Improving Adolescent Violent Trauma Outcomes With a Hospital-Based Violence Prevention Initiative.

BACKGROUND: Violent trauma results in significant morbidity/mortality in Black/Hispanic males aged 15 to 24 years. Hospital- and community-level interventions may improve patient and community outcomes. OBJECTIVE: To determine if a hospital-based violence prevention intervention using community outreach workers was associated with improved violent trauma patient postdischarge follow-up and reinjury rates. METHODS: This is a retrospective, single-center, cohort study of admitted violent trauma patients to a public hospital in the Bronx, NY. Data were collected from a convenience sample of patients aged 15 to 24 years admitted with International Classification of Diseases, 10th Revision, codes for gunshot wound, stab wound, or physical assault from August 2014 to April 2018. The exposure variable was documentation of intervention team evaluation during admission. The outcome variables included attending >50% scheduled postdischarge follow-up visits, and subsequent violent reinjury (gunshot wound, stab wound, blunt assault) during the study time period. Multivariable regression models were used to determine the association between the exposure and outcome variables. RESULTS: A total of 535 patients were evaluated and were primarily male (92.5%), Black (54%)/Latino (36.4%), with mean age of 19.1 years. Patients in the exposure group had increased odds of attending >50% of scheduled clinic postdischarge follow-up visits (odds ratio, 2.29; 95% confidence interval 1.59-3.29) and decreased odds of subsequent violent reinjury presentation (odds ratio, 0.41; 95% confidence interval 0.22-0.75) 3 months after hospital discharge. CONCLUSION: A hospital-based violence prevention intervention may be associated with decreased odds of violent reinjury and increased odds of postdischarge scheduled appointment adherence in admitted pediatric violent trauma patients.

Race-specific characteristics in pediatric eosinophilic esophagitis in an urban inner-city clinic.

BACKGROUND: Manifestations of pediatric eosinophilic esophagitis (EoE) are varied and dictated by multiple factors. The influence of race is limited to small observational cohorts of dichotomized data (Whites vs non-Whites) or single-racial analysis. OBJECTIVE: To better understand phenotypic variability in the manifestation and atopic sensitization of pediatric EoE, from the perspective of race. METHODS: Retrospective observational cohort study performed at a tertiary referral center. Subjects were included if less than 21 years old, with suggestive clinical features and histopathologic (>15 eosinophils/high-power field [hpf]) confirmation of EoE. Statistical computation was performed using Stata/IC 11 on variables of interest. RESULTS: A total of 34 subjects were included in the analysis. The median (interquartile range [IQR]) age for initial atopy was 2 (1-5) years. The median (IQR) age for EoE diagnosis was 5 (3-8) years. Age of EoE diagnosis was higher for Black or African Americans than non-Black or African Americans (P = .01). Between the racial groups, there was no difference in the total number of food sensitizations (P = .13), yet environmental allergy testing revealed that Black or African Americans were more likely to be sensitized for weeds (P = .03), dog (P = .009), and mold (P = .006). On histopathologic analysis, Black or African American subjects were found to have more prominent midesophageal eosinophilia at median 50/hpf (20-80/hpf), whereas Hispanic or LatinXs have more prominent lower esophageal eosinophilia at median 40/hpf (IQR, 20-40/hpf), compared with the other races (P = .04 and P = .04, respectively). CONCLUSION: Black or African Americans are more likely to present at an older age, have aeroallergen sensitization, and have more prominent midesophageal eosinophilia.

The "sugar dilemma".

Type 2 diabetes mellitus is characterized by insulin resistance and elevated blood glucose levels. Treatment protocols generally include dietary restriction of sugar, as well as drugs aiming at a reduction of blood glucose, mainly by activating the insulin system or supplementing insulin. This established approach does not take into account the outstanding physiological role of glucose as a key molecule in metabolism. Glucose is crucial to meet the high energy demand of the brain, which depends on it as an exclusive nutrient. Insulin independent glucose transporters GLUT1 import glucose into the brain. Reduction of blood glucose, as in current treatment concepts, may lead to energy deficiency in the brain and consecutively to worsening of - possibly already impaired - neurocognitive function. Reduced cell membrane fluidity of the vascular endothelium of the bloodbrain-barrier (BBB) - due to malnutrition and/or aging - is considered a major factor in pathogenesis of the cerebral metabolic syndrome, which is a key step in neurodegeneration. Under this aspect we suggest a novel approach to prophylaxis and treatment focusing on a sufficient supply of glucose to the brain.

