A novel small molecule approach for the treatment of propionic and methylmalonic acidemias

Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) are inborn errors of metabolism affecting the catabolism of valine, isoleucine, methionine, threonine and odd-chain fatty acids. These are multi-organ disorders caused by the enzymatic deficiency of propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT), resulting in the accumulation of propionyl-coenzyme A (P-CoA) and methylmalonyl-CoA (M-CoA in MMA only). Primary metabolites of these CoA esters include 2-methylcitric acid (MCA), propionyl-carnitine (C3), and 3-hydroxypropionic acid, which are detectable in both PA and MMA, and methylmalonic acid, which is detectable in MMA patients only (Chapman et al., 2012). We deployed liver cell-based models that utilized PA and MMA patient-derived primary hepatocytes to validate a small molecule therapy for PA and MMA patients. The small molecule, HST5040, resulted in a dose-dependent reduction in the levels of P-CoA, M-CoA (in MMA) and the disease-relevant biomarkers C3, MCA, and methylmalonic acid (in MMA). A putative working model of how HST5040 reduces the P-CoA and its derived metabolites involves the conversion of HST5040 to HST5040-CoA driving the redistribution of free and conjugated CoA pools, resulting in the differential reduction of the aberrantly high P-CoA and M-CoA. The reduction of P-CoA and M-CoA, either by slowing production (due to increased demands on the free CoA (CoASH) pool) or enhancing clearance (to replenish the CoASH pool), results in a net decrease in the CoA-derived metabolites (C3, MCA and MMA (MMA only)). A Phase 2 study in PA and MMA patients will be initiated in the United States.     

MAPLE Deposition of Macromolecules

Macromolecules are poised to feature prominently as components in organic electronics, medical implants, drug delivery systems, and sensors. A common theme for the role polymers will play in all of these is as a thin film. In all applications, it is paramount to have precise control over film thickness, structure, morphology, surfaces roughness, etc. Here, matrix‐assisted pulsed laser evaporation (MAPLE) is reviewed as a route to processing polymer and other soft matter thin films with control over the above‐mentioned parameters. After briefly discussing the experimental setup and current proposed mechanism of film formation via MAPLE, the use of MAPLE to process thin films is highlighted for use in various technologies and applications. Future directions and challenges for MAPLE processing of thin films are also discussed.

     

Value of Extended Warming in Patients Undergoing Elective Surgery

Perioperative temperature management is imperative for positive surgical outcomes. This study assessed the clinical and wellbeing benefits of extending normothermia by using a portable warming gown. A total of 94 patients undergoing elective surgery were enrolled. They were randomized pre-operatively to either a portable warming gown or the standard warming procedure. The warming gown stayed with patients from pre-op to operating room to postrecovery room discharge. Core temperature was tracked throughout the study. Patients also provided responses to a satisfaction and comfort status survey. The change in average core temperature did not differ significantly between groups (P = 0.23). A nonsignificant 48% relative decrease in hypothermic events was observed for the extended warming group (P = 0.12). Patients receiving the warming gown were more likely to report always having their temperature controlled (P = 0.04) and significantly less likely to request additional blankets for comfort (P = 0.006). Clinical outcomes and satisfaction were improved for patients with extended warming.Key words: Perioperative warming, Hypothermia, Warming gown, Patient warming unitIntra-operative management of core temperature has been shown to reduce postoperative complications including infections, risk of blood transfusions, and length of hospital stay.¹ Core temperature at induction has been demonstrated to be a significant risk for development of perioperative hypothermia.² Research findings in support of avoiding hypothermia (core temperature <36°) during surgery and the impact of lower temperature on patient recovery is well documented.^3,4 These include increased bleeding during surgery, increased infection rates, increased length of stay, as well as, ultimately, a higher mortality rate.^1,5,6Perioperative normothermia has also been shown to reduce postoperative complications.³ Most recently it has been suggested that active warming commencing preoperatively is more effective in achieving normothermic admission temperatures to postanesthesia recovery than warming commenced intra-operatively.⁴ That complications are reduced with preoperative warming is well established. These findings further suggest that extended warming significantly reduces rates of hypothermia over the standard warming just during surgery and at this time, no study has been performed.This study was conducted with three objectives in mind. The first objective was to compare rates of hypothermia (core temp < 36°) recorded intra-operatively in both a standard warming procedure group and an extended perioperative warming group. The second objective was to examine the association between normothermia extension and well-being. The third objective was to describe the costs of extended warming (peri-operative warming gown) and compare it to the standard warming procedure.     

