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To present the details of Bacillus Calmette-Guérin (BCG)-vaccine associated complications (VACs) in combined immunodeficiencies (CID) patients.Five centers participated in this retrospective study and completed a data form, which included general patients' information, clinical and laboratory data.Among 236 CID patients, 127 were BCG vaccinated. 41.9% of patients with family history of CID and 17.1% who were diagnosed by screening were BCG vaccinated. Twenty-three patients (18.1%) developed BCG-VACs. The median age of VACs was 6 months and the median time from vaccination to complications was 6 months. The highest rate of BCG-VACs was recorded in patients receiving the Russian BCG strain compared to the Tokyo and Danish strains. Univariate analysis of T-lymphocyte subsets showed increased odds of BCG complications in patients with CD3+, CD4+, and CD8+ counts of ≤250 cells/µL. Only CD8 + count ≤250 cells/µL had increased such odds on multivariate analysis. VACs were disseminated in 13 and localized in 10 patients. Localized complication occurred earlier after vaccination (median: 4 months) compared with disseminated ones (median: 7 months). There were no significant associations between sex, administered vaccine strain, serum immunoglobulins levels, lymphocyte subsets counts, and the chance of having either localized or disseminated BCG-related complications.Although contraindicated, many patients with CID continue to be vaccinated with BCG. Low CD8 + count is a risk factor for BCG-related complications and localized complications occurred earlier than disseminated ones. Considerations should be undertaken by health care authorities especially in countries with high incidence of CID to implement newborn screening, delay the time of BCG vaccine administration beyond 6 months of age and to use the relatively safer strains like the Danish and Tokyo ones.

Background. The Bacillus Calmette–Guérin (BCG) and rotavirus vaccines are live-attenuated preparations. In the United Arab Emirates, these products are universally administered to the young infants. This unguided practice does not account for the children with immunodeficiency, which frequently manifests after the administration of these vaccines. We present here a young infant with immunodeficiency that developed disseminated tuberculosis infection and severe diarrhea due to these improper immunizations. Case Presentation. This young infant was diagnosed at six months of age with “immunodeficiency type 19” (MIM#615617) due to homozygous nonsense variant, NM_000732.4 (CD3D):c.128G > A, p.Trp43∗ (variation ClinVar#VCV000643120.1; pathogenic). This variant creates premature stop-gain in CD3D (CD3 antigen, delta subunit, autosomal recessive; MIM#186790), resulting in loss-of-function. He also had “X-linked agammaglobulinemia” (MIM#300755) due to hemizygous missense variant, NM_001287344.1 (BTK):c.80G > A, p.Gly27Asp (novel). He had a sibling who passed away in infancy of unknown disease and family members with autoimmune disorders. Despite these clear clues, he was immunized with BCG at birth and rotavirus at 2 and 4 months. He was well in the first four months. He then developed high-fever, lymphadenopathy, and refractory diarrhea. Stool was positive for rotavirus, and lymph node biopsy showed acid-fast bacilli, consistent with tuberculosis lymphadenitis. These infections were serious and markedly complicated his clinical course, which included bone marrow transplantation from a matched sibling. Conclusions. These unfortunate events could have been avoided by compiling the available clinical information. This patient underscores the importance of implementing proper policies for BCG and rotavirus vaccinations. International registries of adverse events of universally administered vaccines are crucial.

Background Overdose of paracetamol affects liver cells leading to cell death. This is done through hepatic necrosis, which is characterized by a rupture of the plasma membrane. A variety of investigations has been conducted using herbal extracts to assess liver toxicity induced by paracetamol. Here we examined herbal plant species, Acridocarpus orientalis (A. orientalis), ethanolic extract to study its potential to protect against hepatotoxicity in mice. Serum alanine transaminase (ALT), aspartate transaminase (AST) and reduced glutathione (GSH) enzymes were estimated for all mice groups. A phytochemical screening was also conducted. Results Phytochemical screening showed that A. orientalis contains flavonoids, tannins, carbohydrates and phenolics derivatives. A. orientalis pretreatment showed significant reduction of liver marker enzymes ALT and AST in almost all concentrations. Furthermore, serum GSH levels were significantly increased in A. orientalis pretreated mice groups. In addition, a reduction in liver weights in pretreated mice with A. orientalis showed significant weight loss at dose 250 mg/kg BW (P A. orientalis pretreated mice. Conclusion pretreatment with A. orientalis protects mice against heplatotoxic adverse effects of paracetamol as indicated by reduction of serum ALT and AST enzymes, with elevation of GSH antioxidant protective enzyme, which may have contributed to the main hepatoprotective action of A. orientalis.

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD., Alborz University of Medical Sciences, This work was supported by the vice chancellor for research, Alborz University of Medical Sciences.

