Chronic granulomatous disease in the United Arab Emirates: clinical and molecular characteristics in a single center.

Background: Chronic granulomatous disease (CGD) is a genetic disorder caused by defective oxidative burst within phagocytes, manifesting as recurrent, severe infections as well as hyperinflammation. Objective: This is the first report from the United Arab Emirates (UAE) to describe the demographic, clinical, laboratory, radiological, and genetic characteristics of patients with CGD. Methods: This is a retrospective study that was conducted at Tawam Hospital in the UAE on patients with confirmed CGD between 2017 and 2022. Results: A total of 14 patients were diagnosed with CGD, of whom 13 patients had autosomal recessive (AR) CGD due to NCF1 deficiency. Consanguinity was noted in all patients with AR CGD, whereas positive family history was identified in 50% of cases. The median age of onset of symptoms was 24 months, while the median age at diagnosis was 72 months. Lymphadenitis was the most common clinical feature identified in 71% of patients. Other common infectious manifestations included abscess formation (57%), pneumonia (50%), invasive aspergillosis (21%), oral thrush (14%), and sepsis (14%). Disseminated trichosporonosis was reported in one patient. Autoimmune and inflammatory manifestations included celiac disease in two patients, diabetes mellitus and asymptomatic colitis in one patient each. Genetic analysis was performed in all patients; NCF1 deficiency was diagnosed in 13 (93%) patients, with c.579G>A being the most prevalent pathogenic variant identified. The treatment modalities, as well as treatment of acute infections, treatment modalities included antimicrobial prophylaxis in 12 (86%) patients and hematopoietic stem cell transplant in six patients (42%). Conclusion: This is the first report from the UAE describing the clinical and molecular characteristics of patients with CGD. The homozygous variant c.579G>A causing NCF1 deficiency can be considered as a founder mutation for AR CGD in the UAE.

Epidemiology of combined immunodeficiencies affecting cellular and humoral immunity- a multicentric retrospective cohort study from the Arabian Peninsula.

AIMS: To understand the characteristics of combined immunodeficiency disorders that affect cellular and humoral immunity (CID) in the Arabian Peninsula. METHODS: Retrospective study of 236 patients with CID from the region were enrolled from 2004 to 2022. RESULTS: 236 patients were included with a majority being profound CID. Among patients with a family history of CID, the ages at onset and diagnosis, and the delay in diagnosis were lower compared to those with no family history of CID, but this did not affect time to transplant. HSCT was performed for 51.27% of the patients with median time from diagnosis to HSCT of 6.36 months. On multivariate analysis, patients who underwent early transplant had increased odds of having CD3 count ≤1000 cell/µl, diagnosed by screening or erythroderma. CONCLUSION: There is a delay in diagnosis and treatment of CID in our region. Establishing newborn screening programs and HSCT units in our region are the urgent need.

Predictors of early death risk among untransplanted patients with combined immunodeficiencies affecting cellular and humoral immunity: A multicenter report.

BACKGROUND: There is an increased demand for hematopoietic stem cell transplant (HSCT) to treat various diseases including combined immunodeficiencies (CID), with limited worldwide availability. Variables affecting the decision regarding CID patients' prioritization for HSCT are not known. We aimed to determine general, clinical, and immunologic factors associated with the higher risk of early death (≤6 months after diagnosis) in untransplanted CID patients. METHODS: Data collection was done retrospectively from five centers and included general patients' information, and clinical and laboratory variables. Inclusion criteria were untransplanted patients who are either dead or alive with a follow-up period ≥6 months after diagnosis. RESULTS: Two hundred and thirty-six CID patients were reported by participating centers, of whom 111 were included in the study with a cumulative follow-up period of 278.6 years. Seventy-two patients died with the median age of death of 10.5 months. 35.1% of the patients succumbed within 6 months after the diagnosis. Having a history of Candida infections, sepsis or hepatomegaly was associated with an increased risk of early death. None of the other general or clinical variables was associated with such risk. Bivariate analysis of lymphocyte subsets showed that patients with the following counts: CD3+  < 100, CD4+  < 200, CD8+  < 50, or CD16+ CD56+ <200 cells/µl had increased risk of early death. In adjusted analysis, increased risk of early death was observed among patients with CD3+ count <100 cells/µl. CONCLUSION: Combined immunodeficiencies patients with a history of Candida infections, sepsis, hepatomegaly, or severe T-lymphopenia should be given priority for HSCT to avoid early death.

Combined Treatment with KV Channel Inhibitor 4-Aminopyridine and either γ-Cystathionine Lyase Inhibitor ß-Cyanoalanine or Epinephrine Restores Blood Pressure, and Improves Survival in the Wistar Rat Model of Anaphylactic Shock.

