The locus coeruleus (LC) is activated by noxious stimuli, and this activation leads to inhibition of perceived pain. As two physiological reflexes, the acoustic startle reflex and the pupillary light reflex, are sensitive to noxious stimuli, this review considers evidence that this sensitivity, at least to some extent, is mediated by the LC. The acoustic startle reflex, contraction of a large body of skeletal muscles in response to a sudden loud acoustic stimulus, can be enhanced by both directly (“sensitization”) and indirectly (“fear conditioning”) applied noxious stimuli. Fear-conditioning involves the association of a noxious (unconditioned) stimulus with a neutral (conditioned) stimulus , leading to the ability of the conditioned stimulus to evoke the “pain response”. The enhancement of the startle response by conditioned fear (“fear-potentiated startle”) involves the activation of the amygdala. The LC may also be involved in both sensitization and fear potentiation: pain signals activate the LC both directly and indirectly via the amygdala, which results in enhanced motoneurone activity, leading to an enhanced muscular response. Pupil diameter is under dual sympathetic/parasympathetic control, the sympathetic (noradrenergic) output dilating, and the parasympathetic (cholinergic) output constricting the pupil. The light reflex (constriction of the pupil in response to a light stimulus) operates via the parasympathetic output. The LC exerts a dual influence on pupillary control: it contributes to the sympathetic outflow and attenuates the parasympathetic output by inhibiting the Edinger-Westphal nucleus, the preganglionic cholinergic nucleus in the light reflex pathway. Noxious stimulation results in pupil dilation (“reflex dilation”), without any change in the light reflex response, consistent with sympathetic activation via the LC. Conditioned fear, on the other hand, results in the attenuation of the light reflex response (“fear-inhibited light reflex”), consistent with the inhibition of the parasympathetic light reflex via the LC. It is suggested that directly applied pain and fear-conditioning may affect different populations of autonomic neurones in the LC, directly applied pain activating sympathetic and fear-conditioning parasympathetic premotor neurones. The locus coeruleus (LC) has been implicated in a number of physiological and psychological functions. The LC plays an important role in the promotion and maintenance of arousal Robbins, . It is aIt is known that two physiological reflexes, the acoustic startle reflex, a somatic reflex, and the pupillary light reflex, an autonomic reflex, are both modulated by pain. In this review, the possible involvement of the LC in the effect of pain on these reflexes will be considered. Most of the experimental studies quoted involve acute pain evoked by noxious stimulation; when these studies are referred to, the stimulus is specified either in the text or in brackets after the reference. When the pain condition was chronic , this is made clear in the text.The nociceptive neurones of both the trigeminal sensory nuclei in the brainstem and the dorsal horn of the spinal cord project, via the trigemino-thalamic and spino-thalmic pathways to the somatosensory nucleus of the thalamus, a major pain-processing subcortical relay nucleus. Pain signals from the thalamus reach the somatosensory area of the cerebral cortex, the site of the highest level of pain processing, via the powerful thalamocortical pathway Kiernan, . Apart fThere is extensive evidence showing that noxious stimulation results in an increase in LC activity. Noxious stimuli evoke an increase in the electrical activity of LC neurones, shown by both extracellular [Kimura and Nakamura, 2-adenoceptor agonist clonidine, a drug known to reduce LC activity  leading to enhancement, and over-expression of the receptor to attenuation of the startle response : pairing of a noxious (“unconditioned”) stimulus (US) with a neutral (“conditioned”) stimulus (CS), results in the development of the ability of the CS to evoke the response to the US  pupillae, and the dilator pupillae. The two muscles receive opposing parasympathetic and sympathetic innervations, and thus pupil diameter at any time reflects the intricate balance between the two output systems  of the midbrain; the EWN innervates the postganglionic cholinergic neurones in the ciliary ganglion; the postganglionic neurones innervate the constrictor pupillae muscle.The sympathetic innervation of the iris does not directly participate in the light reflex: its main function is the adjustment of pupil diameter to the level of background illumination. The sympathetic preganglionic neurones are located in the intermedio-lateral column of the cervico-thoracic spinal cord, and project to the noradrenergic postganglionic neurones in the superior cervical ganglion, which innervate the dilator pupillae muscle. A number of premotor nuclei modulate the activity of the preganglionic sympathetic neurones, of which the PVN of the hypothalamus and the LC are the most important Figure  Samuels.The LC plays a dual role in pupillary control: it contributes to sympathetic outflow via an excitatory projection to preganglionic sympathetic neurones, and it also modulates the parasympathetic output to the iris via an inhibitory connection to the EWN. The close relationship between LC activity and pupillary function is illustrated by the observation that fluctuations in the firing rate of LC neurones are closely paralleled by fluctuations in the diameter of the pupil  spinal cord, synapsing in the superior cervical ganglion , may be related to the more pronounced activation of the LC by light in these species.The modulation of LC activity by light is likely to be different between nocturnal and diurnal animals, as highlighted by the effect of light on arousal: in nocturnal animals, light is sleep-promoting  can elicit pupillary dilation” , remains unaffected by noxious stimulation  .The apparent species difference in the mediation of reflex dilation of the pupil evoked by noxious stimuli is consistent with the suggestion that separate populations of LC neurones may function as sympathetic and parasympathetic premotor neurones , it could be predicted that conditioned fear may also affect the pupillary light reflex which is under inhibitory noradrenergic control from the LC . This prediction seemed to be supported by the observation that patients suffering from general anxiety disorder had attenuated light reflex responses, with relatively little change in resting pupil diameter, compared to healthy controls , also modify the fear-inhibited light reflex. It has been reported that both clonidine  and autonomic  functions.Directly applied painful stimuli enhance the acoustic startle response (“sensitization”) by augmenting the facilitation of motoneurone activity by the LC. Noxious stimulation leads to pupil dilation (“reflex dilation”), which seems to be mediated by different mechanisms in diurnal and nocturnal animals. In diurnal animals, reflex dilation is likely to be due to the activation of sympathetic premotor neurones in the LC, whereas in nocturnal animals, it seems to be caused by the inhibition of parasympathetic premotor neurones in the LC. Directly applied pain has no effect on the pupillary light reflex in man .Painful stimuli applied indirectly via fear-conditioning, when a neutral stimulus alone can evoke a state of anticipatory fear/anxiety following its prior association with an aversive (painful) stimulus, also enhance the acoustic startle reflex (“fear-potentiated startle”), but they inhibit the pupillary light reflex (“fear-inhibited light reflex”). Fear-conditioning is mediated by the amygdala which has an excitatory influence on the LC. LC activation by the amygdala enhances the noradrenergic facilitation of motoneurone activity, leading to augmentation of the potentiation of the acoustic startle reflex, arising from the stimulation of the pontine relay nucleus in the reflex pathway. LC activation by the amygdala leads to the attenuation of the pupillary light reflex due to enhancement of the noradrenergic inhibition of the preganglionic parasympathetic neurones in the light reflex pathway. Interestingly, there seems to be some selectivity in the action of pain applied directly or indirectly, via fear conditioning, on premotor autonomic neurones in the LC: while directly applied pain stimulates the sympathetic premotor neurones, leading to pupil dilation, in diurnal animals, fear-conditioning stimulates the parasympathetic premotor neurones, leading to attenuation of the light reflex response.Post-traumatic stress disorder (PTSD) is “a chronic, debilitating psychiatric disorder that can follow exposure to extreme stressful experiences” (Stam, Chronic pain has also been reported to be associated with exaggerated startle responses (Carleton et al., anxiety states have been reported to lead to alterations of the two physiological reflexes. Both enhanced startle reflexes (Bakker et al., There are some clinical conditions, usually involving pain, fear/anxiety and/or stress, that may be associated with abnormalities of the two reflexes. Furthermore, it is likely that these abnormalities reflect altered LC activity. s” Stam, . Cardinas” Stam, . Apart fs” Stam, . Howevers” Stam, . In addis” Stam, . Interess” Stam, . The augs” Stam, . Furthers” Stam, . ChronicIn conclusion, the enhancement of the startle response in PTSD, chronic pain conditions and anxiety states, and the attenuation of the pupillary light reflex response in anxiety disorder, can be interpreted on the basis of the involvement of the LC in the neuronal circuits controlling these two reflexes.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including hemarthroses, leading to musculoskeletal complications. The articular problems of hemophiliac patients begin in infancy. These include: recurrent hemarthroses, chronic synovitis, flexion deformities, hypertrophy of the growth epiphyses, damage to the articular cartilage, and hemophilic arthropathy. The most commonly affected joints are the ankle, the knee, and the elbow. Hematologic prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient's deficient factor is prevented from falling below 1% of normal. Hemarthroses can be prevented by the administration of clotting factor concentrates (prophylaxis). However, high costs and the need for venous access devices in younger children continue to complicate recommendations for universal prophylaxis. Prevention of joint arthropathy needs to focus on prevention of hemarthroses through prophylaxis, identifying early joint disease through the optimal use of cost-effective imaging modalities and the validation of serological markers of joint arthropathy. Screening for effects on bone health and optimal management of pain to improve quality of life are, likewise, important issues. Major hemarthrosis and chronic hemophilic synovitis should be treated aggressively to prevent hemophilic arthropathy. Hemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including hemarthroses, leading to musculoskeletal complications . The patHemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium . Joint dThe articular problems of hemophiliac patients begin in infancy. These include recurrent hemarthroses, chronic synovitis, flexion deformities, hypertrophy of the growth epiphyses, damage to the articular cartilage and hemophilic arthropathy. The most commonly affected joints are the ankle, the knee, the elbow, and the hip. The hemarthroses tend to persist despite the reabsorptive properties of the synovium which eventually becomes hypertrophic and more prone to injury, leading to a vicious circle of bleeding, synovitis, and more bleeding . The paiThe correct management of hemophilic hemarthrosis should include prompt diagnosis, adequate hematological treatment, joint aspiration, physiotherapy and avoidance of rebleeding. Patients with hemarthrosis commonly feel a tingling sensation—the “aura”—before the episode of intraarticular bleeding. The joint becomes warm, swollen, very