Mitochondrial Targeted Therapies: Where Do We Stand in Mental Disorders?

The neurobiology of psychiatric disorders is still unclear, although changes in multiple neuronal systems, specifically the dopaminergic, glutamatergic, and gamma-aminobutyric acidergic systems as well as abnormalities in synaptic plasticity and neural connectivity, are currently suggested to underlie their pathophysiology. A growing body of evidence suggests multifaceted mitochondrial dysfunction in mental disorders, which is in line with their role in neuronal activity, growth, development, and plasticity. In this review, we describe the main endeavors toward development of treatments that will enhance mitochondrial function and their transition into clinical use in congenital mitochondrial diseases and chronic disorders such as types 1 and 2 diabetes, cardiovascular disorders, and cancer. In addition, we discuss the relevance of mitochondrial targeted treatments to mental disorders and their potential to become a novel therapeutic strategy that will improve the efficiency of the current treatments.     

Time trends in <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> bacteremia, 1988–2010, in a tertiary center with high methicillin resistance rates

Introduction

Changes in the epidemiology of Staphylococcus aureus bacteremia (SAB) have been described in recent decades. Decreased mortality has been reported over time, mostly from countries with low methicillin resistance rates. We aimed to describe time trends in SAB in a tertiary center with high methicillin resistance rates.

Methods

We retrospectively analyzed 1692 patients with SAB, and compared between three time periods: 1988–1994 (342 patients), 1998–2004 (597 patients) and 2005–2010 (753 patients).

Results

In our cohort, 30 days mortality increased significantly with time, reaching 42.9 % during 2005–2010. The latter period was characterized by higher rates of older patients (35.1 % aged 80 years and older), with lower functional capacity (46.5 % bedridden) and higher rates of comorbidities (33.6 % renal disease, 24.8 % heart failure, 19.0 % dementia). These patients were more likely to be ventilated (18.7 %) and carry a urinary catheter at presentation (46.6 %); present with septic shock (15.9 %) and have pneumonia (20.5 %) or endocarditis (7.2 %) as source. Similar characteristics were found among patients younger than 50 years and with independent functional status. No significant increase in methicillin resistant Staph aureus (MRSA) rates or inappropriate empirical therapy was demonstrated during 2005–2010.

Conclusions

In our cohort, increased mortality in recent years in patients with SAB can be explained by baseline condition of patients. MRSA or inappropriate empiric therapy did not explain the increase in mortality. The patients afflicted with SAB changed over time. Epidemiology and outcomes of SAB vary with time and according to geographical location. External validity of studies should be taken into consideration.

     

Efficacy and safety of autologous hematopoietic cell transplantation in elderly patients with multiple myeloma: a retrospective national multi-site cohort study

We aimed to test the efficacy and toxicity of autologous hematopoietic cell transplant (HCT) in Multiple Myeloma (MM) patients aged ≥65 years compared to patients aged 60–64. Two hundred twenty consecutive patients (age ≥65, n = 87) with MM aged 60 and above, who underwent HCT as part of an upfront MM treatment, at four Israeli centers between 2000 and 2014 were included. A melphalan dose of 200 mg/m² was more frequent in the 60–64 age group vs. the ≥65 age group (77 vs. 57%, p = 0.002). There were no differences between groups in median day of neutrophil engraftment, incidence of infections, grades 3–4 mucositis, cardiovascular events, or non-relapse mortality at 100 days post HCT (4.7, vs. 5%, p = 0.9). A similar rate of improvement in response level was observed (36, vs. 35%, p = 0.87). At 3 years post HCT progression-free survival (PFS) was higher in the 60–64 age group (42 vs. 29%, p = 0.04); however, it was no longer so after adjustment for disease status prior to HCT (p = 0.49). In a Multivariate analysis, melphalan doses and age did not predict PFS. There was no difference in overall survival (OS) between age groups (p = 0.2). We conclude that toxicity profile, response, PFS, and OS of HCT in aged ≥65 patients with myeloma is similar to patients aged 60–64.     

Interatrial septal aneurysm and patent foramen ovale: diagnosis and dynamic evaluation with electrocardiogram-gated multidetector-row computed tomography imaging

We describe an elderly woman with paroxysmal atrial fibrillation who was evaluated by electrocardiogram-gated multidetector-row computed tomography (MDCT) prior to left atrial radiofrequency ablation therapy to rule out coronary artery disease and to obtain a 3-dimensional anatomical map of the left atrium and pulmonary veins. MDCT documented the dynamic bidirectional motion of an interatrial septal aneurysm associated with a patent foramen ovale. MDCT findings correlated well with transesophageal and intracardiac echocardiograms.     

IL-6 Levels,Nutritional Status,and Mortality in Prevalent Hemodialysis Patients

Summary

Background and objectives

The influence of serum IL-6 levels on nutritional status in chronic hemodialysis (HD) patients remains to be elucidated. The present report describes a prospective longitudinal study of IL-6 levels and nutritional parameters to determine whether high IL-6 levels are independently associated with nutritional status over time in a cohort of prevalent hemodialysis patients.

Design, setting, participants, & measurements

85 clinically stable hemodialysis patients (37.6% women), with a mean age of 66.5 ± 10.6 years, were studied after exclusion of patients with BMI < 20 kg/m² and/or serum albumin <35 g/L. IL-6, dietary energy and protein intake, and biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18, and 24 months following enrollment. Observation of this cohort was continued over 2 additional years.