The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine γ-lyase (ICSE), dl-propargylglycine (DPG) or ß-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of AS. The aim of this study was to demonstrate the ability of L-NAME, ICSE alone or in combination with 4-AP to restore blood pressure (BP) and improve survival in ovalbumin (OVA) rats AS. Experimental groups included non-sensitized Wistar rats (n = 6); AS (n = 6); AS (n = 10 per group) treated i.v. with 4-AP (AS+4-AP), epinephrine (AS+EPI), AS+DPG, AS+BCA, or with L-NAME (AS+L-NAME); or AS treated with drug combinations 4-AP+DPG, 4-AP+BCA, 4-AP+L-NAME, or 4-AP+EPI. AS was induced by i.v. OVA (1 mg). Treatments were administered i.v. one minute after AS induction. Mean arterial BP (MAP), heart rate (HR), and survival were monitored for 60 min. Plasma levels of histamine, prostaglandin E2 (PGE2) and F2 (PGF2α), leukotriene B4 and C4, angiotensin II, vasopressin, oxidative stress markers, pH, HCO3, PaO2, PaCO2, and K+ were measured. OVA induced severe hypotension and all AS rats died. Moreover, 4-AP, 4-AP+EPI, or 4-AP+BCA normalized both MAP and HR and increased survival. All sensitized rats treated with 4-AP alone or with 4-AP+BCA survived. The time-integrated MAP "area under the curve" was significantly higher after combined 4-AP treatment with ICSE. Metabolic acidosis was not rescued and NO, ICSE, and Kv inhibitors differentially alter oxidative stress and plasma levels of anaphylactic mediators. The AS-induced reduction of serum angiotensin II levels was prevented by 4-AP treatment alone or in combination with other drugs. Further, 4-AP treatment combined with EPI or with BCA also increased serum PGF2α, whereas only the 4-AP+EPI combination increased serum LTB4. Serum vasopressin and angiotensin II levels were increased by 4-AP treatment alone or in combination with other drugs. Moreover, 4-AP alone and in combination with inhibition of cystathionine γ-lyase or EPI normalizes BP, increases serum vasoconstrictor levels, and improves survival in the Wistar rat model of AS. These findings suggest possible investigative treatment pathways for research into epinephrine-refractory anaphylactic shock in patients.

Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry.

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.

BCG Vaccine-associated Complications in a Large Cohort of Children With Combined Immunodeficiencies Affecting Cellular and Humoral Immunity.

AIMS: To present the details of Bacillus Calmette-Guérin (BCG)-vaccine associated complications (VACs) in combined immunodeficiencies (CID) patients. METHODS: Five centers participated in this retrospective study and completed a data form, which included general patients' information, clinical and laboratory data. RESULTS: 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. COCLUSIONS: 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.

Genetic and Clinical Characteristics of Patients in the Middle East With Multisystem Inflammatory Syndrome in Children.

Importance: Clinical, genetic, and laboratory characteristics of Middle Eastern patients with multisystem inflammatory syndrome in children (MIS-C) have not yet been documented. Objective: To assess the genetic and clinical characteristics of patients with MIS-C of primarily Arab and Asian origin. Design, Setting, and Participants: 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. Exposures: SARS-CoV-2. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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.

The Spectrum of Inborn Errors of Immunity in the United Arab Emirates: 5 Year Experience in a Tertiary Center.

Purpose: Inborn Errors of Immunity (IEI) are heterogeneous disorders of immunity with variable clinical presentation and outcome. This is the first comprehensive report from the United Arab Emirates aiming to describe the demographics, clinical characteristics, categories, treatment modalities and outcome of patients with IEI. Methods: This retrospective study was conducted on patients who attended Tawam Hospital between 2016-2020. Results: We identified 162 patients with IEI, of whom 152 were children. The age of onset of symptoms ranged between birth to 38 years. About two-thirds of patients were Emirati nationals, 64.2% had consanguineous parents and 38.3% of cases were familial. Patients were classified as; immunodeficiencies affecting cellular and humoral immunity (20.4%), combined immunodeficiencies with associated or syndromic features (38.3%), predominantly antibody deficiencies (16%), immune dysregulation (4.3%), congenital defects of phagocytes number or function (8.6%), defects in intrinsic and innate immunity (1.9%) autoinflammatory disorders (1.9%), complement deficiency (6.2%), bone marrow failure (1.9%) and phenocopies of inborn errors of immunity (0.6%). Genetic testing was performed in 85.2% of patients with a diagnostic yield of 92.7%. Complications included bronchiectasis, neoplasia, and vaccine-related infections. Immunoglobulin therapy and antimicrobial prophylaxis were both used in (51.9%) of patients while (20.4%) underwent hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 10.5%. Conclusion: This report highlights the burden of IEI in the UAE. Ongoing education of physicians, establishment of a national registry and considering changes to early BCG vaccination are measures recommended to improve outcomes.