painful and with an antialgic position in flexion. Clinical diagnosis should be confirmed by means of MRI and/or ultrasonography (US). Radiographs should also be performed, looking for any evidence of radiological involvement. Until recently hemarthroses have been treated by means of intravenous injection of 20–30 U/kg body weight of the deficient coagulation factor under hematological control, short-term rest and immobilization in the antialgic position by means of bandages, plaster splints, bed rest, and analgesics. Only 20% of the countries around the world have sufficient economical power to give their hemophilia population on-demand substitutive therapy. This consists of the intravenous injection of 20–30 units of Factor VIII/kg body weight when a bleed occurs, until the symptoms of an acute hemarthrosis abate . Joint aspiration of hemophilic hemarthrosis remains a controversial issue. Until recently it was considered an extremely dangerous procedure to perform, with a high risk of re-bleeding and infection (septic arthritis). Today, I believe in the efficacy of early joint aspiration. However, the technique must be performed under hematological control and aseptic conditions. The procedure must be repeated many times in the patient's life, starting at a very short age, and it carries some difficulties; therefore, psychological and familiar support is paramount. It is important that the child trusts the orthopedic surgeon carrying out the joint aspiration and some form of local anesthesia should be used in order to minimize pain. Following the procedure, immobilization is recommended for 3–5 days by means of a compressive bandage. Later on, the patient should start a supervised period of physiotherapy as rehabilitation is paramount to halt the development of synovitis. The duration of physiotherapy will depend on the time required to regain full range of movement and muscular strength. Re-bleedings during the recovery period should be avoided as much as possible. Patients must be seen every 3 months at the outpatient clinic for close and careful assessment .The objectives of treatment are to stop the hemarthroses or to control them quickly and to avoid secondary synovitis. Once synovitis has developed, which is inevitable, the aim is to treat it as early and aggressively as possible. Confirmation of the diagnosis is important and can be achieved by ultrasound or MRI. The former is especially useful for the knee, but MRI gives greater precision for the elbow and the ankle. Sometimes standard conservative measures, such as factor replacement and physiotherapy, do not break the vicious cycle of hemarthrosis-synovitis-hemarthrosis. Under these circumstances synovectomy—either chemical, radioactive, or surgical (open or arthroscopic), can reduce the bleeding tendency and so delay the onset of hemophilic arthropathy. Currently we perform ablation of the synovium as soon as synovitis is diagnosed. There are both conservative (RS) and operative methods (synovectomy). The drugs most commonly used in RS are radioactive isotopes such as Yttrium-90 and Phosphorus-32 , 8. In mRadiosynovectomy (RS) affords effective treatment of chronic hemophilic synovitis. RS is effective in all patient groups, independently of the presence of circulating inhibitor antibody, the type of joint involved, the degree of synovial membrane hypertrophy, and the presence of arthropathy . RS is a safe, simple, and effective method for the treatment of chronic haemophilic synovitis. RS with Yttium-90 and rhenium-186 has been shown to decrease the number of bleeding episodes, joint pain, the size of the synovium , muscle strength (MS), ROM, and the WFH clinical score . NonetheAs already stated, an uncontrolled hemarthrosis and synovitis will lead to flexion deformity, sometimes with valgus deviation caused by asymmetrical growth of the epiphyses, Perthes' disease, osteophytes, and subchondral cysts. In infants, adolescents and young adults with flexion deformity, realignment osteotomies may be indicated to prevent development of severe arthropathy , 13. FleAt the hip, a form of Perthes' disease may develop related to recurrent intra-articular bleeding. The initial treatment should be by means of an ambulation-abduction bracing. Because of intraosseous hemorrhages, some hemophiliac patients develop large symptomatic juxta-articular cysts, especially in the proximal tibia. These may threaten the integrity of the articular cartilage and require open curettage and grafting with the use of fibrin sealant . At the Between the second and fourth decades, many hemophiliacs develop severe articular destruction Figures  and 3. AAt the mature elbow, the resection of a hypertrophic radial head usually reduces the incidence of recurrent hemorrhages and improves the range of pronation-supination of the affected joint. For the hip the best solution is a total hip arthroplasty , 17, 18.Bleeds within the muscles are very often associated with direct trauma and the pathology becomes quite evident due to the swelling, pain, local warmth, and bruising that typically appear in the overlying skin . The vasPseudotumor is a serious, but very rare, complication. A progressive cystic swelling involving muscle is produced by recurrent bleeding and there is usually radiological evidence of bone involvement. Most are in adults near the large bones of the proximal skeleton. A few develop distal to the wrist and ankle in younger patients before skeletal maturity. Untreated proximal pseudotumors will destroy soft tissues, erode bone and produce vascular or neurological lesions. Recurrent haemarthroses in patients with severe and moderate hemophilia can result in the development of one or more target joints and subsequent degenerative joint disease . This dePrevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well-of children with hemophilia . GringerIt has been shown that patients with severe hemophilia treated on demand are not as physically active as their healthy peers and often have a sedentary lifestyle that contributes to chronic joint disease . The useThe Spanish Epidemiological Study in Hemophilia carried out in 2006 enrolled 2400 patients (2081–86.7% with haemophilia A and 319–13.3% with haemophilia B ); 465 ofNeutralizing inhibitors develop in 20–30% of patients with severe factor VIII (FVIII) deficiency. It is well established that Blacks have a higher prevalence of inhibitors than Whites . The prePatients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. Leissinger et al.  enrolledHealth economic evaluations provide valuable information for healthcare providers, facilitating the treatment decision-making process in a climate where demand for healthcare exceeds the supply . AlthougAlthough hemophilia is an expensive disorder, no studies have estimated health care costs for Americans with hemophilia enrolled in Medicaid as distinct from those with employer-sponsored insurance (ESI) (GUH). The study of Guh et al.  providedHematologic prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient's deficient factor is prevented from falling below 1% of normal –28. Earl


Community-based education (CBE) can provide contextual learning that addresses manpower scarcity by enabling trainees acquire requisite experiences, competence, confidence and values. In Uganda, many health professional training institutions conduct some form of community-based education (CBE). However, there is scanty information on the nature of the training: whether a curriculum exists , administration and constraints faced. The objective was to make a comprehensive assessment of CBE as implemented by Ugandan health professional training institutions to document the nature of CBE conducted and propose an ideal model with minimum requirements for health professional training institutions in Uganda.ite visits to these institutions and their CBE sites, to assess the learning environment (infrastructure and resources); in-depth interviews with key people involved in running CBE at the institutions and community, to evaluate CBE implementation, challenges experienced and perceived solutions.We employed several methods: documentary review of curricula of 22 institutions, so as to assess the nature, purpose, outcomes, and methods of instruction and assessment; sCBE was perceived differently ranging from a subject, a course, a program or a project. Despite having similar curricula, institutions differ in the administration, implementation and assessment of CBE. Objectives of CBE, the curricula content and implementation strategies differ in similar institutions. On collaborative and social learning, most trainees do not reside in the community, though they work on group projects and write group reports. Lectures and skills demonstrations were the main instruction methods. Assessment involved mainly continuous assessment, oral or written reports and summative examination.This assessment identified deficiencies in the design and implementation of CBE at several health professional training institutions, with major flaws identified in curriculum content, supervision of trainees, inappropriate assessment, trainee welfare, and underutilization of opportunities for contextual and collaborative learning. Since CBE showed potential to benefit the trainees, community and institutions, we propose a model that delivers a minimum package of CBE and overcomes the wide variation in the concept, conduct and implementation of CBE. Community-based education (CBE) has several definitions ,2, but tCBE goes beyond cognitive capacities and encompasses the social and emotional aspects of learning, increasing trainee' experience, confidence and competence -4 and imIn Uganda, many health professional training institutions conduct some form of CBE. However, there is scanty information on the nature of the training: whether a curriculum exists, the objectives related to CBE, intended outcomes, curriculum content. There is also scanty information on the implementation of the CBE curriculum ; administration of CBE ; and challenges faced by the implementation of CBE. Most reports of community-based programmes have been conducted in developed countries, have been largely descriptive, and rarely have assessed outcomes such as learning and rural deployment -11. OtheOur aim was to answer the following questions: What is the nature of CBE conducted? Does CBE promote learning? What challenges do institutions face in implementing CBE and what are potential solutions? The objective of the comprehensive assessment of CBE conducted in health professional training institutions in Uganda was two-fold: 1) To analyze the nature of CBE conducted by different institutions as well as challenges involved; 2) To analyze effectiveness of CBE in promoting learning and acquisition of competences for cadres at different levels . As a spin-off of this comprehensive evaluation, we wish to utilize lessons to propose an ideal model with minimum requirements for health professional training institutions in Uganda. Documentation of this information as well as potential solutions to identified challenges in running CBE programs might not only improve the training of health professionals but also assist in the long-term goal of improving the recruitment, deployment or retention of health workers to rural areas.Through the twinning grant with Johns Hopkins University, Makerere University conducted a comprehensive assessment of CBE implemented by 22 health professional training institutions in Uganda, from October 2009 through May 2010. This assessment involved documentary review of available curricula and other documents related to CBE at 22 health professional training institutions, so as to assess the nature, purpose, intended outcomes, instruction methods and methods of assessment. Site visits to these institutions and two of their CBE sites was also conducted to assess the available infrastructure and learning resources available at these sites.In analyzing whether learning occurs during CBE, we assessed the following:i) whether learning is competence-based or outcome-based ii) whether learning