Fermitin family homolog 3 (FERMT3), alternatively kindlin-3 (KIND3), is an integrin binding protein (of 667 residues) encoded by the FERMT3 gene. The molecule is essential for activating integrin αIIbβ3 (the fibrinogen receptor) on platelets and for the integrin-mediated hematopoietic cell (including platelets, T lymphocytes, B lymphocytes, and granulocytes) adhesion. Its defects are associated with impaired primary hemostasis, described as “Glanzmann's thrombasthenia (MIM#273800)-like bleeding problem.” The defects are also associated with infections, designated as “LAD1 (leukocyte adhesion deficiency, type I; MIM#116920)-like immune deficiency.” The entity that joins the impaired primary hemostasis with the leukocyte malfunction has been termed “leukocyte adhesion deficiency, type III” (LAD3, autosomal recessive, MIM#612840), representing a defective activation of the integrins β1, β2, and β3 on leukocytes and platelets. Here, we report a male toddler with novel compound heterozygous variants, NM_178443.2(FERMT3):c.1800G>A, p.Trp600* (a non-sense variant) and NM_178443.2(FERMT3):c.2001del p.*668Glufs*106 (a non-stop variant). His umbilical cord separated at about 3 weeks of age. A skin rash (mainly petechiae and purpura) and recurrent episodes of severe epistaxis required blood transfusions in early infancy. His hemostatic work-up was remarkable for a normal platelet count, but abnormal platelet function screen with markedly prolonged collagen-epinephrine and collagen-ADP closure times. The impaired platelet function was associated with reduced platelet aggregation with all agonists. The expression of platelet receptors was normal. Other remarkable findings were persistent lymphocytosis and granulocytosis, representing defects in diapedesis due to the integrin dysfunction. The natural history of his condition, structure and sequence analysis of the variations, and comparison with other LAD3 cases reported in the literature are presented.

Background This study aimed to develop an expert consensus regarding the epidemiology, diagnosis, and management of cow’s milk protein allergy (CMPA) in the Middle East. Methods A three-step modified Delphi method was utilized to develop the consensus. Fifteen specialized pediatricians participated in the development of this consensus. Each statement was considered a consensus if it achieved an agreement level of ≥ 80%. Results The experts agreed that the double-blind placebo-controlled oral challenge test (OCT) should be performed for 2–4 weeks using an amino acid formula (AAF) in formula-fed infants or children with suspected CMPA. Formula-fed infants with confirmed CMPA should be offered a therapeutic formula. The panel stated that an extensively hydrolyzed formula (eHF) is indicated in the absence of red flag signs. At the same time, the AAF is offered for infants with red flag signs, such as severe anaphylactic reactions. The panel agreed that infants on an eHF with resolved symptoms within 2–4 weeks should continue the eHF with particular attention to the growth and nutritional status. On the other hand, an AAF should be considered for infants with persistent symptoms; the AAF should be continued if the symptoms resolve within 2–4 weeks, with particular attention to the growth and nutritional status. In cases with no symptomatic improvements after the introduction of an AAF, other measures should be followed. The panel developed a management algorithm, which achieved an agreement level of 90.9%. Conclusion This consensus document combined the best available evidence and clinical experience to optimize the management of CMPA in the Middle East.

Clinical, genetic, and laboratory characteristics of Middle Eastern patients with multisystem inflammatory syndrome in children (MIS-C) have not yet been documented.To assess the genetic and clinical characteristics of patients with MIS-C of primarily Arab and Asian origin.A prospective, multicenter cohort study was conducted from September 1, 2020, to August 31, 2021, in the United Arab Emirates and Jordan. Forty-five patients with MIS-C and a matched control group of 25 healthy children with a confirmed SARS-CoV-2 infection status were recruited. Whole exome sequencing in all 70 participants was performed to identify rare, likely deleterious variants in patients with MIS-C and to correlate genetic findings with the clinical course of illness.SARS-CoV-2.Fever, organ system complications, laboratory biomarkers, whole exome sequencing findings, treatments, and clinical outcomes were measured. The Mann-Whitney U test was used to assess the association between genetic variants and MIS-C attributes. The Fisher exact test was used to compute the genetic burden in MIS-C relative to controls.A total of 45 patients with MIS-C (23 [51.1%] male; 30 [66.7%] of Middle Eastern origin; mean [SD] age, 6.7 [3.6] years) and 25 controls (17 [68.0%] male; 24 [96.0%] of Middle Eastern origin; mean [SD] age 7.4 [4.0] years) participated in the study. Key inflammatory markers were significantly dysregulated in all patients with MIS-C. Mucocutaneous and gastrointestinal manifestations were each reported in 36 patients (80.0%; 95% CI, 66.1%-89.1%), cardiac findings were reported in 22 (48.9%; 95% CI, 35.0%-63.0%), and neurologic findings were reported in 14 (31.1%; 95% CI, 19.5%-45.6%). Rare, likely deleterious heterozygous variants in immune-related genes, including TLR3, TLR6, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%; 95% CI, 29.0%-56.7%), of whom 7 had multiple variants. There was higher enrichment of genetic variants in patients relative to controls (29 vs 3, P .001). Patients with those variants tended to have earlier disease onset (7 patients [36.8%; 95% CI, 19.1%-58.9%] with genetic findings vs 2 [7.7%; 95% CI, 2.1%-24.1%] without genetic findings were younger than 3 years at onset) and resistance to treatment (8 patients [42.1%; 95% CI, 23.1%-63.7%] with genetic findings vs 3 patients [11.5%; 95% CI, 4.0%-29.0%] without genetic findings received 2 doses of intravenous immunoglobulin).The results of this cohort study suggest that rare, likely deleterious genetic variants may contribute to MIS-C disease. This finding paves the way for additional studies with larger, diverse populations to fully characterize the genetic contribution to this new disease entity.