Postpartum bonding: the impact of maternal depression and adult attachment style.

Maternal depression poses a risk for the developing mother-infant relationship. Similarly, maternal insecure attachment styles may limit the ability to adequately connect with the newborn during the postpartum period. The aim of this study was to investigate the effect of maternal depression and insecure attachment (insecure and dual/disorganized) on maternal bonding in a sample of n = 34 women with depression according to DSM-IV and n = 59 healthy women. Maternal depression was assessed 3 to 4 months postpartum with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), bonding with the Postpartum Bonding Questionnaire, and maternal attachment style with the Attachment Style Interview. Women with current and lifetime depression as well as women with dual/disorganized attachment style reported lower bonding. Explorative analysis revealed that depression partially mediated the link between dual/disorganized attachment style and bonding with a medium-sized mediation effect. The combination of maternal depression and dual/disorganized attachment style may pose a special risk constellation for the developing mother-infant bond that should be addressed in prevention and early intervention programs.

Malaria induces anemia through CD8+ T cell-dependent parasite clearance and erythrocyte removal in the spleen.

UNLABELLED: Severe malarial anemia (SMA) in semi-immune individuals eliminates both infected and uninfected erythrocytes and is a frequent fatal complication. It is proportional not to circulating parasitemia but total parasite mass (sequestered) in the organs. Thus, immune responses that clear parasites in organs may trigger changes leading to anemia. Here, we use an outbred-rat model where increasing parasite removal in the spleen escalated uninfected-erythrocyte removal. Splenic parasite clearance was associated with activated CD8(+) T cells, immunodepletion of which prevented parasite clearance. CD8(+) T cell repletion and concomitant reduction of the parasite load was associated with exacerbated (40 to 60%) hemoglobin loss and changes in properties of uninfected erythrocytes. Together, these data suggest that CD8(+) T cell-dependent parasite clearance causes erythrocyte removal in the spleen and thus anemia. In children infected with the human malaria parasite Plasmodium falciparum, elevation of parasite biomass (not the number of circulating parasites) increased the odds ratio for SMA by 3.5-fold (95% confidence intervals [CI95%], 1.8- to 7.5-fold). CD8(+) T cell expansion/activation independently increased the odds ratio by 2.4-fold (CI95%, 1.0- to 5.7-fold). Concomitant increases in both conferred a 7-fold (CI95%, 1.9- to 27.4-fold)-greater risk for SMA. Together, these data suggest that CD8(+)-dependent parasite clearance may predispose individuals to uninfected-erythrocyte loss and SMA, thus informing severe disease diagnosis and strategies for vaccine development. IMPORTANCE: Malaria is a major global health problem. Severe malaria anemia (SMA) is a complex disease associated with partial immunity. Rapid hemoglobin reductions of 20 to 50% are commonly observed and must be rescued by transfusion (which can carry a risk of HIV acquisition). The causes and risk factors of SMA remain poorly understood. Recent studies suggest that SMA is linked to parasite biomass sequestered in organs. This led us to investigate whether immune mechanisms that clear parasites in organs trigger anemia. In rats, erythropoiesis is largely restricted to the bone marrow, and critical aspects of the spleen expected to be important in anemia are similar to those in humans. Therefore, using a rat model, we show that severe anemia is caused through CD8(+) T cell-dependent parasite clearance and erythrocyte removal in the spleen. CD8 activation may also be a new risk factor for SMA in African children.

A vacation for the homeless: evaluating a collaborative community respite programme in Canada through clients' perspectives.

