Search

Background: Radiation plays an essential role in treating malignancies. Radiation exposure of salivary glands often results in permanent loss of their functions; therefore, their protection against radiation is crucial. Nigella sativa oil (NSO) is a useful antioxidant against free radicals. The purpose of this study was to investigate the radio-protective effect of NSO on oxidative injury of parotid glands of gamma-irradiated rats., Methods: Twenty-eight male albino rats were divided into four groups (n = 7): Group 1: Neither NSO nor radiation, Group 2: Rats received NSO 400 mg/kg, Group 3: Rats received 15 Gy cranium gamma irradiation & Group 4: Rats received gamma irradiation and NSO. Rats were sacrificed two weeks after the last NSO dose. Histological sections of parotid glands were stained with H&E, Masson's trichrome and anti-TGF-β antibodies. Area percentage of Masson's trichrome and TGF-β expression was morphometrically examined., Results: Parotid glands of control and NSO groups revealed normal morphology. Gamma-irradiated glands showed loss of normal acinar architecture and slight acinar shrinkage. NSO treatment of gamma-irradiated glands preserved acinar outline and architecture. Masson's trichrome stained samples revealed trace amounts of collagen fibers in control and NSO groups, and excessive amounts of collagen fibers in gamma-irradiated group, in addition to few collagen fibers for gamma-irradiated glands treated with NSO. Additionally, control and NSO groups showed negative TGF-β expression. Gamma-irradiated group showed high TGF-β expression, while NSO treated gamma-irradiated group showed moderate TGF-β expression., Conclusions: Gamma-irradiation adversely affected parotid glands, and in contrast, NSO seemed to positively counteract this adverse effect., (© 2024. The Author(s).)

Background: Radiation triggers salivary gland damage and excess iron accumulates in tissues induces cell injury. Flavonoids are found in some fruits and are utilized as potent antioxidants and radioprotective agents. This study aimed to evaluate the antioxidant and anti-inflammatory effects of hesperidin and rutin on gamma radiation and iron overload induced submandibular gland (SMG) damage and to evaluate their possible impact on mitigating the alteration in mTOR signaling pathway and angiogenesis., Methods: Forty-eight adult male Wistar albino rats were randomly assigned to six groups: group C received a standard diet and distilled water; group H received hesperidin at a dose of 100 mg/kg; four times a week for four weeks; group U received rutin at a dose of 50 mg/kg; three times a week for three weeks; group RF received a single dose (5 Gy) of gamma radiation followed by iron at a dose of 100 mg/kg; five times a week for four weeks; group RFH received radiation and iron as group RF and hesperidin as group H; group RFU received radiation and iron as group RF and rutin as group U. SMG specimens from all groups were removed at the end of the experiment; and some were used for biochemical analysis, while others were fixed for histological and immunohistochemical examination., Results: In the RF group, several genes related to antioxidants (Nrf-2 and SOD) and DNA damage (BRCA1) were significantly downregulated, while several genes related to inflammation and angiogenesis (TNFα, IL-1β and VEGF) and the mTOR signaling pathway (PIK3ca, AKT and mTOR) were significantly upregulated. Acinar cytoplasmic vacuolation, nuclear pyknosis, and interacinar hemorrhage with distinct interacinar spaces were observed as histopathological changes in SMGs. The duct system suffered significant damage, eventually degenerating entirely as the cells were shed into the lumina. VEGF and NF-κB were also significantly overexpressed. Hesperidin and rutin cotreatment generated partial recovery as indicated by significant upregulation of Nrf-2, SOD and BRCA1 and considerable downregulation of TNF-α, IL-1β, VEGF, PIK3ca, AKT, and mTOR. Although some acini and ducts continued to deteriorate, most of them had a normal appearance. There was a notable decrease in the expression of VEGF and NF-κB., Conclusions: In γ-irradiated rats with iron overload, the administration of hesperidin and rutin may mitigate salivary gland damage., (© 2024. The Author(s).)

Background: Diabetes is a common disease that cancer patients may suffer from and may aggravate side effects of radiotherapy. This study aimed to detect whether metformin and/or quercetin will improve gamma-irradiation induced tongue toxicity in diabetic rats., Methods: 35 male albino rats were divided into five groups; NOR no streptozotocin, no radiation and no treatment was given, DR rats were subjected to streptozotocin then gamma-irradiation, DRM rats were subjected to streptozotocin then gamma-irradiation then metformin, DRQ rats were subjected to streptozotocin then gamma-irradiation then quercetin, DRMQ rats were subjected to streptozotocin then gamma-irradiation then metformin and quercetin. Rats were euthanized 24 h after last treatment dose. Mean blood glucose level was recorded. Tongue specimens were stained with H&E and CD68. Histomorphometric analysis of length, diameter and taste buds of lingual papillae and epithelial, keratin and lamina propria thickness and CD68 positive cells were calculated., Results: Blood glucose level of DRMQ was significantly lower than DR, DRM and DRQ, whereas higher than NOR. Metformin or quercetin partially restored tongue structure, papillae length and diameter and tongue layers thickness. The ameliorative effect was superior when metformin and quercetin were used together. Diabetes and irradiation significantly increased number of CD68 positive macrophages in submucosa and muscles. Metformin or quercetin significantly reduced number of lingual macrophages with more noticeable effect for quercetin. Treatment with metformin and quercetin significantly decreased number of macrophages., Conclusions: Combined use of metformin and quercetin might help mitigate the harmful effects of radiotherapy and diabetes on lingual tissues., (© 2024. The Author(s).)

