The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction

A variety of contractile agonists trigger activation of the small GTPase RhoA. An important target of activated RhoA in smooth muscle is Rho-associated kinase (ROK), one of the downstream targets that is the myosin binding subunit (MYPT1) of myosin light chain phosphatase (MLCP). Phosphorylation of MYPT1 at T695 by activated ROK results in a decrease in phosphatase activity of MLCP and an increase in myosin light chain (LC20) phosphorylation catalyzed by Ca²⁺/calmodulin-dependent myosin light chain kinase and/or a distinct Ca²⁺-independent kinase. LC20 phosphorylation in turn triggers cross-bridge cycling and force development. ROK also phosphorylates the cytosolic protein CPI-17 (at T38), which thereby becomes a potent inhibitor of MLCP. The RhoA/ROK pathway has been implicated in the tonic phase of force maintenance in response to various agonists, with no evident role in the phasic response, suggesting this pathway as a potential target for antihypertensive therapy. Indeed, ROK inhibitors restore normal blood pressure in several rat hypertensive models.     

Paget von Schroetter Syndrome Secondary to Exotic Dancing: A Case Study

Axillary vein thrombosis, or Paget von Schroetter syndrome, is a rare clinical condition. It is associated with several thrombogenic states and numerous sporting activities involving excessive use of the arm. We report one such case associated with exotic dancing. In societies where dancing involves excessive arm movement, the physician must be aware of this condition to permit early diagnosis and effective treatment.     

The Effect of Left Ventricular Assist Device Therapy on Cardiac Biomarkers: Implications for the Identification of Myocardial Recovery

Purpose of Review

Left ventricular assist device (LVAD) therapy serves as mainstay therapy for bridge to transplantation and destination therapy. Evidence is now mounting on the role of LVAD therapy as bridge to recovery. In the current review, we will summarize the data on biomarkers of myocardial recovery following LVAD implantation.

Recent Findings

Myocardial recovery can occur spontaneously, following pharmacological intervention and in the setting of mechanical circulatory support such as LVAD. Several biomarkers such as B-type natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), ST2, etc. have been identified and are being used to guide medical therapy in heart failure (HF) patients. However, recent data raised concern that those biomarkers may not be helpful in managing heart failure patients in general, and as such questioned their use in the advanced heart failure population. At this point, the use of biomarker to identify patients with myocardial recovery during LVAD support has not been established, and LVAD explantation remains a decision driven by echocardiographic and hemodynamics improvement.

Summary

HF biomarkers in monitoring myocardial and neurohormonal activation response to mechanical unloading and medical therapy could be valuable. However, at this time, there is inadequate evidence to select a single or a set of HF biomarkers to reliably identify patients bridged to recovery for LVAD explantation.

     

Fluoroquinolone Restriction as an Effective Antimicrobial Stewardship Intervention

Purpose of review

Fluoroquinolones are a commonly prescribed antibiotic class that has come under scrutiny in recent years due to mounting evidence of association between adverse drug events, C. difficile infection and isolation of antibiotic-resistant bacteria.

Recent findings

Inpatient antimicrobial stewardship (AMS) programs have a toolbox of potential interventions to curb inappropriate antibiotic use, prevent antibiotic-associated adverse drug events, and avoid unnecessary costs of care. Fluoroquinolone restriction policies in the acute care setting have demonstrated beneficial effects, including decreased rates of C. difficile infection and ESBL-producing Enterobacteriaceae. However, a simple blanket restriction policy may “squeeze the antibiotic balloon” and will likely be insufficient if not implemented in conjunction with other AMS interventions.

Summary

There is a growing body of evidence to support formulary restriction of fluoroquinolones in the acute care setting to decrease rates of C. difficile infection and development of ESBL-producing organisms. Data on how to best implement these restrictions or how to implement outside of acute care settings is limited.

     

A randomized double-blind placebo-controlled trial showing rifaximin to improve constipation by reducing methane production and accelerating colon transit: A pilot study

Objective

Gut microbe-derived methane may slow colon transit causing chronic constipation (CC). Effect of rifaximin on breath methane and slow-transit CC was evaluated.

Method

Bristol stool form, frequency, colon transit time (CTT), and breath methane were evaluated in 23 patients with CC (10 patients with constipation-predominant irritable bowel syndrome [IBS-C], 13 functional constipation, Rome III) and m-ethane production compared with 68 non-constipating IBS. Methane-producing CC (basal ≥?10 PPM and/or post-lactulose rise by >?10 PPM) was randomized (double-blind) to rifaximin (400-mg thrice/day, 2-weeks) or placebo. Stool forms, frequency, breath methane, and CTT were recorded afterward.

Results

CC patients tended to be methane producer more often (13/23 [56.5%] vs. 25/68 [36.5%], p?=?0.07) and had greater area under curve (AUC) for methane (2415 [435–23,580] vs. 1335 [0–6562.5], p?=?0.02) than non-constipating IBS. Methane producers (8/13 [61.5%]) and 5/10 (50%) non-producers had abnormal CTT (marker retention: 36-h, 53 [0–60] vs. 19 [8–56], p?=?0.06; 60-h, 16 [0–57] vs. 13 [3–56], p?=?0.877). Six and 7/13 methane producers were randomized to rifaximin and placebo, respectively. Rifaximin reduced AUC for methane more (6697.5 [1777.5–23,580] vs. 2617.5 [562.5–19,867.5], p?=?0.005) than placebo (3945 [2415–12,952.5] vs. 3720 [502.5–9210], p?=?0.118) at 1 month. CTT normalized in 4/6 (66.7%) on rifaximin (36-h retention, 54 [44–57] vs. 36 [23–60], p?=?0.05; 60-h, 45 [3–57] vs. 14 [11–51], p?=?0.09) but none on placebo (p?=?0.02) (36-h, 31 [0–60] vs. 25 [0–45], p?=?0.078; 60-h, 6 [0–54] vs. 12 [0–28], p?=?0.2). Weekly stool frequency (3 [1–9] and 7 [1–14], p?=?0.05) and forms improved with rifaximin than placebo.

