TCV-309, a novel platelet activating factor antagonist,inhibits leukocyte accumulation and protects against splanchnic artery occlusion shock

The aim of this study was to evaluate: (1) the accumulation of leukocytes in the ileum and the lung during splanchnic artery occlusion (SAO) shock; (2) the role of platelet-activating factor (PAF) and tumor necrosis factor (TNF-) in this phenomenon. Untreated anesthetized rats subjected to total occlusion of the celiac, superior and inferior mesenteric arteries for 45 min, followed by reperfusion, uniformly died within 90 min after reperfusion. The mean survival time was 93±7 min. The neutrophilic infiltrate was quantitated in the ileum and in the lung using a myeloperoxidase (MPO) assay. MPO activity in the ileum and in the lung averaged 0.05±0.03 and 0.4±0.02 U×10^–3/g protein in animals killed before occlusion. MPO activity did not change in rats killed immediately before reperfusion and was significantly elevated (0.11±0.02 and 1.7±0.6 U×10^–3/g protein in the ileum and the lung, respectively) in those killed 80 min after the beginning of the reperfusion. The histological examination confirmed the accumulation of leukocytes in the mucosa of the ileum and the lung over the 80 min. SAO shocked rats exhibited leukopenia and increased serum levels of TNF-. In order to evaluate the role of PAF and TNF- in SAO shock, a powerful PAF receptor antagonist, TCV-309 (5 g/kg i.v.), was injected 5 min after reperfusion. TCV-309 increased survival time, lowered serum TNF-, reduced MPO activity in both the ileum and the lung and ameliorated leukopenia induced by SAO shock. In addition, the drug significantly reduced ileal necrosis and pulmonary morphological alterations induced by shock. These results suggest an important role for PAF in the adhesion of leukocytes in SAO shock.     

Recurrent mosaic MTOR c.5930C > T (p.Thr1977Ile) variant causing megalencephaly,asymmetric polymicrogyria,and cutaneous pigmentary mosaicism: Case report and review of the literature

Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri‐color of the Blaschko‐linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings. We report a fourth case of a 3‐year‐old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as a targeted gene variant panel from fibroblasts derived from hyperpigmented and non‐hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. Unlike the previously reported cases, the de novo c.5930C > T (p.Thr1977Ile) MTOR variant was detected at 32% mosaicism in our patient only after WES was performed on fibroblast‐derived DNA from the hyperpigmented skin. This case demonstrates the tissue variability in mosaic expression of the recurrent p.Thr1977Ile MTOR variant, emphasizes the need for skin biopsies in the genetic evaluation of patients with skin pigmentary mosaicism, and expands the clinical phenotype associated with this pathogenic MTOR variant.     

Reciprocal expression of lin-41 and the microRNAs let-7 and mir-125 during mouse embryogenesis.

In C. elegans, heterochronic genes control the timing of cell fate determination during development. Two heterochronic genes, let-7 and lin-4, encode microRNAs (miRNAs) that down-regulate a third heterochronic gene lin-41 by binding to complementary sites in its 3'UTR. let-7 and lin-4 are conserved in mammals. Here we report the cloning and sequencing of mammalian lin-41 orthologs. We find that mouse and human lin-41 genes contain predicted conserved complementary sites for let-7 and the lin-4 ortholog, mir-125, in their 3'UTRs. Mouse lin-41 (Mlin-41) is temporally expressed in developing mouse embryos, most dramatically in the limb buds. Mlin-41 is down-regulated during mid-embryogenesis at the time when mouse let-7c and mir-125 RNA levels are up-regulated. Our results suggest that mammalian lin-41 is temporally regulated by miRNAs in order to direct key developmental events such as limb formation.     

Identification of 26 new constitutional RB1 gene mutations in Spanish, Colombian, and Cuban retinoblastoma patients

Constitutional mutations in the RB1 gene predispose to retinoblastoma development. Hence genetic screening of retinoblastoma patients and relatives is important for genetic counseling purposes. In addition, RB1 gene mutation studies may help decipher the molecular mechanisms leading to tumors with different degrees of penetrance or expressivity. In the course of genetically screening of 107 hereditary and non-hereditary retinoblastoma patients (11 familiar bilateral, 4 familiar unilateral, 49 sporadic bilateral and 43 sporadic unilateral) and kindred from Spain, Colombia and Cuba, using direct PCR sequencing, we observed 45 distinct mutations and four RB1 deletions in 53 patients (9 familiar bilateral, 2 familiar unilateral, 31 sporadic bilateral and 11 sporadic unilateral). Most of these mutations (26/45, 57%) have not been reported before. In 32 patients, the predisposing mutations correspond to nonsense (mainly CpG transitions) and small insertions or deletions whose expected outcome is a truncated Rb protein that lacks the functional pockets and tail. Five single aminoacid replacements and seventeen mutations affecting splicing sites were also observed in retinoblastoma patients. Two of these sixteen mutations are of unclear pathogenic nature.     

