Successful treatment of hepatitis C virus infection with direct‐acting antivirals during hematopoietic cell transplant

Current guidelines recommend that hepatitis C virus (HCV) infection be treated completely prior to hematopoietic cell transplantation or delayed until immune reconstitution after transplantation to avoid drug‐drug interactions and treatment interruption. However, these recommendations were informed by outcomes using treatment with ribavirin and pegylated interferon. We report the first case of successful treatment of HCV using direct‐acting antivirals during hematopoietic cell transplantation. This case study suggests that treatment of HCV concurrent with hematopoietic cell transplantation for malignancy may be the best option for some patients in whom it is unsafe to delay treatment for either disease.     

Updates on vaccinating the inflammatory bowel disease patient

Introduction: Many of the therapeutic options for patients with inflammatory bowel disease (IBD) suppress the immune system, which increases the risk of certain infections in these patients. Effective vaccines exist and offer protection against a number of infectious diseases. However, data has shown that IBD patients are inadequately vaccinated and, as a result, are at risk of developing certain preventable infections. Furthermore, gastroenterologists’ knowledge regarding the appropriate immunizations to administer to their IBD patients is suboptimal.

Areas covered: Over the past several years, there has been a considerable amount of research contributing to our knowledge regarding vaccination of patients with IBD.

Expert opinion: This updated review article focuses on the current immunization schedule for the IBD patient and stresses the important role of the gastroenterologist as an active participant in the health maintenance of their IBD patients.     

Adenosine,lidocaine and Mg2+ improves cardiac and pulmonary function,induces reversible hypotension and exerts anti-inflammatory effects in an endotoxemic porcine model

Introduction

The combination of Adenosine (A), lidocaine (L) and Mg²⁺ (M) (ALM) has demonstrated cardioprotective and resuscitative properties in models of cardiac arrest and hemorrhagic shock. This study evaluates whether ALM also demonstrates organ protective properties in an endotoxemic porcine model.

Methods

Pigs (37 to 42 kg) were randomized into: 1) Control (n = 8) or 2) ALM (n = 8) followed by lipopolysaccharide infusion (1 μg∙kg^-1∙h^-1) for five hours. ALM treatment consisted of 1) a high dose bolus (A (0.82 mg/kg), L (1.76 mg/kg), M (0.92 mg/kg)), 2) one hour continuous infusion (A (300 μg∙kg^-1 ∙min^-1), L (600 μg∙kg^-1 ∙min^-1), M (336 μg∙kg^-1 ∙min^-1)) and three hours at a lower dose (A (240∙kg^-1∙min^-1), L (480 μg∙kg^-1∙min^-1), M (268 μg∙kg^-1 ∙min^-1)); controls received normal saline. Hemodynamic, cardiac, pulmonary, metabolic and renal functions were evaluated.

Results

ALM lowered mean arterial pressure (Mean value during infusion period: ALM: 47 (95% confidence interval (CI): 44 to 50) mmHg versus control: 79 (95% CI: 75 to 85) mmHg, P <0.0001). After cessation of ALM, mean arterial pressure immediately increased (end of study: ALM: 88 (95% CI: 81 to 96) mmHg versus control: 86 (95% CI: 79 to 94) mmHg, P = 0.72). Whole body oxygen consumption was significantly reduced during ALM infusion (ALM: 205 (95% CI: 192 to 217) ml oxygen/min versus control: 231 (95% CI: 219 to 243) ml oxygen/min, P = 0.016). ALM treatment reduced pulmonary injury evaluated by PaO₂/FiO₂ ratio (ALM: 388 (95% CI: 349 to 427) versus control: 260 (95% CI: 221 to 299), P = 0.0005). ALM infusion led to an increase in heart rate while preserving preload recruitable stroke work. Creatinine clearance was significantly lower during ALM infusion but reversed after cessation of infusion. ALM reduced tumor necrosis factor-α peak levels (ALM 7121 (95% CI: 5069 to 10004) pg/ml versus control 11596 (95% CI: 9083 to 14805) pg/ml, P = 0.02).

Conclusion

ALM infusion induces a reversible hypotensive and hypometabolic state, attenuates tumor necrosis factor-α levels and improves cardiac and pulmonary function, and led to a transient drop in renal function that was reversed after the treatment was stopped.     