during CBE is problem-based ;iii) whether learning during CBE is contextual ;iv) whether CBE promotes collaborative learning , and perform learning activities such as problem-solving using individual effort, joint effort or external effort;v) whether reflection  occurs;vi) whether CBE promotes lifelong learning .vii) Since students contribute to service during community placements, we assessed whether such service contributes to trainees' learning .viii) Lastly, in-depth and key-informant interviews were conducted with key people involved in running CBE at the institutions and CBE sites to assess how CBE was implemented, challenges experienced and perceived solutions. Interviews with alumni of these institutions and community members at the CBE sites offered insight into the impact of CBE, challenges in CBE implementation and how these challenges may be addressed. Content analysis  was applEthics and research committees of Makerere University College of Health Sciences and Johns Hopkins School of Public Health approved the research. Approval to conduct the research was given by the administrators of all the health institutions that were assessed.Table Table Table Though most interviewees felt the concept of CBE was right, there were many challenges in its conduct, which hinder adequate preparation and implementation. Some of the beneficial aspects of CBE identified were early contact with the community, improved team work in the trainees who leave, work and learn in small groups, improved interpersonal relationships and improved communication skills. That the CBE was outcome-based is indicated by some curricula having clear objectives, learning outcomes, desired competencies and clear implementation strategy. Collaborative learning is indicated by the individual, joint and external collaborations by students to promote learning. CBE offered opportunities for improved clinical, leadership, self-directed learning and research skills. As an outcome of this comprehensive assessment, we identified a critical need to propose an ideal CBE curriculum whose content and implementation would provide a minimum package of CBE. Indeed, such an ideal model might make available human resources with competence to address Uganda's current and evolving priority health problems.We found that though many health professional training institutions in Uganda conduct some form of CBE, the content of the curricula and the extent to which they are implemented is variable. For institutions without a written curriculum, we found no clear explanation why this was so from interviewing the faculty. The tutors, faculty and community members interviewed were in agreement that CBE has the potential to benefit trainees ; the community (whose members benefit from the services of the trainees during the community placements and outreach activities); the institutions (which get a better training context for their students); and the staff at the community training sites (who gain from update of knowledge and skills from interaction and collaboration with staff from the training institutions). CBE also offered opportunities to conduct research on conditions that affect the community (through community diagnosis). Different descriptions were given to CBE in the different institutions, consequently, CBE was administered the differently depending on how it was defined and the resources available. The key personnel ranged from individuals (acting as coordinators), a committee of persons, or an administrative office . Factors considered before CBE site selection and preparation included proximity, available infrastructure, uniqueness of the site in terms of services offered , receptivity of health facility staff and community leadership, ability of the potential site to cater for trainee's welfare, and availability of willing personnel at health facilities to supervise trainees. For the latter, 18 (70%) of the institutions had neither a formal criteria for selection of community supervisors nor formal training of these people.Our findings evaluated the potential effectiveness of CBE in enhancing training of health professions. The methods of evaluation used enable evaluation of the ''curriculum on paper'' , the ''curriculum in action'' (how the curriculum is implemented) and the ''curriculum as experienced'' . Our finIn our assessment, there were wide variations in the curriculum content even for public institutions that offer the same academic award. It was also unclear to some institutions how the curriculum was developed, implemented or evaluated. Developing a generic CBE curriculum should follow a systematic approach that is capable of integrating content area with educational theory and methodology, and indicate evaluation of the impact of this process -24. WhenSome of the CBE curricula documents were unclear about the learning outcomes or desired competences, so it was unclear if the actualized curriculum included them. From the interviews, this was still unclear as some tutors were not conversant with the curriculum content or implementation. Regarding content and outcomes of the ideal CBE curriculum, the professional competences should focus on theoretical and applied knowledge associated with practice, emphasizing values, skills and critical appraisal. This is essential as training and practice/service often occur in situations characterized by complexity, uniqueness, uncertainty and conflicting values . In contWhile pre-placement orientation is essential for success of CBE, it was unclear whether all institutions conducted it. Most of the CBE curricula emphasized knowledge and professional skills. Whereas specialized knowledge and skills are clearly essential for practice, self consciousness (reflection) and continual self critique  are crucial to acquisition of competences . ReflectFew of the institutions employed Problem-based learning (PBL) as an instruction method. Regarding implementation strategies, PBL is ideal for CBE as it effectively brings out the desired competences of the ideal CBE curriculum. Though the exact format of PBL varies considerably, two key features are consistent: emphasis on learner-focused exploration of case-based problems and use of case histories to help students identify learning issues that become the focus of individual or group problem-solving. During CBE, trainees should be exposed to professionally meaningful situations or problems that bear strong resemblance to the situations they will be confronted with in their future profession, which enables acquisition of knowledge, clinical skills and problem-solving skills. Development of critical reflection and critical thinking as professional skills during CBE requires adoption of PBL as the ideal model of instruction -24. IndeThe institutions evaluated conducted assessment of CBE using different and diverse methods, with variations in reliability. For CBE, there is a challenge of designing assessment such that it adequately reflects the desired competences, the instruction methods and the eventual professional role, while making it retain reliability and validity across different settings and assessors ,28. DuriWe acknowledge several limitations. Firstly, the institutions were purposively sampled in order to try to achieve representativeness of rural versus urban institutions, private versus public, the different cadres trained and different academic level of training. There is no guarantee that the institutions that were not sampled have similar constraints or challenges. However, all the government-supported institutions are supposed to follow and implement a similar curriculum. Secondly, the assessment was conducted regionally by four different teams. Since the teams piloted the instruments, there may have been slight variations (across the four teams) in the way interviews were conducted, checklists performed or documents reviewed. Thirdly, no direct observation of conduct of CBE was performed, yet this should be done in an ideal CBE assessment ,32. HoweThis assessment identified deficiencies in the design and implementation of CBE at several health professional training institutions, with major flaws identified in curriculum content, supervision of trainees, inappropriate assessment, trainee welfare, and underutilization of opportunities for contextual and collaborative learning. Despite similar goals, there is wide variation in the concept, conduct and implementation of CBE conducted by different health institutions in Uganda, even in presence of similar curricula. CBE, if well implemented and assessed, has the potential to ensure contextual learning in medical education.Partnership for building the capacity of Makerere University to improve priority health outcomes in Uganda, but have no competing interests.All authors  are faculty of Makerere University College of Health Sciences where community-based education is part of the curricula for undergraduate training of health professionals, and all community sites assessed are used by the university. GB, LWC and SG are team members of the project: All co-authors were involved in the design of the study on comprehensive assessment of community-based education. All except LWC and GB participated in the data collection and data analysis. DKK wrote the first draft of the manuscript. All co-authors contributed by reviewing the subsequent drafts of the manuscript and approved the final versionStep 1: Problem identification and general needs assessment: Identification and critical analysis of the educational need or problem that will be addressed by the curriculum. This step requires substantial research to analyze what is currently being done by practitioners  and educators  and ideally what should be done by practitioners and educators to address the health care problem  and therefore the performance gap. The general needs assessment is usually stated as the knowledge, attitude, and performance deficits that the curriculum will address.Step 2: Needs assessment of targeted learnersStep 3: Goals and objectives: Overall goals and aims for the curriculum are written. Specific measurable knowledge, skill/performance, attitude, and process objectives are written for the curriculum.Step 4: Educational strategies: A plan to maximize the impact of the curriculum, including content and educational methods congruent with the objectives, is prepared.Step 5: Implementation: A plan for implementation, including timelines and resources required, is created. A plan for faculty development should be made to assure consistent implementationStep 6: Evaluation and feedback: Learner and program evaluation plans are created. A plan for dissemination of the curriculum is made.The primary aim should be:1 Trainees to acquire an understanding of health and disease, positioning the prevention and management of disease in the context of the whole individual in his or her place in the family, community and society.2 To develop health professionals with an attitude to learning that is based on curiosity and knowledge exploration rather than passive knowledge acquisition. This enables trainees become reflexive learners who can identify their learning needs, seek the desired information and eventually become life long learners3 To enable trainees integrate the theory and practical aspects, as well as the basic science and clinical/professional aspects of their training. This necessitates introduction of components of problem-based learning in CBE, whereby learning is based on real-life contexts4 To ensure early direct contact with patients/clients and critical appraisal/analysis of their problems, and thereby trainees attain problem-solving skillsThe curriculum should:1. Provide an ideal balance of factual information and practical skills in addition to providing core knowledge, skills and attitudes2. Develop general competence 3. Ensure early clinical contact while strengthening inter-professional collaboration, thereby providing a balance between hospital/community; curative/preventive aspects.4. Cover the wider aspects of health care 5. Ensure that methods of learning/teaching