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Objective:To investigate the treatment outcome in terms of the malocclusion features and the changes in the occlusion of patients undergoing orthodontic/orthognathic treatment using the Peer Assessment Rating (PAR) and the Index of Complexity, Outcome and Need (ICON) and to test the application of the Index of Orthognathic Functional Treatment Need (IOFTN) on this sample as a measure of orthognathic pre-treatment need. Design:Retrospective longitudinal cohort study. Setting:The orthodontic department at the Eastman Dental Hospital. Material and methods:The study models of a sample of 100 orthodontic/orthognathic patients who were treated at the Eastman Dental Hospital were measured using the PAR index and ICON at three stages: pre-treatment, pre-surgery and at debond. Treatment need was assessed by measuring IOTN and IOFTN using start study models. Results:99% of the sample showed an improvement in PAR score, with 82% of the sample being greatly improved. ICON showed that 95% of the sample had an improvement of different degrees with 5% being not improved or worse. The IOFTN qualified 97% of the patients for orthognathic treatment when used retrospectively on the sample while the DHC of IOTN qualified the whole sample for orthodontic treatment. Conclusions:Orthodontic/orthognathic treatment showed improved and acceptable overall results. The PAR index and ICON were valid measures to investigate the outcome of orthognathic treatment. IOFTN proved to be a useful tool in determining and prioritizing orthognathic treatment based purely on functional need. [ABSTRACT FROM AUTHOR]

Introduction: Plastic surgery is an essential yet underdeveloped field in many African nations, especially in rural areas. The demand for plastic surgery is increasing, but differences in access to respective services between rural and urban domiciles remain ever existent, despite the exponentiation of trauma, burns, and congenital disorders. According to this review, urban areas have access to better facilities and specialized surgeons, while rural areas frequently lack infrastructure, educated healthcare personnel, and medical resources. This review compares the quality and accessibility of plastic surgery services in African rural and urban settings in order to determine the variables influencing said differences in access., Methods: This literature review was performed using electronic search databases comprising PubMed/MEDLINE, Google Scholar, and Africa Journals online (AJOL). Regional medical journals were also reviewed using keywords and associated Boolean operators pertaining to "plastic surgery", "plastic surgery in rural" and plastic surgery in urban" by selecting studies based on their relevance and content quality. Studies focusing on plastic surgery in Africa were included. A total of 37 articles were analyzed to provide insights into the disparities between rural and urban access to plastic surgery services in Africa. Studies not focusing on plastic surgery were excluded., Results: The review highlighted significant disparities in access to plastic surgery services between Africa's rural and urban areas. Rural areas usually lack medical resources, specialized surgeons, infrastructure, while urban areas have access to better facilities and specialized surgeons. Urban regions not only hail more training opportunities for surgeons but also foster further specialized facilities, greater training options, access to modern surgical equipment, sterile facilities and advanced instruments, contributing to clinical and surgical excellence alongside patient satisfaction and outcomes. However, there is a scarcity of qualified plastic surgeons in rural regions, including antiquated technology and a dearth of resources and expertise. Besides, socioeconomic variables that hinder said indifference between rural and urban areas, such as poverty, education, money, and cultural attitudes, precipitated limited access to critical surgical intervention in rural populations., Conclusion: Further research should be done on how plastic surgery services differ in urban and rural areas. Availability of financial expertise and specialists who can provide specialized care in rural settings is recommended. To enhance patient outcomes, the implementation of technological innovation, improved healthcare infrastructure, and effective training initiatives should be implemented in rural Africa. Also, in the field of plastic surgery, emphasizing the use of telemedicine and mobile surgical units may aid universal healthcare for residents in rural domiciles. Significant progress towards ensuring equitable access to high-quality plastic surgery in rural Africa may be achieved through these initiatives., Competing Interests: Declarations. Ethics approval and consent to participate: Not Applicable. Consent for publication: Not Applicable. All co-authors approved the final manuscript. All co-authors have read and approved the submission. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Motivated by the cellular heterogeneity in complex tissues, particularly in brain and induced pluripotent stem cell (iPSC)-derived brain models, we developed a complete workflow to reproducibly characterize cell types in complex tissues. Our approach combines a flow cytometry (FC) antibody panel with our computational pipeline CelltypeR, enabling dataset aligning, unsupervised clustering optimization, cell type annotating, and statistical comparisons. Applied to human iPSC derived midbrain organoids, it successfully identified the major brain cell types. We performed fluorescence-activated cell sorting of CelltypeR-defined astrocytes, radial glia, and neurons, exploring transcriptional states by single-cell RNA sequencing. Among the sorted neurons, we identified subgroups of dopamine neurons: one reminiscent of substantia nigra cells most vulnerable in Parkinson's disease. Finally, we used our workflow to track cell types across a time course of organoid differentiation. Overall, our adaptable analysis framework provides a generalizable method for reproducibly identifying cell types across FC datasets in complex tissues., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Background: Sepsis is one of the most common causes of multiorgan failure. Sepsis requires the presence of infection with a resultant systemic inflammatory state. Organ dysfunction occurs from the combination of the two processes. Sepsis is the main cause of mortality at intensive care units, with 30-50% mortality rate for all septic episodes. MicroRNA (miRNA) profile data could be beneficial as a specific diagnostic biomarker for sepsis and systemic inflammatory response syndrome (SIRS)., Methods: Expression of miRNAs -122, -181b, -223 and -146a levels were assayed by quantitative real time polymerase chain reaction (qRT-PCR) in a prospective case control study, where forty septic cases were compared to 40 healthy controls of matched age and gender., Results: miRNAs -122 and -181b were significantly upregulated during early septic conditions, indicating that they could be sensitive and specific biomarkers for diagnosing sepsis. miRNA-223 and miRNA-146a could also represent highly specific and sensitive diagnostic biomarkers, as they were found to be significantly down-regulated. Serum levels of miRNA-223 could be used to predict poor prognosis with 70% sensitivity and 75% specificity, whereas the other three miRNAs could not predict prognosis., Conclusion: Our study shows that all tested miRNAs can be used for early detection of sepsis, with miRNA-223 being predictive of mortality, hence preventing multi-organ failure and reducing mortality, and predicting poor outcomes, thereby assisting in early categorization of ICU patients for rapid appropriate treatment and medico legal aspects.