Conclusion

Rifaximin improves CC by altering methane production and colon transit.

Trial registration

Clinical Trial Registry, India: REF/2012/01/003216

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Evaluation and characterization of tumor lysis syndrome before and after chemotherapy among pediatric oncology patients in Tikur Anbessa specialized hospital,Addis Ababa,Ethiopia

Background

Tumor lysis syndrome (TLS) is a life-threatening emergency disorder, caused by an abrupt release of intracellular metabolites after tumor cell death. It is characterized by a series of metabolic manifestations, especially hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. The aim of this study was to evaluate and characterize the incidence of tumor lysis syndrome among pediatric oncology patients before and after treatment.

Methods

Hospital based prospective cohort study was conducted for 6 months on 61 newly diagnosed pediatric oncology patients. Socio-demographic data was collected by interview administered questionnaire. Patients were followed and the physical diagnosis, imaging and laboratory results were interpreted by senior physicians. Data was entered to and analyzed by SPSS version 23.

Results

Among 61 pediatric oncology patients 39(63.9%) were males. The mean (±SD) age of the pediatric patients was 6.39 (±?3.67) years ranging from 2 months to 14 years. 29.5% of patients were found to have TLS. There were 11.5% and 18.0% of laboratory TLS (LTLS) and clinical TLS (CTLS) cases respectively. There were72.2% spontaneous and 27.8% treatment induced TLS cases with 23% and 21.3% cases of hyperuricemia and 4.9% and 6.6% cases of hyperkalemia incidence before and after treatment respectively. Only two patients died, in the study period, due to TLS.

Conclusion

There was high incidence of TLS irrespective of socio-demographic variation among study participants, suggesting that children with cancer are at risk of developing TLS. As TLS is a life-threatening complication of malignancies, early identification of patients at risk and reducing morbidity and mortality is crucially important.

     

Non-suppressive regulatory T cell subset expansion in pulmonary arterial hypertension

Regulatory T cells (Tregs) have been reported to play a pivotal role in the vascular remodeling of pulmonary arterial hypertension (PAH). Recent studies have revealed that Tregs are heterogeneous and can be characterized by three phenotypically and functionally different subsets. In this study, we investigated the roles of Treg subsets in the pathogenesis of PAH in eight patients with PAH and 14 healthy controls. Tregs and their subsets in peripheral blood samples were analyzed by flow cytometry. Treg subsets were defined as CD4⁺CD45RA⁺FoxP3^low resting Tregs (rTregs), CD4⁺CD45RA^?FoxP3^high activated Tregs (aTregs), and CD4⁺CD45RA^?FoxP3^low non-suppressive Tregs (non-Tregs). The proportion of Tregs among CD4⁺ T cells was significantly higher in PAH patients than in controls (6.54 ± 1.10 vs. 3.81 ± 0.28 %, p < 0.05). Of the three subsets, the proportion of non-Tregs was significantly elevated in PAH patients compared with controls (4.06 ± 0.40 vs. 2.79 ± 0.14 %, p < 0.01), whereas those of rTregs and aTregs were not different between the two groups. Moreover, the expression levels of cytotoxic T lymphocyte antigen 4, a functional cell surface molecule, in aTregs (p < 0.05) and non-Tregs (p < 0.05) were significantly higher in PAH patients compared with controls. These results suggested the non-Treg subset was expanded and functionally activated in peripheral lymphocytes obtained from IPAH patients. We hypothesize that immunoreactions involving the specific activation of the non-Treg subset might play a role in the vascular remodeling of PAH.     

“Experience Keeps a Dear School”: the Effects of Ethnicity and Caregiving Experience on Hiring a Healthcare Advocate

In the present study, ethnic differences in evaluating the severity and associated needs of medical complications experienced by an elderly man and the likelihood of seeking professional assistance (i.e., hire a healthcare advocate [HCA]) to care for him, and for one’s own family or parent should they become ill, as a function of previous caregiving experience, were investigated. The 974 participants were White, Black, Hispanic, or Asian/Pacific Islander. They read a hypothetical vignette about a 75-year-old man, Daryl, who was experiencing health problems. Participants were instructed to imagine that they were James, Daryl’s son, and asked to indicate how severe his condition(s) were, how much medical assistance he would require, and how likely they would be to hire an HCA to assist him. They were also asked to report whether they previously had assisted a parent with activities of daily living (Assistance) and whether they would be likely to hire an HCA in the future if 1) a family member or 2) a parent, specifically, became ill. Two, 2 (Assistance) × 4 (Ethnicity) multivariate analyses of covariance (MANCOVA) were performed to assess differential responses among individuals of different ethnicities as a function of previous caregiver experience. A priori interaction contrasts were examined to determine whether Black, Hispanic, or Asian/Pacific Islander participants differed on the outcomes from White participants as a function of previous caregiver experience. There were no significant differences between Black or Asian/Pacific Islander and White participants, but Hispanic participants assigned significantly higher severity and need for medical assistance ratings and were significantly more likely to indicate that they would seek assistance from an HCA with respect to the vignette and for their own parents in the future if they had provided caregiving to a parent in the past, whereas White participants were less likely to seek assistance from an HCA if they had provided caregiving in the past to a parent. Although ethnic differences in evaluations of Daryl’s condition and in the reported likelihoods of hiring an HCA in various contexts as a function of previous caregiving experience were limited, there are important inter-cultural differences to recognize. It may be important in future research to assess ethnic differences in the expectations and experiences of caregiving.