Background: Radiation therapy is the primary treatment for neck and head cancer patients; however, it causes the development of oral mucositis accompanied by tissue structure destruction and functional alteration. This study was conducted to evaluate the effect of different doses of vitamin E as a treatment for radiationinduced oral mucositis in rat model., Methods: 35 male albino rats were randomly divided into five groups: control, untreated radiation mucositis (single dose of 20 Gy), treated radiation mucositis; radiation (single dose of 20 Gy) then vitamin E at doses of 300, 360 and 500 mg/Kg for seven days started 24 h after irradiation. Body weight and food intake were evaluated for each rat. The mucositis score was assessed every day. Rats were sacrificed once at the end of the experiment, and tongue specimens were stained with hematoxylin and eosin, anti P53 and anti Ki67 antibodies., Results: Results indicated more food intake and less weight reduction in vitamin E treated groups and the contrary for gamma-irradiated group. Additionally, vitamin E delayed the onset and decreased the severity and duration of mucositis. It also restored the histological structure of lingual tongue papillae. Vitamin E treated groups showed a significant higher Ki67 and lower P53 expression as compared to untreated radiation group. The overall improvement increased as vitamin E dose increased. Finally, the amelioration can be attributed to the decreased apoptosis and increased proliferation of cells., Conclusions: Vitamin E especially at dose of 500 mg/Kg could be an effective treatment for radiation-induced oral mucositis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Migraine frequently is associated with White Matter Hyperintensities (WMHs). We aimed to assess the frequency of WMHs in migraine and to assess their risk factors., Methods: This is cross-sectional study included 60 migraine patients of both genders, aged between 18 and 55 years. Patients with vascular risk factors were excluded. We also included a matched healthy control group with no migraine. Demographic, clinical data, and serum level of homocysteine were recorded. All subjects underwent brain MRI (3 Tesla)., Results: The mean age was 38.65 years and most of our cohort were female (83.3). A total of 24 migraine patients (40%) had WMHs versus (10%) in the control group, (P < 0.013). Patients with WMHs were significantly older (43.50 + 8.71 versus. 35.92+ 8.55 years, P < 0.001), have a longer disease duration (14.54+ 7.76versus 8.58+ 6.89 years, P < 0.002), higher monthly migraine attacks (9.27+ 4. 31 versus 7.78 + 2.41 P < 0.020) and high serum homocysteine level (11.05+ 5.63 versus 6.36 + 6.27, P < 0.006) compared to those without WMHs. WMHs were more frequent in chronic migraine compared to episodic migraine (75% versus 34.6%; P < 0.030) and migraine with aura compared to those without aura (38.3% versus 29,2; P < 0.001). WMHs were mostly situated in the frontal lobes (83.4%), both hemispheres (70.8%), and mainly subcortically (83.3%)., Conclusion: Older age, longer disease duration, frequent attacks, and high serum homocysteine level are main the risk factors for WMHs in this cohort. The severity or duration of migraine attacks did not increase the frequency of WMHs. The number of WMHs was significantly higher in chronic compared to episodic migraineurs., (© 2022. The Author(s).)

Background: Coronavirus disease-19 is caused by the severe acute respiratory syndrome coronavirus 2 Headache is a common symptom during and after Coronavirus disease-19. We aimed to study headache character in relation to COVID-19., Methods: This was a cross-sectional study. Patients who had Coronavirus disease-19, confirmed by reverse transcription polymerase chain reaction technique and presented to the headache clinic within 3 months after the onset of infections were identified to the study. Study included patients diagnosed as primary headache disorders according to The International Classification of Headache Disorders, 3rd edition. Participants were grouped into categories according to having previous or de novo headache. Descriptive data, paired sample t-test and the chi-squared test (X 2 ) were used for statistical analyses of the data., Results: A total of 121 patients were included in this study. Their mean age was 35.29 + 9.54 and most of them were females (83.5%). Prior to Coronavirus disease-19 infections, 78 (64.5%) had migraine and 11(9.1%) experienced a tension-type headache while 32 (26.4) reported de novo headache post Coronavirus disease-19. Patient had significant increase in headache days 11.09 ± 8.45 post Coronavirus disease-19 compared with 8.66 ± 7.49 headache days before Coronavirus disease-19 infection (p < 0.006). Post Coronavirus disease-19, the usage of analgesic increased significantly by the patient with migraine (2.31 ± 1.65 vs 3.05 ± 2.09, p = 0.002) while the patient with tension type headache had statistically significant increase in severity (5.556 ± 1.86 vs 7 ± 2.25, p = 0.033) and frequency (7 ± 6.29 vs 12.72 ± 7.96, p = 0.006) of headache attacks. Bi-frontal and temporal headache are the most reported (40.6% each) headache site among de novo headache group. Patients younger than 40 years had longer duration of the headache attack (18.50 ± 16.44 vs 5.5 ± 9.07, p = 0.045) post COVID-19. Male patients compared to females (8.66 ± 1.15 versus 5.93 ± 2.01 p = 0.04) had more severe headache post Coronavirus disease-19. De novo headache resolved within 1 month in most of patients (65.3%)., Conclusion: Primary headache get worse after Coronavirus disease-19. De novo primary headache is frequent post Coronavirus disease-19 and resolve within 1 month. Headaches related to Coronavirus disease-19 are severe, present as migraine phenotype. Young male patients with Coronavirus disease-19 tend to have worse headache., (© 2021. The Author(s).)

