Antihypertensive pharmacotherapy and long‐term outcomes in pediatric kidney transplantation

Hypertension (HTN) is common in pediatric recipients following kidney transplantation (KT). We retrospectively assessed the impact of HTN on long‐term (>10‐yr) outcomes in pediatric KT recipients (aged < 18 yr) at our center. Two hundred and ninety‐three pediatric KT recipients (83% living donor [LD]) with graft survival (GS) for ≥5 yr were studied. HTN was defined by antihypertensive medication use at five yr post‐KT. One hundred and sixty (55%) recipients did not have HTN, and 133 (45%) had HTN at five yr post‐KT. There were no differences in actuarial patient survival between cohorts. Actuarial GS at 15 and 20 yr was 68% and 53% for recipients without HTN, and 53% and 33% for recipients with HTN (p = 0.006). Among LD recipients using one antihypertensive, GS at 15 yr was 100% for those using an angiotensin‐converting enzyme inhibitor (ACEI) and 44% for those not using an ACEI (p = 0.04). Among these recipients, HTN treated with no ACEI was a significant risk factor for graft failure at >5 yr (hazard ratio [HR] = 2.5, p = 0.02), but HTN treated with an ACEI was not (HR = 0.6, p = 0.7). HTN at five yr post‐KT is associated with poorer long‐term GS in pediatric recipients, but ACEI therapy may enable better outcomes and should be studied further.     

Dostęp skalisty tylny – analiza techniki operacyjnej na podstawie symulacji na zwłokach

The aim of the study was to present consecutive stages of the posterior petrosal approach (PPA).Eighteen simulations of PPA were performed on non-fixed human cadavers without any known pathologies in the head and neck. The consecutive stages of the procedure were documented with photographs and schemes.The starting point for PPA is a temporal craniotomy, suboccipital craniectomy and mastoidectomy with keeping the bony labyrinth intact. Approach to the middle part of the clivus is achieved by raise of the temporal lobe and section of the superior petrosal sinus and tentorium and by mobilization the sigmoid sinus.Posterior petrosal approach is a reproducible technique, which provides surgical penetration of the middle clivus and related regions. It reduces the operating distance and allows to limit the cerebellum and temporal lobe traction and to preserve the anatomic integrity of the brain stem and cranial nerves of the cerebellopontine angle.     

General anxiety symptoms after acute lung injury: Predictors and correlates

Objective

Acute lung injury (ALI) is common in the intensive care unit (ICU), typically requiring life support ventilation. Survivors often experience anxiety after hospital discharge. We evaluated general anxiety symptoms 3 months after ALI for: (1) associations with patient characteristics and ICU variables, and (2) cross-sectional associations with physical function and quality of life (QOL).

Methods

General anxiety was assessed as part of a prospective cohort study recruiting patients from 13 ICUs at four hospitals in Baltimore, MD using the Hospital Anxiety and Depression Scale — Anxiety Subscale (HAD-A), with associations evaluated using multivariable linear and logistic regression models.

Results

Of 152 patients, 38% had a positive screening test for general anxiety (HAD-A ≥ 8). Pre-ICU body mass index and psychiatric comorbidity were associated with general anxiety (OR, 95% confidence interval (CI): 1.06 (1.00, 1.13) and 3.59 (1.25, 10.30), respectively). No ICU-related variables were associated with general anxiety. General anxiety was associated with the number of instrumental ADL dependencies (Spearman's rho = 0.22; p = 0.004) and worse overall QOL as measured by EQ-5D visual analog scale (VAS) (rho = − 0.34; p < 0.001) and utility score (rho = − 0.30; p < 0.001), and by the SF-36 mental health domain (rho = − 0.70; p < 0.001) and Mental Component Summary score (rho = − 0.73; p < 0.001).

Conclusion

Many patients have substantial general anxiety symptoms 3 months after ALI. General anxiety was associated with patient characteristics and impaired physical function and quality of life. Early identification and treatment of general anxiety may enhance physical and emotional function in patients surviving critical illnesses.     

Neuropathy-Inducing Effects of Eribulin Mesylate Versus Paclitaxel in Mice with Preexisting Neuropathy

