Insulin Use During Gestational and Pre-existing Diabetes in Pregnancy: A Systematic Review of Study Design.

INTRODUCTION: Insulin is the first-line pharmacologic therapy for women with diabetes in pregnancy. However, conducting well-designed randomized clinical trials (RCTs) and achieving recommended glycemic targets remains a challenge for this unique population. This systematic literature review (SLR) aimed to understand the evidence for insulin use in pregnancy and the outcome metrics most often used to characterize its effect on glycemic, maternal and fetal outcomes in gestational diabetes mellitus (GDM) and in pregnant women with diabetes. METHODS: An SLR was conducted using electronic databases in Medline, EMBASE via Ovid platform, evidence-based medicine reviews (2010-2020) and conference proceedings (2018-2019). Studies were included if they assessed the effect of insulin treatment on glycemic, maternal or fetal outcomes in women with diabetes in pregnancy. Studies on any type of diabetes other than gestational or pre-existing diabetes as well as non-human studies were excluded. RESULTS: In women diagnosed with GDM or pre-existing diabetes, most studies compared treatment of insulin with metformin (n = 35) followed by diet along with lifestyle intervention (n = 24) and glibenclamide (n = 12). Most studies reporting on glycemic outcomes compared insulin with metformin (n = 22) and glibenclamide (n = 4). Fasting blood glucose was the most reported clinical outcome of interest. Among the studies reporting maternal outcomes, method of delivery and delivery complications were most commonly reported. Large for gestational age, stillbirth and perinatal mortality were the most common fetal outcomes reported. CONCLUSION: This SLR included a total of 108 clinical trials and observational studies with diverse populations and treatment arms. Outcomes varied across the studies, and a lack of consistent outcome measures to manage diabetes in pregnant women was observed. This elucidates a need for global consensus on study design and standardized clinical, maternal and fetal outcomes metrics.

SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling.

Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5+ adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines.

The Battle against COVID 19 Pandemic: What we Need to Know Before we "Test Fire" Ivermectin.

The world is faced with the dire challenge of finding an effective treatment against the rampaging COVID 19 pandemic. Amidst the crisis, reports of in vitro inhibitory activity of ivermectin, an approved anthelmintic, against the causative SARSCoV2 virus, have generated lot of optimism. In this article, we have fished and compiled the needed information on the drug, that will help readers and prospective investigators in having a quick overview. Though the primordial biological action of the drug is allosteric modulation of helminthic ion channel receptor, its in vitro activity against both RNA and DNA viruses is known for almost a decade. In the past two years, efficacy study in animal models of pseudorabies and zika virus was found to be favourable and unfavourable respectively. Only one clinical study evaluated the drug in dengue virus infection without any clinical efficacy. However, the proposed mechanism of drug action, by inhibiting the importin family of nucleus-cytoplasmic transporters along with favourable pharmacokinetics, warrants exploration of its role in COVID 19 through safely conducted clinical trials. Being an available and affordable drug, enlisted in WHO List of Essential Medicine, and a long track record of clinical safety, the drug is already in clinical trials the world over. As the pandemic continues to ravage human civilisation with unabated intensity, the world eagerly waits for a ray of hope emanating from the outcome of the ongoing trials with ivermectin as well as other drugs.

Extensive Recovery of Embryonic Enhancer and Gene Memory Stored in Hypomethylated Enhancer DNA.

Developing and adult tissues use different cis-regulatory elements. Although DNA at some decommissioned embryonic enhancers is hypomethylated in adult cells, it is unknown whether this putative epigenetic memory is complete and recoverable. We find that, in adult mouse cells, hypomethylated CpG dinucleotides preserve a nearly complete archive of tissue-specific developmental enhancers. Sites that carry the active histone mark H3K4me1, and are therefore considered "primed," are mainly cis elements that act late in organogenesis. In contrast, sites decommissioned early in development retain hypomethylated DNA as a singular property. In adult intestinal and blood cells, sustained absence of polycomb repressive complex 2 indirectly reactivates most-and only-hypomethylated developmental enhancers. Embryonic and fetal transcriptional programs re-emerge as a result, in reverse chronology to cis element inactivation during development. Thus, hypomethylated DNA in adult cells preserves a "fossil record" of tissue-specific developmental enhancers, stably marking decommissioned sites and enabling recovery of this epigenetic memory.

The lineage-specific transcription factor CDX2 navigates dynamic chromatin to control distinct stages of intestine development.

Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic loss of CDX2 triggers homeotic transformation of intestinal fate, whereas adult-onset loss compromises crucial physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program; rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or mature intestinal function. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

Loss of Hepatic Oscillatory Fed microRNAs Abrogates Refed Transition and Causes Liver Dysfunctions.

Inability to mediate fed-fast transitions in the liver is known to cause metabolic dysfunctions and diseases. Intuitively, a failure to inhibit futile translation of state-specific transcripts during fed-fast cycles would abrogate dynamic physiological transitions. Here, we have discovered hepatic fed microRNAs that target fasting-induced genes and are essential for a refed transition. Our findings highlight the role of these fed microRNAs in orchestrating system-level control over liver physiology and whole-body energetics. By targeting SIRT1, PGC1α, and their downstream genes, fed microRNAs regulate metabolic and mitochondrial pathways. MicroRNA expression, processing, and RISC loading oscillate during these cycles and possibly constitute an anticipatory mechanism. Fed-microRNA oscillations are deregulated during aging. Scavenging of hepatic fed microRNAs causes uncontrolled gluconeogenesis and failure in the catabolic-to-anabolic switching upon feeding, which are hallmarks of metabolic diseases. Besides identifying mechanisms that enable efficient physiological toggling, our study highlights fed microRNAs as candidate therapeutic targets.

Enhancer, transcriptional, and cell fate plasticity precedes intestinal determination during endoderm development.

After acquiring competence for selected cell fates, embryonic primordia may remain plastic for variable periods before tissue identity is irrevocably determined (commitment). We investigated the chromatin basis for these developmental milestones in mouse endoderm, a tissue with recognizable rostro-caudal patterning and transcription factor (TF)-dependent interim plasticity. Foregut-specific enhancers are as accessible and active in early midgut as in foregut endoderm, and intestinal enhancers and identity are established only after ectopic cis-regulatory elements are decommissioned. Depletion of the intestinal TF CDX2 before this cis element transition stabilizes foregut enhancers, reinforces ectopic transcriptional programs, and hence imposes foregut identities on the midgut. Later in development, as the window of chromatin plasticity elapses, CDX2 depletion weakens intestinal, without strengthening foregut, enhancers. Thus, midgut endoderm is primed for heterologous cell fates, and TFs act on a background of shifting chromatin access to determine intestinal at the expense of foregut identity. Similar principles likely govern other fate commitments.

Homeopathy for Allergic Rhinitis: A Systematic Review.

OBJECTIVE: The aim of this study was to evaluate the efficacy and effectiveness of homeopathic intervention in the treatment of seasonal or perennial allergic rhinitis (AR). METHOD: Randomized controlled trials evaluating all forms of homeopathic treatment for AR were included in a systematic review (SR) of studies published up to and including December 2015. Two authors independently screened potential studies, extracted data, and assessed risk of bias. Primary outcomes included symptom improvement and total quality-of-life score. Treatment effect size was quantified as mean difference (continuous data), or by risk ratio (RR) and odds ratio (dichotomous data), with 95% confidence intervals (CI). Meta-analysis was performed after assessing heterogeneity and risk of bias. RESULTS: Eleven studies were eligible for SR. All trials were placebo-controlled except one. Six trials used the treatment approach known as isopathy, but they were unsuitable for meta-analysis due to problems of heterogeneity and data extraction. The overall standard of methods and reporting was poor: 8/11 trials were assessed as "high risk of bias"; only one trial, on isopathy for seasonal AR, possessed reliable evidence. Three trials of variable quality (all using Galphimia glauca for seasonal AR) were included in the meta-analysis: nasal symptom relief at 2 and 4 weeks (RR = 1.48 [95% CI 1.24-1.77] and 1.27 [95% CI 1.10-1.46], respectively) favored homeopathy compared with placebo; ocular symptom relief at 2 and 4 weeks also favored homeopathy (RR = 1.55 [95% CI 1.33-1.80] and 1.37 [95% CI 1.21-1.56], respectively). The single trial with reliable evidence had a small positive treatment effect without statistical significance. A homeopathic and a conventional nasal spray produced equivalent improvements in nasal and ocular symptoms. CONCLUSIONS: The low or uncertain overall quality of the evidence warrants caution in drawing firm conclusions about intervention effects. Use of either Galphimia glauca or a homeopathic nasal spray may have small beneficial effects on the nasal and ocular symptoms of AR. The efficacy of isopathic treatment of AR is unclear.

Central metabolic sensing remotely controls nutrient-sensitive endocrine response in Drosophila via Sir2/Sirt1-upd2-IIS axis.