Experiences of childhood trauma (abuse and neglect) are disproportionately higher in those with opioid use disorder (OUD). Childhood trauma may affect the reinforcing and rewarding properties of opioid drugs and responses to pain, potentially via developmental changes to the endogenous opioid system. This has been supported by preclinical research, yet this has not been investigated in non-addicted humans. Physically healthy participants with either a history of severe childhood trauma or no previous history of childhood trauma attended two sessions where they received either an intramuscular active dose of morphine (0.15 mg/kg) or a very low dose control (0.01 mg/kg) in a randomised, double-blind crossover design. Sessions were held 1 week apart. Participants' physical pain threshold and tolerance were measured pre- and post-drug administration using the cold water pressor test, alongside acute subjective and behavioural responses over 2.5 h. The trauma group reported liking the effects of morphine, feeling more euphoric and wanting more of the drug over the session, as well as feeling less nauseous, dizzy, and dislike of the effects of morphine compared to the non-trauma comparison group. Morphine increased pain threshold and tolerance, yet this did not differ between the groups. Childhood trauma may therefore sensitise individuals to the pleasurable and motivational effects of opioids and reduce sensitivity to the negative effects, providing compelling evidence for individual differences in opioid reward sensitivity. This may explain the link between childhood trauma and vulnerability to OUD, with consequent implications on interventions for OUD, the prescribing of opioids, and reducing stigmas surrounding OUD., (© 2021 Society for the Study of Addiction.)

Introduction: The final adult height (FAH) of patients with congenital adrenal hyperplasia (CAH) is often lower than the predicted adult height (PAH) using the Bayley-Pinneau (B&P) method. The aim of the current work was to test the validity of B&P in predicting FAH from a bone age (BA) measurement performed at onset of puberty., Material and Ethods: This was a retrospective longitudinal observational convenience single-centre study. The study included 54 patients (male and female) with classic CAH, whether salt-wasting (SW) or simple virilising (SV), who had reached FAH. The results of auxological measurements and hormonal data around the time of puberty were retrieved from files. Predicted adult height (PAH) was calculated from a BA taken at onset of puberty and compared with FAH., Results: The median PAH SDS at the onset of puberty (-1.5) was significantly greater than the median FAH SDS (-2.2) (p < 0.001). The median target height SDS (-0.8) was significantly higher than the median FAH SDS (-2.2) (p < 0.001). FAH and FAH SDS were significantly worse in females (150.36 ± 7.23; -2.05 ± 1.13) than in their male counterparts (162.86 ± 3.30; -1.53 ± 0.51) (p value < 0.001; 0.048). In patients with good control, there was no difference between PAH SDS (-1.7) and FAH SDS (-1.5) (p value = 0.37). In patients with poor control (over- or under-treated) FAH SDS (-2.1) was significantly lower than PAH SDS (-1.4) (p value < 0.001)., Conclusion: The B&P method was able to accurately predict FAH in children with classic CAH, who were medically well controlled (based on 17-hydroxyprogesterone levels), but overestimated it by a significant 0.7 SD in poorly-controlled patients.

