Guardian crypt-base-goblet-cells protect the human colonic stem cell niche by triggering cholinergic calcium signal-dependent MUC2 secretion and luminal flushing

Mucus secreting goblet cells play a vital role in the maintenance of tissue homeostasis. Here we report the discovery of an enigmatic mechanism for the generation of calcium signals that couple cholinergic input to secretion of hydrated mucus in the human colonic stem cell niche. Mechanistic insights for this study were derived from native human colonic crypts and crypt-like organoids expressing MUC2-mNEON. Importantly, we demonstrate that the human colonic stem cell niche is also a cholinergic niche, and that activation of muscarinic receptors initiates calcium signals at the apical pole of intestinal stem cells and neighbouring crypt-base-goblet-cells. The calcium signal trigger zone is defined by a microdomain of juxtaposed calcium stores expressing TPC1 and InsP3R3 calcium channels. Co-activation of TPC1 and InsP3R3 is required for generation of cholinergic calcium signals and downstream secretion of hydrated mucus, which culminates in the flushing of the colonic stem cell niche.

Seizures and Sepsis: A Narrative Review

Patients with sepsis-associated encephalopathy (SAE) can develop convulsive or nonconvulsive seizures. The cytokine storm and the overwhelming systemic inflammation trigger the electric circuits that promote seizures. Several neurologic symptoms, associated with this disease, range from mild consciousness impairment to coma. Focal or generalized convulsive seizures are frequent in sepsis, although nonconvulsive seizures (NCS) are often misdiagnosed and prevalent in SAE. In order to map the trigger zone in all patients that present focal or generalized seizures and also to detect NCS, EEG is indicated but continuous EEG (cEEG) is not very widespread; timing, duration, and efficacy of this tool are still unknown. The long-term risk of seizures in survivors is increased. The typical stepwise approach of seizures management begins with benzodiazepines and follows with anticonvulsants up to anesthetic drugs such as propofol or thiopental, which are able to induce burst suppression and interrupt the pathological electrical circuits. This narrative review discusses pathophysiology, clinical presentation, diagnosis and treatment of seizures in sepsis.

Mucoadhesive Buccal Patch Role in Emesis: Tweaked up by the Pivotal Permeation Enhancer: Sodium Lauryl Sulphate

Background: It has been observed that several diseases either acute or chronic have a specific symptom that is emesis. Emesis leads to depletion and removal of several salts and biological essentials required in the body. Domperidone is a D2 receptor antagonist, which triggers the chemoreceptor trigger zone (CTZ) and hence used in the management of nausea and vomiting. Objective: The objective of this project was to formulate a buccal patch of domperidone with the use of several polymers with a permeation enhancer. Since the oral bioavailability of domperidone is low due to gastric degradation, hence a buccal patch was prepared to determine its bioavailability. The purpose of this study was to formulate a buccal patch for better bioavailability and observe the effect of permeation enhancer with polymers. Method: The mucoadhesive buccal patch was prepared using the solvent cast method. The characterization studies were done along with the drug content and compatibility studies through FTIR. Results: It was observed that the polymers; sodium carboxy methyl cellulose (SCMC) & polyvinyl alcohol(PVA) without sodium lauryl sulphate (SLS) had low drug release, which was around 68% and 72%, respectively whereas polymers with SLS had markedly increased drug release, which was around 89% and 91%, respectively. Conclusion: In order to obtain the maximum therapeutic efficacy of domperidone, buccal patches are considered much more beneficial than oral dosage form. Permeation enhancer also helps to synergize the effect of polymers which helps in better drug release and ultimately leads to better bioavailability.

Gastroenterology

Nausea and vomiting can be defined, respectively, as the urge to or the actual act of expelling undigested food from the stomach. It is thought to be an evolutionary defence mechanism to protect against toxic insult (drugs or mi­crobes) and over- eating, while it can also be triggered during pregnancy, or by unpleasant sights or smells. In some instances, it may be the symptom of a more severe underlying pathology. Severity of nausea and vomiting varies considerably between individuals exposed to the same stimulus and symptoms can be highly detrimental to patient quality of life affecting not only their nutritional intake, but also mood and well- being. Although nausea itself is a subjective term, vomiting is a pathophysiological reflex triggered by the vomiting centre located in the medulla. The vomiting centre re­ceives signals from a number of afferent inputs, i.e. the chemoreceptor trigger zone (CTZ), vestibular nucleus, ab­dominal and cardiac vagal afferents, and cerebral cortex (Table 6.1). It may also be activated by hormonal triggers, which accounts for hyperemesis in pregnancy, and the increased incidence of nausea and vomiting associated with the female gender. As the vomiting centre is located close to centres responsible for salivation and breathing, vomiting is often associated with hypersalivation and hyperventilation. The CTZ is highly vascularized and lo­cated at the floor of the fourth ventricle, just outside the blood– brain barrier and, therefore, is itself directly sensi­tive to chemical stimuli. Afferent inputs activate the vomiting centre through several known neurotransmitter pathways; dopamine (D₂), serotonin (5- HT₃, 5- HT₄), acetylcholine (ACh), and substance P (neurokinin 1; NK₁). Each of which provides a potential pharmacological target in the management of nausea and vomiting, once the cause has been established. Efferent pathways from the vomiting centre induce autonomic changes, including vasoconstriction, pallor, tachycardia, salivation, sweating, and relaxation of the lower oesophagus and fundus of the stomach. In vomiting, oesophageal relaxation leads to contraction of the pyloric sphincter, thereby emptying the contents of the jejunum, duodenum, and pyloric stomach into the relaxed fundus. Coordination of muscle contraction occurs within the dia­phragm and abdomen, and retrograde contractions from the intestine then expel the contents of the fundus.

