Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa.

AIMS: Colorectal carcinoma (CRC) is a common cause of morbidity and mortality worldwide, and an emerging public health problem in sub-Saharan Africa. Several authors have described an increased frequency of mismatch repair-deficient (dMMR) CRC in sub-Saharan Africa, but these tumours remain poorly characterised molecularly. We sought to interrogate the somatic molecular genetic landscape of dMMR CRC in a cohort of young patients to better inform Lynch syndrome (LS) screening strategies and personalised medicine approaches in our setting. METHODS: 32 patients (aged <60 years) were identified with dMMR CRC. DNA was extracted from selected formalin-fixed paraffin-embedded (FFPE) tissue resection samples and subjected to amplicon-based next-generation sequencing (NGS). RESULTS: Pathogenic or likely pathogenic variants were detected in the corresponding MMR gene in 14 of 18 (78%) MLH1/PMS2-deficient tumours, 5 of 8 (63%) MSH2/MSH6-deficient tumours, 1 of 4 (25%) tumours with isolated MSH6 loss and 0 of 2 tumours with isolated PMS2 loss. Previously unreported variants were identified in MLH1 (three) and MSH2 (one). Cases with a variant allele frequency suggesting a germline mutation were identified in MLH1 (eight), MSH2 (two) and MSH6 (one). Only one MMR gene variant was detected in more than one patient (MLH1 p.Q510*). Four POLE/POLD1 exonuclease domain variants were identified, one of which was previously unreported. CONCLUSION: The spectrum of disease-causing MMR gene variants in our population necessitates NGS testing for LS screening. This study also highlights the role of somatic testing on readily available FFPE samples to generate data on the epidemiology of CRC in different settings.

Relationship between infectious screening and early unconjugated hyperbilirubinemia in well-appearing neonates.

BACKGROUND: Neonatal hyperbilirubinemia (NH) may be the initial and solitary sign of infectious condition in neonates. This retrospective cohort study aims to evaluate the risk of sepsis or urinary tract infection in well-appearing infants with NH below 7 days old. METHODS: All neonates (n = 8779) born in Taipei Veterans General Hospital from 2013 to 2017 were evaluated retrospectively. A total of 2523 initially well-appearing babies were admitted because of NH. After being hospitalized, patients were categorized into two groups according to the initial transcutaneous bilirubin (TCB) level. Infectious screening results, which include C-reactive protein (CRP), differential count, blood culture, urinalysis, and urine culture, were analyzed. RESULTS: Regarding CRP, 2.7% (18/667) of neonates with NH had elevated CRP (≥1 mg/dL). Among 547 blood cultures, eight were positive, with 0.4% (2/547) non-coagulase-negative staphylococcus (CoNS) bacteremia and 1.1% (6/547) CoNS bacteremia. In urinalysis, 16.6% (182/1094) of NH neonates had pyuria, and 6.7% (25/372) had positive urine cultures. NH with a higher initial TCB level was related to an increased chance of elevated CRP (4.7% vs. 1.5%, odds ratio: 3.29, p = 0.024) and pyuria (20.6% vs. 12.6%, odds ratio: 1.79, p < 0.001). The rate of positive urine culture between the higher and lower TCB groups had no significant difference (6.6% vs. 6.9%, p > 0.99). Significant bacteriuria was more common in NH neonates admitted at later age (>2 days) (4.9% vs. 11.5%, p = 0.035). CONCLUSION: In well-appearing neonates below 7 days old, NH with a higher initial TCB is associated with an increased rate in pyuria and abnormal CRP. No difference was found in the rate of positive urine culture between higher and lower TCB levels. Significant bacteriuria was more common in older NH neonates. Septicemia is rare among well-appearing neonates with NH.

Ability of preschoolers to achieve maximal exercise and its correlation with oxygen uptake efficiency slope ∼ an observational study by direct cardiopulmonary exercise testing.