The Contribution of Anxiety Sensitivity to Obsessive–Compulsive and Anxiety Symptoms in a Naturalistic Treatment Setting

Anxiety sensitivity (AS), a fear of arousal-related sensations, is prevalent in a number of disorders. We examined the relationship between internalizing symptoms and the anxiety sensitivity components of physical, social, and cognitive concerns in a sample of 165 patients seeking treatment in a clinic specializing in cognitive behavioral therapy for anxiety-related disorders. Social anxiety symptoms were associated with greater social concerns. Cognitive concerns were characteristic of both depression and generalized anxiety symptoms, suggesting these two classes of symptoms may share AS symptomatology. Physical concerns were specifically related to panic symptoms. Although obsessive–compulsive symptoms were related to cognitive concerns using univariate regression, these symptoms were not strongly related to any of the anxiety sensitivity components when the correlation between disorders was taken into account. Thus, within the internalizing symptoms studied here, the anxiety sensitivity domains were most relevant to panic, social anxiety, generalized anxiety, and depressive symptoms and less related to obsessive–compulsive symptoms.     

Cardiovascular disease: the effect of erectile dysfunction on adherence to cardiovascular disease medication

Due to their similar aetiologies, cardiovascular disease (CVD) and erectile dysfunction (ED) are closely linked, with the prevalence of ED being approximately 75% for individuals at high risk of CVD. ED can have a detrimental effect on quality of life not only for the individual but also his sexual partner which in turn impacts upon their intimate relationship. Some CVD medications have been found to have a negative effect on erectile function and therefore act as an influential factor for the cessation of important CVD medication. Low adherence to CVD medication has been linked to increased health costs, hospitalizations and importantly, a higher risk of mortality. Research has shown that men find it difficult to seek medical help in relation to ED which is also compounded by the notion that health care providers do not address sexual issues adequately. Patients' beliefs about CVD medication are modifiable and therefore an opportunity exists not only for health care providers to facilitate discussions in relation to ED and medication adherence but also encompass an opportunity to increase adherence to CVD medication through intervention.     

Assessment of capacity for surgery,obstetrics and anaesthesia in 17 Ghanaian hospitals using a WHO assessment tool

Objectives To survey infrastructure characteristics, personnel, equipment and procedures of surgical, obstetric and anaesthesia care in 17 hospitals in Ghana. Methods The assessment was completed by WHO country offices using the World Health Organization Tool for Situational Analysis to Assess Emergency and Essential Surgical Care, which surveyed infrastructure, human resources, types of surgical interventions and equipment in each facility. Results Overall, hospitals were well equipped with general patient care and surgical supplies. The majority of hospitals had a basic laboratory (100%), running water (94%) and electricity (82%). More than 75% had the basic supplies needed for general patient care and basic intra‐operative care, including sterilization. Almost all hospitals were able to perform major surgical procedures such as caesarean sections (88%), herniorrhaphy (100%) and appendectomy (94%), but formal training of providers was limited: a few hospitals had a fully qualified surgeon (29%) or obstetrician (36%) available. Conclusions The greatest barrier to improving surgical care at district hospitals in Ghana is the shortage of adequately trained medical personnel for emergency and essential surgical procedures. Important future steps include strengthening their number and qualifications.     

AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in whole-body AMPK α2, β2, and γ3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle α, β, or γ subunits.     

Ventilatory efficiency slope correlates with functional capacity,outcomes, and disease severity in pediatric patients with pulmonary hypertension

Background

Cardiopulmonary exercise testing is widely used in a variety of cardiovascular conditions. Ventilatory efficiency slope can be derived from submaximal exercise testing. The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension.

Methods

Seventy six children and young adults with a diagnosis of pulmonary hypertension (PH) performed 258 cardiopulmonary exercise tests from 2001 to 2011. Each individual PH test was matched to a control test. Ventilatory efficiency slope was compared to traditional measures of functional capacity and disease severity including WHO functional classification, peak oxygen consumption, and invasive measures of pulmonary arterial pressures and pulmonary vascular resistance.

Results

Ventilatory efficiency slope was significantly higher in patients with pulmonary arterial hypertension, with an estimated increase of 7.2 for each increase in WHO class (p < 0.0001), compared with normal control subjects (38.9 vs. 30.9, p < 0.001). Ventilatory efficiency slope correlated strongly with invasive measures of disease severity including pulmonary vascular resistance index (r = 0.61), pulmonary artery pressure (r = 0.58), mean pulmonary artery pressure/mean aortic pressure ratio (r = 0.52), and peak VO₂ (r = − 0.58). Ventilatory efficiency slope in 12 patients with poor outcomes (9 death, 3 lung transplant), was significantly elevated compared to patients who did not (51.1 vs. 37.9, p < 0.001).

Conclusions

Ventilatory efficiency slope correlates well with invasive and noninvasive markers of disease severity including peak VO₂, WHO functional class, and catheterization variables in pediatric patients with PH. Ventilatory efficiency slope may be a useful noninvasive marker for disease severity.     

CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis

The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3(+)CD86(acq+) and CD3(+) HLA-G(acq+) cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38(++) side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G(+) T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.