Objectives Inborn errors of immunity (IEI) are prevalent in tribal cultures due to frequent consanguineous marriages. Many of these disorders are autosomal recessive, resulting from founder mutations; hence they are amenable to prevention. The primary objective of this study was to evaluate the pathogenicity of novel variants of IEI found among Emiratis. Methods This retrospective data collection study reports novel variants of IEI detected by diagnostic exome sequencing. Pathogenicity prediction was based on scoring tools, amino acid alignment, and Jensen–Shannon divergence values. Results Twenty-one novel variants were identified; nine were frameshift, three nonsense, four intronic (one pathogenic), and five missense (two pathogenic). Fifteen variants were likely pathogenic, of which 13 were autosomal recessive and two uncertain inheritance. Their clinical spectra included combined immunodeficiency, antibody deficiency, immune dysregulation, defects in intrinsic/innate immunity, and bone marrow failure. Conclusion The described novel pathogenic variants are core to a planned national screening program that aims toward IEI prevention. Future studies, however, are needed to confirm their natural history in individual patients and estimate their prevalence in the community.

Background Little is known about the etiology of childhood diarrhea in the United Arab Emirates (UAE) especially after the introduction of rotavirus vaccines. This study aimed to identify gastrointestinal pathogens in children with diarrhea (cases) and the carriage rate of these pathogens in asymptomatic children (controls). Methods Stool samples were collected from 203 cases and 73 controls who presented to two major hospitals in Al Ain city, UAE. Samples were analyzed with Allplex™ Gastrointestinal Full Panel Assay for common entero-pathogens. The association between diarrhea and the isolated pathogens was calculated in a multivariate logistic regression model. The adjusted attributable fractions (aAFs) were calculated for all pathogens significantly associated with cases. Results At least one pathogen was identified in 87 samples (42.8%) from cases and 17 (23.3%) from controls (P Conclusions Multiplex PCR revealed high positivity rates in both cases and controls which demand a cautious interpretation. Rotavirus remains the main childhood diarrhea pathogen in UAE. Effective strategies are needed to better control rotavirus and other causative pathogens.

Phosphorescence O2 analyzer was used to measure calvarial bone cellular respiration (cellular mitochondrial O2 consumption) in Taylor Outbred mice in the presence and absence of zoledronic acid. This potent bisphosphonate inhibits osteoclast-mediated calcium resorption, and its effects on bone respiration have not been previously investigated. The change of O2 concentration with time was measured in closed vials containing phosphate-buffered saline (PBS), 5 mM glucose and 5–25 mg calvarial bone fragments, and it was complex for t = 0–30 h. Cyanide (specific inhibitor of cytochrome oxidase) halted O2 consumption, confirming the oxidation occurred in the respiratory chain. Initial rate of respiration was estimated from the zero-order plots d[O2]/dt for t = 0–4 h. For untreated specimens, the rate (mean ± SD) was 2.0 ± 1.2 µM O2 h−1 mg−1 (n = 6). This value was 7–10 times lower than that of other murine organs, but similar to that reported for rat and Guinea pig calvaria (averaging, 2.7 nmol O2 h−1 mg−1). The corresponding rate in the presence of 10–100 µM zoledronic acid was 2.7 ± 0.7 µM O2 h−1 mg−1 (n = 11), p = 0.216. The first-order plots ln ([O2] t ÷ [O2] t=0) versus time for t = 0–30 h were also used to compare treated and untreated specimens. The rate (h−1 mg−1 103) for specimens incubated in PBS without glucose was 1.3 ± 0.6 (n = 3, p = 0.007), in PBS + glucose it was 10.7 ± 6.9 (n = 10), in PBS + glucose + 10 µM zoledronic acid it was 12.1 ± 6.7 (n = 10, p = 0.579), in PBS + glucose + 20 µM zoledronic acid it was 12.9 ± 3.3 (n = 9, p = 0.356), and in PBS + glucose + 100 µM zoledronic acid it was 13.7 ± 7.7 (n = 9, p = 0.447). Thus, exposure to high-doses of zoledronic acid over several hours imposed a statistically insignificant increase in calvarial bone cellular respiration.

