Selective caudate atrophy in multiple sclerosis: a 3D MRI parcellation study

Deep gray matter damage may be an important component of the multiple sclerosis (MS) disease process. We tested whether caudate atrophy occurs in MS, and whether it correlates with conventional MRI or clinical markers of disease progression. Caudate nuclei of 24 MS patients and 10 age-matched healthy controls were traced, normalized, reconstructed and visualized from MRI scans. Normalized bicaudate volume was 19% lower in MS controls ( p< 0.001), an effect that persisted after adjusting for whole-brain atrophy ( p< 0.008). Caudate volume did not correlate with disease duration, physical disability score, whole-brain atrophy, or total T2 hyperintense or T1 hypointense lesion load (all p > 0.05). We conclude that selective caudate atrophy is associated with MS and may occur through direct mechanisms.     

Identification of bacterial genes required for in-vivo survival.

Genetic approaches used for in-vivo studies of bacterial pathogenesis are providing insights into how bacteria disrupt host defences and exploit host molecules for their own advantage. Signature tagged mutagenesis (STM) provides a means of identifying the genes involved in the process of infection, particularly those genes that are important for bacterial proliferation in-vivo. In this review, the application of STM to the understanding of bacterial pathogenesis and findings from work on three human pathogens, Salmonella typhimurium, Mycobacterium tuberculosis and Neisseria meningitidis, are discussed. The next challenge is to understand how these and other genes influence the infective process at the molecular and cellular levels and to design novel interventions to block the progression of disease.     

Project Muskan: Social responsibility of the plastic surgeon

Although exact statistics are not available, Indian plastic surgeons see around 7,00,000–8,00,000 burn admissions annually with around 10,00,000 cleft patients yet to be operated. In spite of this voluminous load, India does not have national health programs for the various deformities Indian plastic surgeons typically treat. As Plastic Surgeons, it is our social responsibility to treat these patients and bring ‘muskan’ (smile in Hindi) back into their lives. Project Muskan was initiated as an innovative model for targeting these patients and is probably one of its kind in the field of plastic surgery in our country. It is unique because it is a perfect collaboration of government institutions, a Non Government Organization (NGO), and cooperative sectors providing free health care at the doorstep. Identification of the patients was done with the help of the extensive milk dairy network in the state of Gujarat. Provision of transport and other facilities was done by the NGOs and quality health care provision was taken care of by the government hospital. Project Muskan started from a single village but now covers around 3000 villages and tribal areas of Gujarat. It is a system that can be easily reproducible in all hospitals and has reestablished the faith of the common man in government institutes.     

Biodistribution, pharmacokinetic, and imaging studies with 186Re-labeled NR-LU-10 whole antibody in LS174T colonic tumor-bearing mice

Biodistribution, pharmacokinetic, and radioimaging studies were performed with 186Re-labeled NR-LU-10 whole antibody in athymic nude mice bearing the LS174T tumor growing either s.c. or in an experimental hepatic metastasis model. NR-LU-10 is an IgG2b murine monoclonal antibody (MAb) that reacts with virtually all human tumors of epithelial origin. NR-BC-1, a IgG2b murine MAb that reacts with normal human B-cell and B malignancies, was used as an isotype-matched control. These MAbs were radiolabeled with 186Re (3.7-day physical half-life; 1.07-MeV beta particle and 137-keV gamma, 9% abundance) by a preformed chelate approach by using the triamide thiolate ligand system. 186Re-labeled NR-LU-10 (50 microCi) was injected into nude mice bearing LS174T tumors growing s.c. Biodistribution studies revealed that the LS174T tumor retained the highest concentration of 186Re-labeled NR-LU-10 (5.3% injected dose/g) at day 6. The tumor:blood ratio ranged from 0.1:1 to 10.8:1 by day 6, the last day of analysis. In contrast the tumor:blood ratio of 186Re-labeled NR-BC-1, the isotype-matched MAb control, was 1:1 on day 6. Pharmacokinetic analysis indicated that the t1/2 beta of NR-LU-10 for blood and other tissues ranged from 21 to 25 h, while the t1/2 beta for the LS174T tumor averaged 52 h. The area under the curve for tumor compared to blood was 2.8- to 5.7-fold higher than the area under the curve for all other tissues and organs. The mean residence time for NR-LU-10 in blood and all other organs ranged from 23 to 26 h, while the mean residence time for NR-LU-10 in the LS174T tumor was 72 h. Scintigraphic images revealed selective uptake of the 186Re-labeled NR-LU-10, but not of the 186Re-labeled NR-BC-1, at the LS174T tumor site. Studies in an experimental model of hepatic metastasis revealed a similar selective pattern of 186Re-labeled NR-LU-10 accumulation. Scintigraphic images of the LS174T tumor growing within the athymic nude mouse liver were obtained. The biodistribution, pharmacokinetic, and scintigraphic image results suggest that 186Re-labeled NR-LU-10 shows promise as a therapeutic agent for gastrointestinal cancer.     

