Increased activation of the fear neurocircuitry in children exposed to violence

Most studies investigating the effect of childhood trauma on the brain are retrospective and mainly focus on maltreatment, whereas different types of trauma exposure such as growing up in a violent neighborhood, as well as developmental stage, could have differential effects on brain structure and function. The current magnetic resonance imaging study assessed the effect of trauma exposure broadly and violence exposure more specifically, as well as developmental stage on the fear neurocircuitry in 8‐ to 14‐year‐old children and adolescents (N = 69). We observed reduced hippocampal and increased amygdala volume with increasing levels of trauma exposure. Second, higher levels of violence exposure were associated with increased activation in the amygdala, hippocampus, and ventromedial prefrontal cortex during emotional response inhibition. This association was specifically observed in children younger than 10 years. Finally, increased functional connectivity between the amygdala and brainstem was associated with higher levels of violence exposure. Based on the current findings, it could be hypothesized that trauma exposure during childhood results in structural changes that are associated with later risk for psychiatric disorders. At the same time, it could be postulated that growing up in an unsafe environment leads the brain to functionally adapt to this situation in a way that promotes survival, where the long‐term costs or consequences of these adaptations are largely unknown and an area for future investigations.     

Use of a somatostatin analogue, octreotide acetate, in the management of acute gastrointestinal graft-versus-host disease

PURPOSE: Because the secretory diarrhea of acute graft-versus-host disease (GvHD) of the gut induces serious metabolic and nutritional disturbances, this study was initiated to assess the use of a somatostatin analogue, octreotide acetate, as adjunctive therapy for severe GvHD of the gut with massive diarrhea. PATIENTS AND METHODS: In a pilot study, six patients with biopsy-confirmed acute gut GvHD after allogeneic bone marrow transplantation received octreotide 50 to 250 micrograms three times a day subcutaneously. RESULTS: Three of the six treated patients had a prompt and dramatic reduction in stool volume within 1 to 3 days of initiation of octreotide therapy. CONCLUSIONS: Somatostatin and its analogues have been used successfully in diarrheal states by antagonism of neuropeptide overproduction, although other potential therapeutic mechanisms include inhibition of fluid secretion, enhanced salt absorption, and inhibition of gut motility. Somatostatin and its analogues may be promising adjunctive agents in the treatment of gastrointestinal GvHD, although assessment in a controlled trial will be required to confirm their therapeutic efficacy.     

Cocrystallization of an immunoglobulin light chain dimer with bis(dinitrophenyl) lysine: tandem binding of two ligands, one with and one without accompanying conformational changes in the protein

Previous studies showed that the Mcg dimer of immunoglobulin light chains bound bis(dinitrophenyl)lysine both in trigonal crystals and in solution. On prolonged storage in ammonium sulfate, mixtures of ligand and protein produced small trigonal cocrystals in low frequency. These crystals were nearly isomorphous with those of the unliganded dimer in which the subunits were covalently linked by an interchain disulfide bond. By difference Fourier analyses at 3.5 A resolution and subsequent crystallographic refinement, the cocrystals were found to contain molecules with two ligands aligned in tandem along the interface of the variable (V) domains of the protein. One ligand molecule adopted an almost fully extended conformation, with the epsilon-DNP ring situated near the floor, the alpha-carboxyl group directed toward the solvent at the entry, and the alpha-DNP ring outside the rim of the main cavity. As if architecturally designed, the ligand was located symmetrically between the two domains in an orientation that was compatible with both the unaltered structure of the cavity lining and with the known crystal packing interactions of neighboring protein molecules. The second ligand molecule in the cocrystal lodged in the deep pocket immediately under the floor of the main cavity. The ligand adopted a very compact conformation with the two DNP rings roughly antiparallel to each other. This molecule appeared to be semi-permanently sequestered in the pocket since it could not be dislodged by exhaustive perfusion with ammonium sulfate crystallizing media. Relative to its volume in the native dimer, the pocket was expanded to accommodate the oversized ligand. Within a single protein molecule, therefore, two types of binding of a flexible ligand were observed, one with and one without accompanying conformational changes in the protein. The number of cocrystals which could be produced was markedly increased if the interchain disulfide bond between the Mcg monomers was first reduced and alkylated.     