Background The Bacillus Calmette-Guérin (BCG) preparations are live-attenuated derivatives of Mycobacterium bovis. These products are used to vaccinate infants at birth, a practice that may result in a disseminated infection in those patients who have an unidentified immunodeficiency. Case presentation Patients who were immunized at birth with BCG and who developed a disseminated infection are reported here to emphasize the importance of taking an extensive medical history before ‎giving the BCG vaccine. Patient 1 has a sibling who had familial hemophagocytic lymphohistiocytosis. Patient 2 has a severe immunodeficiency with profound lymphopenia. Patient 3 has a sibling who had a disseminated BCG infection. Patient 4 has two siblings with an immunodeficiency disorder; one sibling passed away in infancy and one is receiving regular immunoglobulin infusions. Patient 5 has profound lymphopenia and his brother had cytomegalovirus (CMV) pneumonitis and passed away in infancy. Conclusions These unfortunate events could have been avoided by compiling the relevant clinical and laboratory information. These cases also underscore the importance of a strict adherence to the BCG vaccine policies. Local and international registries that estimate the birth prevalence of primary immune deficiencies are needed prior to implementing universal BCG vaccination administration.

Anaphylactic shock (AS) is a life-threatening, multisystem disorder arising from sudden release of mast cell- and basophil-derived mediators into the circulation. In this study, we have used a Wistar rat model to investigate AS-associated histopathologic changes in various organs. Rats were sensitized with ovalbumin (1 mg s.c), and AS was induced by intravenous injection of ovalbumin (1 mg). Experimental groups included nonallergic rats (n = 6) and allergic rats (n = 6). Heart rate and blood pressure were monitored during one hour. Organs were harvested at the end of the experiment and prepared for histologic and immunohistochemical studies. Lung, small bowel mucosa and spleen were found to undergo heavy infiltration by mast cells and eosinophils, with less prominent mast cell infiltration of cardiac tissue. The mast cells in lung, small bowel and spleen exhibited increased expression of tryptase, c-kit and induced nitric oxide synthase (iNOS). Increased expression of endothelial nitric oxide synthase (eNOS) by vascular endothelial cells was noted principally in lung, heart and small bowel wall. The Wistar rat model of AS exhibited accumulation of mast cells and eosinophils in the lung, small bowel, and spleen to a greater extent than in the heart. We conclude that lung and gut are principal inflammatory targets in AS, and likely contribute to the severe hypotension of AS. Targeting nitric oxide (NO) production may help reduce AS mortality.

A cross-over study was conducted in 16 healthy adult volunteers to describe the urinary excretion of polyphenols from date seeds and investigate the antioxidant effect after consumption of different doses of date seeds powder (DSP), bread (DSB) and extract (DSE). After 12 h of fasting, one of the six treatments (0.25 g and 0.5 g/kg bodyweight DSP, 360 g of 10% and 15% DSB, 30 mg and 60 mg/kg bodyweight DSE) was provided along with breakfast, with a two weeks wash-out period between 2 consecutive treatments. Blood was drawn at baseline, 1, 2, 8 and 24 h post intake. Urine was collected at baseline, 3, 8, and 24 h post intake. An abundant release of polyphenols was detected in urine within the 0–3 h post intake, reached a peak at 8 h, then decreased with polyphenols still being detected up to 24 h post intake. The antioxidant defence system, as measured by reduced glutathione (GSH), was strengthened as soon as 1 h and up to 8 h post intake. Markers of protein and lipid oxidative damages were reduced from 1 h and up to 8 and 24 h post intake, respectively. This supports an antioxidant effect of date seeds products in humans, most probably due to their polyphenols., This project was funded by the Zayed Center-Based research grant 2013, United Arab Emirates University (Fund 31 R023-Research Center- ZCHS -9-2013).

