Post-transplant infections: single center experience from the developing world.

OBJECTIVE: To describe our experience of post-transplant infections in allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. METHODS: From July 2001 to September 2006, patients with malignant and non-malignant hematological disorders having human leukocyte antigen (HLA)-matched sibling donors were selected for transplant. Pre-transplant infection surveillance was carried out, and strict prophylaxis against infection was observed. After admission to the hospital, patients were kept in protective isolation rooms, equipped with a HEPA filter positive-pressure laminar airflow ventilation system. Bone marrow and/or peripheral blood stem cells were used as the stem cell source. Cyclosporin and prednisolone were used as prophylaxis against graft-versus-host disease (GVHD). The engraftment was monitored with cytogenetic/molecular analysis and change of blood group. Survival was calculated from the date of transplant to death or last follow-up. RESULTS: One hundred and fifty-four patients received allogeneic stem cell transplants from HLA-matched siblings for various hematological disorders at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan between July 2001 and September 2006. Indications for transplant included aplastic anemia (n=66), beta-thalassemia major (n=40), chronic myeloid leukemia (n=33), acute leukemia (n=8), and miscellaneous disorders (n=7). One hundred and twenty patients were male and 34 were female. The median age of the patient cohort was 14 years (range 1 1/4-54 years). One hundred and thirty-six patients and 135 donors were cytomegalovirus (CMV) IgG-positive. One hundred and forty patients (90.9%) developed febrile episodes in different phases of post-transplant recovery. Infective organisms were isolated in 150 microbiological culture specimens out of 651 specimens from different sites of infections (23.0% culture positivity). Post-transplant infections were confirmed in 120 patients (77.9%) on the basis of clinical assessment and microbiological, virological, and histopathological examination. Mortality related to infections was 13.0%. Fatal infections included CMV disease (100% mortality, 6/6), disseminated aspergillosis (66.7% mortality, 4/6), pseudomonas septicemia (42.9% mortality, 9/21), and tuberculosis (25% mortality, 1/4). CONCLUSIONS: More than 90% of our patients developed febrile episodes with relatively low culture yield. The majority of infections were treated effectively, however CMV, aspergillosis, and pseudomonas infections remained problematic with high mortality.     

Gastrointestinal perforation in children due to blunt abdominal trauma in Hazara,Northern Pakistan

A retrospective study of 25 children with gastrointestinal perforation due to blunt abdominal trauma in a single region of Pakistan is presented. The age, sex, aetiology, site of perforation, abdominal and X-ray findings, associated injuries, surgical procedures and outcome were analysed. There were 20 boys and 5 girls: mean age was 10 years. The injuries were the result of road traffic accidents 12 (48%), falls 11 (44%) and 'struck by animals' two (8%). Associated injuries occurred in 19 (76%). On admission 20 (80%) patients had peritonitis while 18 (72%) had pneumoperitoneum. Mean time from trauma to admission was 10 hours and admission to operation was 5 hours. Ileum was the most common site of perforation. Simple closure was the most common surgical procedure. Complications occurred in nine (36%) patients--six (24%) died. Delay in presentation and operation was associated with increased morbidity and mortality. Frequent evaluation of the child and abdominal X-rays are still the important tools for early diagnosis of gastrointestinal perforation following blunt abdominal trauma.     

Life's Simple 7 and Nonalcoholic Fatty Liver Disease: The Multiethnic Study of Atherosclerosis