support aims of the curriculum, and likewise, ensure that assessment methods employed support and rhyme with aims of the curriculum (are they reliable in assessing the competences?)The minimum competences of the trainees should include:1. Knowledge and skills in caring for the community's health with emphasis on primary care, disease prevention and promotion of healthy lifestyle, and in involving patients, families and communities in healthcare decision-making2. Understanding the factors that influence health and disease at household level, as well the roles and responsibilities of different players in the healthcare system3. Innovation and problem solving skills necessary to provide cost-effective care using technology appropriately4. Skills in collection, analysis and utilization information on health systems5. Understanding the role of the physical, social and political environment in health6. Life long learning 7. Professionalism The curriculum content should include:1. Broad education in both the clinical and basic sciences and integration of CBE into the science of profession2. Clearly defined objectives and intended outcomes of CBE3. Emphasis on methods and processes of acquisition of knowledge, professional skills, lifelong learning skills, values and attitudes (such as indicating examples of what activities trainees should be involved in)4. Emphasis on utilization of educational sites beyond the training institution 5. Emphasis on adapting training to meet the challenges produced by ongoing changes in the organization, structure, financing and delivery of health care1. To identify suitable teaching resources and to conduct feedback and trainee appraisal2. To design educational programs for trainees as well as identify suitable problems to deliver effective educational events for learning3. To utilize appropriate teaching methods that employ large and small groups4. To provide individual assistance depending on student needs5. To assess the trainees used a variety of assessment methods that include portfolios6. To evaluate the CBE program in context of the health professional training courseThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6920/11/7/prepub


Amygdala Theory of Autism, fail to elucidate the complex pattern of impairments observed in this population, which extends beyond the social domain. As posited by the Relevance Detector theory . Given that the amygdala is a component structure of the “social brain,” several theoretical explanations compatible with amygdala dysfunction have been proposed to account for socio-emotional impairments in ASDs, including abnormal eye contact, gaze monitoring, face processing, mental state understanding, and empathy. Nevertheless, many theoretical accounts, based on the r theory , the hum Autism spectrum disorders (ASDs) are pervasive developmental disorders characterized by a triad of symptoms including abnormal socio-emotional processing, verbal and non-verbal communication problems, and restricted interests and repetitive behaviors . AlthougTheory of Mind  studies, It is noteworthy that, in comparison with studies reporting gray matter changes, there are few studies investigating the anatomical connection between the amygdala and other cortical–subcortical structures in ASDs. Preliminary diffusion tensor imaging (DTI) studies have reported, among other structures, altered fractional anisotropy (FA), a measure of fiber tracts integrity, in regions surrounding the amygdala  or in trhypoactivation or hyperactivation of this structure. According to the “hypo-active models,” the amygdala fails to process social stimuli as meaningful with the result that they do not receive preferential attention  the attainment of his or her goals, the satisfaction of his or her needs, the maintenance of his or her well-being, and the well-being of his or her species. According to this view, fearful and angry faces represent relevant information because they potentially obstruct one’s goal and signal the presence of a danger for the organism and his or her con-specifics.”As posited by the “Relevance Detection Theory” , the humFrom a phylogenetic perspective, in the primitive mammalian brain, the amygdala is part of a modular system shaped by evolution to detect potentially threatening physical events and biological stimuli , and to prepare the organism for action by facilitating escape and avoidance . MacLeanCross-species comparative studies have provided evidence of the co-evolution of the amygdaloid complex and the prefrontal areas in the neocortex  substantintrinsic and the extrinsic types of salience. While certain stimuli are intrinsically (or innately) self-relevant, because of their biological significance  or physical features , the extrinsic salience is flexibly acquired through context-dependant and conscious appraisal processes. Thus, the computational role of the human amygdala is twofold: on the one hand, it automatically and rapidly detects physically and biologically relevant information, via bottom-up processes, reflecting its more primary function; on the other hand, it integrates multiple salience signals originated via a top-down processes so as to create a priority map of intrinsically and extrinsically self-relevant information. Importantly, while the amygdala is specifically responsible for processing stimulus or event salience, which is a more fundamental feature since it is a measure of its importance, in a strict biological sense, value signals coding positivity for appetitive stimuli and negativity for aversive stimuli  and beyond their social dimension.As proposed by basolateral nuclei, have evolved under evolutionary selectional pressure to increase the ability to manipulate information necessary to subserve sophisticated social relationships , to flexibly respond to a larger variety of self-relevant evolutionarily unprecedented circumstances.The same neural system is rarely capable of solving different adaptive problems fast and efficiently since different information-processing systems usually instantiate distinct procedures for their successful solution . What weIn the following, we argue that the complex pattern of emotional and socio-behavioral impairments typically reported in individuals with ASDs reflects a disruption of the neural system devoted to the processing of self-relevant information, primarily relying on the functional and connectivity integrity of the fronto-amygdala circuit. Indeed, as we discussed above, although the amygdala can process relevant stimuli in a reflexive and unconscious manner , it servA previous study on electrical stimulation suggested that the limbic system has a special role in bringing experience to a conscious level by associating affective and motivational significance with sensory information . NeurobiResearch focused on emotional dysfunctions and theoretical accounts have emphasized the notion that the mechanisms mediating the self-regulation of behavior during social–emotional exchanges are severely impaired in ASDs . PioneerDifferent lines of behavioral research have reported disturbance in processing self-related information in individuals with ASDs, in terms of monitoring self-performed actions , or in cRelevance Detection Theory of Autism predicts that the amygdala specifically responds to self-relevant information. The literature is, however, extremely varied with respect to the physiological responses to socio-emotional events, associated with amygdala functionality in ASDs. In fact, ASD individuals are found to be either hyper- or hypo-aroused in response to simple sensory stimuli, or stimuli varying in emotional valence or social dimensions , the mensions . The Relents see .Relevance Detection System might lead to abnormal sustained activation of this subcortical route and to failure to detect meaningful aspects of the environment, in accordance of a “priority map” integrating intrinsic and extrinsic salience stimuli.Among the social stimuli, the eyes constitute an special source of relevant information. The ability to discriminate eye direction is thought to reflect an innate predisposition and a primitive function . For manThis explanation is in accordance with previous studies showing altered functional connectivity between vMPFC and amygdala, associated with diminished habituation of amygdala response to emotional faces . IntriguAccording to It is likely that reduced eye contact, perceived as potentially aversive stimuli, would preclude the development of perceptual expertise for faces, and hamper the ability to process different types of self-relevant social information acquired through faces, such as emotions, intentions, and trustworthiness , and theInterestingly, the administration of oxytocin, a neuropeptide, which is known to be lower in individuals with autism , enhanceRelevance Detection System might lead to the abnormal capture of attention by low-level, bottom-up visual properties of the stimuli , due to enhanced sensitivity of the physical attributes of the stimulus  may reflect reduced modulatory affect exercised by prefrontal regions on amygdala activity.priority map of self-relevant events that might be accessible to and modulated by conscious evaluative processes. This priority map includes stimuli whose salience is determined by their intrinsic biological significance, the physical properties or the extrinsic contextual situation. In this view, physically intense stimulation and emotionally arousing events, associated with the amygdala hyperactivation, are actively avoided thus producing reduced attendance to meaningful aspects of the environment, including the social ones, and deficits in the self-regulation of behavior. At the neural level, our theory is in accordance with the fronto-amygdala disconnectivity explanation and the hyper-active models which posit that the amygdala hyperactivation results from a defective top-down modulation by prefrontal areas involved in conscious evaluative processes. Moving away from the classical account of the amygdala as a threat detector or a socio-emotional processing submodule would favor the design of studies that might provide the opportunity to account for heterogeneities of cognitive phenotype and symptomatology across the autistic spectrum.In the present review, we have proposed that an early emerging neurological insult to the interconnected fronto-amygdala circuit disrupting the ability to flexibly and adaptively orient attention toward self-relevant stimuli might be a primary deficit of ASDs. Specifically, the amygdala is responsible, in concert with the vMPFC, of the formation of a The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In calcific tendinopathy (CT), calcium deposits in the substance of the tendon, with chronic activity-related pain, tenderness, localized edema and various degrees of decreased range of motion. CT is particularly common in the rotator cuff, and supraspinatus, Achilles and patellar tendons. The presence of calcific deposits may worsen the clinical manifestations of tendinopathy with an increase in rupture rate, slower recovery times and a higher frequency of post-operative complications. The aetiopathogenesis of CT is still controversial, but seems to be the result of an active cell-mediated process and a localized attempt of the tendon to compensate the original decreased stiffness. Tendon healing includes many sequential processes, and disturbances at different stages of healing may lead to different combinations of histopathological changes, diverting the normal healing processes to an abnormal pathway. In this review, we discuss the theories of pathogenesis behind CT. Better understanding of the pathogenesis is essential for development of effective treatment modalities and for improvement of clinical outcomes. In calcific tendinopathy (CT) calcium deposits in the substance of the tendon. CT is particularly common in the rotator cuff tendons (RCTs) and supraspinatus tendon, and Achilles tendon and patellar tendon. CT of the rotator cuff is common in Caucasian populations, with a reported prevalence of 2.7% to 22%, mostly affecting