Maternal-infant bonding is an affective maternal-driven process that occurs primarily to her infant. Prophylactic interventions or treatment of disordered bonding include infant massage. Evidence suggests that oxytocin plays an important role in facilitation of mother-infant bonding. Main objective is to assess the effect of infant massage on salivary oxytocin level of mothers and their infant during postpartum period. And to assess the difference of oxytocin level in normal and disordered maternal-infant bonding. This study is a quasi-experimental study, carried out on 37 pairs of mothers and their infants from second to sixth month postpartum, attending Basateen Gharb primary health care center (PHC) in Albasateen district, Cairo, Egypt. Postpartum Bonding Questionnaire (PBQ) was used to differentiate between mothers with normal and disordered bonding. Pre and post massage salivary samples were taken from mothers and their infants. Tappan's technique of infant massage was used. Results showed that 48.6% (N = 18) of mothers had disordered maternal infant bonding. Mothers and infants with normal bonding showed a positive relationship with their salivary oxytocin level post massage. On the other hand, mothers and infants with disordered bonding showed no change in their salivary oxytocin level post massage. Salivary oxytocin level in male infants has decreased post massage, while oxytocin level in female infants has increased post massage in mothers with normal bonding. We concluded that infant massage increases salivary oxytocin level in mothers and infants with normal bonding and it has no effect on salivary oxytocin level of mothers and infants with disordered bonding.

Objectives Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder caused by defects in the CYP21A2 gene. We aimed to determine the prevalence of the most commonly reported mutations among 21-OHD Egyptian patients and correlate genotype with phenotype. Methods Molecular analysis of the CYP21A2 gene was performed for the detection of the six most common point mutations (p.P30L, p.I172N, p.V281L, p.Q318X, the splice site mutation Int2 [IVS2-13A/C>G], and the cluster of three mutations [p.I236N, p.V237E, and p.M239K] designed as CL6). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed on 47 unrelated Egyptian 21α-OH deficiency patients and their available parents to detect the presence of the six most common point mutations. Results Screening for the six most common point mutations in CYP21A2 gene, revealed mutations in 87.2% (82/94) of the studied alleles corresponding to 47 Egyptian patients. The most common mutation among the studied cases was IVS2-13C/A>G that was found to be presented in a frequency of 46.8% (44/94). The genotype/phenotype correlations related to null, A, and B groups were with PPV of 100, 55.5, and 83.3%, respectively. Conclusions The described method diagnosed CAH in 80.8% of the studied patients. Good correlation between genotype and phenotype in salt wasting and simple virilizing forms is determined, whereas little concordance is seen in nonclassical one. Furthermore, studying the carrier frequency of 21-OHD among the normal population is of great importance.