BackgroundThe American Heart Association (AHA) has defined Life's Simple 7 (LS7) as a measure of overall cardiovascular health . Nonalcoholic fatty liver disease (NAFLD) has been involved as a risk factor for cardiovascular disease. We evaluated the association between LS7 and NAFLD.MethodsWe evaluated participants form the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Cardiovascular health score was calculated from the Life's Simple 7 metrics. A score of 0-8 was considered inadequate, 9-10 average, and 11-14 optimal. NAFLD was defined using noncontrast cardiac computed tomography (CT) and a liver/spleen attenuation ratio (L/S) < 1. Multivariable regression were performed to evaluate the association.ResultsOur cross-sectional analysis of 3901 participants showed 19% (n = 747) had optimal cardiovascular health, 33% (n = 1270) had average, and 48% (n = 1884) had inadequate. White participants were most likely to have an optimal score (51%, n = 378), whereas African American participants had the lowest proportion with optimal scores (16%, n = 120; P < 0.001). The overall prevalence of NAFLD was 18% with a distribution of 7%, 14%, and 25% in the optimal, average, and inadequate score categories, respectively (P < 0.001). Adjusted for risk factors, average and optimal health categories had lower odds of NAFLD compared to those with inadequate scores: odds ratio for average, 0.44 (95% confidence interval 0.36-0.54); optimal, odds ratio 0.19 (95% confidence interval 0.14-0.26). This association was similar across gender, race and age groups.ConclusionA more favorable cardiovascular health score was associated with a lower prevalence of NAFLD. This study may suggest a potential of Life's Simple 7 in the prevention of liver disease.     

Investigational agents for treatment of traumatic brain injury

Introduction: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. To date, there are no pharmacologic agents proven to improve outcomes from TBI because all the Phase III clinical trials in TBI have failed. Thus, there is a compelling need to develop treatments for TBI.

Areas covered: The following article provides an overview of select cell-based and pharmacological therapies under early development for the treatment of TBI. These therapies seek to enhance cognitive and neurological functional recovery through neuroprotective and neurorestorative strategies.

Expert opinion: TBI elicits both complex degenerative and regenerative tissue responses in the brain. TBI can lead to cognitive, behavioral, and motor deficits. Although numerous promising neuroprotective treatment options have emerged from preclinical studies that mainly target the lesion, translation of preclinical effective neuroprotective drugs to clinical trials has proven challenging. Accumulating evidence indicates that the mammalian brain has a significant, albeit limited, capacity for both structural and functional plasticity, as well as regeneration essential for spontaneous functional recovery after injury. A new therapeutic approach is to stimulate neurovascular remodeling by enhancing angiogenesis, neurogenesis, oligodendrogenesis, and axonal sprouting, which in concert, may improve neurological functional recovery after TBI.     

Mechanical and tribological performance of a hybrid MMC coating deposited on Al–17Si piston alloy by laser composite surfacing technique

Laser composite surfacing (LCS) is a photon driven manufacturing technology that can be utilized for depositing hybrid metal matrix composite coatings (HMMC) on softer Ti/Al/Mg alloys to enhance their tribo-mechanical properties. LCS offers the advantages of higher directionality, localized microstructural refinement and higher metallurgical bonding between coating and substrate. The current research presents the tribo-mechanical evaluation and characterization of solid lubricant based Ni–WC coatings deposited by LCS on Al–Si piston alloy by varying the concentration of graphite between 5-to-15-weight percentage. The tribological behavior of LCS samples was investigated using a ball-on-plate tribometer. Results indicate that the surface hardness, wear rate and friction coefficient of the Al–Si hypereutectic piston alloy were improved after LCS of graphite based HMMC coatings. The maximum surface hardness of 781H_v was acquired for the Ni–WC coating containing 5 wt% graphite. The friction coefficient of Al–Si under dry sliding conditions was reduced from 0.47 to 0.21. The reduction in the friction coefficient was attributed to the formation of a shearable transfer layer, which prevented delamination and reduced adhesion, abrasion and fatigue cracking.

The addition of graphite as solid lubricant has significantly reduced the friction coefficient and wear of a Ni–WC composite coating.     

Differences in outcomes between the JoyBar control and standard wheelchair joystick control on two maneuverability tasks: a pilot study

Purpose: To determine if older adult, novice wheelchair users who drive a power wheelchair with a JoyBar control complete maneuverability tasks in less time and with less error than those who drive a power wheelchair with a standard joystick control.