women between 30 and 50 years. The most frequently involved tendon is the supraspinatus tendon, and in 10% of patients the condition is bilateral . CT of the rotator cuff shows a tendency toward spontaneous resorption of the deposits and symptoms often resolve spontaneously, although some authors described persistent pain at long time follow-up and persistent reduction of ROM ,6. OsteoThe clinical course of insertional CT has been poorly investigated, although experience suggests that pain seems to improve in older patients even though the insertional calcification persists. Generally, the presence of calcific deposits worsens the clinical manifestations of tendinopathy with an increase in rupture rate, slower recovery times and a higher frequency of post-operative complications .As previously discussed, the nomenclature of CT is confusing, perhaps in part because of the many terms classically used to describe localized deposits of calcium in tendons , includiAt the beginning of the 1950s, it was clear that local degeneration of the involved tendon precedes the deposition of calcium salts , and thaet al. and Uhthoff et al. suggested the occurrence of an initial cartilage metaplasia of the tendon, followed by an active multifocal and cell-mediated calcifying process [Sandstrom, in 1938, speculated that necrosis of the tendon secondary to local ischemia and vascular changes was the first step to promote deposition of calcified material . Bishop  process ,16. Rece process .32-) occupy in the hydroxyapatite (HAP). They are defined as A-type carbonate apatite and B-type carbonate apatite [Specimens of RCTs obtained during surgery consist of a gritty mass of sandy material or a toothpaste-like fluid, and the deposits were described as a white amorphous mass composed of many small round or ovoid bodies. Later, X-ray diffraction and infrared spectrometry and other techniques identified the material of calcific deposits as calcium carbonate apatite -20. Comp apatite . Gartner apatite  observed apatite . They noRecently, matrix vesicles have been isolated in mature porcine patellar tendons . Matrix The aetiopathogenesis of CT is largely unknown, especially because it remains difficult to clarify the steps which induce crystal deposition into the tendon. Furthermore, biopsies of the pathologic RCTs are obtained only towards the end of the natural history of the condition, when patients are symptomatic . Many diUhthoff and coworkers hypothesized that a favorable environment permits an active process of cell-mediated calcification, usually followed by spontaneous phagocytic resorption . They deAchilles and patellar tendon calcifications are formed by a process resembling endochondral ossification, with bone formation and remodeling mediated by population of osteoblasts and osteoclasts.Benjamin and coworkers proposed a model of insertional Achilles CT based on a rat study . They suLui et al. studied the histological features of collagenase-induced patellar tendon ossification in a rat model . Many chOther authors thought that ectopic bone derives from metaplasia of tendon cells into osteogenic cells. Injection of recombinant human bone morphogenetic protein-2 (rhBMP-2)  into theMesenchymal stem cells are present in tendon tissues . Human aWhich condition or stimulus is able to cause this erroneous differentiation of TDSCs? Many proteins could be involved in tendon degeneration, calcification and rearrangement processes, playing different roles in the various phases of calcification and resorption. Among the possible candidates are bone morphogenetic proteins (BMPs) and transglutaminases (TGs). Recently, Zang and Wang suggested that BMP-2-mediated effects on human TDSCs may contribute to the formation of calcific deposits in CT . We obseThe mRNA and protein expression of major proteoglycans of extracellular matrix, including decorin, aggrecan, biglycan and fibromodulin and their relationship with ectopic chondrogenesis, ossification and loss of matrix organization, has been observed in a calcific tendinopathy model . DecorinAn association between CT and diabetes and thyroid disorders has been shown, but the precise mechanism is still unknown . PatientA familial predisposition and inherited genetic components have also been postulated as a cause of CT in some circumstances -67. VariThe aetiopathogenesis of CT is still controversial, especially because it remains difficult to clarify the first steps causing this condition and those involved in the development of calcifications.Rather than being formed by precipitation of inorganic ions, CT results from an active cell-mediated process in which resident progenitor cells with multidifferentiation potential may play a determinant role .Many different factors such as acute injury, repetitive microtrauma, and chemical-induced injury may cause damage to the tendon and start the natural healing process. Tendon healing includes many sequential processes such as matrix synthesis and remodeling, synthesis of pro-inflammatory cytokines, neovascularization, neural modulations, recruitment of healing cells, multipotent cells, TDSCs, proliferation, apoptosis . DisturbSince ossified tendons will have increased stiffness, ossification can be seen as a localized attempt to compensate for the original decreased stiffness of the weak tendon. It is possible that the erroneous differentiation of tendon progenitor cells into chondrocytes or osteoblasts instead of tenocytes may contribute to the pathogenesis of CT. The mechanism leading to the erroneous differentiation of TDSCs is not completely understood. Probably, the expression of BMPs, biglycan, fibromodulin and an unfavorable micro-environment induced by overuse modify the natural healing process of the tendon. Conservative management modalities such as non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids are often prescribed, and may further influence the pathways of the failed healing . NSAIDs Many questions remain unanswered about the pathogenesis of CT. Calcium carbonate apatite appears the only component of calcific deposits, but inorganic component of Achilles and patellar CT has been less investigated than CT of the RCTs. Histological and imaging studies show that the three-dimensional structure of calcific deposits is quite different. Calcific depositions in the RCTs appear as a toothpaste-like fluid, while calcific deposits in the Achilles and patellar tendons have a porous structure  and a va'Calcific tendinopathy' and 'insertional calcific tendinopathy' are caused by two distinct pathogenetic mechanisms. In RCTs, degenerative changes in the extracellular matrix seem to play an important role for the formation of calcific deposits. The pathogenesis of CT involves matrix vesicles, macrophages and multinucleated giant cells with a typical osteoclast phenotype, producing a toothpaste-like material ,29. No vThe mechanism of insertional CT has been clarified by Benjamin and coworkers, and essentially accepted worldwide  Table 33. IncreaCT of the rotator cuff has been investigated with histological studies of specimens obtained from human biopsies, while the study of CT of Achilles and patellar tendons is based on animal models of collagenase-induced tendinopathy. Therefore, we do not know whether the pathogenesis of CT of the rotator cuff can be compared to CT of the Achilles and patellar tendons. Moreover, no pathogenetic studies on the rotator cuff have been published since the late 1970s, and no animal CT studies are present in literature . We do nFurthermore, no clinical or imaging classification has been published in the literature, except for the CT of RCTs . Also, iThe involvement of mesenchymal stem cells (MSCs) in the pathogenesis of the CT process  and the While emerging data seem to indicate an association between tendinopathies and endocrine disorders such as diabetes, hypercholesterolemia, hypertriglyceridemia, thyroid disorders, and estrogen levels alterations ,82, the The aetiopathogenesis of CT is still controversial, but it seems to be the results of an active cell-mediated process. We advocate use of the terms 'calcific tendinopathy' and 'insertional calcific tendinopathy' to differentiate conditions that seem to be caused by two different pathogenetic mechanisms. Better understanding of the pathogenesis is essential for development of effective treatment modalities and for the improvement of clinical outcomes.The authors declare that they have no competing interests.FO and NM conceived the study. FO and AGV undertook the literature search. AGV wrote the first draft. All the authors revised the manuscript, and approved the final draft.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/10/95/prepub


Altogether, these studies, which provide important information regarding the pharmacology of the urotensinergic system and the conformational requirements for binding and activation, will ultimately lead to the development of potent and selective drugs.The urotensinergic system plays central roles in the physiological regulation of major mammalian organ systems, including the cardiovascular system. As a matter of fact, this system has been linked to numerous pathophysiological states including atherosclerosis, heart failure, hypertension, diabetes as well as psychological, and neurological disorders. The delineation of the (patho)physiological roles of the urotensinergic system has been hampered by the absence of potent and selective antagonists for the urotensin II-receptor (UT). Thus, a more precise definition of the molecular functioning of the urotensinergic system, in normal conditions as well as in a pathological state is still critically needed. The recent discovery of nuclear UT within cardiomyocytes has highlighted the cellular complexity of this system and suggested that UT-associated biological responses are not only initiated at the cell surface but may result from the integration of extracellular and intracellular signaling pathways. Thus, such nuclear-localized receptors, regulating distinct signaling pathways, may represent new therapeutic targets. With the recent observation that urotensin II (UII) and urotensin II-related peptide (URP) exert different biological effects and the postulate that they could also have distinct pathophysiological roles in hypertension, it appears crucial to reassess the recognition process involving UII and URP with UT, and to push forward the development of new analogs of the UT system aimed at discriminating UII- and URP-mediated biological activities. The recent development of such compounds,  Gillichthys mirabilis, urotensin II (UII), a somatostatin-like peptide, was first characterized as a spasmogenic agent  and endothelin-1 (ET-1), in driving a variety of cardiac and vascular disease processes  located on the inner nuclear membrane  with the C-terminal of the protein being localized either within or outside the nucleus. In fact, the topology of the nuclear membrane lumen is very similar to the extracellular space, which makes it a favorable environment for a binding site  of rat and mouse UT isoforms but is absent in the primate (human and monkey) receptor  , for the treatment of diabetic nephropathy. Similarly, GlaxoSmithKline started a phase I clinical trial for the use of an UT antagonist, i.e. SB1440115 , for the treatment of asthma. Finally, over the past few years, Boehringer-Ingelheim (European patent application EP2155748) as well as Janssen Pharmaceutical  filled several patents regarding UT antagonists but no phase I clinical trial was yet reported. With the recent discovery that UII and URP could exert common as well as different biological activities  physiological roles of the urotensinergic system i.e. to emanate from the initial activation of the receptor. However, multiple studies pointed out the ability of some ligands to selectively trigger specific signaling pathways, therefore having collateral and not linear efficacy  respectively, showed a specific behavior that has set them apart from known UT antagonists  played by the UII/URP/UT receptor system in physiology and pathology.These