Background: Whilst diagnostic pathways for children with rare conditions have shown marked improvement, concerns remain about the care children with rare conditions receive at the level of the health care provider. There is, therefore, a need to improve our understanding of the health care received and explore the development of benchmarks that can be regularly monitored., Methods: Patients and parents with rare conditions at a tertiary children's hospital were approached to complete a questionnaire-based survey that enquired on their experience of clinical care. The survey explored six key themes: diagnosis; provision of information; availability of support; satisfaction with healthcare team; awareness and support for life-limiting conditions; and participation in research., Results: 130 questionnaires were completed on behalf of 134 patients between 2018 and 2020. Of these, 114 (85%) had received a formal diagnosis, 5 (4%) had a suspected diagnosis and 15 (11%) were undiagnosed. Of the 114 who had received a diagnosis, 24 (20%) were diagnosed within 6 months of developing symptoms, and 22 (20%) within 1-3 years. Seventy patients (53%) reported that they were given little or no information around the time of diagnosis, whilst 81 (63%) felt they were currently well supported, mostly from family members, followed by friends, hospital services, school, other community based healthcare services and lastly, primary care. Of the 127 who were asked, 88 (69%) reported a consistent team of healthcare professionals taking overall responsibility for their care, 86 (67%) felt part of the team, 74 (58%) were satisfied with the level of knowledge of the professionals, and 86 (68%) knew who to contact regarding their condition. Of the 91 who were asked, 23 (25%) were aware their child had a life limiting condition, but only 4 (17%) were receiving specialist support for this. Of 17 who were asked about research, 4 (24%) were actively participating in research, whilst the remainder were all willing to participate in future research., Conclusions: The survey provides a unique insight into the experience of patients and parents within a specialist centre and the benchmarks that it has revealed can be used for future improvement in services.

Background: Primary headache disorders have being increasingly reported in younger populations. They can have significant effects on their quality of life and academic achievement and may cause significant distress to their families., Aims and Objectives: To assess the burden of primary headache disorder and its impact on the quality of life on school student in Kuwait., Methods: A cross-sectional study was conducted among Kuwaiti primary and middle school students of both genders in randomly selected schools located in two governorates in 2018/2019 academic year. Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire for children and adolescents was used to assess the impact of primary headaches on the quality of life., Results: One thousand and ninety-one questionnaires were completed by primary and middle school students of both genders; of whom 466 students (girls 321 (68.88%) were diagnosed with primary headache disorders with mean age 11.98 ± 2.03 years. In the month prior to the survey, the effect of the headache was variable. The students lost a mean of 1.99 ± 2.015 days of school while they could not perform their usual activities for a mean of 2.84 ± 4.28 days. Their parents lost a mean of 2 ± 2.03 days of work because of headaches of their children and parents prohibited 5.7% of the students to engage in any activity due to their headaches. Difficulties in concentrations were reported as never sometimes (39.1%), often (24.8%), and always (26%). Majority of the students (51.5%) experienced a feeling of sadness ranging from sometimes to always. Most of the students (67.3%) struggled to cope with the headache and 22.4% were never able to cope. Additionally, 19.4% of students reported they did not want others noticing their headache., Conclusion: Primary headache disorder can have a significant impact on the quality of life in children. It can affect their engagement in activities and academic achievement. Implementing strategies to properly manage schoolchildren with primary headaches can have profound effects on their quality of life.

Background: There is a paucity of tools that can be used in routine clinical practice to assess the psychosocial impact of Disorders/Differences of Sex Development (DSD) on parents and children., Objective: To evaluate the use of short Parent Self-Report and Parent Proxy-Report questionnaires that can be used in the outpatient setting., Methods: Previously validated DSD-specific and generic items were combined to develop a Parent Self-Report questionnaire and a Parent Proxy-Report questionnaire for children under 7 years. Of 111 children approached at one tertiary paediatric hospital, the parents of 95 children (86%) with DSD or other Endocrine conditions completed these questionnaires., Results: Questionnaires took under 10 min to complete and were found to be easy to understand. Compared to reference, fathers of children with DSD reported less stress associated with Clinic Visits ( p  = 0.02) and managing their child's Medication ( p  = 0.04). However, parents of children with either DSD or other Endocrine conditions reported more symptoms of Depression ( p  = 0.03). Mothers of children with DSD reported greater Future Concerns in relation to their child's condition (median SDS - 0.28; range - 2.14, 1.73) than mothers of children with other Endocrine conditions (SDS 1.17; - 2.00, 1.73) ( p  = 0.02). Similarly, fathers of children with DSD expressed greater Future Concerns (median SDS -1.60; - 4.21, 1.00) than fathers of children with other Endocrine conditions (SDS 0.48; - 2.13, 1.52) ( p  = 0.04)., Conclusion: DSD was associated with greater parental concerns over the child's future than other Endocrine conditions. Brief parent-report tools in DSD can be routinely used in the outpatient setting to assess and monitor parent and patient needs., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2020.)