Endocrine signaling is central in coupling organismal nutrient status with maintenance of systemic metabolic homeostasis. While local nutrient sensing within the insulinogenic tissue is well studied, distant mechanisms that relay organismal nutrient status in controlling metabolic-endocrine signaling are less well understood. Here, we report a novel mechanism underlying the distant regulation of the metabolic endocrine response in Drosophila melanogaster We show that the communication between the fat body and insulin-producing cells (IPCs), important for the secretion of Drosophila insulin-like peptides (dILPs), is regulated by the master metabolic sensor Sir2/Sirt1. This communication involves a fat body-specific direct regulation of the JAK/STAT cytokine upd2 by Sir2/Sirt1. We have also uncovered the importance of this regulation in coupling nutrient inputs with dILP secretion, and distantly controlling insulin/IGF signaling (IIS) in the intestine. Our results provide fundamental mechanistic insights into the top-down control involving tissues that play key roles in metabolic sensing, endocrine signaling and nutrient uptake.

Reduction of Cullin-2 in somatic cells disrupts differentiation of germline stem cells in the Drosophila ovary.

Signaling from a niche consisting of somatic cells is essential for maintenance of germline stem cells (GSCs) in the ovary of Drosophila. Decapentaplegic (Dpp), a type of bone morphogenetic protein (BMP) signal, emanating from the niche, is the most important signal for this process. Cullin proteins constitute the core of a multiprotein E3-ligase important for their functions viz. degradation or modification of proteins necessary for different cellular processes. We have found that a Cullin protein called Cullin-2 (Cul-2) expresses in both somatic and germline cells of the Drosophila ovary. Reduction of Cul-2 in somatic cells causes upregulation of Dpp signal and produces accumulation of extra GSC-like cells inside germarium, the anteriormost structure of the ovary. Our results suggest that Cullin-2 protein present in the somatic cells is involved in a non cell-autonomous regulation of the extent of Dpp signaling and thus controls the differentiation of GSCs to cystoblasts (CBs).

Homeopathy for allergic rhinitis: protocol for a systematic review.

BACKGROUND: Allergic rhinitis is a global health problem that is often treated with homeopathy. The objective of this review will be to evaluate the effectiveness of homeopathic treatment of allergic rhinitis. METHODS/DESIGN: The authors will conduct a systematic review. We will search Medline, CENTRAL, CINAHL, EMBASE, AMED, CAM-Quest, Google Scholar and reference lists of identified studies up to December 2013.The review will include randomized controlled trials that evaluate homeopathic treatment of allergic rhinitis. Studies with participants of all ages, with acute or chronic comorbidities will be included. Patients with immunodeficiency will not be included. The diagnosis will be based on the published guidelines of diagnosis and classification. Studies of all homeopathy modalities (clinical, complex and classical homeopathy, and isopathy) will be included. We will include trials with both active controls (conventional therapy, standard care) and placebo controls.The primary outcomes are: an improvement of global symptoms recorded in validated daily or weekly diaries and any scores from validated visual analogue scales; the total Quality of Life Score (such as the Juniper RQLQ);individual symptoms scores which include any appropriate measures of nasal obstruction, runny nose, sneezing, itching, and eye symptoms; and number of days requiring medication. Secondary outcomes selected will include serum immunoglobin E (IgE) levels, individual ocular symptoms, adverse events, and the use of rescue medication.Treatment effects will be measured by calculating the mean difference and the standardized mean difference with 95% confidence interval (CI) for continuous data. Risk ratio or, if feasible, odds ratio will be calculated with 95% CI for dichotomous data. After assessing clinical and statistical heterogeneity, meta-analysis will be performed, if appropriate. The individual participant will be the unit of analysis. Descriptive information on missing data will be included about participants missing due to drop out, whether there was intention to treat or per protocol analysis and missing statistics. A number of subgroups, homeopathic potency, age groups, and types of allergic rhinitis (seasonal or perennial) will be analyzed. Sensitivity analysis will be performed to explore the impact of risk of bias on overall treatment effect. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013006741.

SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK.

Efficient coupling of cellular energy production to metabolic demand is crucial to maintain organismal homeostasis. Here, we report that the mitochondrial Sirtuin Sirt4 regulates mitochondrial ATP homeostasis. We find that Sirt4 affects mitochondrial uncoupling via the adenine nucleotide translocator 2 (ANT2). Loss of Sirt4 expression leads to decreased cellular ATP levelsin vitro and in vivo while Sirt4 overexpression is associated with increased ATP levels. Further, we provide evidence that lack of Sirt4 activates a retrograde signaling response from the mitochondria to the nucleus that includes AMPK, PGC1α, key regulators of ß-oxidation such as Acetyl-CoA carboxylase, and components of the mitochondrial respiratory machinery. This study highlights the ability of Sirt4 to regulate ATP levels via ANT2 and a feedback loop involving AMPK.

