the physical examination. 3D-CT was performed for those patients who met the above criteria and who had an obvious femoral head-neck bump and acetabular retroversion on the plain radiographs. The ALT observed on the MR-arthrogram was graded according to the classification of Czerny et al.18)The ALT patients who presented with severe pain underwent arthroscopy for making the definite diagnosis and treatment. The patient was placed in the supine position under epidural anesthesia or general anesthesia. With the hip in 25° of abduction, traction was applied to the leg in the neutral position. In this position, around 8-10 mm of joint space widening was identified with a C-arm image intensifier. With the aid of a C-arm intensifier, a 15 gauge, long spinal needle was inserted at the anterolateral portal and 20-30 cc saline water was injected into the joint after the identification of the presence of air in the joint. A guide needle was inserted through the spinal needle and a 5 mm trocar was introduced into the joint. The trocar was replaced by the arthroscope, and the acetabulum and femoral head  were observed through it. Anterior and posterolateral portals were additionally used, if necessary, for arthroscopic examination and treatment.The arthroscopically identified ALT was removed. In patients with ALT accompanied by FAI, a bump at the head-neck junction (the cam-type FAI) was removed by a burr (bumpectomy), acetabular retroversion (the pincer-type FAI) was treated with acetabuloplasty and the damage to the acetabular cartilage was done with chondroplasty.According to the modified classification of ALT by Beck et al.,p-values ≤ 0.05 were considered statistically significant.The Harris Hip Score (HHS), the Hip Outcome Score (HOS) the sports scale score and the percentage of patients returning to their preinjury sports were measured before and after the arthroscopic treatment, and during a mean of 27 months  of the follow-up period and these values were compared to evaluate the treatment outcomes. All statistical analyses were done with using the Mann-Whitney U test, which is a non-parametric test. The The most common type of tear was degenerative tear in 32 cases (78%). Partial tear was found in 9 cases (22%) and complete tear was not observed. Of the 41 patients, FAI accompanied the tear in 30 patients (73%): there were 23 cases (56%) of the cam-type FAI, 5 cases (12%) of the pincer-type FAI and 2 cases (5%) of the cam + pincer-type FAI .p = 0.023).For the 23 patients with the cam-type FAI, the mean age at the onset of symptoms was 23 years  and there were 20 (87%) males and 3 (13%) females. The cam-type FAI was found in 9 patients (64%) out of the 14 patients with injuries that were due to martial arts activities such as Taekwondo and Hapgido, and the cam-type FAI was found in 14 (52%) out of the 27 patients who were injured during non-martial arts activities. Therefore, the cam-type FAI appeared to be more common in those patients who were involved in martial arts activities (p = 0.041)  and there were 2 (40%) males and 3 (60%) females. Four (15%) of the 5 cases were found in patients who had been involved in non-martial arts activities such as golf and gymnastics and 1 (7%) was found in a martial arts athlete. Therefore, the pincer-type FAI seemed more prevalent in non-martial arts athletes (= 0.041) .The prevalence of cam-type symptoms was higher in the martial arts athletes while the prevalence of pincer-type symptoms was higher in the non-martial arts athletes .p = 0.032) (p = 0.033). The number of patients who recovered to play sports at a less intense level or they changed their type of sports activities was significantly high among the martial arts athletes (p = 0.018): 5 (36%) of the martial arts athletes and 4 (15%) of the non-martial arts athletes (p = 0.018). The number of patients who quit playing sports after surgery was larger among the martial arts athletes (p = 0.027)  . Of the = 0.027) : 2 (14%)Since Altenberg24)ALT frequently occur in relatively young patients in their 20s to 40s and it usually causes piercing pain deep in the inguinal area in the squatting position, when sitting and standing from a chair and when getting on and off a vehicle.Kim and Azuma28)There are many reports on ALT combined with FAI in athletes.20)Therefore, we now better understand the mechanism of pain in ALT patients. Athletes who have FAI without pain can go through intermittent pain when a partial acetabular labral tear occurs due to repetitive stimuli, which also leads to a degenerative tear that causes constant pain.To interrupt such a mechanism of pain, arthroscopic treatment of FAI is used, and FAI the main cause of ALT. This procedure attempts to prevent ALT by removing the bony protrusion  that causes ALT and repair the damage to the acetabular cartilage. However, considering that the efficacy of preventive treatment has not been fully examined, we believe that more studies that focus on its efficacy should be conducted. As of now, performing a screening test for asymptomatic FAI on young athletes and making sure they are aware of the risk of ALT appears to be the proper approach. In the current study, no patients underwent preventive treatment and ALT occurred in all of the patients. To treat this, we performed arthroscopic bumpectomy or acetabuloplasty, and we obtained remarkable outcomes.We subdivided ALT into the degenerative, partial and complete tears.Byrd et al.According to Philippon et al.,In this current study, a statistical significance was found for improved HHS and HOS sports scale scores following arthroscopic treatment in all the cases. However, when the treatment results of martial arts players and non-martial arts players were compared, the former group was less likely to resume their preoperative sports and they were more likely to change or quit sports . We attrConclusively, we believe that professional athletes and would-be professionals with hip pain should under go screening tests for ALT and FAI. In addition, we recommend that the patients diagnosed with ALT undergo arthroscopic examination and treatment for symptomatic improvement and resumption of their preoperative sports activities.