DNA polymerase mu gene expression in B-cell non-Hodgkin's lymphomas: an analysis utilizing in situ hybridization

DNA polymerase mu (pol mu) is a novel error-prone DNA repair enzyme bearing significant structural homology with terminal deoxynucleotidyltransferase. Whereas other human error-prone DNA polymerases identified thus far show no preferential lymphoid tissue distribution, the highest levels of pol mu mRNA have been detected in peripheral lymphoid tissues, particularly germinal center B cells. Conceivably, up-regulation of the pol mu gene may be biologically significant in lymphomagenesis, especially in the development of B-cell non-Hodgkin's lymphomas (B-NHLs), because of enhanced error-prone DNA repair activities. To explore this possibility, we generated a digoxigenin-labeled riboprobe to pol mu mRNA and used the probe and in situ hybridization to examine the expression pattern of the pol mu gene in formalin-fixed, paraffin-embedded tissue sections of 37 B-NHLs. This included eight chronic lymphocytic leukemia/small lymphocytic lymphomas, six mantle cell lymphomas, seven follicular lymphomas, nine diffuse large B-cell lymphomas, three splenic marginal zone lymphomas, two Burkitt's lymphomas, and two precursor B-lymphoblastic lymphomas. We also correlated the pol mu mRNA expression levels with the tumor proliferation index, which was assessed in each case by image analysis of Ki-67 immunostained slides. Nineteen of 21 (90%) B-NHLs arising from postgerminal center B cells (follicular lymphomas, diffuse large B-cell lymphomas, splenic marginal zone lymphomas, and Burkitt's lymphomas) exhibited high expression of pol mu mRNA. In contrast, only 2 of 16 (13%) B-NHLs arising from pregerminal center B cells (chronic lymphocytic leukemia/small lymphocytic lymphomas, mantle cell lymphomas, and precursor B-lymphoblastic lymphomas) expressed significant levels of pol mu mRNA. Pol mu gene expression did not seem to correlate with the proliferation index, especially because a significant level of pol mu mRNA was not detected in either case of precursor B-lymphoblastic lymphomas. In conclusion, pol mu gene expression is highly associated with B-NHLs of postgerminal center B-cell derivation. Furthermore, the expression level is independent of the proliferation rate and thus is unrelated to the biological aggressiveness of the tumors. These findings, along with the error-prone nature of the enzyme, suggest that up-regulation of pol mu gene expression may be a contributing factor to the pathogenesis of a subset of B-NHLs through DNA repair-associated genomic instability.     

Localization of endogenous galactoside-binding lectin during morphogenesis ofXenopus laevis

Summary A monoclonal antibody has been produced againstXenopus laevis galactoside-binding neural-creststage lectin. This antibody inhibits lectin-mediated hemagglutination. Using this antibody in conjunction with immunohistochemical techniques, lectin deposition has been studied in embryos and tadpoles at different stages of morphogenesis, from initial neural crest migration, up to the formation of a swimming tadpole. Lectin levels change during development in different regions of the embryo and tadpole, decreasing in migratory cells, and increasing in sites where cells become more adhesive to one another. The results suggest that galactoside-binding lectins may be an important class of cellular adhesion molecules during these stages of development.     

Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.     

Efficacy and safety of recombinant human activated protein C for severe sepsis

BACKGROUND: Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS: A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.     