Background Congenital adrenal hyperplasia (CAH) is a chronic disorder causing adrenal insufficiency and hyperandrogenism affecting the quality of life (QOL). The objective of the study was to assess the health-related QOL (HRQOL) in Egyptian children and adolescents with CAH and to identify factors affecting it. Methods This cross-sectional study included 200 CAH patients (with 21-hydroxylase deficiency [21-OHD]) who were assessed according to their age, sex, clinical phenotype, timing of genitoplasty, hospital admissions within the last year, compliance to treatment, regularity of follow-up, presence of complications and hormonal control. HRQOL was assessed using the World Health Organization (WHO)QOL-BREF questionnaire with four domains analyzed independently including physical, psychological, social and environmental domains, with higher scores indicating better QOL. Results The study included 140 females and 60 males with a mean age of 6.6 ± 4.5 years, and 88% were salt-wasting (SW). Older patients had significantly lower QOL scores (r = - 0.151, p = 0.033). The physical domain correlated significantly with the degree of virilization (r = - 0.491, p = 0.001) and frequency of hospitalization (r = - 0.495, p < 0.001). The psychological domain was affected by age (r = - 0.157, p = 0.026) and timing of genitoplasty (r = - 0.326, p = 0.001), while the social domain was affected by age (r = -0.277, p < 0.005) and pubertal stage (r = - 0.195, p = 0.006). Females had lower scores at the psychological domain (p < 0.001), whereas males had lower scores at the physical domain (p = 0.003). Salt-losing patients had lower scores at the physical domain (p = 0.001). Patients with good hormonal control had higher scores at the physical domain (p = 0.03). Genitoplasty affected both psychological and social domains (p = 0.003 and 0.01, respectively). Patients with hypertension and hirsutism had lower QOL scores (p < 0.05). Conclusions HRQOL was relatively more affected in CAH patients with older age, poor hormonal control, high frequency of hospital admissions and those who developed complications.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is widely known for its positive acute effects on social behaviour, such as increasing empathy, whilst also attenuating the negative impact of social exclusion. However there is a scarcity of research that investigates the long-term impact of recreational MDMA use on these fundamental social processes., Method: Sixty-seven individuals were split into three groups based on their drug-use history: poly-drug MDMA users ( n = 25), poly-drug users who do not use MDMA ( n = 19), alcohol-only users ( n = 23), and were tested in an independent groups design. Participants completed both a self-report measure of emotional and cognitive empathy, along with the Multifaceted Empathy Task - a computerised assessment of empathy - and the Cyberball Game - a social exclusion paradigm., Results: MDMA users had significantly greater subjective emotional empathy, and greater cognitive empathy on the computer task compared with the poly-drug users who do not use MDMA. There were no significant differences in subjective responses to social exclusion between the groups. Indices of MDMA use did not correlate with empathy., Conclusions: Long-term MDMA users in this sample exhibited normal psychosocial functioning in regard to empathy and social pain and had higher subjective emotional empathy. This conflicts with previous suggestions that moderate, long-term MDMA use may cause heightened social distress, and is further evidence of the safety of the drug, which is relevant to considerations of its therapeutic use.

In autoimmunity, the balance of different helper T (Th) cell subsets can influence the tissue damage caused by autoreactive T cells. Pro-inflammatory Th1 and Th17 T cells are implicated as mediators of several human autoimmune conditions such as multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (aHSCT) has been tested in phase 2 clinical trials for MS patients with aggressive disease. Abrogation of new clinical relapses and brain lesions can be seen after ablative aHSCT, accompanied by significant reductions in Th17, but not Th1, cell populations and activity. The cause of this selective decrease in Th17 cell responses following ablative aHSCT is not completely understood. We identified an increase in the kinetics of natural killer (NK) cell reconstitution, relative to CD4 + T cells, in MS patients post-aHSCT, resulting in an increased NK cell:CD4 + T cell ratio that correlated with the degree of decrease in Th17 responses. Ex vivo removal of NK cells from post-aHSCT peripheral blood mononuclear cells resulted in higher Th17 cell responses, indicating that NK cells can regulate Th17 activity. NK cells were also found to be cytotoxic to memory Th17 cells, and this toxicity is mediated through NKG2D-dependent necrosis. Surprisingly, NK cells induced memory T cells to secrete more IL-17A. This was preceded by an early rise in T cell expression of RORC and IL17A mRNA, and could be blocked with neutralizing antibodies against CD58, a costimulatory receptor expressed on NK cells. Thus, NK cells provide initial co-stimulation that supports the induction of a Th17 response, followed by NKG2D-dependent cytotoxicity that limits these cells. Together these data suggest that rapid reconstitution of NK cells following aHSCT contribute to the suppression of the re-emergence of Th17 cells. This highlights the importance of NK cells in shaping the reconstituting immune system following aHSCT in MS patients.

Background: The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated., Methods: We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells., Results: Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease., Conclusions: Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.