Fine motor skills disorders belong to the neurological manifestation of Wilson's disease. The aim of this study is to investigate if fine motor performance changes during the course of the disease and with therapy.In 15 neurological patients with Wilson's disease, severity of neurological symptoms was assessed with a neurology score. A test battery consisting of the hand writing of a test sentence, lines of “double-I” and retracing a circle was carried out for analysis. By means of a computer-aided analysis of the patient's handwriting, 10 kinematic parameters of the writing trace were calculated. These parameters were determined once at the very beginning of the study and then again after 7 years.Improvement of clinical symptoms was observed after onset of therapy only within the first 2 years. In contrast to the standard population, a reduced degree of automation could be detected both at the beginning and at the end of the 7-year interval. There was no significant change in 8 out of the 10 kinematic parameters during the observation period, 2 deteriorated.The absence of a significant increase in fine motor disturbances proves, on the one hand, the efficacy of the therapy regime applied. On the other hand, the end point of a possible reversibility had been reached. A computer-aided analysis of the patient's handwriting allows for a sensitive detection of the “functional scar” in the extrapyramidal control and can subsequently prompt a timely correction of therapy in case of progression. ATP7B-gene have been identified. The The32] TP < 0.05.By subjecting the resulting data matrix of fine motor skills parameters to the Kolmogorow-Smirnov test, a normal distribution could be ruled out. Consequently, the median was hence used as localization criterion. For the purpose of comparing the two cohorts, dependent random samples had to undergo the Wilcoxon test, whereas the Mann-Whitney U test was applied to all independent random samples. The level of significance was set at The study substantiated improvements of neurological symptoms in all patients compared with their respective pathology at the time when therapy was first initiated. The files of the follow-up examinations carried out at intervals of 1 or 2 years documented that symptoms continued to improve for the first two years of therapy. Thereafter, symptoms remained constant until the time of the first examination (1999) that was carried out in the context of the present study. The median degree of improvement is 2 points in the neurology score. In the following 7-year observation interval, no further clinical-neurological improvements or changes occurred .At the time of the first examination in 1999, the kinematic parameters of all three tests  show a disturbance in the fine motor control of the writing motor function in contrast to the standard population. Raised median values of both the NIV and NIA are indicative of this, whereas the median frequency of the writing trace (up-and down-strokes) still remains within the lower normal range at 2.99 Hz (test sentence), 2.29 Hz (“double-l”) and 3.02 Hz (circle). The time required to complete the test sentence does not exceed the set time limit. A total of 6 out of the 10 median values of the kinematic parameters determined are abnormal .p < 0.05) and are abnormal. The NIV median (3.25) is also raised in this test but does not differ significantly from the value determined in 1999.Eight out of the 10 kinematic parameters present no significant change at the end of the 7-year interval. Over the course, the median NIA (6.43) and median frequency (1.64 Hz) during the “circle test” show substantial deviations (deteriorations) compared to 1999  and the median time required to write the test sentence (16.81 sec) deviate from the norm. The “double-l test” continues to present abnormal values of the NIV (2.26) and NIA (3.95), while the frequency still remains within the norm. In contrast to the control group, 7 out of 10 fine motor parameters show abnormal median values .The 15 patients were divided into two therapy cohorts according to the type of subsequent long-term therapy that followed their initial therapy regime with chelating agents: 6 patients on zinc salts and 9 patients under further therapy with DPA or trientine .Between 1999 and 2006, the therapeutic effect that had been achieved with initial therapy of DPA or trientine was maintained under both the chelating agent therapy and the changeover to treatment with zinc salts. Neither cohort showed any changes in the neurology score.p < 0.05), and is much higher under DPA therapy.The difference between the 10 kinematic parameter values of 1999 and 2006 was calculated for the purpose of reviewing possible effects of therapy on the patient's fine motor performance. The resulting values were attributed to the two therapy groups (chelating agents vs. zinc) and tested for significant differences by carrying out the Mann-Whitney U test. In 9 out of the 10 parameters examined, these differential values were in fact independent of the therapy regime applied. Only the difference of the writing frequency during the “circle test” was significant  over a period of 7 years marks both long-term drug therapies – with zinc salts as well as with the chelating agents trientine and D-penicillamine – as equally efficient. This fact is further substantiated by the fine motor analysis of the patient's handwriting skills at subsequent follow-up examinations. Both therapy cohorts achieve similar results in 9 out of the 10 parameters during the 7-year period.The decisive factor influencing the extent of the persisting fine motor disorders is primarily an early initiation of therapy rather than the actual choice of copper-removing medication administered, provided that a negative copper balance is thus constantly attainable.The study confirms that a sensitive registration of the fine motor disorders of the patient's handwriting skills is made possible by applying the CS system. The continuation of therapy serves to prevent progression of the disease and can be monitored by checking the fine motor control of the patient's handwriting.