This study assesses the Urban Breakaway Project, a collaborative project offering a structured vacation in the countryside of the province of Quebec intended for homeless (or street) youths. The objective of this study was to document participants' perspectives regarding this project by examining their satisfaction, intention to change following their stay and perceived improvement with respect to their life situation. Another goal of this research was to investigate the relationship between satisfaction level and perceived improvement of participants. One hundred and seven individuals participated in the study, during Urban Breakaway's first year of operation. Satisfaction with the project, assessed with the global Client Satisfaction Questionnaire-3 score, revealed a positive relationship with global scores of perceived improvement, as measured by the Perceived Improvement Questionnaire [PIQ; r = 0.37 (67), 95% CI (0.15; 0.56)]. Regarding intention to change, the data indicated that 95% of participants had moderate-to-definite intentions to do something to change their lives. Participants reported an improvement for most items covered by the PIQ. They experienced the greatest changes in relation to mood, leisure, appetite, physical condition and self-esteem. Results indicate that the Urban Breakaway Project reaches not only street youths but also an older homeless population. Participants, regardless of their age, were found to be very satisfied with services obtained, and their satisfaction was significantly correlated with the perceived improvement in their situation. Qualitative data indicate that characteristics of the programme, such as the countryside setting, the focus on basic needs, the climate and the opportunity for socialisation, peer support (or belonging) and personal growth were appreciated.

Estimating infectivity rates and attack windows for two viruses.

Cells exist in an environment in which they are simultaneously exposed to a number of viral challenges. In some cases, infection by one virus may preclude infection by other viruses. Under the assumption of independent times until infection by two viruses, a procedure is presented to estimate the infectivity rates along with the time window during which a cell might be susceptible to infection by multiple viruses. A test for equal infectivity rates is proposed and interval estimates of parameters are derived. Additional hypothesis tests of potential interest are also presented. The operating characteristics of these tests and the estimation procedure are explored in simulation studies.

Deletion of a malaria invasion gene reduces death and anemia, in model hosts.

Malaria parasites induce complex cellular and clinical phenotypes, including anemia, cerebral malaria and death in a wide range of mammalian hosts. Host genes and parasite 'toxins' have been implicated in malarial disease, but the contribution of parasite genes remains to be fully defined. Here we assess disease in BALB/c mice and Wistar rats infected by the rodent malaria parasite Plasmodium berghei with a gene knock out for merozoite surface protein (MSP) 7. MSP7 is not essential for infection but in P. falciparum, it enhances erythrocyte invasion by 20%. In vivo, as compared to wild type, the P. berghei Δmsp7 mutant is associated with an abrogation of death and a decrease from 3% to 2% in peak, circulating parasitemia. The Δmsp7 mutant is also associated with less anemia and modest increase in the size of follicles in the spleen. Together these data show that deletion of a single parasite invasion ligand modulates blood stage disease, as measured by death and anemia. This work is the first to assess the contribution of a gene present in all plasmodial species in severe disease.

A rapid murine coma and behavior scale for quantitative assessment of murine cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is a neurological syndrome that includes coma and seizures following malaria parasite infection. The pathophysiology is not fully understood and cannot be accounted for by infection alone: patients still succumb to CM, even if the underlying parasite infection has resolved. To that effect, there is no known adjuvant therapy for CM. Current murine CM (MCM) models do not allow for rapid clinical identification of affected animals following infection. An animal model that more closely mimics the clinical features of human CM would be helpful in elucidating potential mechanisms of disease pathogenesis and evaluating new adjuvant therapies. METHODOLOGY/PRINCIPAL FINDINGS: A quantitative, rapid murine coma and behavior scale (RMCBS) comprised of 10 parameters was developed to assess MCM manifested in C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). Using this method a single mouse can be completely assessed within 3 minutes. The RMCBS enables the operator to follow the evolution of the clinical syndrome, validated here by correlations with intracerebral hemorrhages. It provides a tool by which subjects can be identified as symptomatic prior to the initiation of trial treatment. CONCLUSIONS/SIGNIFICANCE: Since the RMCBS enables an operator to rapidly follow the course of disease, label a subject as affected or not, and correlate the level of illness with neuropathologic injury, it can ultimately be used to guide the initiation of treatment after the onset of cerebral disease (thus emulating the situation in the field). The RMCBS is a tool by which an adjuvant therapy can be objectively assessed.

Bariatric surgery in obesity: changes of glucose and lipid metabolism correlate with changes of fat mass.