Anaphylactic shock is associated with severe hypotension. Potassium channel blockers, such as 4-aminopyridine, induce vasoconstriction. The objective of this study was to test the ability of 4-aminopyridine to restore blood pressure and increase survival in anaphylactic shock.Experimental study.Physiology laboratory.Adult male Wistar rats.Rats were sensitized with ovalbumin (1 mg SC), and anaphylactic shock was induced by IV injection of ovalbumin (1 mg). Experimental groups included non-allergic rats (NA) (n = 6); allergic rats (Controls) (n = 6); allergic rats treated with 4-aminopyridine (4-aminopyridine) (1 mg/kg) (n = 6); and allergic rats treated with epinephrine (EPI) (10 µg/kg) (n = 6). Treatments were administered 1 minute after induction of anaphylactic shock.Mean arterial blood pressure, heart rate, and survival were measured for 60 minutes. Plasma levels of histamine, leukotriene B4, prostaglandin E2, prostaglandin F2, pH, and HCO3 were measured. Mean arterial blood pressure was normal in the NA group; severe hypotension and high mortality were observed in controls; normalization of mean arterial blood pressure, heart rate, and increased survival were observed in 4-aminopyridine and EPI groups. All allergic 4-aminopyridine-treated rats survived after the induction of anaphylactic shock. Histamine level was higher in controls and the 4-aminopyridine group but reduced in the EPI group. Prostaglandin E2 increased in controls and EPI group and decreased in 4-aminopyridine group; prostaglandin F2 increased in controls but decreased in 4-aminopyridine and EPI groups. Leukotriene B4 decreased in 4-aminopyridine and EPI groups. Metabolic acidosis was prevented in the 4-aminopyridine group.Our data suggest that voltage-dependent K+ channel inhibition with 4-aminopyridine treatment restores blood pressure and increases survival in the Wistar rat model of anaphylactic shock. 4-aminopyridine or related voltage-dependent K channel blockers could be a useful additional therapeutic approach to treatment of refractory anaphylactic shock.

The polyphenolic content in date seeds, a promising functional ingredient for food, was characterised in three forms viz., date seed powder (DSP), date seed pita bread (DSB) and date seed extract (DSE). Bioaccessibility of the polyphenols from the samples was assessed by in-vitro digestion coupled with transport using Caco-2 cells. HPLC-ESI-UV/MS/MS-(IT) analysis recorded the presence of phenolic acids, flavanols, flavonols and flavones. Flavan-3-ols was the most significant group with the highest concentration in DSP, 47.91 ± 0.13 g/kg, after depolymerisation. Phenolic acids such as protocatechuic acid, vanillic acid and caffeoylshikimic acid were recovered from DSP and DSE after in-vitro digestion. In comparison, the recovery was significantly lower in the bread sample. Similarly, transport of protocatechuic acid, p-hydroxybenzoic acid, caffeoylshikimic acid, p-coumaric acid, syringic acid hexoside and diosmin through Caco-2 monolayer was observed in DSP and DSE, while protocatechuic acid and p-hydroxybenzoic acid were the only polyphenols transported from digested DSB.

Objectives: Aflatoxin B 1 (AFB 1 ) is a naturally occurring carcinogenic and immunosuppressive compound. This study was designed to measure its toxic effects on human peripheral blood mononuclear cells (PBMC). Methods: The study recruited 7 healthy volunteers. PBMC were isolated and cellular respiration was monitored using a phosphorescence oxygen analyser. The intracellular caspase activity was measured by the caspase-3 substrate N-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin. Phosphatidylserine exposure and membrane permeability to propidium iodide (PI) were measured by flow cytometry. Results: Cellular oxygen consumption was inhibited by 2.5 μM and 25 μM of AFB1. Intracellular caspase activity was noted after two hours of incubation with 100 μM of AFB1. The number of Annexin V-positive cells increased as a function of AFB 1 concentration and incubation time. At 50 μM, a significant number of cells became necrotic after 24 hours (Annexin V-positive and PI-positive). Conclusion: The results show AFB 1 is toxic to human lymphocytes and that its cytotoxicity is mediated by apoptosis and necrosis.

This case demonstrates successful immune reconstitution following hematopoietic stem cell transplantation in NIK deficiency.

α+-Thalassemia trait and iron deficiency anemia are frequent causes of microcytosis and a common diagnostic challenge in Arabian children. In this study, their prevalences and effects on the red cell parameters were evaluated in 28,457 children aged one day to 6 years. α+-Thalassemia trait was considered to be present when mean cell volume (MCV) was 14.5%. The prevalence of α+-thalassemia trait was 15.7% (502/3,191), which was similar to previously reported values for adults (9-14%). Iron deficiency anemia peaked at 7 months (53%) and then declined at a rate of 8% per year. The nadirs of red blood cell count (RBC) and hemoglobin concentration (Hb) occurred at two months of age (physiological anemia). Subsequently, Hb increased at a rate similar to that of MCV, demonstrating the two processes are coupled. The third percentile MCV in children older than 3 months was ≤64 fL, which was significantly lower than that in European children. The third percentile Hb, on the other hand, was similar to that in European children. Thus, α+-thalassemia trait and iron deficiency anemia are exceptionally frequent in Arabian children and their red cell indices are considerably different from European-based norms. Careful interpretation of red cell parameters is required for the evaluation of microcytic anemia in Arabian children.