Dynorphin A-(1-17) induces alterations in free fatty acids, excitatory amino acids, and motor function through an opiate-receptor-mediated mechanism

The endogenous opioid dynorphin A-(1-17) (Dyn A) has been implicated as a mediator of tissue damage after traumatic spinal cord injury (TSCI) and causes hindlimb paralysis when administered intrathecally. Motor impairment following intrathecal Dyn A is attenuated by antagonists of excitatory amino acids (EAAs); whether opioid receptors mediate such injury has been questioned. TSCI causes various biochemical changes associated with secondary tissue damage, including alterations in tissue amio acids, phospholipids, and fatty acids. Such changes reflect injury severity and correlate with motor dysfunction. The present studies examined whether dynorphin administration causes similar biochemical alterations and whether effects of Dyn A can be modified by treatment with opioid-receptor antagonists. At 24 hr after intrathecal Dyn A, there were significant declines in tissue levels of glutamate, aspartate, and glycine. Increases in total free fatty acids were found at 2 and 24 hr, reflecting changes in both saturated and unsaturated components, which were associated with significant decreases in tissue cholesterol and phospholipid phosphorus at the earlier time point. Each of these neurochemical changes, as well as corresponding motor deficits, were limited by pretreatment with the opioid antagonist nalmefene. In separate experiments, both nalmefene and the selective kappa-opioid antagonist nor-binaltorphimine (nor-BNI) limited dynorphin-induced motor dysfunction; effects of nor-BNI were dose related, and those of nalmefene were stereospecific. Therefore, behavioral and neurochemical consequences of Dyn A administration are mediated in part through opiate receptors, most likely kappa-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal Injury Results in Sex-Dependent Nociceptive Hypersensitivity and Social Behavioral Deficits During Adolescence,Without Altering Morphine Response

Neonatal injury is associated with persistent changes in sensory function and altered nociceptive thresholds that give rise to aberrant pain sensitivity in later life. Although these changes are well documented in adult rodents, little is known about the consequences of neonatal injury during adolescence. Because adolescence is a critical developmental period during which persistent pain conditions can arise, we examined the effect of neonatal injury on nociception, social behavior, and response to morphine in adolescent Sprague Dawley rats. Male and female rats exposed to plantar incision injury at postnatal day 3 displayed mechanical hypersensitivity that resolved by 24 hours after incision. When these animals reached adolescence (postnatal day 28–40), neonatally-injured male rats showed ipsilaterally restricted mechanical, heat, and cold hypersensitivity, as well as social behavioral deficits. In contrast, these effects were not seen in female rats. Neonatal injury did not alter acute morphine antinociception or the development of analgesic tolerance in either sex. Morphine-induced conditioned place preference, behavioral sensitization, and physical withdrawal were also not affected by neonatal incision. Thus, early-life injury results in sex-dependent pain-related hypersensitivity and social behavior deficits during adolescence, without altering the response to opioids.

A practical guide to interpreting germline variants that drive hematopoietic malignancies,bone marrow failure,and chronic cytopenias

PurposeThe American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for germline variant interpretation are implemented as a broad framework by standardizing variant interpretation. These rules were designed to be specified, but this process has not been performed for most of the 200 genes associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias. Because guidelines on how to perform these gene specifications are lacking, variant interpretation is less reliable and reproducible.MethodsWe have used a variety of methods such as calculations of minor allele frequencies, quasi-case–control studies to establish thresholds, proband counting, and plotting of receiver operating characteristic curves to compare different in silico prediction tools to design recommendations for variant interpretation.ResultsWe herein provide practical recommendations for the creation of thresholds for minor allele frequencies, in silico predictions, counting of probands, identification of functional domains with minimal benign variation, use of constraint Z-scores and functional evidence, prediction of nonsense-mediated decay, and assessment of phenotype specificity.ConclusionThese guidelines can be used by anyone interpreting variants associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias to develop criteria for reliable, accurate, and reproducible germline variant interpretation.     

Independent contributions of cortical gray matter atrophy and ventricle enlargement for predicting neuropsychological impairment in multiple sclerosis

The primary goal of this study was to investigate associations between regional gray matter (GM) atrophy and neuropsychological function in multiple sclerosis (MS), while accounting for the influence of central brain atrophy (i.e. third ventricle enlargement). Using a cross-sectional design, we studied 59 MS patients with brain MRI and neuropsychological testing. Regional gray matter fractions (rGMFs) were calculated from MRI images for 11 homologous brain areas using the semiautomatic brain region extraction (SABRE) technique. Neuropsychological testing followed consensus panel guidelines and included tests emphasizing episodic memory, working memory and processing speed. The analytic approach was stepwise linear regression, with forward selection and p<0.05 threshold for significance. Consistent with previous research, there were significant correlations between third ventricle width and neuropsychological tests. Stepwise linear regression analyses controlling for third ventricle width retained rGMFs obtained from specific regions within the prefrontal cortex. Left frontal atrophy was associated with tests emphasizing auditory/verbal memory. Right frontal atrophy was associated with impairment in visual episodic and working memory. For the first time, we show an independent relationship between cortical atrophy and cognitive impairment after accounting for the effects of central atrophy.