Fat body dSir2 regulates muscle mitochondrial physiology and energy homeostasis nonautonomously and mimics the autonomous functions of dSir2 in muscles.

Sir2 is an evolutionarily conserved NAD(+)-dependent deacetylase which has been shown to play a critical role in glucose and fat metabolism. In this study, we have perturbed Drosophila Sir2 (dSir2) expression, bidirectionally, in muscles and the fat body. We report that dSir2 plays a critical role in insulin signaling, glucose homeostasis, and mitochondrial functions. Importantly, we establish the nonautonomous functions of fat body dSir2 in regulating mitochondrial physiology and insulin signaling in muscles. We have identified a novel interplay between dSir2 and dFOXO at an organismal level, which involves Drosophila insulin-like peptide (dILP)-dependent insulin signaling. By genetic perturbations and metabolic rescue, we provide evidence to illustrate that fat body dSir2 mediates its effects on the muscles via free fatty acids (FFA) and dILPs (from the insulin-producing cells [IPCs]). In summary, we show that fat body dSir2 is a master regulator of organismal energy homeostasis and is required for maintaining the metabolic regulatory network across tissues.

Small changes, big effects: chromatin goes aging.

Aging is a complex trait and is influenced by multiple factors that are both intrinsic and extrinsic to the organism (Kirkwood et al. 2000; Knight 2000). Efforts to understanding the mechanisms that extend or shorten lifespan have been made since the early twentieth century. Aging is characteristically associated with a progressive decline in the overall fitness of the organism. Several studies have provided valuable information about the molecular events that accompany this process and include accumulation of nuclear and mitochondrial mutations, shortened and dysfunctional telomeres, oxidative damage of protein/DNA, senescence and apoptosis (Muller 2009). Clinical studies and work on model organisms have shown that there is an increased susceptibility to conditions such as neurological disorders, diabetes, cardiovascular diseases, degenerative syndromes and even cancers, with age (Arvanitakis et al. 2006; Lee and Kim 2006; Rodriguez and Fraga 2010).

dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner.

Sir2, an evolutionarily conserved NAD(+)-dependent deacetylase, has been implicated as a key factor in mediating organismal life span. However, recent contradictory findings have brought into question the role of Sir2 and its orthologs in regulating organismal longevity. In this study, we report that Drosophila Sir2 (dSir2) in the adult fat body regulates longevity in a diet-dependent manner. We used inducible Gal4 drivers to knock down and overexpress dSir2 in a tissue-specific manner. A diet-dependent life span phenotype of dSir2 perturbations (both knockdown and overexpression) in the fat body, but not muscles, negates the effects of background genetic mutations. In addition to providing clarity to the field, our study contrasts the ability of dSir2 in two metabolic tissues to affect longevity. We also show that dSir2 knockdown abrogates fat-body dFOXO-dependent life span extension. This report highlights the importance of the interplay between genetic factors and dietary inputs in determining organismal life spans.

dSir2 deficiency in the fatbody, but not muscles, affects systemic insulin signaling, fat mobilization and starvation survival in flies.

Sir2 is an evolutionarily conserved NAD+ dependent protein. Although, SIRT1 has been implicated to be a key regulator of fat and glucose metabolism in mammals, the role of Sir2 in regulating organismal physiology, in invertebrates, is unclear. Drosophila has been used to study evolutionarily conserved nutrient sensing mechanisms, however, the molecular and metabolic pathways downstream to Sir2 (dSir2) are poorly understood. Here, we have knocked down endogenous dSir2 in a tissue specific manner using gene-switch gal4 drivers. Knockdown of dSir2 in the adult fatbody leads to deregulated fat metabolism involving altered expression of key metabolic genes. Our results highlight the role of dSir2 in mobilizing fat reserves and demonstrate that its functions in the adult fatbody are crucial for starvation survival. Further, dSir2 knockdown in the fatbody affects dilp5 (insulin-like-peptide) expression, and mediates systemic effects of insulin signaling. This report delineates the functions of dSir2 in the fatbody and muscles with systemic consequences on fat metabolism and insulin signaling. In conclusion, these findings highlight the central role that fatbody dSir2 plays in linking metabolism to organismal physiology and its importance for survival.