Background: Traditional Medicine (TM) is widely accepted to be used for the treatment headache disorders in Kuwait however, researches remain poorly documented. We aimed to study the frequency of TM use and its impact in the primary headache patients., Methods: This is a cross sectional self-reported efficacy study, which was conducted in Headache clinic in Kuwait throughout 6 months. Patients who were diagnosed with primary headache disorders of both genders aged from 18 to 65 years were included. Self-reported questionnaires were distributed to patients who used TM in the previous year. It included demographic, and characteristics of headache (headache frequency, duration, number of analgesic used in days per month and severity of headache). TM queried included blood cupping (Hijama), head banding, herbal medicine (sabkha), and diet modification. It assessed characters of headache before and 3 months after the final TM session. Independent sample t test, paired sample t test and Chi-square test were used to compare between different values. P < 0.05 is considered significant., Results: A total of 279 patients were included. The mean age is 40.32 ± 11.75 years; females represented 79.6% of the cohort. Most patients (n = 195; 69.9%) reported the use of TM before presentation to headache clinic, mainly Hijama (47.3%). Cultural / religious beliefs were the cause of seeking TM in 51.3% versus 10% used it due to ineffective medical treatment and 8.6% used it because of intolerance of medical treatment. Patients used TM were older at the onset of headache (24.24 ± 10.67 versus 20.38 ± 8.47; p < 0.003), and had longer headache disease duration (19.26 ± 13.13 versus 16.12 ± 11.39; p < 0.044). All patients with chronic headache (100%) and most of episodic migraine patients (90.4%) sought TM while only (31.5%) of Tension type headache sought TM; p < 0.047. Patients who sought TM had more frequent episodes of headache, longer duration of attacks and higher number of days of analgesic-usage respectively over last 3 months before presentation to our side (9.66 ± 7.39 versus 4.14 ± 2.72; p < 0.001), (41.23 ± 27.76 versus 32.19 ± 23.29; p <. 0009), (8.23 + 7.70 versus 3.18 ± 3.06; p < 0.001). At 3 months after the final TM session, there was no significant reduction of frequency of headache days per month (9.19 ± 7.33 versus 8.99 ± 7.59; p < 0.50), days of analgesic use per month (7.45 ± 7.43 versus 6.77 ± 6.93; p < 0.09) and duration of headache (41.23 ± 27.76 versus 41.59 ± 27.69; p < 0.78). However, there was a significant reduction of the severity of headache (p < 0.02). Few patients (17.9%) reported adverse events with TM. Most of TM cohorts were not satisfied after receiving this type of medicine., Conclusion: TM was widely used in Kuwait for primary headache. Patients sought TM before seeking physician because they found them more congruent with their own cultural and religious beliefs. Health care professionals involved in the management of headache should be aware of this and monitor potential benefits or adverse events of TM. The usage of TM was not effective in reducing headache attacks and severity.

Background: Migraine prevalence and disability imprints on Kuwaiti population are underreported. We aimed to measure the prevalence of migraine and to assess its burden in Kuwait., Methods: A cross-sectional community-based study was conducted which included biologically unrelated Kuwaiti adult population aged 18-65 years. They were randomly recruited from all six governments of Kuwait using stratified multistage cluster sampling. Trained interviewers visited the samples in door-to-door approach. The Headache-Attributed Restriction, Disability, and Social Handicap and Impaired Participation (HARDSHIP) questionnaire was used to collect the data. Demographic enquires were followed by diagnostic and disability questions., Results: A total of 15,523 subjects were identified; of whom 3588 (23%) were diagnosed as episodic migraine and 845 (5.4%) as chronic headache. Prevalence of episodic migraine was 31.71% in female versus 14.88% in males (P < 0.01) with a mean age of 34.56 ± 10.17 years. Most of migraine cohort (64.4%) sought medical advice with respect to their migraine headaches and the majority (62.4%) were seen by general practitioners (GPs) while 17.2% were assessed by neurologists and 3.7% was seen by other specialties. Tension type headache and sinus-related headaches were diagnosed in 8.9% and 2.1% of migraine subjects respectively. The majority (94.6%) of migraine subjects used symptomatic drugs for headache attacks, whereas 39.9% were taking preventive medication. In the preceding 3 months to the survey, subjects with episodic migraine had lost a mean of 1.97 days from their paid work or school attendance compared to 6.62 days in chronic headache sufferers (P < 0.001). Additionally, subjects with episodic migraine lost a mean of 1.40 days from household work compared to 5.35 days in subjects with chronic headache (P < 0.001). Participants with episodic migraine and chronic headache missed a mean of 2.81 and 3.85 days on social occasions, in the preceding 3 months (P < 0.001)., Conclusions: Migraine in Kuwait is highly prevalent and it has a significant impact on activity of daily living, schooling/ employment and social occasions of patients. Accurate diagnosis, effective abortive and preventive treatments of migraine are paramount to improve quality of life and as well as cost saving.