HbA1C is not directly associated with complications of bariatric surgery

IntroductionBariatric surgery is effective therapy for weight loss and diabetes control. While patients with poorly controlled type 2 diabetes (T2D) experience significant benefit from bariatric surgery, the impact of hyperglycemia on perioperative risks is unclear.ObjectiveThis study aims to investigate effect of elevated glycated hemoglobin (HbA1C) on perioperative risks for patients undergoing sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB).Settings117,644 patients undergoing RYGB or SG between the years of 2017 and 2018 in the United Stated were analyzed. Data was obtained using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database.MethodsThree commonly used cutoff levels of HbA1C were selected (6.5, 7.0, and 8.5). Complications were compared between groups of patients above and below each HbA1C level. Multivariable logistic regression models were used to account for confounders.ResultsWithout risk adjustment, HbA1C is indirectly associated with increased rates of surgical complications. However, after adjusting for underlying co-morbidities, HbA1C is not associated with overall complications, including 30 day readmissions, reoperations, reinterventions, or death at any HbA1C cutoff: 6.5 (odds ratio [OR] 1.041, P value = .219), 7.0 (OR 1.020, P value = .551), or 8.5 (OR 1.051, P value = .208).ConclusionThere is no direct relationship between HbA1C and early postoperative complications of SG and RYGB. Thus, optimizing preoperative HbA1C values alone, may not translate into decreased surgical complications of bariatric surgery. (Surg Obes Relat Dis 2020;17:271–275.) © 2020 American Society for Metabolic and Bariatric Surgery. All rights reserved.     

Incidence and outcomes of anterior cruciate ligament reconstruction among U.S. Army aviators

BACKGROUND: The incidence, injury history and aeromedical disposition of anterior cruciate ligament (ACL) reconstruction among Army aviators is unknown. METHODS: The U.S. Army Aviation Epidemiology Data Register was queried for the study period of calendar years 1988-95. Factors considered included age, gender, type and mechanism of injury, prior history of ACL reconstruction, and final aeromedical disposition. The population was divided into two groups: Group I aviators had no history of ACL injury before entering aviation service, while Group II aviators had ACL reconstructions prior to entering aviation service. The data set was analyzed to determine the incidence of ACL reconstruction, to characterize the type and mechanism of injury and to determine the risk of aeromedical termination from service. RESULTS: The ACL reconstruction rate (ACL reconstructions/1000 aviators per year) was 0.52 overall, 0.50 for males and 1.39 for females. Sports accounted for 76% of the injuries requiring ACL reconstruction. The ACL reconstruction rate in Group I was 0.050%, while that of Group II was 63.3%. Among Group I aviators requiring ACL reconstruction, 94.3% returned to aviation service, 2.3% were aeromedically terminated and 3.4% were lost to follow-up. Among Group II aviators requiring revision ACL reconstruction, 60% returned to aviation service and 40% were aeromedically terminated. CONCLUSION: Female aviators and Group II aviators had the greatest risk of requiring ACL surgery. Group II aviators had a greater likelihood of undergoing a revision ACL reconstruction and subsequent aeromedical termination compared with an initial ACL reconstruction for Group I aviators.     

Atypical presentations of actinomycosis

BACKGROUND: Actinomycotic infections of the cervicofacial region are uncommon. Most major medical centers report approximately one case per year. Presenting clinical manifestations are confusing because they often mimic other disease processes. Diagnosis may be difficult due to a general lack of familiarity with the disease and the fastidious nature of the organism in culture. The cervicofacial manifestations of actinomycosis are varied, and a high index of suspicion is required to make an accurate and timely diagnosis. METHODS: Retrospective chart review with the presentation of four unusual cases of actinomycosis were performed. RESULTS: Two patients were initially seen with dysphagia from a tongue base mass. The third patient was initially seen with a 3-week history of worsening hoarseness and stridor. Examination revealed an ulcerative lesion of the left hemilarynx and pyriform sinus. All three patients were thought to have a neoplastic process. Diagnosis was made on histologic examination of a tissue biopsy. The fourth patient was initially seen with a buccal space mass that was draining externally. Culture of the purulent drainage revealed Actinomyces. In all four cases, symptoms resolved after appropriate antimicrobial therapy. CONCLUSIONS: Actinomycosis of the head and neck, although rare, is an important entity to the otolaryngologist. A confusing clinical presentation combined with the fastidious nature of the organism make for a difficult diagnosis. A high index of suspicion is required to make an accurate diagnosis and institute the appropriate antibiotic therapy.