Tactile feedback contributes to consistency of finger movements during typing

Touch typing movements are typically too brief to use on-line feedback. Yet, previous studies have shown that blocking tactile feedback of the fingertip of typists leads to an increase in typing errors. To determine the contribution of tactile information to rapid fine motor skills, we analyzed kinematics of the right index finger during typing with and without tactile feedback. Twelve expert touch typists copy-typed sentences on a computer keyboard without vision of their hands or the computer screen. Following control trials, their right index fingertip was anesthetized, and sentences were typed again. The movements of the finger were recorded with an instrumented glove and electromagnetic position sensor. During anesthesia, typing errors of that finger increased sevenfold. While the inter-keypress timing and average kinematics were unaffected, there was an increase in variability of all measures. Regression analysis showed that endpoint variability was largely accounted for by start location variability. The results suggest that tactile cues provide information about the start location of the finger, which is necessary to perform typing movements accurately.     

Anesthesia using microcannula and sharp needle in upper blepharoplasty: A randomized,double-blind clinical trial evaluating pain,bruising, and ecchymoses

IntroductionWith the emergence of blunt-tipped microcannulas, there is a hypothesis that these could cause less damage and reduce pain as compared to conventional sharp needles in eyelid surgery. The purpose is to determine whether an 18G blunt-tipped cannula can be better than a 26G needle.MethodsThis prospective, observer-blinded, randomized clinical trial was conducted from June 2017 to December 2018. Sixty-eight patients were randomized to receive local anesthesia injections for upper blepharoplasty. Infiltration was performed by using a 26-gauge sharp needle on one side and on the other side, infiltration was performed by using an 18-gauge stainless-steel blunt-tipped microcannula. A numeric rating scale (NRS) from 0 to 10 was used to blindly assess pain in patients receiving anesthesia injections with both needle types. Photographs of the eyelids of each patient were taken in five different periods and used by three blinded observers to identify bruise or ecchymoses.ResultsA total of 136 eyelid operations were performed. There was no statistically significant difference when both groups were compared; however, the average score of pain was higher in patients taking the infiltration through the needle (2.85 versus 2.50). Regarding the evaluation of bruising and ecchymoses, the results showed that, in the five periods evaluated, there was no statistical difference in bruising and ecchymosis in the eyelids when taking the infiltration through a sharp needle when compared with that of the eyelids taking infiltration through a (blunt-tipped) microcannula.ConclusionThe evaluation of the blunt-tipped microcannula showed a lower pain score mean than that obtained for the sharp needle (2.5 versus 2.85) (p > 0.05). There was no statistically significant difference in the bruising and ecchymosis courses.     

Nutrient intake among elderly in southern Peninsular Malaysia

Studies were conducted in selected areas in three states namely Johor (n=117, male=55, female=62), Negeri Sembilan (n=130, male=52, female=78) and Malacca (n=97, male=33, female=64) involving free living elderly (age range from 60 to 93 years old). Respondents were divided into three age cohort groups that is 60 to 69 years, 70 to 79 years and above 80 years old. Assessment of macro and micronutrients were obtained from 24-hour diet recall for three consecutive days. Household measurements were used to estimate the amount of food consumed. Mean energy intake for both sexes were lower than the Malaysian RDA. Mean energy intake were also found to decline with age increment. The percentage of carbohydrate from total calories is higher compared to fat and protein. No respondents were found to consume less than 1/3 RDA for protein. Although no significant difference in nutrient intake was noted among age cohort groups, there was a decline in the intake of protein, fat and carbohydrate. Significantly (p <0.05) lower carbohydrate intake was noted in cohort group above 80 years. As for vitamins and minerals consumption, more than 50% of the elderly population studied consumed less than 2/3 RDA for vitamin A, thiamine, riboflavin, niacin and calcium. Very low intake of nutrient may lead to many health problems. Overall mean energy intake indicate the respondents consume less than the Malaysian RDA for all three age cohort groups. Total mean energy intake were also found to decline with age increment for both sexes. Due to the low energy intake, higher percentage of elderly were found consuming less than 2/3 RDA for thiamine (65%), riboflavin (63%) and niacin (90%). Other nutrients which were also being consumed less than 2/3 RDA by the respondents are vitamin A (67%) and calcium (65%). The intake of calcium which was found to be extremely low (ranged from 277 to 303 mg) could lead to problems like osteoporosis.