The oxygen uptake efficiency slope (OUES) is a well-established substitute for maximum oxygen uptake ((Equation is included in full-text article.)O2 max) in submaximal exercise effort among adolescents and adults. Few studies have analyzed the exercise capacity (EC) and OUES of children aged 4 to 6 (preschoolers). Body fat has been proved to negatively affect EC among schoolchildren. The purposes of this study were to assess the capacity of preschoolers in achieving (Equation is included in full-text article.)O2 max and evaluate the correlation of peak metabolic equivalent (peak MET) and peak oxygen consumption (peak O2) with OUES. We also evaluated if body fat affected EC among preschoolers.Forty-three preschoolers under the ramped Bruce protocol of treadmill exercise testing had been retrospectively studied. The criteria for achieving (Equation is included in full-text article.)O2 max included respiratory exchange ratio (RER) >1.1, heart rate (HR) >85% of age-predicted maximum, and HR >200 bpm. OUES was calculated by the 75% (OUES-75) and the entire (OUES-100) duration of the testing and normalized by body surface area. Body fat was measured using vector bioelectrical impedance analysis. The fat mass (FM) index and fat-free mass index (FFMI) were defined as FM or FFM (kg) divided by height squared (m), respectively.The mean age of the participants was 5.70 ±â€Š0.56. Seventy-nine percent of preschoolers met at least 1 criterion, 36.84% met 2 criteria, and none met all 3 criteria for (Equation is included in full-text article.)O2. OUES-75 was moderately positively correlated with peak MET (P = .034; Spearman's rho = 0.324) and peak O2 (P <.001; Spearman's rho = 0.667). OUES-100 was moderately to highly positively correlated with peak MET (P <.001; Spearman's rho = 0.592) and peak O2 (P <.001; Spearman's rho = 0.825). There were moderate to high positive correlations between FFMI and peak O2 (P <.001; Spearman's rho = 0.668), OUES-75 (P <.001; Spearman's rho = 0.642), and OUES-100 (P < .001; Spearman's rho = 0.670).None of the preschoolers reached all 3 criteria for (Equation is included in full-text article.)O2max. OUES-75 and OUES-100 might be indicators of peak O2 at submaximal effort. Preschoolers with higher FFMI had better EC during treadmill exercise testing.

Oxygen uptake efficiency slope and peak oxygen consumption predict prognosis in children with tetralogy of Fallot.

BACKGROUND: Oxygen uptake efficiency slope (OUES) and peak oxygen consumption (VO2peak) are exercise parameters that can predict cardiac morbidity in patients with numerous heart diseases. But the predictive value in patients with tetralogy of Fallot is still undetermined, especially in children. We evaluated the prognostic value of OUES and VO2peak in children with total repair of tetralogy of Fallot. DESIGN: Retrospective cohort study. METHODS: Forty tetralogy of Fallot patients younger than 12 years old were recruited. They underwent a cardiopulmonary exercise test during the follow-up period after total repair surgery. The results of the cardiopulmonary exercise test were used to predict the cardiac related hospitalization in the following two years after the test. RESULTS: OUES normalized by body surface area (OUES/BSA) and the percentage of predicted VO2peak appeared to be predictive for two-year cardiac related hospitalization. Receiver operating characteristic curve analysis demonstrated that the best threshold value for OUES/BSA was 1.029 (area under the curve = 0.70, p = 0.03), and for VO2peak was 74% of age prediction (area under the curve = 0.72, p = 0.02). The aforementioned findings were confirmed by Kaplan-Meier plots and log-rank test. CONCLUSIONS: OUES/BSA and VO2peak are useful predictors of cardiac-related hospitalization in children with total repair of tetralogy of Fallot.

Rapid onset of rhabdomyolysis after switching to a raltegravir-based antiretroviral regimen.