Background: With the proliferation of rare disease registries, there is a need for registries to undergo an assessment of their quality against agreed standards to ensure their long-term sustainability and acceptability.This study was performed to evaluate the I-DSD and I-CAH Registries and identify their strengths and weaknesses., Methods: The design and operational aspects of the registries were evaluated against published quality indicators. Additional criteria included the level of activity, international acceptability of the registries and their use for research., Results: The design of the I-DSD and I-CAH Registries provides them with the ability to perform multiple studies and meet the standards for data elements, data sources and eligibility criteria. The registries follow the standards for data security, governance, ethical and legal issues, sustainability and communication of activities. The data have a high degree of validity, consistency and accuracy and the completeness is maximal for specific conditions such as androgen insensitivity syndrome and congenital adrenal hyperplasia. In terms of research output, the external validity is strong but the wide variety of cases needs further review. The internal validity of data was condition specific and highest for conditions such as congenital adrenal hyperplasia. The shift of the registry from a European registry to an international registry and the creation of a discrete but linked CAH registry increased the number of users and stakeholders as well as the international acceptability of both registries., Conclusions: The I-DSD and I-CAH registries comply with the standards set by expert organisations. Recent modifications in their operation have allowed the registries to increase their user acceptability.

Background: Despite optimal therapy, many children with Crohn's disease (CD) experience growth retardation. The objectives of the study are to assess the feasibility of a randomised control trial (RCT) of injectable forms of growth-promoting therapy and to survey the attitudes of children with CD and their parents to it., Methods: A feasibility study was carried out to determine study arms, sample size and numbers of eligible patients. A face-to-face questionnaire surveyed willingness to consent to future participation in the RCT. Eligibility to the survey was any child under 18 (with their parent/guardian) with CD whose height standard deviation score (HtSDS) was ≤+1. Of 118 questionnaires, 94 (80%) were returned (48 by children and 46 by parents)., Results: The median age of the patients in the survey was 14.3 years (range 7.0 to 17.7), and 35 (73%) were male. Their median HtSDS was -1.2 (-3.01, 0.23), and it was lower than the median mid-parental HtSDS of -0.6 (-3.1, 1.4). We analysed the willingness of the children whose HtSDS <-1 to take part in the proposed RCT, being those most likely to require treatment. Overall, 18 (47%) children and 17 (46%) parents were willing. This increased to 61% of children who were slightly concerned about their height and 100% (4/4) of those very concerned. A common reason for not taking part in the RCT was fear of injections (44%); 111 children are required for randomisation into three study arms from nine centres., Conclusions: Almost half of children and parents surveyed would take part in an RCT of growth-promoting therapy. Allaying fears about injections may result in higher recruitment rates.

Background: To explore the current models of practice in centres delivering specialist care for children with disorders of sex development (DSD), an international survey of 124 clinicians, identified through DSDnet and the I-DSD Registry, was performed in the last quarter of 2014., Results: A total of 78 (63 %) clinicians, in 75 centres, from 38 countries responded to the survey. A formal national network for managing DSD was reported to exist in 12 (32 %) countries. The paediatric specialists routinely involved in the initial evaluation of a newborn included: endocrinologist (99 %), surgeon/urologist (95 %), radiologist (93 %), neonatologist (91 %), clinical geneticist (81 %) and clinical psychologist (69 %). A team consisting of paediatric specialists in endocrinology, surgery/urology, clinical psychology, and nursing was only possible in 31 (41 %) centres. Of the 75 centres, 26 (35 %) kept only a local DSD registry and 40 (53 %) shared their data in a multicentre DSD registry. Attendance in local, national and international DSD-related educational programs was reported by 69, 78 and 84 % clinicians, respectively. Participation in audits/quality improvement exercises in DSD care was reported by 14 (19 %) centres. In addition to complex biochemistry and molecular genetic investigations, 40 clinicians (51 %) also had access to next generation sequencing. A genetic test was reported to be more preferable than biochemical tests for diagnosing 5-alpha reductase deficiency and 17-beta hydroxysteroid dehydrogenase 3 deficiency by 50 and 55 % clinicians, respectively., Conclusion: DSD centres report a high level of interaction at an international level, have access to specialist staff and are increasingly relying on molecular genetics for routine diagnostics. The quality of care provided by these centres locally requires further exploration.