Background Blocking mTOR (molecular target of rapamycin) by sirolimus has been shown to suppress cellular respiration. The bearing of this impaired cellular bioenergetics on the mode-of-action of mTOR inhibitors has yet to be illustrated. Methods This study investigated in vitro effects of several molecularly-targeted therapies on O2 consumption in thymic fragments from C57BL/6 mice. Results Thymocyte respiration (µM O2 min−1 mg−1) was reduced by sirolimus and everolimus (p ≤ 0.007). In contrast, the dual PI3K (phosphatidylinositol-3-kinase)/mTOR inhibitors BEZ235, GDC0980 and GSK2126458, the highly-selective PI3 K-p110-δ inhibitor idelalisib and the calcineurin inhibitor tacrolimus had no effects on thymocyte respiration. Sirolimus was administered intraperitoneally on Days 0–3 and the thymus was then examined on Days 4 and 14. Cortex involution associated with increased cytochrome c and caspase-3 positive cells (apoptosis) were observed on Day 4; these changes were resolved on Day 14 (10 days after sirolimus treatment). On Day 4, the residual thymus (mostly medulla) had normal cellular respiration, decreased caspase activity and increased glutathione. Intraperitoneal administration of sorafenib (a multikinase inhibitor) or idelalisib had no effects on thymus size. Conclusion Thus, the highly-selective mTOR inhibitors imposed specific effects on the thymus, manifested by suppression of cellular respiration and induction of apoptosis.

Background and Purpose: The primary cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-tetrahydrocannabinol (Δ8-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O2 consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs. Experimental Approach: A phosphorescence analyzer that measures the time-dependence of O2 concentration in cellular or mitochondrial suspensions was used for this purpose. Key Results: A rapid decline in the rate of respiration was observed when Δ9-THC or Δ8-THC was added to the cells. The inhibition was concentration-dependent, and Δ9-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Δ9-THC and Δ8-THC were not mediated by the cannabinoidreceptors. Inhibition of O2 consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain. Δ9-THC inhibited the respiration of isolated mitochondria from beef heart. Conclusions and Implications: These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.

This study identifies a novel ORAI1 mutation that abolishes protein expression, but permits robust lymphocyte proliferation to mitogens. It is important to consider ORAI1 deficiency in the setting of a combined immunodeficiency with normal T cell numbers and residual T cell function.

Chronic diseases (diabetes, cardiovascular diseases and cancer), are by far the leading causes of mortality and morbidity worldwide. Oxidative stress is one of the underlying mechanism in the development and enhancement of chronic diseases. Polyphenols are particularly abundant in date seeds and can contribute in the progress of chronic diseases due to antioxidant properties. The present work studies the effects of date seeds and examines the oxidative stress status on serum and organs of Male Wistar rats after feeding them with basal diet comprising 0, 2, 4 or 8 g/kg date seed powder (DSP) for a period of 13 weeks. Isonitrogenous and isocaloric diets were subjected to all the four groups. Antioxidant status, protein and lipid oxidative biomarkers were measured in the serum and organs and histopathology was done. The results showed that DSP suggestively (P < 0.05) elevated the antioxidant defense system of the serum and organs. DSP decreased protein and lipid oxidative damages in the liver, muscle and brain. In addition, DSP did not alter the organs’ function based on the analysis of biochemical markers. The results indicate that oxidative stress-related diseases could be possibly prevented by the DSP bioactive antioxidants.

Introduction: The main purpose of this study was to report on the acute neurotoxicity of ammonia, using cellular respiration and ATP as surrogate metabolic biomarkers. Cellular respiration (mitochondrial O2 consumption), ATP and glutathione (GSH) were measured in forebrain specimens after intraperitoneal administration of 3.8 to 28.8 μmol/g ammonia to Taylor Outbred mice; the lethal dose was ≥ 30 μmol/g. Methods: Cortical fragments were collected in phosphate-buffered saline plus 5 mM glucose and immediately processed for measuring O2 consumption, using a phosphorescence O2 analyzer. Cellular ATP was determined with the luciferase/luciferin system. Cellular GSH was labeled with monobromobimane and the bimane derivatives were separated on HPLC and detected by fluorescence. In the presence of the tissue specimen in a vial sealed from air, O2 concentration declined linearly with time, confirming zero-order kinetics of O2 consumption. This process was inhibited by cyanide, confirming the oxidation occurred in the respiratory chain. Results: For untreated mice, cellular respiration was 0.32 ± 0.12 μM O2 min-1 mg-1 (n=36 mice), ATP was 238 ± 45 pmol.mg-1 (n=9 mice) and GSH was 300 ± 50 pmol.mg-1 (n=6 mice). For treated mice, cellular respiration was 0.26 ± 0.09 μM O2 min-1 mg-1 (n=22 mice; 19% lower, p=0.034), ATP was 183 ± 34 pmol mg-1 (n=9 mice; 23% lower, p=0.008) and GSH was 320 ± 160 pmol mg-1 (n=6 mice, p=0.700). Conclusion: Acute ammonia intoxication significantly lowered forebrain cellular bioenergetics. These changes would be are difficult to monitor at lethal doses, but the results are expected to be more pronounced.