Eribulin mesylate (E7389, INN:eribulin mesilate Halaven^®) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone. In the current study, we compared additional PN induced by paclitaxel versus eribulin mesylate when administered to mice with preexisting paclitaxel-induced PN. Initially, paclitaxel at 0.75 × its maximum tolerated dose (MTD; 22.5 mg/kg) was given on a Q2Dx3 regimen for 2 weeks. The second chemotherapy was 0.5 MTD eribulin mesylate (0.875 mg/kg) or paclitaxel (15 mg/kg) on a similar regimen, starting 2 weeks after the first. Initial paclitaxel treatment produced significant decreases in caudal nerve conduction velocity (NCV; averaging 19.5 ± 1 and 22.2 ± 1.3 %, p < 0.001) and amplitude (averaging 53.2 ± 2.6 and 72.4 ± 2.1 %, p < 0.001) versus vehicle when measured 24 h or 2 weeks after dosing cessation, respectively. Additional 0.5 MTD paclitaxel further reduced caudal NCV and amplitude relative to immediately before initiation of the second regimen (by 11 ± 2.1 and 59.2 ± 5 %, p < 0.01, respectively). In contrast, 0.5 MTD eribulin mesylate caused no further decrease in caudal NCV. In conclusion, unlike additional paclitaxel treatment, eribulin mesylate administered to mice with preexisting paclitaxel-induced PN had limited additional deleterious effects at 6 weeks. These preclinical data suggest that eribulin mesylate may have reduced tendency to exacerbate preexisting paclitaxel-induced PN in clinical settings.     

Relationship of Right Ventricular Size and Function with Respiratory Status in Duchenne Muscular Dystrophy

The relationship between pulmonary function and right ventricle (RV) in Duchenne muscular dystrophy (DMD) has not been evaluated. Using cardiac magnetic resonance (CMR), we describe the relationship of RV size and function with spirometry in a DMD cohort. Fifty-seven boys undergoing CMR and pulmonary function testing within 1 month at a single center (2013–2015) were enrolled. Comparisons of RV ejection fraction (RVEF) and end-diastolic volume index (RVEDVI) were made across categories of percent forced vital capacity (FVC%), and relationships were assessed. Mean age was 15.5 ± 3.5 years. Spirometry and CMR were performed within 3.9 ± 4.1 days. Median FVC% was 92.0 % (67.5–116.5 %). Twenty-three (40 %) patients had abnormal FVC% (<80 %) of which 13 (57 %) had mild (FVC% 60–79 %), 6 (26 %) had moderate (FVC% 40–59 %), and 4 (17 %) had severe (FVC <40 %) reductions. Mean RVEF was 58.3 ± 3.7 %. Patients with abnormal FVC% were older and had lower RVEF and RVEDVI. Both RVEF and RVEDVI were significantly associated with FVC% (r = 0.31, p = 0.02 and r = 0.39, p = 0.003, respectively). In a large DMD cohort, RVEF and RVEDVI were related to FVC%. Worsening respiratory status may guide monitoring of cardiac function in these patients.     

Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation

It is uncertain whether environmental factors contribute to the formation of senile plaques and neurofibrillary tangles, the abnormal features that define the Alzheimer's disease (AD) brain. We previously proposed that herpes simplex virus type 1 (HSV1) is a strong risk factor for AD when it is present in the brains of people who possess the type 4 allele of the apolipoprotein E gene (APOE-epsilon4); however a direct biochemical link between viral infection and the development of the AD pathological features has never previously been examined. Here we show that infection of cultured neuronal and glial cells with HSV1 leads to a dramatic increase in the intracellular levels of beta-amyloid (Abeta) 1-40 and 1-42, whilst levels of amyloid precursor protein (APP) in cells decrease. Similarly, Abeta1-42 deposits are present in mouse brain after HSV1 infection. In the cultured cells the mechanism involves increased Abeta production, rather than merely greater retention of cellular Abeta, as levels of beta-site APP-cleaving enzyme (BACE-1) and of nicastrin, a component of gamma-secretase, both increase in HSV1-infected cells. These novel data show that HSV1 can directly contribute to the development of senile plaques.     

Investigating the human immunodeficiency virus type 1-infected monocyte-derived macrophage secretome

Mononuclear phagocytes (bone marrow monocyte-derived macrophages, alveolar macrophages, perivascular macrophages, and microglia) are reservoirs and vehicles of dissemination for the human immunodeficiency virus type-1 (HIV-1). How virus alters mononuclear phagocyte immunoregulatory activities to complete its life cycle and influence disease is incompletely understood. In attempts to better understanding the influence of virus on macrophage functions, we used one-dimensional electrophoresis, and liquid chromatography tandem mass spectrometry to analyze the secretome of HIV-1-infected human monocyte-derived macrophages. We identified 110 proteins in culture supernatants of control (uninfected) and virus-infected cells. Differentially expressed cytoskeletal, enzymes, redox, and immunoregulatory protein classes were discovered and validated by Western blot tests. These included, but were not limited to, cystatin C, cystatin B, chitinase 3-like 1 protein, cofilin-1, l-plastin, superoxide dismutase, leukotriene A(4) hydrolase, and alpha-enolase. This study, using a unique proteomics platform, provides novel insights into virus-host cell interactions that likely affect the functional role of macrophages in HIV disease.