Materials and methods: A parallel randomized controlled trial design conducted at a medical rehabilitation and research centre with ambulatory older adults aged 60 and above (n?=?27). The intervention was the JoyBar alternative wheelchair control. The primary outcome measure was total time to complete each of the two maneuverability tasks. The secondary outcome measure was total number of errors during each of the maneuverability tasks.

Results: An independent, two sampled t-test was conducted and revealed that the JoyBar group took a greater amount of time to complete both maneuverability tasks than the control group (p?p?Conclusions: Maneuverability of a powered wheelchair by novice wheelchair users was not improved through the use of the JoyBar when compared to a standard wheelchair joystick, as measured by rates of error and time to complete maneuverability tasks.

• Implications for rehabilitation

• Clients who are new to powered wheelchair use may perform maneuverability tasks faster, with equivalent accuracy, using a standard joystick versus the JoyBar.

• Clients who use a JoyBar may require adjustments to the programming of their wheelchair to ensure optimal performance.

• Additional training may be required to achieve proficiency in maneuverability tasks with a JoyBar versus a standard joystick.

     

Aspects of control and substance use among middle‐aged and older adults with bipolar disorder

High prevalence rates of alcohol and substance use disorders have been reported among persons with bipolar disorder (BD). In the present study, we explored the daily experiences of middle‐aged and older adults living with BD who reported regular substance use and the ways in which participants expressed ‘control’ in relation to their use of alcohol and other substances. Semistructured, in‐depth interviews were conducted with 12 participants (nine women and three men), aged 36–57 years of age (mean = 49 years). Thematic analyses identified emergent themes and patterns in participants’ life histories. The theme of ‘control’ emerged as central to participants’ reports, and was organized into four categories: (i) substance use to control BD symptoms; (ii) substance use provides a sense of being in control; (iii) methods of controlled substance use; and (iv) not having control: overreliance on substances. Implications of the present study include the need for nurses to openly discuss the use of alcohol and other drugs with persons with BD, provide health information and screening, and determine whether persons with BD feel they have control over their substance use. Several lines of research with persons who have BD and use substances are suggested.     

Phage Display Selection, <Emphasis Type="Italic">In Vitro</Emphasis> Characterization,and Correlative PET Imaging of a Novel HER3 Peptide

Purpose

HER3 (ERBB3) is a receptor tyrosine kinase that is implicated in treatment resistance across multiple cancers, including those of the breast, lung, and prostate. Overexpression of HER3 following targeted therapy can occur rapidly and heterogeneously both within a single lesion and across sites of metastasis, making protein quantification by biopsy highly challenging. A global, non-invasive methodology such as positron emission tomography (PET) imaging can permit serial quantification of HER3, providing a useful approach to monitor HER3 expression across the entire tumor burden both prior to and following treatment. PET imaging of HER3 expression may permit a more personalized approach to targeted therapy by allowing for detection of HER3-mediated resistance, in addition to informing clinical trial patient selection for novel therapies targeting HER3.

Procedures

Phage display selection targeting the HER3 extracellular domain was performed in order to develop a peptide with optimal blood clearance and highly accurate HER3 quantification.

Results

The selection converged to a consensus peptide sequence that was subsequently found to bind HER3 with an affinity of 270 ± 151 nM. The peptide, termed HER3P1, was bound with high selectivity to HER3 over other similar receptor tyrosine kinases such as EGFR and HER2. Furthermore, HER3P1 was able to distinguish between high and low HER3-expressing cells in vitro. The peptide was radiolabeled with Ga-68 and demonstrated to specifically bind HER3 by in vivo PET imaging. Uptake of [⁶⁸Ga]HER3P1 was highly specific for HER3-positive tumors, with tumor-to-background ratios ranging from 1.59–3.32, compared to those of HER3-negative tumors, ranging from 0.84–0.93. The uptake of [⁶⁸Ga]HER3P1 also demonstrated high (P < 0.001) correlation with protein expression as quantified by Western blot and confirmed by biodistribution.

Conclusions

HER3P1 accurately quantifies expression of HER3 by PET imaging and has potential utility as a clinical imaging agent.