latest findings about the urotensinergic system will probably generate a considerable interest within the scientific community. First, the discovery of UT on the nuclear membrane and the presence of intracellular ligands open up new avenues in UT signaling physiology. In general, nuclear-localized receptors may regulate distinct signaling pathways, suggesting that biological responses mediated by GPCRs are not only initiated at the cell surface but might result from the integration of extracellular and intracellular signaling pathways. These receptors are therefore well-positioned to play major roles in the physiological and pathophysiological responses associated with their endogenous ligands. Finally, the discovery of allosteric modulators of the urotensinergic systems such as urocontrin, UCA, and rUII(1–7), will surely enable a better understanding of the urotensinergic system by allowing to discriminate The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The midbrain represents the uppermost portion of the brainstem, containing numerous important nuclei and white matter tracts, most of which are involved in motor control, as well as the auditory and visual pathways. Notable midbrain nuclei include the superior and inferior colliculus nuclei, red nucleus, substantia nigra, oculomotor nuclear complex, and trochlear nucleus. In addition, white matter tracts include the brachium conjunctivum, medial and lateral lemniscus, spinothalamic tracts, and the fiber tracts within the cerebral peduncles. Although neurologically vital, many of these small midbrain nuclei and white matter tracts are not easily individually identified on neuroimaging. However, given their diverse functions, midbrain pathology often leads to distinct clinical syndromes. A review and understanding of the location and relationships between the different midbrain nuclei and fiber tracts will allow more precise correlation of radiologic findings with patient pathology and symptomatology. Particular syndromes associated with midbrain pathology include the Weber, Claude, Benedikt, Nothnagel, and Parinaud syndromes. The oculomotor and trochlear cranial nerves also reside at this level. An understanding of their functions as well as their projected courses from the midbrain towards the eye allows identification of distinct locations which are particularly vulnerable to pathology. The midbrain is the proximal brainstem bound rostrally by the diencephalon  and adjoined by the pons along its caudal aspect. Because of its close proximity to the cerebral cortex, cerebellum and caudal brainstem, the midbrain contains multiple small fiber tracts which relay vital information amongst these structures. Its role is important in the processing of visual and auditory information, as well as governing motor control. However, many of these tracts as well as midbrain nuclei are not well discriminated by today's neuroimaging techniques. Therefore, the identification of distinct external gross anatomy, including the superior and inferior colliculi and crus cerebri of the midbrain, provides landmarks for evaluation of internal midbrain nuclei, their projections, and their vascular supply. A review of this internal anatomy allows a better understanding of the location of these vital midbrain structures and their functions. Pathology, including infarction and tumor, involving the midbrain, may result in a distinct set of symptoms depending on the portion of midbrain affected. Given the close proximity between these midbrain structures, syndromes may overlap in clinical findings depending on regions of involvement.Additionally, the oculomotor and trochlear nuclei and cranial nerves originate from this level of the brainstem and extend to the orbit. Evaluation of these cranial nerve projections allows examination of the possible points of pathology and compression that lead to cranial nerve palsies.It is noted that a review of midbrain anatomy and classical midbrain syndromes may be useful both to clinical neurologists and neuroimagers attempting to correlate imaging findings to clinical signs and symptoms .The interior contents of the midbrain can be anatomically segmented in a dorsal to ventral fashion, including the tectum, tegmentum, and basis . The tecThe external midbrain displays distinct landmarks for easy identification. The cerebral peduncles lie along the ventral aspect of the midbrain, just superior to the pons. In addition, the quadrigeminal plate includes the superior and inferior colliculi, which are noted as two paired eminences along the dorsal surface of the midbrain. The oculomotor nerve  can be identified along the ventral midbrain within the groove formed between the cerebral peduncles. The trochlear nerve  emerges from the dorsal midbrain near the inferior colliculus.In the study of neuroanatomy, axial sectioning of the midbrain is commonly performed at the inferior colliculus . The infThe tegmentum contains the majority of the midbrain white matter tracts and nuclear groups at the level of the inferior colliculus . MultiplThe brachium conjunctivum is the largest and most centrally located of these tracts, representing the deccussation of cerebellar axons arising from the superior cerebellar peduncles. These fiber bundles continue to the thalamus and red nucleus and are involved in motor coordination. Sensory fibers course through the lateral tegmentum within the medial lemniscus, trigeminal lemniscus, and spinothalamic tracts. These bundles primarily project to the thalamus. The medial lemniscus relays information regarding proprioception and discriminative touch from the periphery and posterior columns of the spinal cord. Axons from the anterolateral portion of the spinal cord ascend through the spinothalamic tract, conveying sensations of pain and temperature. Facial sensations of pain, temperature, and touch are relayed to the thalamus via the trigeminal lemniscal tract. The medial longitudinal fasciculai are a pair of centrally located fiber tracts, controlling eye movement through connections with the oculomotor (CNIII), trochlear (CN IV) and abducens (CN VI), nerves as well as the vestibulocochlear nerves (CN VIII).Multiple important nuclear groups are found within the tegmentum at this level .Just dorsal to the substantia nigra, the nucleus parabrachialis pigmentosus is a continuation of the tegemental area of Tsai. The ventral tegmental nucleus resides dorsal to the brachium conjunctivum and receives fibers from the mammillary bodies to assist in regulating emotion and behavior. Within close proximity, the nucleus supratrochlearis  represents the largest serotonergic nucleus within the brain. Projections from the supratrochlearis nucleus extend to the substantia nigra, basal ganglia and cerebral cortex. The dorsal tegmental nucleus is located within the periaqueductal gray matter and sends projections to the reticular formation and autonomic nuclei of the brainstem. The pedunculopontine nucleus, lateral dorsal tegemental nucleus, and parabigeminal areas are cholenergic nuclei within the lateral tegementum. The pedunculopontine nucleus (PPN) receives input from cortical, pallidal, and nigral fibers and is involved in locomotion. The PPN has also been described as a site involved in progressive supranuclear palsy. The parabigeminal areas respond to visual stimuli projecting to and from the superior colliculi. The locus ceruleus is a noradrenergic nucleus with projections throughout the central nervous system, mainly through projections in the central tegmental tract, dorsal longitudinal fasiculus, and the medial forebrain bundle.The trochlear nucleus may also be identified at the level of the inferior colliculus, residing midline and ventral to the cerebral aqueduct .Axons from the trochlear nucleus traverse dorsal and lateral to the cerebral aqueduct with the trochlear nerve emerging from the dorsal surface of the midbrain. Externally, the trochlear nerve then courses anteriorly along the surface of the cerebral peduncle. At the ventral surface of the midbrain, these fibers travel next to the oculomotor nerve and together pass between the superior cerebellar and posterior cerebral arteries. The trochlear nerve then continues through the superior orbital fissure to innervate the superior oblique muscle, directing inward torsional gaze.The superior colliculus nuclei reside within the tectum as noted externally by the eminences of the superior colliculi .These nuclei are highly layered structures which govern ocular movements and visual reflexes through afferent connections with the cerebral cortex, retina, spinal cord, inferior colliculus, as well as several additional white matter tracts .The tegmentum is comprised of several nuclear bodies, with the red nucleus and oculomotor complex being the most notable. The red nucleus resides medially within the rostral tegmentum. Little is known about the function of the red nucleus, but its vast afferent pathways are known to include the cerebral and cerebellar cortex. Additionally, efferent projections to the spinal cord, cerebellum, reticular formation, and inferior olive have been noted. Continuations of the previously described white matter tracts within the tegmentum at the level of the inferior colliculus are again seen at this more superior level of the superior colliculus.The oculomotor nucleus lies ventral of the periaqueductal gray matter within the medial tegmentum. Afferent projections to the oculomotor nucleus originate from the cerebral cortex, cerebellum, mesencephalon, pons, and medulla. The oculomotor nucleus is comprised of a lateral somatic motor column and a medial visceral cell column. The lateral somatic motor column contains three subnuclei: the lateral, medial, and central subnuclei. The lateral subnucleus provides innervation to the ipsilateral inferior rectus, inferior oblique, and medial rectus muscles. The medial subnucleus supplies the contralateral superior rectus muscle. Innervation of the bilateral levator palpebrae superioris is provided by the central subnucleus.The somatic and visceral fibers from these nuclei coelesce and course ventrally through the midbrain tegmentum and near the red nucleus as well as the inner portion of the cerebral peduncles. Exiting the midbrain within the interpeduncular fossa as the oculomotor nerve, these fibers travel between the superior cerebellar and the posterior cerebral arteries adjacent to the trochlear nerve. Both of these cranial nerves continue to course anteriorly within the subarachnoid space to eventually penetrate the dura into the cavernous sinus. The oculomotor nerve then divides into a superior and inferior division. The superior division innervates the superior rectus and the levator palpebrae superioris muscles, governing upward gaze and lid elevation, respectively. The inferior division provides innervation to the inferior oblique, inferior rectus, and medial rectus muscles. The inferior oblique muscle affects outward torsional gaze. The inferior rectus muscle lowers the eye, while the medial rectus muscle allows adduction.The Edinger-Westphal nucleus resides within the visceral cell column and is located dorsal to the somatic oculomotor complex. Preganglionic axons coalesce and travel with oculomotor somatic fibers throughout the pathway to the eye .Upon entering the orbit, the parasympathetic fibers separate from the nerve to project to the ciliary ganglion. Postsynaptic fibers project to the ciliary body and iris to innervate the sphincter pupillae and ciliaris muscles. The pupillary light reflex allows transmittal of light-activated afferent signals through the optic nerve to project to bilateral Edinger-Westphal nuclei. Therefore, light cast upon one eye results in bilateral and symmetric pupillary constriction. The accommodation reflex directs pupillary constriction, increasing lens curvature and eye convergence with near vision .The ventral midbrain appears similar at both the level of the superior and inferior colliculi. Principle structures within this region include the cerebral peduncle and the substantia nigra .The cerebral peduncles contain