Results

IL-6 levels increased with time in both unadjusted (linear estimate: 2.57 ± 0.44 pg/ml per 2 yrs; P = 0.001) and adjusted models (linear estimate: 2.35 ± 0.57 pg/ml per 2 yrs; P = 0.049). Significant reductions of daily energy intake, laboratory markers (albumin, transferrin, cholesterol, creatinine), and body composition (fat mass) with higher IL-6 levels were observed over the duration of the longitudinal observation period. However, none of the studied parameters were associated with changes in IL-6 levels over time (IL-6-by-time interactions were NS). Furthermore, cumulative incidences of survival were correlated with the baseline serum IL-6 levels (P = 0.004 by log-rank test). Finally, for each pg/ml increase in IL-6 level, the hazard ratio for death from all causes was 1.06 (95% CI 1.01 to 1.10) after adjustment for demographic and clinical parameters.

Conclusions

Our results suggest that higher serum IL-6 levels are associated with all-cause mortality without additional changes in clinical and laboratory markers of nutritional status in clinically stable HD patients.     

Significant correlation between peripheral blood CD34+ cell count in children prior to aphaeresis and CD34+ cell yield following aphaeresis: A single‐center experience

Numerous adults’ studies demonstrated that preaphaeresis CD34+ cells significantly correlate with the number of CD34+ cells collected by the aphaeresis procedure. Equivalent studies in children are scarce. We studied retrospectively 92 aphaeresis procedures performed following chemotherapy (44) or in steady state (48) in 60 pediatric patients (40 males, 20 females), median age of 7.5 years. Aphaeresis procedures were performed using a SPECTRA Optica (TERUMOBCT) continuous flow cell separator. CD34+ cell concentrations were assessed using flow cytometry. A highly significant correlation between peripheral CD34 cell count on the day of aphaeresis and CD34 cell yield per kg (R² = .824, P < .0001) was demonstrated. A higher preaphaeresis CD34 cell count was demonstrated in patients with higher preaphaeresis white blood cell count, in patients with brain tumors, and in patients who received chemotherapy as part of their mobilization protocol. A threshold number of 20 peripheral CD34+ cell/μL was found to predict harvesting of 3 × 10⁶ stem cells/kg, and 30 peripheral CD34+ cell/μL for harvesting of 5 × 10⁶ stem cells/kg. This significant correlation between peripheral CD34 cell count and CD34 cell yield, and the threshold number of peripheral CD34 found to predict adequate harvesting can be useful in planning the optimal time for aphaeresis in children.     

Sonographic appearance of the uterus in the early puerperium in vaginal versus cesarean deliveries: a prospective study

Purpose: The purpose of this study is to compare uterine sonographic characteristics in early puerperium, following vaginal versus cesarean deliveries; and in women with abnormal third stage of labor, compared to uncomplicated vaginal delivery.

Materials and methods: This is a prospective study of women after delivery of singleton, appropriate-for-gestational-age weight, term neonates; 66 women delivered vaginally and 33 delivered by cesarean section. Sonographic uterine dimensions (height, length, and width), intracavitary thickness and its echogenicity (at level of fundus, midcavity and cervix) were recorded at less than and after 24?h from delivery, and compared between women delivered vaginally and by cesarean section. Among women delivered vaginally, data were further analyzed according to whether women underwent manual revision of the uterine cavity.

Results: Sonographic evaluations were taken at 15.4 (4.3–24.0) and 39.5 (28.8–108.8) hours after delivery (median, range). We found no clinically significant differences in uterine characteristics according to mode of delivery or according to manual revision of the uterine cavity. The sonographic appearance of the uterus was similar when performed at less than or after 24?h from delivery.

Conclusions: Postpartum sonographic evaluation of the uterus appears similar after vaginal and cesarean deliveries.     

Inhibition of milk ingestion and growth after administration of a neutral cannabinoid CB1 receptor antagonist on the first postnatal day in the mouse

We have shown previously that neonatal exposure to the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (SR141716) interfered with suckling and development. However, it was not clear whether the developmental deficiencies were induced by neutral CB1 receptor blockade, thereby inhibiting endogenous cannabinoid "tone," or by inverse agonist reduction of constitutive CB1 receptors. CB1 receptor blockade supports our hypothesis that low CB1 receptor concentrations and/or reduced endocannabinoid levels underlie infant nonorganic failure to thrive (NOFTT). Inverse agonism implies that lower constitutive CB1 receptor activity may be responsible for impaired food intake in newborns. In the present study, we injected the neutral CB1 receptor antagonist 5-(4-chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole (VCHSR1) to 1-d-old mouse pups and recorded weight gain, gastric milk contents (milkbands), axillary temperature, and survival between age 1 and 10 d. The results showed a dose-related interference with all measures. These data show that (1) growth failure induced by rimonabant is generalized to another CB1 antagonist and (2) cannabinoid CB1 receptor activation by endocannabinoids is essential for normal milk ingestion and development in mice. This supports our hypothesis that endocannabinoid deficiency and perhaps CB1 receptor dysfunction represents the uncharacterized biologic vulnerability, which underlies NOFTT.     

Clinical Features and Comparison of Kingella and Non–Kingella Endocarditis in Children,Israel

Kingella spp. have emerged as an important cause of invasive pediatric diseases. Data on Kingella infective endocarditis (KIE) in children are scarce. We compared the clinical features of pediatric KIE cases with those of Streptococcus species IE (StIE) and Staphylococcus aureus IE (SaIE). A total of 60 patients were included in the study. Throughout the study period, a rise in incidence of KIE was noted. KIE patients were significantly younger than those with StIE and SaIE, were predominately boys, and had higher temperature at admission, history of oral aphthae before IE diagnosis, and higher lymphocyte count (p<0.05). Pediatric KIE exhibits unique features compared with StIE and SaIE. Therefore, in young healthy children <36 months of age, especially boys, with or without a congenital heart defect, with a recent history of oral aphthae, and experiencing signs and symptoms compatible with endocarditis, Kingella should be suspected as the causative pathogen.