Connective Tissue Growth Factor Modulates Adult β-Cell Maturity and Proliferation to Promote β-Cell Regeneration in Mice

Stimulation of endogenous β-cell expansion could facilitate regeneration in patients with diabetes. In mice, connective tissue growth factor (CTGF) is expressed in embryonic β-cells and in adult β-cells during periods of expansion. We discovered that in embryos CTGF is necessary for β-cell proliferation, and increased CTGF in β-cells promotes proliferation of immature (MafA⁻) insulin-positive cells. CTGF overexpression, under nonstimulatory conditions, does not increase adult β-cell proliferation. In this study, we tested the ability of CTGF to promote β-cell proliferation and regeneration after partial β-cell destruction. β-Cell mass reaches 50% recovery after 4 weeks of CTGF treatment, primarily via increased β-cell proliferation, which is enhanced as early as 2 days of treatment. CTGF treatment increases the number of immature β-cells but promotes proliferation of both mature and immature β-cells. A shortened β-cell replication refractory period is also observed. CTGF treatment upregulates positive cell-cycle regulators and factors involved in β-cell proliferation, including hepatocyte growth factor, serotonin synthesis, and integrin β1. Ex vivo treatment of whole islets with recombinant human CTGF induces β-cell replication and gene expression changes consistent with those observed in vivo, demonstrating that CTGF acts directly on islets to promote β-cell replication. Thus, CTGF can induce replication of adult mouse β-cells given a permissive microenvironment.     

Quality of life for families with spina bifida in Kenya

Spina bifida (SB) affects children worldwide. Studies from developed nations have explored the impact of SB on the quality of life of children and their parents. However, there are no such studies available from developing countries. We have therefore undertaken to document the impact of the disability on the families of affected children in Kenya. A questionnaire was administered to 40 mothers and their children, who were receiving treatment for SB at our institution. The results of this study should indicate where community and governmental resources and educational efforts for the disabled should be directed.     

Impact of the Combination of Daptomycin and Trimethoprim-Sulfamethoxazole on Clinical Outcomes in Methicillin-Resistant Staphylococcus aureus Infections

Complicated Staphylococcus aureus infections, including bacteremia, are often associated with treatment failures, prolonged hospital stays, and the emergence of resistance to primary and even secondary therapies. Daptomycin is commonly used as salvage therapy after vancomycin failure for the treatment of methicillin-resistant S. aureus (MRSA) infections. Unfortunately, the emergence of daptomycin resistance, especially in deep-seated infections, has been reported, prompting the need for alternative or combination therapy. Numerous antibiotic combinations with daptomycin have been investigated clinically and in vitro. Of interest, the combination of daptomycin and trimethoprim-sulfamethoxazole (TMP-SMX) has proved to be rapidly bactericidal in vitro to strains that are both susceptible and nonsusceptible to daptomycin. However, to date, there is limited clinical evidence supporting the use of this combination. This was a multicenter, retrospective case series of patients treated with the combination of daptomycin and TMP-SMX for at least 72 h. The objective of this study was to describe the safety and effectiveness of this regimen in clinical practice. The most commonly stated reason that TMP-SMX was added to daptomycin was persistent bacteremia and/or progressive signs and symptoms of infection. After the initiation of combination therapy, the median time to clearance of bacteremia was 2.5 days. Microbiological eradication was demonstrated in 24 out of 28 patients, and in vitro synergy was demonstrated in 17 of the 17 recovered isolates. Further research with this combination is necessary to describe the optimal role and its impact on patient outcomes.     

Association between children's exposure to a violent event and objectively and subjectively measured sleep characteristics: a pilot longitudinal study

Although sleep disturbances are commonly reported among children exposed to violence, objective evidence of such disturbances is rare. This longitudinal, home‐based study assessed the effects of a known community‐ or family‐violence incident on both actigraphy‐derived and subjectively reported sleep outcomes of an ethnically mixed, urban sample of children aged 8–16 years. We hypothesized that increased event severity (child physical assault, witnessed homicide) would be associated with lower sleep duration and poorer sleep quality both at baseline and at 3‐month follow‐up. Covariate‐adjusted analyses based on a generalized estimating equations approach showed that children physically assaulted during the event showed lower sleep duration and sleep efficiency and greater wake after sleep onset than those not physically assaulted. Physically assaulted children were more likely to have a later bedtime than non‐assaulted children, but this difference decreased at 3 months. Children witnessing a homicide showed greater wake after sleep onset at baseline and reported greater sleep problems than those witnessing a non‐homicide event, but these differences decreased at 3 months. They were also somewhat more likely to have greater nightly variation in sleep duration. Collectively, results suggest that violence exposure influences children's sleep, but that specific dimensions of sleep may exhibit different susceptibility to different characteristics of violence, especially over time.     

Training and Education in Clinical Psychology in the Context of the Patient Protection and Affordable Care Act

The Patient Protection and Affordable Care Act of 2010 (ACA) is revamping the access, quality, and financing of the health and mental health systems. However, its impact on training and education in clinical psychology is unclear. This article aims to identify specific components of the ACA, in particular the Mental and Behavioral Health Education and Training Grants, that are expected to affect training and education in the field. The article further connects the ACA with four paradigm shifts in clinical psychology that have broad implications for training and education—evidence‐based practices, research methodology, interprofessionalism, and the quality indicator movement. The overarching goal of this article is to begin timely discussions on the future directions of the field under the current healthcare reform.