BACKGROUND AND AIM: Bariatric surgery induces significant weight loss and improves glucose metabolism in obese patients (BMI>35 kg/m(2)). Our aim was to compare restrictive (LAGB, laparoscopic gastric banding) and malabsorptive approaches (BIBP, biliary-intestinal bypass) on the loss of fat-free mass (FFM), fat mass (FM), and on changes of glucose and lipid metabolism. METHODS AND RESULTS: Body composition (bio-impedance analysis, BIA), blood glucose (BG), insulin, triglycerides, total- and HDL-cholesterol, liver enzymes (AST and ALT) were measured at baseline and 1 year after surgery in patients undergoing LAGB, BIBP, and in diet-treated control patients. In the main study, with patients matched for initial BMI (43-55 kg/m(2), LAGB=24, BIBP=12, controls=6), decreases of BMI, FM, BG and cholesterol were greater in patients with BIBP than with LAGB (p<0.01), while decreases of FFM, insulin, HOMA-IR and triglycerides were similar. No effects on BMI, FM, FFM, BG, insulin, HOMA-IR or cholesterol were observed in the control patients. Decreases of BG, insulin, HOMA-IR, cholesterol and triglycerides correlated with FM but not with FFM decrease. Similar results were obtained in an additional study in patients with a different initial BMI (LAGB=25, BIBP=6, controls=24) and when considering all subjects together. A decrease of liver enzymes (ALT) was greater with LAGB than with BIBP, and HDL-cholesterol increased with LAGB and decreased with BIBP. CONCLUSION: BMI, FM, BG and cholesterol decrease more with malabsorptive than with restrictive surgery, while FFM, insulin, HOMA-IR and triglycerides decrease in a similar way. FFM loss is of low entity. Changes of glucose and lipid metabolism are proportional to a decrease of fat mass but not of fat-free mass.

A Plasmodium falciparum host-targeting motif functions in export during blood stage infection of the rodent malarial parasite Plasmodium berghei.

Plasmodium falciparum (P. falciparum) secretes hundreds of proteins--including major virulence proteins--into the host erythrocyte. In order to reach the host cytoplasm, most P. falciparum proteins contain an N terminal host-targeting (HT) motif composed of 11 amino acids. In silico analyses have suggested that the HT motif is conserved throughout the Plasmodium species but experimental evidence only exists for P. falciparum. Here, we show that in the rodent malaria parasite Plasmodium berghei (P. berghei) a reporter-like green fluorescent protein expressed by the parasite can be exported to the erythrocyte cytoplasm in a HT-specific manner. This provides the first experimental proof that the HT motif can function as a signal for protein delivery to the erythrocyte across Plasmodium species. Further, it suggests that P. berghei may serve as a model for validation of P. falciparum secretome proteins. We also show that tubovesicular membranes extend from the vacuolar parasite into the erythrocyte cytoplasm and speculate that these structures may facilitate protein export to the erythrocyte.

Phosphorylation of the Saccharomyces cerevisiae La protein does not appear to be required for its functions in tRNA maturation and nascent RNA stabilization.

An abundant nuclear phosphoprotein, the La autoantigen, is the first protein to bind all newly synthesized RNA polymerase III transcripts. Binding by the La protein to the 3' ends of these RNAs stabilizes the nascent transcripts from exonucleolytic degradation. In the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the La protein is required for the normal pathway of tRNA maturation. Experiments in which the human protein was expressed in S. pombe have suggested that phosphorylation of the La protein regulates tRNA maturation. To dissect the role of phosphorylation in La protein function, we used mass spectrometry to identify three sites of serine phosphorylation in the S. cerevisiae La protein Lhp1p. Mutant versions of Lhp1p, in which each of the serines was mutated to alanine, were expressed in yeast cells lacking Lhp1p. Using two-dimensional gel electrophoresis, we determined that we had identified and mutated all major sites of phosphorylation in Lhp1p. Lhp1p lacking all three phosphorylation sites was functional in several yeast strains that require Lhp1p for growth. Northern blotting revealed no effects of Lhp1p phosphorylation status on either pre-tRNA maturation or stabilization of nascent RNAs. Both wild-type and mutant Lhp1 proteins localized to both nucleoplasm and nucleoli, demonstrating that phosphorylation does not affect subcellular location. Thus, although La proteins from yeast to humans are phosphoproteins, phosphorylation does not appear to be required for any of the identified functions of the S. cerevisiae protein.

A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule.

PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.

Multiple functional interactions between components of the Lsm2-Lsm8 complex, U6 snRNA, and the yeast La protein.