Vitamin D is a secosteroid hormone that plays an important regulatory role in calcium homeostasis and bone metabolism. Immune cells can both produce and respond to 1,25(OH)2D3. CD4+ T cells from vitamin D receptor (VDR) KO mice produce higher levels of IFN-γ and IL-17 than their wild type counterparts, and play a crucial role in the pathogenesis of autoimmune diseases (AID). We are particularly interested in studying the effect of vitamin D on pathogenic Th17 cells in humans. We investigated the in vitro effect of 1,25(OH)2D3 and 25(OH)D3 on the differentiation and cytokine production of primary CD4+ T cells from normal donors, and cultured in Th17 polarizing conditions. Both forms of vitamin D reduced the expression of pathogenic Th17 markers and their secretion of pro-inflammatory cytokines (IL-17A, IFN-γ). Furthermore, both vitamin D forms induced an expansion of CD25hi cells and upregulated their expression of CTLA-4 and Foxp3 regulatory markers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is one of the leading causes of death and disabilities worldwide. It affects approximately 1.5 million people each year and is associated with severe post-TBI symptoms such as sensory and motor deficits. Several neuro-therapeutic approaches ranging from cell therapy interventions such as the use of neural stem cells (NSCs) to drug-based therapies have been proposed for TBI management. Successful cell-based therapies are tightly dependent on reproducible preclinical animal models to ensure safety and optimal therapeutic benefits. In this chapter, we describe the isolation of NSCs from neonatal mouse brain using the neurosphere assay in culture. Subsequently, dissociated neurosphere-derived cells are used for transplantation into the ipsilateral cortex of a controlled cortical impact (CCI) TBI model in C57BL/6 mice. Following intra-cardiac perfusion and brain removal, the success of NSC transplantation is then evaluated using immunofluorescence in order to assess neurogenesis along with gliosis in the ipsilateral coronal brain sections. Behavioral tests including rotarod and pole climbing are conducted to evaluate the motor activity post-treatment intervention.

Multiple sclerosis (MS) is an inflammatory demyelination of the central nervous system. We investigated the prevalence of EBV seropositivity and other known risk factors for MS (age, smoking, low vitamin D) and their effect on anti-EBV antibody titers. We retrospectively studied 249 MS patients receiving care at the American University of Beirut Medical Center and 230 controls, during 2010-2014. EBV seropositivity was higher in MS patients compared to controls for both anti-VCA (99.5%; 97.2%) and anti-EBNA-1 (96.3%; 89.4%), and the titers were significantly higher in MS patients. MS patients had a significantly lower vitamin D level (15.5 ± 8.3 ng/ml) compared to controls (20.4 ± 11.3 ng/ml). The proportion of heavy smokers and overweight individuals was significantly higher in MS patients. Lebanese MS patients have risk factors similar to those in western countries. Older age and female gender were associated with a higher anti-VCA titer and male gender with a higher anti-EBNA-1., (Copyright © 2015. Published by Elsevier Inc.)

Background: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. It leads to progressive deterioration in cardiac and skeletal muscles. Corticosteroids are considered an effective therapy., Objective: This study aimed to evaluate the role of short-term prednisone therapy in improving left ventricular (LV) systolic function, LV mass (LVM), and motor power in cases of muscular dystrophies., Patients and Methods: Twenty-five cases of muscular dystrophy including 17 cases of DMD, 3 cases of Becker muscular dystrophies, and 5 cases of female patients with DMD-like phenotype were included in the study. The diagnosis of 12 patients was confirmed by muscle biopsy with immunohistochemistry; the patients were subjected to motor assessment, measurement of creatine kinase level, and echocardiographic examination before and after prednisone therapy. Transthoracic echocardiographic assessment of the LV systolic function (fractional shortening) was done. Myocardial performance index and LVM were calculated. Intermittent dosage of prednisone was administered 5 mg/kg per day on 2 consecutive days weekly for 3 months., Results: Fractional shortening improved on prednisone therapy (P = 0.009) and LVM increased (P = 0.012); improvement in walking was detected in 77% of the patients, climbing stairs improved in 88.9%, Gower sign improved in 70%, and rising from chair improved in 60%. Prednisone had no effect on the patients with marked motor impairment (on wheelchair). The creatine kinase level was significantly lower after steroid therapy (P = 0.04)., Conclusions: Three months of intermittent prednisone therapy could improve cardiac and skeletal muscle function in congenital muscular dystrophy.

