T helper type 1 polarizing γδ T cells and Scavenger receptors contribute to the pathogenesis of Pemphigus vulgaris

γδ T cells and Scavenger receptors are key parts of the innate immune machinery, playing significant roles in regulating immune homeostasis at the epithelial surface. The roles of these immune components are not yet characterized for the autoimmune skin disorder Pemphigus vulgaris (PV). Phenotyping and frequency of γδ T cells estimated by flow cytometry have shown increased frequency of γδ T cells (6·7% versus 4·4%) producing interferon‐ γ (IFN‐γ; 35·2% versus 26·68%) in the circulation of patients compared with controls. Dual cytokine‐secreting (IFN‐γ and interleukin‐4) γδ T cells indicate the plasticity of these cells. The γδ T cells of patients with PV have shown higher cytotoxic potential and the higher frequency of γδ T cells producing IFN‐γ shows T helper type 1 polarization. The increased expression of Scavenger receptors expression (CD36 and CD163) could be contributing to the elevated inflammatory environment and immune imbalance in this disease. Targeting the inflammatory γδ T cells and Scavenger receptors may pave the way for novel therapeutics.     

Neurodegenerative disorders and gut-brain interactions

Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut-innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, are affected by or involved in the etiology of these debilitating and progressive disorders has been understudied. Studies in recent years have shown how CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other’s functions. These studies underscore the importance of exploring the gut-innervating and gut-brain connecting neurons of the CNS and gut function in health, as well as the etiology and progression of dysfunction in NDs. In this Review, we discuss our current understanding of how the various gut-innervating neurons and gut physiology are involved in the etiology of NDs, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, to cause progressive CNS and persistent gut dysfunction.

Neurodegenerative disorders (NDs) are chronic and progressive disorders that disproportionately affect the elderly and have been characterized by selective loss of neurons in the CNS (1). Their prevalence is increasing — partly owing to extensions in lifespan — and by 2030, individuals affected by NDs will account for more than 8 million patients in the United States (2). Various NDs can be characterized and differentiated by their primary clinical features, the anatomical location of the neurodegeneration, the various cell types they affect, and/or the principal molecular abnormality that causes them (3).Prior to the considerable progress made in recent years that will be discussed here, psychiatrists, neurologists, and gastroenterologists alike supported the idea of the existence of a disease called the “institutional colon.” This term described the presence of an amotile and/or elongated and largely distended colon with resulting gut dysfunctions in psychiatric patients who lived in mental health institutions (4). That such a disease existed was often questioned by contemporary physicians, and the confluence of gut and behavioral dysfunction was ascribed to the side effects of medicines, incorrect or inadequate diets, or inattention. To prove that the “institutional colon” is a true disease, Sonnenberg et al. (4) combed through millions of medical records at the US Veterans Affairs to show that patients with presenile dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), or Huntington’s disease (HD) had significantly higher odds of also experiencing colonic dysfunction. The authors pointed out that “not all neurons involved in control of intestinal motility are located within the enteric nervous system, but may originate, for instance, in the vagal nuclei at the medulla oblongata or in the sacral segments of the spinal cord” and that “any referral to the loss of neuronal control of colonic motility does not allude to a common pathway, and leaves a multitude of heterogeneous mechanisms possible” (4). This landmark study showing the involvement of both gut and brain dysfunction in NDs paved the way for the studies discussed in this Review.Here, we review the processes associated with ND etiology and how various gut-innervating and gut-brain connecting neurons are either affected in NDs or are involved in their etiology. We also review the role of microbiota in driving NDs and discuss some open questions in this field. This Review will focus on the classical NDs — PD, AD, HD, and ALS — given that these are not only the major NDs but are also the diseases for which substantial information is available about associated gut dysfunctions.     

Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women

PROBLEM: Despite progress in immunobiology, pre-eclampsia (PE) remains one of the most common reasons for women to die during pregnancy. The widespread pathophysiological mechanisms are endothelial dysfunction, oxidative stress and inflammation. The aim of this study was to assess the alteration in the levels of leptin, interleukin (IL)-10 and inflammatory cytokines [tumour necrosis factor (TNF)-alpha, IL-6 & IL-8] in pre-eclamptic (severe and mild), healthy pregnant and non-pregnant women and correlate these parameters with disease severity. METHOD OF STUDY: The levels of leptin, IL-10 and inflammatory cytokines were measured by high sensitivity enzyme-linked immunoabsorbant assay. The study subjects were 54 pre-eclamptic women (ten severe and 45 milder), compared by age matched 50 healthy pregnant and 27 non-pregnant women. Kruskal-Wallis non-parametric analyses of variance followed by Mann-Whitney U-test were used for statistical analysis. RESULTS: The levels of leptin, TNF-alpha, IL-6 & IL-8 in pre-eclamptic subjects were increased significantly when compared with the healthy control pregnant and non-pregnant (P < 0.000). The concentration of IL-10 has shown different pattern as its level decreased significantly (0.001) in pre-eclamptic women (overall) in comparison with control subjects (pregnant & non-pregnant). A combination of 80% or higher sensitivity and specificity was seen in the parameters analysed, except IL-8 and IL-10. CONCLUSION: Our findings suggest a relationship among TNF-alpha, IL-6, IL-8, IL-10 and leptin and indicate that altered levels of above markers in PE might be used as markers of pro-inflammation/anti-inflammation and endothelial dysfunction in pre-eclamptic pregnancies. These results also advocate the abnormal leptin and cytokine responses in mother, which might be involved in the pathogenesis of PE.     