corticocerebellar, corticobulbar, and corticospinal fibers. The corticospinal tract occupies roughly the middle three fifths of the cerebral peduncle, with the efferent cortical motor axons arranged somatotopically from medially to laterally as arm, face, and leg. The medial and lateral aspects of the peduncles are composed of corticopontine fibers from the frontal and parieto-occipital regions, respectively. These synapse in the pons, and decussate to enter the contralateral cerebellum through the middle cerebellar peduncles. Corticobulbar fibers, destined for the cranial nerve nuclei, occupy a dorsomedial position in relation to the corticospinal tracts.The substantia nigra is identified as a pigmented band of tissue just dorsal to the cerebral peduncle. It is composed of two zones, a dorsal zona compacta and a ventral zona reticulata. The substantia nigra is noted to play a role in several pathways, including motor control and reward. Involvement of the substatia nigra has been described with Parkinson's disease, Huntington's disease, and multisystem atrophy, with each disease showing a characteristic pattern of neuronal loss. Dopaminergic neurons form the center of the zona compacta, for example, are lost in idiopathic Parkinson's disease . The midbrain vasculature is primarily supplied by the posterior cerebral circulation, including the basilar, superior cerebellar, and posterior cerebral arteries .The complexity of this blood supply is demonstrated by variations in vascularity at the inferior colliculus, superior colliculus and pretectal levels. These three levels are further divided axially into medial and lateral zones. The medial zone at each level is supplied by the basilar artery and its paramedian branches. At the level of the inferior colliculus, the lateral zone receives branches from the superior cerebellar artery. The lateral zone at the level of the superior colliculus is supplied by the posterior cerebral artery. However, the superior colliculus and adjacent tectum are vascularized by the superior cerebellar artery. The posterior cerebral artery primarily supplies the lateral zone at the pretectal level .Injury to the oculomotor nerve results in paralysis of the intraocular and extraocular muscles, as well as the levator palpebrae muscle. Damage to the extraocular muscles results in downward and lateral deviation of the eye. Involvement of the intraocular muscles presents with mydriasis as well as divergent gaze. In addition, paralysis of the levator palpebrae muscle causes ptosis .The oculomotor nerve is susceptible to injury at several points along its course to the orbit. The oculomotor fibers exit the midbrain within the interpeduncular fossa. Displacement of the cerebral peduncle, as seen with temporal lobe herniation, may lead to compression of this nerve. After exiting the interpeduncular fossa, the oculomotor nerve courses between the posterior cerebral artery and superior cerebellar artery. Aneurysmal compression of the nerve at this level may present with isolated cranial nerve III palsy. The oculomotor nerve continues through the cavernous sinus and may suffer from injury at this site when there is cavernous sinus infection, venous thrombosis, or mass lesion. Cavernous sinus pathology, however, typically results in the paralysis of multiple cranial nerves, including the trigeminal (V1 and V2), trochlear (CN IV), and abducens (CN VI) nerves. In addition, carcinomatosis or infectious processes, such as tuberculous meningitis involving the optic chiasm, temporal lobes, or pons, may also affect the oculomotor nerve .Lesions within the midbrain may result in distinct syndromes, but given the close proximity of these vital nuclei and fiber tracts, these distinct syndromes often result in overlapping symptomatology , 2, 4.Parinaud's syndrome, also known as the dorsal midbrain syndrome, represents a constellation of symptoms related to compression of the rostral midbrain and pretectum near the level of the superior colliculus, usually due to mass effect from an adjacent pineal tumor –7 Figur.Limited upward gaze is the distinguishing symptom, as the vertical gaze center lies in close vicinity to the superior colliculus, with some of the main nuclei being the interstitial nucleus of Cajal and the rostral interstitial nucleus of the MLF. Interestingly, downward gaze is often preserved. This is in distinction to progressive supranuclear palsy, which also presents with a vertical gaze palsy, but one which preferentially affects downward gaze , 9. The Infarction of the ventromedial midbrain results in distinct symptoms of Weber Syndrome .This is characterized predominantly by an ipsilateral third nerve palsy and contralateral weakness , 4. A coSymptoms related to the involvement of cranial nerve III fibers include eye deviation (down and out), diplopia, ptosis, and afferent pupillary defect. Contralateral hemiparesis and lower facial weakness are due to infarction of the crus cerebri, including the corticospinal and corticobulbar tracts respectively. Other possible findings include contralateral parkinsonian rigidity from involvement of the substantia nigra. When the midbrain infarct involves the short circumflex branches and is ventrolateral in the midbrain involving only the cerebral peduncle, there can be sparing of the 3rd nerve .Claude Syndrome is described as ipsilateral oculomotor nerve palsy with contralateral cerebellar ataxia , 10–12 .Originally characterized as the result of dorsal tegmentum infarction, involvement of the cranial nerve III nucleus and/or nerve fibers leads to oculomotor nerve palsy. Insult to the red nucleus, brachium conjunctivum, or fibers of the superior cerebellar peduncle results in incoordination and cerebellar hemiataxia .A lesion within the tegmentum of the midbrain may also produce Benedikt Syndrome .As with Claude's syndrome, symptoms include incoordination and oculomotor nerve palsy due to involvement of the superior cerebellar peduncle and/or red nucleus, as well as the oculomotor nucleus. In addition, damage to the corticospinal tract resulting in contralateral hemiparesis is the distinct finding in Benedikt's syndrome  2]. Sym. Sym2]. Nothnagel's syndrome has been described as unilateral or bilateral oculomotor nerve paralysis and ipsilateral cerebellar ataxia , 13. TheAlthough the majority of midbrain nuclei and fiber tracts are not well differentiated on CT or MRI, the use of visible midbrain anatomy may be used to delineate locations of other vital structures. An understanding of the functions and relationships between these different midbrain structures allows for better correlation between regions of pathologic involvement and patient symptomatology.


Chemotherapy has been used for cancer treatment already for almost 70 years by targeting the proliferation potential and metastasising ability of tumour cells. Despite the progress made in the development of potent chemotherapy drugs, their toxicity to normal tissues and adverse side effects in multiple organ systems as well as drug resistance have remained the major obstacles for the successful clinical use. Cytotoxic agents decrease considerably the quality of life of cancer patients manifesting as acute complaints and impacting the life of survivors also for years after the treatment. Toxicity often limits the usefulness of anticancer agents being also the reason why many patients discontinue the treatment. The nutritional approach may be the means of helping to raise cancer therapy to a new level of success as supplementing or supporting the body with natural phytochemicals cannot only reduce adverse side effects but improve also the effectiveness of chemotherapeutics. Various plant-derived compounds improve the efficiency of cytotoxic agents, decrease their resistance, lower and alleviate toxic side effects, reduce the risk of tumour lysis syndrome, and detoxify the body of chemotherapeutics. The personalised approach using various phytochemicals provides thus a new dimension to the standard cancer therapy for improving its outcome in a complex and complementary way. Chemotherapy is one of the principal modes of the treatment of cancer patients . It was  By definition, chemotherapy treatment should interfere with the biochemical program that is involved or committed to cellular replication and cause selective cell death. At that, the host cell should be able to adapt and recover from toxicity . Many ch Cancer treatment is targeted at its proliferation potential and its ability to metastasise; hence, the majority of chemotherapy drugs take advantage of the fact that cancer cells divide rapidly . Chemoth Cancer is a highly heterogeneous disease, especially in its advanced forms , and sucversus monotherapy ; tumourthe host –28); multhe host ); and ththe host . Circadithe host –37. It hthe host , 35, 36.the host , 35, 37.the host , 35, 37.Cancer is a systemic and not a local disease . MetastaAlthough the desired goal of chemotherapy is to eliminate the tumour cells, diverse ranges of normal cell types are also affected, leading to many adverse side effects in multiple organ systems , 39–43.  Knowing how the chemotherapy agent works is important in predicting its side effects. For instance, treatment with alkylating agents and topoisomerase II inhibitors increases the risk of secondary cancer (acute leukaemia); anthracyclines (like doxorubicin) induce cardiotoxicity; and mitotic inhibitors have the potential to cause peripheral nerve damage . The most common acute complaints of cancer patients undergoing cytotoxic therapy are fatigue, nausea, vomiting, malaise, diarrhoea, mucositis, pain, rashes, infections, headaches, and other problems , 46, 47.Most cytotoxic drugs have immune suppressive side effects. Many chemotherapeutics kill dividing haematopoietic cells manifesting as profound neutropenia and cytopenia resulting in decreased immunity, increased susceptibility to infections, and elevated risk of bleeding , 3. ComiCancer patients frequently complain of neurological side effects . Such efThe most common long-term health problems of adjuvant chemotherapy include poor memory and concentration, visual deterioration, musculoskeletal complaints including early onset osteoporosis, poor sleep patterns, skin changes, sexual dysfunction, and chronic fatigue . This coMost chemotherapy drugs are genotoxic likely causing epigenetic and genetic damage , 44, 53.Current treatment protocols often apply multiagent chemotherapy  and thisThe efficacy of standard oncologic therapies  has reached a plateau for most of solid tumours . General Thus, nutritional approach may be the means of helping to raise cancer therapy to a new level of success, whereas supplementing or supporting the body with natural compounds may be the answer in not only reducing the side effects but also improving the effectiveness of chemotherapy . At the Intervention with dietary agents in chemotherapy has several aims. It increases the efficacy of treatment and decreases its side effects, improves cancer killing through apoptosis rather than necrosis, reduces drug resistance or increases drug accumulation within cancer cells, detoxifies body of chemotherapeutics, decreases weight loss and malnutrition, improves the quality of life, and reduces severity of comorbid conditions. Dietary compounds may enhance the efficacy of cancer therapeutics by modifying the activity of key cell proliferation and survival pathways , 61, 62.Oxidant stress shifts the mechanisms of cell killing away from apoptosis to necrosis inducing inflammation and promoting cancer progression. Necrosis will increase also the risk of developing tumour lysis syndrome. Regulating the oxidant state with specific antioxidants, supporting mitochondrial function, and increasing their numbers within cancer cells can promote the apoptosis-induced death of chemotherapy. This reduces the side effects associated with chemotherapy and may also lower the resistance to anticancer agents and the progression of tumour , 9.Drug resistance is one of the primary obstacles of successful chemotherapy. Inhibiting the function of ABC