Background: Casitas B-lineage lymphoma (Cbl or c-Cbl) is a RING ubiquitin ligase that negatively regulates protein tyrosine kinase (PTK) signalling. Phosphorylation of a conserved residue (Tyr371) on the linker helix region (LHR) between the substrate-binding and RING domains is required to ubiquitinate PTKs, thereby flagging them for degradation. This conserved Tyr is a mutational hotspot in myeloproliferative neoplasms. Previous studies have revealed that select point mutations in Tyr371 can potentiate transformation in cells and mice but not all possible mutations do so. To trigger oncogenic potential, Cbl Tyr371 mutants must perturb the LHR-substrate-binding domain interaction and eliminate PTK ubiquitination. Although structures of native and pTyr371-Cbl are available, they do not reveal how Tyr371 mutations affect Cbl's conformation. Here, we investigate how Tyr371 mutations affect Cbl's conformation in solution and how this relates to Cbl's ability to potentiate transformation in cells., Results: To explore how Tyr371 mutations affect Cbl's properties, we used surface plasmon resonance to measure Cbl mutant binding affinities for E2 conjugated with ubiquitin (E2-Ub), small angle X-ray scattering studies to investigate Cbl mutant conformation in solution and focus formation assays to assay Cbl mutant transformation potential in cells. Cbl Tyr371 mutants enhance E2-Ub binding and cause Cbl to adopt extended conformations in solution. LHR flexibility, RING domain accessibility and transformation potential are associated with the extent of LHR-substrate-binding domain perturbation affected by the chemical nature of the mutation. More disruptive mutants like Cbl Y371D or Y371S are more extended and the RING domain is more accessible, whereas Cbl Y371F mimics native Cbl in solution. Correspondingly, the only Tyr371 mutants that potentiate transformation in cells are those that perturb the LHR-substrate-binding domain interaction., Conclusions: c-Cbl's LHR mutations are only oncogenic when they disrupt the native state and fail to ubiquitinate PTKs. These findings provide new insights into how LHR mutations deregulate c-Cbl.

Background: Adolescents with childhood onset growth hormone deficiency (CO-GHD) require re-evaluation of their growth hormone (GH) axis on attainment of final height to determine eligibility for adult GH therapy (rhGH)., Aim: Retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition., Patients: Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005 and 2013 were reviewed. Median (range) age at initial diagnosis of CO-GHD was 10.7 years (0.1-16.4) with a stimulated GH peak of 2.3 μg/l (0.1-6.5). Median age at initiation of rhGH was 10.8 years (0.4-17.0)., Results: Of the 130 CO-GHD adolescents, 74/130(57 %) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74 (82 %) remained GHD with 51/74 (69 %) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Of the remaining 56/130 (43 %) patients who were not re-tested, 34/56 (61 %) were transferred to adult services on rhGH without biochemical retesting and 32/34 of these had MPHD. The proportion of adults who were offered rhGH without biochemical re-testing in the four centres ranged between 10 and 50 % of their total cohort., Conclusions: A substantial proportion of adults with CO-GHD remain GHD, particularly those with MPHD and most opt for treatment with rhGH. Despite clinical guidelines, there is significant variation in the management of CO-GHD in young adulthood across Scotland.

Background: Unusual presentations of multiple sclerosis (MS) at onset may post a diagnostic dilemma to the treating neurologists. Spinal myoclonus is rare in MS and may lead to perform extensive investigations to rule out other etiologies affecting the spinal cord., Case Presentation: We described a 31-year-old male who presented with involuntary brief jerky movements of the left shoulder and arm with significant wasting of shoulder muscles. In retrospect, the patient had a progressive right leg weakness one year prior to his presentation. Needle electromyography confirmed the presence of rhythmic irregular burst discharges in motor units of muscles expanding from the third to the sixth cervical region with normal nerve conduction parameters. There was no evidence of cortically generated myoclonic jerks using time-locked electroencephalogram. Magnetic Resonance Imaging of the brain and cervical cord along with the presence of oligoclonal bands in cerebral spinal fluid confirmed the diagnosis of MS. Based on the history and progressive clinical features, a diagnosis of primary progressive MS was established., Conclusion: Spinal myoclonus can be the presenting manifestation of MS in association with demyelinating plaques in the root exit zones of the spinal cord. Spinal myoclonus may pose a diagnostic challenge when it presented at the disease onset and especially in patients with progressive course at onset. Our patient represents the first reported primary progressive MS case in the literature with spinal myoclonus presentation.

Background: Urinary steroid metabolite ratios may improve the diagnostic yield of potential disorders of steroid hormone synthesis., Objectives: To investigate the range of ratios and their predictive value in children with suspected disorders of steroid synthesis., Design and Methods: Twelve ratios were calculated on steroid metabolite data analysed by gas chromatography-mass spectrometry in urine samples collected between 2008-2010 from 93 children. Urine samples were also analysed in 252 children with no known endocrine concerns., Results: Of the 252 controls, 115 (46%) were male with a median age of 10 yr (range 1 month,18.5 years). Of the 93 cases, 38 (41%) were male with a median age of 6.5 yr (1 day,18.5 yrs). Of these, 41 (44%) had at least one ratio greater than the 95% percentile for controls. The most frequently abnormal ratio, found in 18/93 (19%) cases was (THS/(THE + THF + 5αTHF)) suggestive of 11β-hydroxylase deficiency. Over this period, 8 (9%) children were subsequently diagnosed with a steroid hormone disorder; 4 with 21-hydroxylase deficiency, 2 with11β-hydroxylase deficiency and 2 with 5α-reductase deficiency. All except one of these children had at least 1 raised ratio., Conclusions: Urinary steroid metabolite ratios in suspected disorders of hormone synthesis often exceed the reference range for normal children. The predictive value of steroid metabolite ratios in identifying a genetic abnormality may be condition specific and needs further study to improve its clinical utility.