The U6 small nuclear ribonucleoprotein is a critical component of the eukaryotic spliceosome. The first protein that binds the U6 snRNA is the La protein, an abundant phosphoprotein that binds the 3' end of many nascent small RNAs. A complex of seven Sm-like proteins, Lsm2-Lsm8, also binds the 3' end of U6 snRNA. A mutation within the Sm motif of Lsm8p causes Saccharomyces cerevisiae cells to require the La protein Lhp1p to stabilize nascent U6 snRNA. Here we describe functional interactions between Lhp1p, the Lsm proteins, and U6 snRNA. LSM2 and LSM4, but not other LSM genes, act as allele-specific, low-copy suppressors of mutations in Lsm8p. Overexpression of LSM2 in the lsm8 mutant strain increases the levels of both Lsm8p and U6 snRNPs. In the presence of extra U6 snRNA genes, LSM8 becomes dispensable for growth, suggesting that the only essential function of LSM8 is in U6 RNA biogenesis or function. Furthermore, deletions of LSM5, LSM6, or LSM7 cause LHP1 to become required for growth. Our experiments are consistent with a model in which Lsm2p and Lsm4p contact Lsm8p in the Lsm2-Lsm8 ring and suggest that Lhp1p acts redundantly with the entire Lsm2-Lsm8 complex to stabilize nascent U6 snRNA.

Practical aspects of preparation of foods for double-blind, placebo-controlled food challenge.

Recipes for double-blind, placebo-controlled food challenge developed and tested in our department are presented. The taste and smell of offending foods were disguised by using substances with a strong taste and flavor. The texture of active foods was more difficult to simulate in the placebo food.

A phase I/II evaluation of oral L-2-oxothiazolidine-4-carboxylic acid in asymptomatic patients infected with human immunodeficiency virus.

A randomized double-blind, placebo-controlled study was conducted in 37 asymptomatic HIV-infected individuals (mean CD4 count 707 cells/mm3) to characterize the safety, pharmacokinetics, and effect on blood thiols of three dosage levels of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid (OTC; Procysteine; Clintec Technologies, Deerfield, IL). Single-dose administration of OTC resulted in measurable plasma levels at all dosages, with a mean peak plasma concentration of 734 +/- 234 nmol/mL at the highest dosage studied. After 4 weeks of administration three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3,000 mg dose groups compared with the placebo group. A significant increase in whole blood cysteine and peripheral blood mononuclear cell (PBMC) glutathione was not seen during the study period.

Sequence-dependent hematological toxicity associated with the 3-hour paclitaxel/cyclophosphamide doublet.

Paclitaxel is active in metastatic breast cancer. Combination studies have demonstrated complex interactions between paclitaxel and other cytotoxic agents, including sequence-dependent cytotoxic, toxicological, and pharmacological effects. The principal objectives of this study were to determine the maximum tolerated doses of paclitaxel (3-h infusion) and cyclophosphamide (1-h infusion) administered every 3 weeks with granulocyte colony-stimulating factor (Filgrastim) and to determine if the sequence-dependent toxicological effects that have previously been observed with this combination when paclitaxel was administered over 24 h were evident when paclitaxel was administered over 3 h. Fifteen women with metastatic breast cancer were treated. Starting doses were 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, with granulocyte colony-stimulating factor (5 micrograms/kg/day) given s.c. beginning 24 h after chemotherapy. Doses of both drugs were escalated in cohorts of at least four patients. The sequence of drug administration was alternated with each consecutive patient and with each subsequent course of therapy in each individual patient, enabling the evaluation of sequence-dependent toxicological and pharmacological effects. Severe myelosuppression was the principal dose-limiting toxicity for this regimen, precluding dose escalation above 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, the maximum tolerated dose for this combination on this schedule. As has been previously demonstrated with this combination, when paclitaxel is administered over 24 h, the hematopoietic toxicity was sequence dependent. Paired analysis of toxicity data using each patient as her own control indicated more severe hematological toxicity in courses in which paclitaxel was administered first. There was no evidence of sequence-dependent effects on the pharmacokinetics of these drugs that might account for this phenomenon. The impact of drug sequencing on toxicity should be considered in the further development of combination therapy containing alkylating agents and paclitaxel, when the latter is administered over 3 h.