Unlabelled: Cryptorchidism is one of the most common genital malformations in newborn males, but its etiology remains largely unknown. The observation of geographical variability in the prevalence of cryptorchidism suggests a role for environmental factors. The aim of this study was to determine the prevalence of this condition among Egyptian neonates., Methods: The initial study population comprised 1000 neonates recruited from El Galaa maternity teaching hospital. To determine the risk factors for cryptorchidism in Egypt, 40 healthy full term infants were selected randomly during the same time period as a control group., Results: Twenty-nine cases of cryptorchidism per 1000 newborn males were detected, i.e. a frequency of 2.9%; 10 (34.5%) had bilateral cryptorchidism while 19 (65.5%) had a unilateral lesion. Other congenital anomalies were detected in 5 (17.2%) of the cryptorchid newborns. Five factors were significantly associated with higher risk of cryptorchidism: gestational age of 37 weeks or less, birth weight equal to or less than 2.75 kg, cesarean delivery, steroid therapy and twin pregnancy. Using logistic regression, birth weight ≤ 2.75 kg was the only independent factor predicting cryptorchidism, with an odds ratio of 10.3 and 95% confidence interval of 2.9-36.4., Conclusion: These results highlight low birth weight as the cardinal risk factor for cryptorchidism. A larger scale multi-centric study is needed to clearly identify all the risk factors for cryptorchidism in Egyptian neonates., (Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the predictors of growth response to growth hormone treatment in a group of isolated idiopathic growth hormone (GH)., Patients and Methods: 477 GH deficient (GHD) children with GH therapy were included in the study. Patients were followed up for a minimum of 1 year and up to 6 years. Multiple linear regressions were performed to identify predictors of growth response to rhGH in the first 4 years of treatment., Results: In the first year, three significant predictors of growth were identified: GH peak [ln (ug/L)], age of onset of therapy and target height-height SDS. In the second and third years of therapy, growth velocity (GV) was both significantly and positively correlated to the GV (cm/year) of the previous year., Conclusion: Prediction models offer a valuable tool for individualization and assuring adherence to rhGH and thus a cost effective treatment, which is the ultimate goal of GH therapy.

Objective: To study antibody-independent contributions of B cells to inflammatory disease activity, and the immune consequences of B-cell depletion with rituximab, in patients with multiple sclerosis (MS)., Methods: B-Cell effector-cytokine responses were compared between MS patients and matched controls using a 3-signal model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 T-cell responses in MS patients were assessed both ex vivo and in vivo, together with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical trials in relapsing-remitting MS., Results: B Cells of MS patients exhibited aberrant proinflammatory cytokine responses, including increased lymphotoxin (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor (TNF)-alpha secretion, when activated in the context of the pathogen-associated TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-gamma, respectively. B-Cell depletion, both ex vivo and in vivo, resulted in significantly diminished proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble products from activated B cells of untreated MS patients reconstituted the diminished T-cell responses observed following in vivo B-cell depletion in the same patients, and this effect appeared to be largely mediated by B-cell LT and TNFalpha., Interpretation: We propose that episodic triggering of abnormal B-cell cytokine responses mediates 'bystander activation' of disease-relevant proinflammatory T cells, resulting in new relapsing MS disease activity. Our findings point to a plausible mechanism for the long-recognized association between infections and new MS relapses, and provide novel insights into B-cell roles in both health and disease, and into mechanisms contributing to therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.

Objective: To investigate the prevalence of thyroid dysfunction and autoimmunity in type 2 diabetic patients., Methods: The study was conducted at the National Center for Diabetes, Endocrinology and Genetics, Jordan University Hospital, Amman, Jordan, between March 2000 and September 2000. A group of 908 type 2 diabetic patients (T2DM) were recruited in the study and underwent investigations for thyroid functions; free thyroxine (FT4), free tri-iodothyronine (FT3) and thyroid stimulating hormone (TSH). Six hundred had performed thyroid autoantibodies, thyroid peroxidase antibodies (TPOab) or antimicrosomal antibodies (AMA) and thyroglobulin antibodies (Tgab). They were compared with 304 non-diabetics, of those 282 had performed thyroid antibodies., Results: Fifty-three (5.9%) of diabetic patients were known to have thyroid disease. As a direct result of screening, new thyroid disease cases were diagnosed in 6.6% of the patients. Thus, the overall prevalence of thyroid disease was found to be 12.5%. The most common was subclinical hypothyroidism (4.1%). In the control group, the prevalence of thyroid disease was 6.6%. The most common was subclinical hypothyroidism (5%). There was a significant difference between diabetics and control subjects p=0.0064. Positive TPOab was found in 8.3% of T2DM patients (N=600) versus 10.3% in the control group (N=282) p=0.412. Positivity for both TPOab and Tgab was found to be 2.5% of T2DM versus 6% of the control subjects p=0.0155., Conclusion: This study suggests that diabetic patients should be screened for asymptomatic thyroid dysfunction.