Raltegravir is the first integrase inhibitor antiretroviral agent that has been demonstrated to have antiviral efficacy and safety. However, the US Food and Drug Administration has recommended use with caution in patients with risk factors for rhabdomyolysis, based on four case reports of rhabdomyolysis in patients with identifiable risk factors. We present a 32-year-old Asian man with human immunodeficiency virus (HIV), but without other underlying diseases, who developed rapid-onset, raltegravir-associated rhabdomyolysis and hyperlactatemia. Our patient lacked predisposing factors for rhabdomyolysis, and the rapid onset time of 4 days was the shortest reported. Therefore, clinicians should exercise caution when using raltegravir and closely monitor all patients for the symptoms of muscle pain and weakness. This case has been reported to the National Adverse Drug Reactions Reporting System of the Department of Health in Taiwan.

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

Estrogen effects on skeletal muscle insulin-like growth factor 1 and myostatin in ovariectomized rats.

Previous work showed that estrogen replacement attenuates muscle growth in immature rats. The present study examined muscle insulin-like growth factor-1 (IGF-1) and myostatin expression to determine whether these growth regulators might be involved in mediating estrogen's effects on muscle growth. IGF-1 and myostatin message and protein expression in selected skeletal muscles from 7-week-old sham-ovariectomized (SHAM) and ovariectomized rats that received continuous estrogen (OVX/E2) or solvent vehicle (OVX/CO) from an implant for 1 week or 5 weeks was measured. In the 1-week study, ovariectomy increased IGF-1 mRNA expression in fast extensor digitorum longus and gastrocnemius muscles; the increase was reversed by estrogen replacement. A similar trend was observed in the slow soleus muscle, although the change was not statistically significant. In contrast to mRNA, muscle IGF-1 protein expression was not different between SHAM and OVX/ CO animals in the 1-week study. One week of estrogen replacement significantly decreased IGF-1 protein level in all muscles examined. Myostatin mRNA expression was not different among the 1-week treatment groups. One week of estrogen replacement significantly increased myostatin protein in the slow soleus muscle but not the fast extensor digitorum longus and gastrocnemius muscles. There was no treatment effect on IGF-1 and myostatin expression in the 5-week study; this finding suggested a transient estrogen effect or upregulation of a compensatory mechanism to counteract the estrogen effect observed at the earlier time point. This investigation is the first to explore ovariectomy and estrogen effects on skeletal muscle IGF-1 and myostatin expression. Results suggest that reduced levels of muscle IGF-1 protein may mediate estrogen's effect on growth in immature, ovariectomized rats. Increased levels of muscle myostatin protein may also have a role in mediating estrogen's effects on growth in slow but not fast skeletal muscle.

Estrogen response element-independent regulation of gene expression by genistein in intestinal cells.

Isoflavone, genistein, was shown to have antioxidant and antitumor activities. We have reported the stimulatory effect of genistein on the expression of antioxidant and metal-binding protein, metallothionein IIA (MTIIA), in human intestinal Caco-2 cells. Genistein has been shown to up-regulate the expression of other genes through estrogen response element (ERE) but the ERE sequence is not in the MTIIA promoter. In this paper, we investigated the ERE-independent mechanism that mediates the stimulatory effect of genistein. Genistein enhanced the expression of human MTIIA promoter (up to -426)-containing reporter genes, thus supporting a promoter-specific transcriptional regulation. A shorter MTIIA promoter (-83 to +27) was found to be able to mediate the full reporter gene response to genistein in a dose- and time-dependent fashion. Further deletion and mutation analysis revealed that the GC-rich Sp1 binding sequence was the target of the stimulation. Genistein was known to bind to estrogen receptors (ER). When cells were cotransfected with ER beta, the stimulatory effect of genistein on the reporter gene containing the GC-rich promoter sequence increased further and a similar result was observed for breast cancer MCF-7 cells. Inhibitors of protein kinase A could block the response to genistein but the phosphorylation of Sp1 protein per se was not affected by the genistein treatment. Our observation could help to evaluate the biological significance of genistein, which is used widely as a supplement.