Case Report: Reactive Lymphohistiocytic Proliferation in Infant With a Novel Nonsense Variant of IL2RG Who Received BCG Vaccine.

We present here a male young infant with X-linked severe combined immunodeficiency (MIM#300400) due to the novel nonsense variant of IL2RG (interleukin 2 receptor, gamma; MIM#308380), NM_000206.2(IL2RG):c.820_823dup p.Ser275Asnfs*29. He developed aggressive reactive lymphohistiocytic proliferation after receiving the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine at birth. This report advocates for modifying the current practice of early use of BCG. The natural history of his disease also suggests considering IL2RG variants as a potential cause of "X-linked recessive Mendelian susceptibility to mycobacterial disease" (MSMD). His reactive lymphohistiocytic proliferation and massive hepatosplenomegaly simulated hemophagocytic lymphohistiocytosis (HLH, likely triggered by the BCG disease). This entity was masked by the absence of fever and markedly elevated inflammatory biomarkers. Thus, his findings stimulate discussion on the need to modify the diagnostic criteria of HLH, in order to accommodate conditions, such IL2RG variants that block systemic inflammation.

Consensus statement on the epidemiology, diagnosis, prevention, and management of cow's milk protein allergy in the Middle East: a modified Delphi-based study.

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.

Case Report: A Case of Leukocyte Adhesion Deficiency, Type III Presenting With Impaired Platelet Function, Lymphocytosis and Granulocytosis.

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 αIIbß3 (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 ß1, ß2, and ß3 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.

Case Report: BCG-Triggered Hemophagocytic Lymphohistiocytosis in an Infant With X-Linked Recessive Mendelian Susceptibility to Mycobacterial Disease Due to a Variant of Chronic Granulomatous Disease.

In the United Arab Emirates, BCG (Bacillus Calmette-Guérin) is administered to all newborns. We present here a young infant with an inborn error of immunity (IEI) who developed fatal adverse events to this live-attenuated vaccine. This male infant received BCG (Serum Institute of India Pvt., Ltd., India) on Day 11 of life. On Day 25, he developed fever, followed by cervical lymphadenitis and bilateral otitis media with fluid drainage. On Day 118, he was admitted with severe hemophagocytic lymphohistiocytosis (HLH), and passed away on Day 145. The diagnostic exome sequencing test identified a hemizygous nonsense variant, NM_000397.3(CYBB):c.676C>T, p.Arg226* (rs137854592). Pathogenic variants of CYBB [cytochrome b(-245), beta subunit; Mendelian Inheritance in Man [MIM] accession code, 300481] are known to cause "immunodeficiency 34, mycobacteriosis, X-linked" (IMD34, MIM#300645) and "chronic granulomatous disease, X-linked" (CGDX, MIM#306400). The natural history of his illness is consistent with "X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD)." This entity is responsible for his BCG disease and is a likely trigger of his HLH. This disastrous event underlines the importance of developing worldwide policies that target BCG disease prevention, especially in communities with high prevalence of IEI. Moreover, screening for genetic causes of MSMD in the community could pave the way, at least partially, for scale-up of tuberculosis (TB) prevention.

Novel genetic variants of inborn errors of immunity.

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.

Etiology of diarrhea by multiplex polymerase chain reaction among young children in the United Arab Emirates: a case-control study.

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 < 0.001). Rotavirus, norovirus GII and adenovirus were significantly more prevalent in cases. Their aAFs with 95% ci are 0.95 (0.64, 1.00) for rotavirus, 0.86 (0.38, 0.97) for norovirus GII and 0.84 (0.29, 0.96) for adenovirus. None of the 13 bacteria tested for were more commonly found in the cases than in controls. Cryptosporidium spp. were more significantly detected in cases than in controls. Co-infections occurred in 27.9% of the children. Viruses and parasites were significantly more likely to occur together only in the cases. 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.

Adverse Events of the BCG (Bacillus Calmette-Guérin) and Rotavirus Vaccines in a Young Infant with Inborn Error of Immunity.

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.

Polyphenol characterisation of Phoenix dactylifera L. (date) seeds using HPLC-mass spectrometry and its bioaccessibility using simulated in-vitro digestion/Caco-2 culture model.

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.

Urine Metabolites and Antioxidant Effect after Oral Intake of Date (Phoenix dactylifera L.) Seeds-Based Products (Powder, Bread and Extract) by Human.

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.

Cellular and Immunohistochemical Changes in Anaphylactic Shock Induced in the Ovalbumin-Sensitized Wistar Rat Model.

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.

Zoledronic acid and bone cellular respiration.

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.