Infections with herpes simplex virus type 1 (HSV-1) in humans and in animal models are accompanied by enhanced natural killer (NK) activity. In vitro, HSV-1 also enhances the NK activity of human peripheral blood mononuclear cells (PBMC). The molecular basis of this enhanced NK activity, however, is not well characterized. We investigated the role of human interleukin-15 (IL-15) in this phenomenon and report here that HSV-1-mediated enhanced NK activity was abrogated by neutralizing antibodies for IL-15 but not for other cytokines (i.e., IL-2, IL-12, gamma interferon [IFN-gamma], tumor necrosis factor alpha, or IFN-alpha). Anti-CD122 antibodies which block signaling through IL-2 receptor beta chain, and therefore neutralize the effects of IL-15 (and IL-2), also abrogated this enhancement. Furthermore, HSV-1 increased the levels of IL-15 mRNA and the production of IL-15 in HSV-1-infected PBMC cultures. The neutralization of IL-15 in cocultures of PBMC with HSV-1-infected cells significantly increased HSV-1 production. These results strongly suggest a role for IL-15 in the HSV-1-mediated in vitro enhancement of NK activity and in the PBMC-mediated suppression of HSV-1 replication.

IL-15 is a recently identified cytokine that belongs to the four alpha-helix bundle cytokine family and possesses biological activities similar to those of IL-2. Its ability to induce effectors of NK activity suggests its involvement in innate immunity. In this study, we analyzed the effect of different viruses (HSV, EBV, respiratory syncitial virus, vesicular stomatitis virus, influenza virus, reovirus, and Sendai virus) on the up-regulation of NK activity in vitro. Exposure of human PBMC to the these viruses resulted in an immediate up-regulation of NK activity of PBMC via IL-15 induction; this effect was abrogated in the presence of mAbs to IL-15. Results of experiments conducted in parallel using mAbs to IL-15, as well as to other cytokines (IL-2, IL-12, IFN-gamma, and TNF-alpha), clearly indicated that IL-15 was specifically responsible for the observed effect. Furthermore, supernatants of virus-infected PBMC cultures significantly enhanced NK activity of uninfected PBMC in vitro. An increase of IL-15 protein levels 20 h postinfection was also confirmed in a bioassay using the IL-2-dependent cell line CTLL. Kinetic analysis of IL-15 mRNA expression using a semiquantitative RT-PCR revealed that the level of IL-15 messages peaked at different time points (up to 12 h) postinfection, depending on the nature of the virus. Taken together, these results suggest that the IL-15 response of the host to viral infection and the subsequent NK cell activation represent an important effector mechanism of the innate immune surveillance of the host against viral infections.

We studied two of the three patients with a hereditary defect in the biosynthesis of aldosterone originally described by Visser and Cost in 1964. All three presented as newborns with salt-losing syndrome and failure to thrive. The original biochemical studies showed a defect in the 18-hydroxylation of corticosterone. According to the nomenclature proposed by Ulick, this defect would be termed corticosterone methyl oxidase deficiency type I. We measured plasma steroids in the untreated adult patients and performed molecular genetic studies. Aldosterone and 18-OH-corticosterone were decreased, whereas corticosterone and 11-deoxycorticosterone were elevated, thus confirming the diagnosis of corticosterone methyl oxidase deficiency type I. Cortisol and its precursors were in the normal range. Genetic defects in the gene CYP11B2 encoding aldosterone synthase (P450c11Aldo) have been described in a few cases. We identified a homozygous single base exchange (G to T) in codon 255 (GAG) causing a premature stop codon E255X (TAG). This mutation destroys a Aoc II restriction site. Digestion of a PCR fragment containing exon 4 of CYP11B2 (261 bp) with this restriction enzyme revealed in the two patients homozygous for the E255X mutation only a 261-bp fragment, whereas the heterozygous parents had three fragments (261 bp from the mutant allele and 194 and 67 bp from the wild-type allele). The mutant enzyme had lost the five terminal exons containing the heme binding site, and thus there was a loss of function enzyme. We conclude that the biochemical phenotype of these prismatic cases of congenital hypoaldosteronism can be explained by the patients genotype.