Background: Extended-spectrum β-lactamases (ESBLs), including the AmpC type, are important mechanisms of resistance among Enterobacteriaeceae. CTX-M type extended-spectrum β- lactamases, of which there are now over 90 variants, are distributed globally, yet appear to vary in regional distribution. AmpC β-lactamases hydrolyze third generation cephalosporins, but are resistant to inhibition by clavulanate or other β-lactamase inhibitors in vitro. Fecal carriage and rates of colonization by bacteria harboring these resistance mechanisms have been reported in patients with community-acquired infections and in healthy members of their households. Expression of these ESBLs compromises the efficacy of current antibacterial therapies, potentially increasing the seriousness of hospital- and community-acquired Escherichia coli (E. coli) infections.To investigate the occurrence of ESBL-producing E. coli in human fecal flora isolated from two pediatric populations residing in the Libyan cities Zleiten and Abou El Khoms. Isolates were further studied to characterize genes encoding β-lactam resistance, and establish genetic relationships., Methods: Antibiotic resistance profiles of phenotypically characterized E. coli isolates recovered from the stools of 243 Libyan children during two surveillance periods in 2001 and 2007 were determined by the disk diffusion method. ESBL-screening was performed using the cephalosporin/clavulanate double synergy disc method, and the AmpC-phenotype was confirmed by the aminophenyl-boronic acid test. ESBL genes were molecularly characterized. Phylogenetic group and multilocus sequence typing (MLST) were determined for ESBL-producing isolates and PFGE was performed to compare banding profiles of some dominant strains., Results: ESBLs were identified in 13.4% (18/134) of E. coli isolates, and nine isolates (6.7%) demonstrated AmpC activity; all 18 isolates contained a CTX-M gene. Three CTX-M gene families (CTX-M-1, n=9; CTX-M-15, n=8 and CTX-M-3, n=1) were distributed in diverse E. coli backgrounds (phylogenetic group D, 39%; B2, 28%; B1, 22% and A, 11%). MLST analysis revealed 14 sequence type (ST) with six new sequence types. The gene encoding the CMY-2 enzyme was detected in five AmpC-positive E. coli., Conclusions: These results identified heterogeneous clones of CTX-M-producing E. coli in the fecal isolates, indicating that the intestinal tract acts as a reservoir for ESBL-producing organisms, and a trafficker of antibiotic resistance genes.

Background: Medical students routinely have triggers, notably stress and irregular sleep, which are typically associated with migraine. We hypothesized that they may be at higher risk to manifest migraine. We aimed to determine the prevalence of migraine among medical students in Kuwait University., Methods: This is cross-sectional, questionnaire-based study. Participants who had two or more headaches in the last 3 months were subjected to two preliminary questions and participants with at least one positive response were asked to perform the validated Identification of Migraine (ID Migraine™) test. Frequency of headache per month and its severity were also reported., Results: Migraine headache was suggested in 27.9% subjects based on ID-Migraine™. Migraine prevalence (35.5% and 44%, versus 31.1%, 25%, 21.1%, 14.8%, 26.5%, p < 0.000), frequency (5.55 + 1.34 and 7.23 + 1.27, versus 3.77 ± 0.99, 2.88 ± 0.85, 3.07 ± 0.96, 2.75 ± 0.75, 4.06 ± 1.66, p < 0.000); and severity of headache (59.1% and 68.2%, versus 28.3%,8.3%, 6.7%,16.7%, p < 0.000; were significantly increased among students in the last 2 years compared to first five years of their study. Stress 43 (24.9%), irregular sleep 36 (20.8%), and substantial reading tasks 32 (18.5%), were the most common triggering factors cited by the students., Conclusion: The prevalence of migraine is higher among medical students in Kuwait University compared to other published studies. The migraine prevalence, frequency and headache severity, all increased in the final two years of education.

Background: Sinusitis is the most frequent misdiagnosis given to patients with migraine.Therefore we decided to estimate the frequency of misdiagnosis of sinusitis among migraine patients., Methods: The study included migraine patients with a past history of sinusitis. All included cases fulfilled the International Classification of Headache Disorders, 3rd edition (ICHD-III- beta) criteria. We excluded patients with evidence of sinusitis within the past 6 months of evaluation. Demographic data, headache history, medical consultation, and medication intake for headache and effectiveness of therapy before and after diagnosis were collected., Results: A total of 130 migraine patients were recruited. Of these patients 106 (81.5%) were misdiagnosed as sinusitis. The mean time delay of migraine diagnosis was (7.75 ± 6.29, range 1 to 38 years). Chronic migraine was significantly higher (p < 0.02) in misdiagnosed patients than in patients with proper diagnosis. Medication overuse headache (MOH) was reported only in patients misdiagnosed as sinusitis. The misdiagnosed patients were treated either medically 87.7%, or surgically12.3% without relieve of their symptoms in 84.9% and 76.9% respectively. However, migraine headache improved in 68.9% after proper diagnosis and treatment., Conclusions: Many migraine patients were misdiagnosed as sinusitis. Strict adherence to the diagnostic criteria will prevent the delay in migraine diagnosis and help to prevent chronification of the headache and possible MOH.