Regular vs ad-lib albuterol for patients hospitalized with acute asthma

STUDY OBJECTIVES: Inhaled, short-acting beta-agonists and systemic corticosteroids form the mainstay of therapy in acute asthma exacerbation. Asthma, however, is an inflammatory disease of the airways, and its underlying pathology is not impacted by short-acting beta-agonists. While the efficacy of ad-lib beta-agonist administration in outpatient management of asthma symptoms is well established, little data exist to support this strategy in patients with acute, severe asthma. We postulate that as long as patients hospitalized with severe asthma exacerbation receive systemic corticosteroids, regular, scheduled administration of short-acting beta-agonists is unnecessary. Similar therapeutic outcomes can be achieved with the ad-lib administration of the short-acting beta-agonists. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Pulmonary floor of a 600-bed municipal hospital.Patients or participants: Sixty-two patients hospitalized for acute asthma. INTERVENTIONS: Patients were randomized to receive either albuterol nebulizations (regular albuterol group) or saline solution nebulizations (ad-lib group) every 4 h with management of breakthrough symptoms with albuterol metered-dose inhaler or nebulizations for both groups. All patients received systemic corticosteroids. Peak expiratory flows, asthma symptoms, and need for rescue bronchodilator were followed up on each patient until discharge. RESULTS: There was no significant difference in the length of hospitalization (median length, 48 h for ad-lib group vs 57.5 h for regular albuterol group, p = 0.82), rate of improvement in peak flow, or symptoms between the two groups. Ad-lib beta-agonist use compared to regular albuterol scheduled use resulted in a significant reduction in the total number of albuterol treatments administered (median, 7 treatments vs 19 treatments, p = 0.001) during hospitalization. CONCLUSIONS: In the management of asthma exacerbation, ad-lib administration of albuterol is therapeutically as effective as regular, scheduled administration. This method of drug administration also reduces the total dose of beta-agonists received by the hospitalized patient.     

The impact of food order on postprandial glycaemic excursions in prediabetes

Data suggest that nutrient order during a meal significantly impacts postprandial glucose and insulin excursions in type 2 diabetes, while its effects in prediabetes have not been reported. Fifteen participants with prediabetes consumed the same meal on 3 days in random order: carbohydrate first, followed 10 minutes later by protein and vegetables (CF); protein and vegetables first, followed 10 minutes later by carbohydrate (PVF); or vegetables first followed by protein and carbohydrate (VF). Blood was sampled for glucose and insulin measurements at 0, 30, 60, 90, 120, 150 and 180 minutes. Incremental glucose peaks were similarly attenuated by >40% in the PVF and VF meal conditions compared with CF. The incremental area under the curve for glucose was 38.8% lower following the PVF meal order, compared with CF, and postprandial insulin excursions were significantly lower in the VF meal condition compared with CF. The CF meal pattern showed marked glycaemic variability whereas glucose levels were stable in the PVF and VF meal conditions. Food order presents a novel, simple behavioural strategy to reduce glycaemic excursions in prediabetes.     

Efficacy and Cost Comparisons of Bronchodilatator Administration Between Metered Dose Inhalers with Disposable Spacers and Nebulizers for Acute Asthma Treatment

Background: Despite demonstration of equivalent efficacy of beta agonist delivery using a metered dose inhaler (MDI) with spacer vs. nebulizer in asthma patients, use of a nebulizer remains standard practice. Objectives: We hypothesize that beta agonist delivery with a MDI/disposable spacer combination is an effective and low-cost alternative to nebulizer delivery for acute asthma in an inner-city population. Methods: This study was a prospective, randomized, double-blinded, placebo-controlled trial with 60 acute asthma adult patients in two inner-city emergency departments. Subjects (n = 60) received albuterol with either a MDI/spacer combination or nebulizer. The spacer group (n = 29) received albuterol by MDI/spacer followed by placebo nebulization. The nebulizer group (n = 29) received placebo by MDI/spacer followed by albuterol nebulization. Peak flows, symptom scores, and need for rescue bronchodilatator were monitored. Median values were compared with the Kolmogorov-Smirnov test. Results: Patients in the two randomized groups had similar baseline characteristics. The severity of asthma exacerbation, median peak flows, and symptom scores were not significantly different between the two groups. The median (interquartile range) improvement in peak flow was 120 (75–180) L/min vs. 120 (80–155) L/min in the spacer and nebulizer groups, respectively (p = 0.56). The median improvement in the symptom score was 7 (5–9) vs. 7 (4–9) in the spacer and nebulizer groups, respectively (p = 0.78). The median cost of treatment per patient was $10.11 ($10.03–$10.28) vs. $18.26 ($9.88–$22.45) in the spacer and nebulizer groups, respectively (p < 0.001). Conclusion: There is no evidence of superiority of nebulizer to MDI/spacer beta agonist delivery for emergency management of acute asthma in the inner-city adult population. MDI/spacer may be a more economical alternative to nebulizer delivery.