Background and objectives Allergic rhinitis is a morbid condition that is frequently overlooked by patients and physicians. This type of atopy has not been adequately investigated in the United Arab Emirates.Methods This cross-sectional, population-based observational study was conducted in the seven Emirates (Abu Dhabi, Dubai, Sharjah, Ajman, Umm Al-Quwain, Ras Al-Khaimah, and Fujairah). It used the European Community Respiratory Health Survey (ECRHS II) to screen for allergic rhinitis in people living in this region.Results Symptoms of allergic rhinitis were present in 85 (7%) of the 1,229 study population. Only 33 (39%) patients received treatment. Seventy-six (89%) patients had asthma. Thirty-seven (44%) patients were poly-sensitized. Symptoms were aggravated by dust (59%), grass/pollens (44%) and proximity to animals (21%). Winter was the peak season (37%), followed by spring (30%), autumn (18%) and summer (15%). Grass/pollen allergies were clustered in the winter, spring and summer (p ≤ 0.001). Dust was non-seasonal (p ≥ 0.121) and animal allergy was worse in the winter (p = 0.024) and spring (p = 0.044). Spring symptoms were less common in people living in the inner city (p = 0.003).Conclusions At least 7% of the studied population had allergic rhinitis. Most (71%) of these patients had environmental triggers and remained untreated. Allergic rhinitis awareness and measures to control allergens and dust are needed. The impact of preventing allergic rhinitis on other common atopies in the region deserves future studies. Keywords: Allergens, Nasal mucosa, Pollen, Air pollution, Fine dust, Constructions, Gulf region

Out of 103 children, 63 (61.2%) are tested positive to at least one allergen. Forty-three (68.3%) are males. The highest rate of the positive tests are at the age group 5-12 years (27, 42.9%), followed by age group 2-5 years (19, 30.2%). This trend is the same between both sexes. Nineteen children are positive to 3 allergens (30.2%), 15 to 2 allergens (23.8%) and 11 to 1 allergen (17.5%). The commonest indoor aeroallergens are house dust mites (Der f 16%, Der p 13.5%) dog (11.5%), and cockroaches (10.9%). The commonest food allergens found are horse chestnut (20%), sesame (14%) and cow’s milk (12%). Collectively, the indoor aeroallergens are twice positive as food allergens.

Background Primary immunodeficiency (PID) is a cluster of serious disorders that requires special alertness on the part of the medical staff for prompt diagnosis and management of the patient. This study explored PID knowledge and experience among pediatricians of wide educational backgrounds, practicing in the United Arab Emirates (UAE). Method A self-administered questionnaire was used to determine the competency of pediatricians in their knowledge of PID disorders. This study questionnaire included questions on PID signs and symptoms, syndromes associated with immunodeficiency, screening tests, interpreting laboratory tests and case management. The participants were 263 pediatricians of diverse education working in the 27 governmental hospitals in all regions of UAE. Results The overall performance of the pediatricians did not differ based on their age, gender, origin of certification, rank, or years of experience. Of the 50 questions, 20% of pediatricians answered correctly Conclusions There was a noteworthy deficiency in PID work-up. Therefore, implementing effective educational strategies is needed to improve the competency of pediatricians to diagnose and manage PID disorders.

Background No population study has explored the population distribution of adult asthma in the United Arab Emirates (UAE). The objective is to estimate asthma prevalence in general population in UAE. Methods Using standard European Community Respiratory Health Survey (ECRHS) questionnaires and tools, this is a cross-sectional assessment of a random sample of the population in established quotas of the seven Emirates in the UAE. We surveyed 1,220 participants, of which 63.2% were male, and 20.1% were UAE Nationals, with a mean (SD) age of 32.9 (14.1) years. Results Prevalence of individual respiratory symptoms from the ECRHS screening questionnaire in all participants were generally ranging 8 - 10%, while participants 20-44 years presented lower prevalence in all symptoms (p < 0.05). The expected male:female ratio of reported wheezing and asthma attacks and its treatment by age was not observed. Participating women reported more individual symptoms than men. Overall, there were 15.4% (95% C.I. 13.5 - 17.5) participants who fulfilled our screening criteria for asthma, while for consistency with ECRHS, there were 12.1% (95% C.I. 10.4 - 14.1) participants who fulfilled the ECRHS asthma definition, being 9.8% (95% C.I. 7.8 - 12.2) of those 20-44 years, that is 8.6% of male and 11.8% of female young adults participating. Conclusion We conclude that asthma is common in the UAE, and gender differences are not observed in reported asthma symptoms in young adults. This being the first population based study exploring the prevalence of asthma and its determinants in the United Arab Emirates based on the ECRHS.