Background: Klebsiella pneumoniae outbreaks possessing extended-spectrum β-lactamase- (ESBL) mediated resistance to third-generation cephalosporins have increased significantly in hospital and community settings worldwide. The study objective was to characterize prevalent genetic determinants of TEM, SHV and CTX-M types ESBL activity in K. pneumoniae isolates from Egypt., Methods: Sixty five ESBL-producing K. pneumoniae strains, isolated from nosocomial and community-acquired infections from 10 Egyptian University hospitals (2000-2003), were confirmed with double disc-synergy method and E-test. blaTEM, blaSHV and blaCTX-m genes were identified by PCR and DNA sequencing. Pulsed-field gel electrophoresis (PFGE) was conducted for genotyping., Results: All isolates displayed ceftazidime and cefotaxime resistance. blaTEM and blaSHV genes were detected in 98% of the isolates' genomes, while 11% carried blaCTX-m. DNA sequencing revealed plasmid-borne SHV-12,-5,-2a (17%), CTX-m-15 (11%), and TEM-1 (10%) prevalence. Among SHV-12 (n=8), one isolate displayed 100% blaSHV-12 amino acid identity, while others had various point mutations: T17G (Leu to Arg, position 6 of the enzyme: n=2); A8T and A10G (Tyr and Ile to Phe and Val, positions 3 and 4, respectively: n=4), and; A703G (Lys to Glu 235: n=1). SHV-5 and SHV-2a variants were identified in three isolates: T17G (n=1); A703G and G705A (Ser and Lys to Gly and Glu: n=1); multiple mutations at A8T, A10G, T17G, A703G and G705A (n=1). Remarkably, 57% of community-acquired isolates carried CTX-m-15. PFGE demonstrated four distinct genetic clusters, grouping strains of different genetic backgrounds., Conclusions: This is the first study demonstrating the occurrence of SHV-12, SHV-5 and SHV-2a variants in Egypt, indicating the spread of class A ESBL in K. pneumoniae through different mechanisms.

Background: Shigella flexneri serotype 1c emerged as a critical isolate from children in Egypt and Pakistan. The pattern of antimicrobial susceptibility (AMS) and resistance genes of this serotype have yet to be characterized., Findings: Sixty nine S. flexneri 1c isolates isolates were identified from both Egypt (n-46) and Pakistan (n = 23) and tested for AMS by disk diffusion method and minimal inhibitory concentrations were also determined. Isolates were genotyped by pulsed field gel electrophoresis (PFGE) and five relevant resistance genes (bla(TEM), bla(SHV), bla(OXA), sulI and sulII) were detected by polymerase chain reaction (PCR) and confirmed by DNA sequencing. High resistance was observed in all isolates for ampicillin (AM >96%); trimethoprim-sulphamethoxazole and tetracycline (>88%). Most AM-resistant isolates from Egypt (70%) harbored bla(TEM) resistance, while 52% of isolates from Pakistan expressed bla(OXA). All isolates were closely related by PFGE, irrespective of source or time of collection. The sulII gene was present in 100% of isolates from pediatric cases in Egypt, 65% of Pakistan isolates, and 53% of isolates from older Egyptian patients., Conclusions: While different Shigella serotypes gathered in specific genotypic groups, 1c serotype isolates formed multiple clusters. Although AMS was considerably high to most commonly used drugs, genetic determinants were variable between countries over time. The data stress the need for a more careful selection of antibiotics in the treatment of shigellosis.

Background: Non-invasive screening investigations are rarely used for assessing the activation and progression of the hypothalamic-pituitary gonadal axis through puberty. This study aimed to establish a normal range for urinary gonadotrophins in children progressing through puberty., Methods: Urine samples were collected from 161 healthy school children (76 boys, 85 girls) aged 4-19 yrs. Height and weight were converted to standard deviation score. Pubertal status, classified by Tanner staging, was determined by self-assessment. Urinary gonadotrophins were measured by chemiluminescent microparticle immunoassay. Results were grouped according to pubertal status (pre-pubertal or pubertal)., Results: Of the 161 children, 50 were pre-pubertal (28 boys; 22 girls) and 111 were pubertal (48 boys; 63 girls). Overall, urinary gonadotrophins concentrations increased with pubertal maturation. All pre-pubertal children had a low urinary LH:Creatinine ratio. LH:Creatinine ratios were significantly higher in pubertal compared to pre-pubertal boys (p<0.001). In girls, FSH:Creatinine ratios were significantly higher in the pubertal group (p = 0.006). However, LH:FSH ratios were a more consistent discriminant between pre-pubertal and pubertal states in both sexes (Boys 0.45 pubertal vs 0.1 pre-pubertal; girls 0.23 pubertal vs 0.06 pre-pubertal)., Conclusion: Urinary gonadotrophins analyses could be used as non-invasive integrated measurement of pubertal status which reflects clinical/physical status.