Trigeminal Neuralgia: Microvascular Decompression is the Ultimate Answer

Trigeminal neuralgia also known as ‘Fothergill’s disease’ or ‘tic douloureux’ is a very peculiar disease. The severe pain is paroxystic and can be triggered by a mild cutaneous stimulus on the face or “trigger zone”. The disease has a wide variety of etiology and clinical presentation. The management will include both medical and a surgical approach. A 58-year-old female patient had reported with a complaint of pain for 8 years. On thorough history taking and clinical examination, we were able to confirm the final diagnosis as trigeminal neuralgia (TN). We present a case of trigeminal neuralgia of the maxillary and mandibular division along with clinical history, MRI (Magnetic Resonance Imaging) findings and treatment approach. Bang. J Neurosurgery 2019; 8(2): 105-107

Associations of vomiting and antiemetic use in pregnancy with levels of circulating GDF15 early in the second trimester: A nested case-control study

Background: Although nausea and vomiting are very common in pregnancy, their pathogenesis is poorly understood. We tested the hypothesis that circulating growth and differentiation factor 15 (GDF15) concentrations in early pregnancy, whose gene is implicated in hyperemesis gravidarum, are associated with nausea and vomiting. Methods: Blood samples for the measurement of GDF15 and human chorionic gonadotrophin (hCG) concentrations were obtained early in the second trimester (median 15.1 (interquartile range 14.4-15.7) weeks) of pregnancy from 791 women from the Cambridge Baby Growth Study, a prospective pregnancy and birth cohort. During each trimester participants completed a questionnaire which included questions about nausea, vomiting and antiemetic use. Associations with pre-pregnancy body mass indexes (BMI) were validated in 231 pregnant NIPTeR Study participants. Results: Circulating GDF15 concentrations were higher in women reporting vomiting in the second trimester than in women reporting no pregnancy nausea or vomiting: 11,581 (10,977-12,219) (n=175) vs. 10,593 (10,066-11,147) (n=193) pg/mL, p=0.02). In women who took antiemetic drugs during pregnancy (n=11) the GDF15 levels were also raised 13,157 (10,558-16,394) pg/mL (p =0.04). Serum GFD15 concentrations were strongly positively correlated with hCG levels but were inversely correlated with maternal BMIs, a finding replicated in the NIPTeR Study. Conclusions: Week 15 serum GDF15 concentrations are positively associated with second trimester vomiting and maternal antiemetic use in pregnancy. Given GDF15’s site of action in the chemoreceptor trigger zone of the brainstem and its genetic associations with hyperemesis gravidarum, these data support the concept that GDF15 may be playing a pathogenic role in pregnancy-associated vomiting.

How do we prevent the burden of extremely harmful and clinically nonbeneficial drug–drug interactions among chronic kidney disease patients?

The chronic intake of different medications by chronic kidney disease (CKD) patients predisposes them to extremely harmful and clinically nonbeneficial drug–drug interactions (DDIs) which can ultimately lead to increase in morbidity, mortality, healthcare cost, and frequency and length of hospitalization. This produces a negative deteriorating and counter-efficient outcome on the health, quality of life and treatment response of these patients. This was an 18-month prospective descriptive study that reviewed the medical case records of consented adult CKD patients attending the Nephrology medical outpatient clinic of a Nigerian Tertiary Healthcare Centre from January 2015 to June 2016. The Medscape drug reference database was used to evaluate patients’ medications for extremely harmful, clinically nonbeneficial DDIs. This study involved 123 consented adult CKD patients comprising of 82 (66.67%) males and 41 (33.33%) females with a mean age of 53.81 ± 16.03 years. In this study, the prevalence of extremely harmful, clinically nonbeneficial DDIs (type D or type X interaction categories only) was 24.4%, while the overall prevalence for all the observed DDIs was 95.9%. The most frequent extremely harmful, clinically nonbeneficial DDIs in this study was between α-methyldopa and metoclopramide: 16 (0.9%) interactions in eight (6.5%) patients. Furthermore, α-methyldopa decreases the antiemetic effects of metoclopramide by pharmacodynamics antagonism at the chemoreceptor trigger zone site D2-receptors (type X; pharmacodynamics). In addition, metoclopramide decreases the level of α-methyldopa by inhibition of gastrointestinal tract (GIT) absorption, as this applies to only oral formulations of both agents (type D; pharmacokinetic). The occurrence and burden of extremely harmful, clinically nonbeneficial DDIs is significantly high among these CKD patients. There is also a critical need to minimize the number of prescribed medications for these patients in order to optimize their care.