Food allergy is common in children, and its occurrence is strongly associated with other allergies including anaphylaxis. Both genetic (e.g., CD14, STAT6, IL-10, SPINK5, and FOXP3 genes) and environmental (e.g., early exposure to highly allergic food) factors appear to contribute to food allergy.Cross-sectional study involved children in public primary schools in Al-Ain city (United Arab Emirates). 660 students from the chosen classes were provided with 35 questions to be answered by their parents with a response rate 60.2%. The objective of the study was to determine predictors for food allergy in children.Significant associations were found between childhood food allergy and a history of personal allergy (atopic dermatitis, asthma or allergic rhino-conjunctivitis) or immediate family members with food allergy or other allergic diseases. The best predictors for childhood food allergy were a personal history of asthma (p0.001), a personal history of atopic dermatitis (p0.001), a paternal history of atopic dermatitis (p = 0.005) and a paternal history of allergic rhino-conjunctivitis (p = 0.012).These results are consistent with the notion that "various forms of allergy, including childhood food allergy are hereditarily coupled". Thus, predicting childhood food allergy provides an opportunity to prevent or ameliorate the symptoms.

We report on the pneumatocyte structure and function of mouse lung specimens exposed in vitro to two calcined mesoporous silica particles, MCM41-cal (spheres, ∼300 to 1000 nm in diameter) and SBA15-cal (irregular rods averaging ∼500 nm in diameter and ∼1000 nm in length). These mesoporous silica particles are in consideration for potential medical application as delivery vehicles for genes, drugs, and bio-imagers. In the study, lung specimens (about 10 mg each) were excised from male Balb/c mice, immediately immersed in Krebs-Henseleit buffer, ice-cold, and continuously gassed with O(2):CO(2) (95:5). The samples were incubated at 37°C in the same buffer with and without 200 μg/mL MCM41-cal or SBA15-cal for 5-14 h. The tissues were then rinsed thoroughly and processed for light and electron microscopy. Normal alveolar morphology was evident in all the studied specimens. There was no significant difference in the number of apoptotic cells between the treated and untreated samples. Despite their relatively large sizes, the particles were abundantly present in pneumocytes, macrophages, endothelial cells, fibroblasts, and interstitium. They were seen in different areas of the cytoplasm, suggesting intracellular movements. Their presence did not appear to disturb cellular configuration or micro-organelles. Due to their rigidity and surface charges, some were firmly attached to (indenting) the nuclear membrane. The rate of respiration (cellular mitochondrial O(2) consumption, in μM O(2)/min/mg) in specimens exposed to 200 μg/mL particles for up to 12 h was the same as untreated specimens. These findings confirm "reasonable" bioavailability and biocompatibility of calcined mesoporous silicas with mouse lung within at least 5-14 h of exposure time.

Introduction A novel in vitro system was developed to measure O2 consumption by murine tissues over several hours. Methods Tissue specimens (7–35 mg) excised from male Balb/c mice were immediately immersed in ice-cold Krebs–Henseleit buffer, saturated with 95% O2:5% CO2. The specimens were incubated at 37 °C in the buffer, continuously gassed with O2:CO2 (95:5). [O2] was determined as a function of time from the phosphorescence decay rates (1 / τ) of Pd(II) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. The values of 1 / τ were linear with [O2]: 1 / τ = 1/τo + kq [O2]; 1 / τo = the decay rate for zero O2, kq = the rate constant in s−1 μM−1. Results NaCN inhibited O2 consumption, confirming oxidation occurred in the mitochondrial respiratory chain. The rate of respiration in lung specimens incubated in vitro for 3.9 ≤ t ≤ 12.4 h was 0.24 ± 0.03 μM O2 min−1 mg−1 (mean ± SD, n = 28). The corresponding rate for the liver was 0.27 ± 0.13 (n = 11, t ≤ 4.7 h), spleen 0.28 ± 0.07 (n = 10, t ≤ 5 h), kidney 0.34 ± 0.12 (n = 7, t ≤ 5 h) and pancreas 0.35 ± 0.09 (n = 10, t ≤ 4 h). Normal tissue histology at hour 5 was confirmed by light and electron microscopy. There was negligible number of apoptotic cells by caspase 3 staining. Discussion This approach allows accurate assessment of tissue bioenergetics in vitro.