Effect of Sirolimus/Metformin Co-Treatment on Hyperglycemia and Cellular Respiration in BALB/c Mice.

Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4-6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.

Recurrence and survival for patients with thyroid carcinoma in the pediatric age group in the Emirate of Abu Dhabi: retrospective analysis of a multicentre cohort.

OBJECTIVES: Pediatric thyroid cancer represents 2.3 % of thyroid cancers, and its long-term outcome data are sparse. There have not been studies in the UAE delineating its epidemiology, clinical and histological characteristics, and follow-up outcomes. We aimed to evaluate the clinical-pathological behavior, recurrence and survival rates in pediatrics with all types of thyroid cancer in the UAE. METHODS: Multicentre retrospective chart review analysis of pediatric patients with thyroid carcinoma from January 2010 to December 2020 in Abu Dhabi, UAE. RESULTS: Thirty-four patients were included, 85 % being females. Papillary thyroid carcinoma (PTC) was the commonest type of thyroid cancer (88 %) vs. follicular thyroid carcinoma (FTC) (11.8 %). Almost half of our patients had a multifocal disease, 26 % had lymphovascular invasion (LVI), and 21 % had extrathyroidal extension (ETE). There were no mortalities during follow-up. 85 % of patients exhibited complete remission, while 15 % of patients showed evidence of progressive residual or recurrent disease. One patient had metastasis to lymph nodes and lungs. CONCLUSIONS: There were similar trends of incidence, sex prevalence, and histopathological patterns as the ones observed internationally. Potential risk factors in our population include a family history of thyroid cancer and obesity. The lower rate of ETE, LVI, metastasis, and recurrence indicates a possibly less aggressive disease.

Leptomeningeal Carcinomatosis and Palliative Care: A Case Report.

Leptomeningeal carcinomatosis (LC) is a rare but serious complication of cancer in which cancer cells spread to the leptomeninges, the membranes that surround the brain and spinal cord. The diagnosis and treatment of LC can be challenging due to the non-specific symptoms and the difficulty of accessing the leptomeninges for a biopsy. In this case report, we describe a patient with advanced breast cancer who was diagnosed with LC and underwent treatment with chemotherapy. Despite aggressive treatment, the patient's condition worsened over time, and she was referred to palliative care, where adequate symptom control was achieved, and she was discharged to her home country as per her wish. Our case highlights the difficulties associated with the diagnosis and treatment of LC and the need for continued research to improve outcomes for patients with this condition. It specifically highlights the approach a palliative care team can take for this condition.

Cytological Sub-Classification of Atypia of Undetermined Significance May Predict Malignancy Risk in Thyroid Nodules.

BACKGROUND: Atypia/follicular lesion of undetermined significance (AUS/FLUS) carries a malignancy risk reaching up to 50%. Based on the reported malignancy rate in a given population, the clinical practice towards such a category varies. We hereby identify clinical parameters for risk stratification to aid in decision-making for either surgical referral or a clinical follow-up. Our aim is to identify clinical parameters that guided both clinicians and patients at our institutions to reach a clinical decision including atypia types. METHODS: A retrospective review of patients with Bethesda III category thyroid nodules from tertiary centres in the Emirate of Abu Dhabi during January 2011 through December 2015 was carried out. Malignancy risk in Bethesda category III nodules and repeat FNA utility were calculated. Parameters that guided both clinicians and patients for appropriate referral to surgery were studied. RESULTS: Two hundred and two cases were included in the study. Of these, 101 cases underwent surgery initially following the first FNA and 10 cases following FNA repeat. Histology confirmed malignancy in (41%) of cases that went initially to surgery and in (40%) of cases that underwent a repeat FNA. Repeat FNA resulted in 17 (44.74%) cases being re-classified into benign category, 10 (26.3%) being AUS/FLUS category, 6 (15.7%) being both suspicious and malignant, and 5 (13.16%) being unsatisfactory. Repeating FNA resulted in a definitive diagnostic utility in 50% of the cases. Eighty percent of malignant cases demonstrated nuclear atypia. CONCLUSION: The relatively high malignancy rate in our institutions, the suspicious radiographic features, the atypia groups, and the repeat FNA predictive value stratified Bethesda III category nodules for proper malignancy prediction and appropriate management.

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.

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.

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.