transporters, such as P-gp and MRP-s, may lead to overcoming drug resistance providing a possible mechanism to improve chemotherapeutic effects , 20. AltThe body needs to be detoxified of chemotherapeutics after the treatment is completed. Many of the anticancer agents are carcinogenic themselves and the patients may suffer secondary cancers following primary remission from the initial tumour . Nutritional status of cancer patients is associated with the outcome of malignant disease while weight loss is related to shortened survival and lowered response to chemotherapy , 47. MalCancer patients may be antioxidant deficient and chemotherapy further generates free radicals that cause oxidative damage in different organs. It is important to keep comorbid conditions in mind considering the state of the entire patient and not just to focus on the cancer. The antioxidant status of the patient can remain depressed for some months after the cancer treatment and nutritional support helps to ensure the best possible general health state . The optimal nutritional program proceeds from each individual case and considers the needs of a certain patient. Dietary phytochemical agents influence various aspects of chemotherapy treatment and their involvement in the cure of cancer patients is absolutely indicated and needful. Different natural compounds can improve efficiency of chemotherapeutic agents, decrease the resistance of chemotherapeutic drugs, lower and alleviate the adverse side effects of chemotherapy, reduce the risk of tumour lysis syndrome, and detoxify the body of chemotherapeutics. At the same time, it is important to be aware that some phytochemical agents can have also toxic effects and influence the treatment results adversely. in vitro cell systems or in vivo animal experiments , resveratrol, indole-3-carbinol, and proanthocyanidin have been shown to be able to affect the efficacy of traditional chemotherapeutic agents , 61. SupSaponins from Chinese ginseng enhance the therapeutic effect and behave as adaptogens reducing haematopoietic complications induced by systemic chemotherapy , 78. LabPolyphenol quercetin is able to potentiate the cytotoxic effect of cisplatin while protecting normal renal cells from cisplatin toxicity. Quercetin can work synergistically with busulfan against human leukaemia cells and with doxorubicin in cultured multidrug-resistant human breast cancer cells. It increases cytotoxic effect of CY and decreases resistance to gemcitabine, topotecan, vincristine, tamoxifen, paclitaxel, and doxorubicin , 71, 90.Catechins from green tea can increase the therapeutic effect of doxorubicin in drug-resistant tumours in animal studies . Adminis Curcumin can also enhance the tumoricidal efficacy of cytotoxic chemotherapy  and behaHowever, administration of soy isoflavones has led to contradictory results emphasising the necessity to maintain caution in excessive consumption of dietary agents and supplements during treatment with chemotherapy. While genistein can potentiate the action of tamoxifen to inhibit the tumour cell growth in oestrogen receptor-negative human breast cancer cells, this isoflavone can attenuate the tumoricidal activity of tamoxifen in oestrogen-dependent breast carcinoma cells see . Also, ain vitro, suggesting that such interactions could occur also in vivo [Several naturally occurring plant agents like flavonoids can enhance the drug bioavailability by inhibiting ATP transporters-mediated drug efflux  in vivo . It is r in vivo . To ensure the removal of toxic waste products, it is important that phase II detoxification enzymes are stimulated and restored. For this purpose, cancer patients should increase the intake of isothiocyanates , naringin (in grapefruit), and parsley and spice their food with curcumin . DetoxifIt is becoming more and more clear that vitamins can reduce the side effects of chemotherapy treatment. Thus, vitamin A reduces adverse effects of cyclophosphamide in rats  and its in vitro [ Vitamin C reduces the adverse effects of some chemotherapeutic agents on normal cells, such as those from doxorubicin. This vitamin can lower tamoxifen-induced hyperlipidemia in women with breast cancer and has been shown to reduce bleomycin-induced chromosomal breakage in human lymphoid cells in vitro . In expein vitro . α-tocopheryl succinate that can be used as an adjunct to standard cancer therapies in order to improve their efficacy on tumour cells while protecting normal cells against some of their toxicities [ Animal studies carried out mainly with rats and rabbits have shown the ability of vitamin E to reduce bleomycin-induced lung fibrosis, doxorubicin-induced cardiac toxicity, and doxorubicin-induced skin necrosis. It lowers also doxorubicin-induced toxicity in liver, kidney, and intestinal mucosa. Coadministration of vitamin E and vitamin C can reduce the tamoxifen-induced hyperlipidemia in women with breast cancer . The mosxicities , 93.  Vitamin K3 can act synergistically when combined with several conventional chemotherapeutic agents . However Last but not least, vitamin-like compound coenzyme Q10 has also been shown to ameliorate the side effects of chemotherapies . It help These data demonstrate the potential of dietary agents to reduce the symptoms of adverse side effects of chemotherapy treatment and relieve the situation of patients, improving their quality of life. Therefore, nutritional support programme built upon the personal necessities and clinical purposes is an absolutely important part of treatment scheme for all cancer patients. Despite a huge amount of studies published about the benefits of nutrient supplementation in chemotherapy there are still a lot of sceptics and opponents among both physicians as well as patients. On the one hand, this can be due to the lack of knowledge; on the other hand, spread of misconceptions and false beliefs also play an important role. It is estimate that roughly 50% of cancer patients use some kind of dietary supplements . Many stCurrently, a number of scientists hold the position that antioxidants do not interfere with chemotherapy and at commonly used dosages they enhance the success of the treatment. Except for some specific interactions (including flavonoids with tamoxifen) , 9, the Developing the rational strategies for fighting the cancer requires first a clear understanding of the causes and pathogenesis of the disease . This co Although the novel chemotherapeutic agents will be more and more effective against the tumour cells, their toxicity to normal tissues as well as drug resistance remains the major obstacles for clinical use. Personalised approach using various phytochemical compounds provides a new dimension to the standard cancer therapy for improving its outcome in a complex and complementary way.


Planococcuscitri, presumed by earlier observations of mating behavior, was confirmed using microsatellite genotyping of pools of over 400 eggs resulting from controlled crosses of one female with two males. The genetic contribution of both mated males was confirmed in 13 out of 43 crosses. In three crosses it was possible to determine that only the first male fertilized the eggs, which may be due to sperm competition or unviable sperm supply. The microsatellite analysis also allowed the confirmation of aspects of the chromosomal inheritance detected previously in cytogenetic studies in Planococcuscitri, namely that only one of the alleles is transmitted by the male, indicating that the males are functionally haploid, supporting the observation of Paternal Genome Elimination (PGE) in these insects.The occurrence of polyandry in  Polyandry is a widespread phenomenon in insects and may have significant fitness consequences for both sexes . The actPolyandry might have evolved as a result of selection against selfish genetic elements –7. On thHemiptera, Pseudococcidae) constitute the second largest family of scale insects (Coccoidea) and include many economic important pest species of different crops worldwide [Pseudococcuslongispinus (Targioni-Tozzetti), Pseudococcusviburni (Signoret), Pseudococcusmaritimus (Ehrhorn), Planococcusficus (Signoret) [Pseudococcuscalceolariae (Maskell), and Planococcuscitri (Risso)  ,12, PsRisso)  , the genetic system of mealybugs, the sex determination mechanism involves the inactivation by heterochromatization of one haploid set of chromosomes in males, whereas in females both sets are active . The inaPcitri.  [Pcitri. , the progeny of each cross consists of a high number of embryos of both sexes . As genCitrus sinensis (L.)) trees, and reared in climatic chambers  inside plastic containers with sprouted potatoes (Solanum tuberosum L.). In order to maximize the allele diversity between parents, different geographical origins were used: Agualva, Camarate, Mafra, Silves and Tavira, from Portugal, and Xirumi-Serravalle, from Italy. Field collected individuals were periodically added to the laboratory colonies, in order to refresh the rearing.The mealybugs used in the bioassays were collected from sweet orange . Mealybug males develop from diploid zygotes and are functionally haploid in the sense that only the maternal genome is transmitted to the progeny [Pcitri.  males, and differently from the haplodiploid case, the allele frequencies of males and females at each generation are not expected to be different, assuming random mating, random gamete fusion and random sex determination.DNA extraction was done with E.Z.N.A. Tissue DNA Isolation kit (Omega) following the manufacturer’s protocol. Amplification of microsatellite loci was performed as detailed in  using th progeny . TherefoMost approaches available for parentage analysis are based on the assumption of mendelian segregation of the alleles and in the estimation of allele frequencies of the population under study ,34. In oIS were generally high (> 0.2) and significant (<0.0001) for all loci except for Pci-7 and Pci-14, for which FIS were near zero and non-significant. These deviations in Hardy-Weinberg equilibrium indicate a significant deficit of heterozygotes which are likely caused by substructure due to the different geographic origins of the parents (Wahlund effect).The number of alleles at each locus ranged from 2 to 5, and the observed and the expected heterozygosity, calculated only from the parents, ranged from 0.089 to 0.512 and from 0.281 to 0.698, respectively  were the ones that allowed single-locus detection of polyandry. The other loci generally allowed attribution of paternity to one father but were not informative concerning the other one  that were not detected in the progeny. In two of these the excluded male was heterozygote in the locus that gave such indication and so the possibility of false exclusion due to null alleles is discarded.Pcitri.  transmitted genes to the progeny of doubly mated females in at least 30% of controlled crosses. This result constitutes the first genetic evidence of polyandry in any scale insect, supporting the behavioral evidence recently published . In this context, Waterworth and colleagues [Increased fertility and fecundity are among the reported benefits of polyandry . Howelleagues  suggestelleagues . Due to lleagues  and funclleagues , mealybulleagues ,7, the plleagues , may alsChemical control is still the most common control tactic used against pest mealybugs. However, insecticides are often ineffective due to the peculiar biological characteristics of mealybugs, e.g. cryptic behavior, wax body cover, and overlapping generations ,43. PherThe cost-effective approach described here for detecting polyandry, i.e. genotyping pools of eggs instead of single individuals, can be applied in other situations where the number of descendants is very high and would be very expensive and laborious to genotype every single individual. This type of approach has been previously successfully applied to the analysis of the sperm contained within the spermatheca of female insects, trying to detect microsatellite alleles of different males to have an estimate of the number of inseminations but not of the successful fertilizations ,49.