Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection.

Human cytomegalovirus (HCMV) is a large DNA herpesvirus that is highly prevalent in the human population. HCMV can result in severe direct and indirect pathologies under immunosuppressed conditions and is the leading cause of birth defects related to infectious disease. Currently, the effect of HCMV infection on host cell metabolism as an increase in glycolysis during infection has been defined. We have observed that oxidative phosphorylation is also increased. We have identified morphological and functional changes to host mitochondria during HCMV infection. The mitochondrial network undergoes fission events after HCMV infection. Interestingly, the network does not undergo fusion. At the same time, mitochondrial mass and membrane potential increase. The electron transport chain (ETC) functions at an elevated rate, resulting in the release of increased reactive oxygen species. Surprisingly, despite the stress applied to the host mitochondria, the network is capable of responding to and meeting the increased bioenergetic and biosynthetic demands placed on it. When mitochondrial DNA is depleted from the cells, we observed severe impairment of viral replication. Mitochondrial DNA encodes many of the ETC components. These findings suggest that the host cell ETC is essential to HCMV replication. Our studies suggest the host cell mitochondria may be a therapeutic target.IMPORTANCE Human cytomegalovirus (HCMV) is a herpesvirus present in up to 85% of some populations. Like all herpesviruses, HCMV infection is for life. No vaccine is currently available, neutralizing antibody therapies are ineffective, and current antivirals have limited long-term efficacy due to side effects and potential for viral mutation and resistance. The significance of this research is in understanding how HCMV manipulates the host mitochondria to support bioenergetic and biosynthetic requirements for replication. Despite a large genome, HCMV relies exclusively on host cells for metabolic functions. By understanding the dependency of HCMV on the mitochondria, we could exploit these requirements and develop novel antivirals.

Association of Diet Quality and Dietary Components with Clinical Resolution of HPV.

Nutrient deficits have been repeatedly linked to cervical human papillomavirus (HPV) persistence, cervical neoplasia, and cervical cancer in case-control studies. This study sought to examine the relationship between overall diet quality and dietary components with the spontaneous resolution of cervical HPV over one year. A prospective observational cohort study was performed. Women with low-grade cervical cytology and/or positive HPV test completed a 24-hour dietary recall, from which the Healthy Eating Index (HEI)-2010, a score of overall diet quality, and scores in dietary categories were calculated. Participants were managed clinically according to national management guidelines. Those whose subsequent testing demonstrated normalization of cytology and/or HPV testing ("HPV resolution") were compared to those whose abnormalities persisted or progressed ("HPV non-resolution"). Twenty-six women were included in the HPV resolution group and 38 in the non-resolution group. They were observed for a median of 428 and 412 day, respectively (p = 0.09). There was no difference in overall diet quality between the groups. Intake of total and whole fruit, and seafood/plant protein were associated with HPV resolution in a logistic regression model (all p < 0.05). These findings could have important implications for the counseling and management of individuals with HPV infection of the cervix.

CD4+ T helper 17 cell response of aged mice promotes prostate cancer cell migration and invasion.

BACKGROUND: Aging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion. METHODS: C57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4+ T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling. RESULTS: Aged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve CD4+ T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4+ T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4+ T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice. CONCLUSIONS: These results indicate that age-related CD4+ T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.

Impact of Obesity on Ventricular Assist Device Outcomes.

BACKGROUND: Obesity remains a relative contraindication for heart transplantation, and hence, obese patients with advanced heart failure receive ventricular assist devices (VADs) either as a destination or "bridge to weight loss" strategy. However, impact of obesity on clinical outcomes after VAD implantation is largely unknown. We sought to determine the clinical outcomes of obese patients with body mass index (BMI) ≥ 35 kg/m2) following contemporary VAD implantation. METHODS: The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry was queried for patients who underwent VAD implantation. Patients were categorized into BMI groups based on World Health Organization classification. RESULTS: Of 17,095 patients, 2620 (15%) had a BMI ≥ 35 kg/m2. Obese patients were likely to be young, non-white, females with dilated cardiomyopathy and undergo device implantation as destination. Survival was similar amongst BMI groups (P = .058). Obese patients had significantly higher risk for infection (hazard ratio [HR]: 1.215; P = .001), device malfunction or thrombosis (HR: 1.323; P ≤ .001), cardiac arrhythmia (HR: 1.188; P = .001) and hospital readmissions (HR: 1.073; P = .022), but lower risk of bleeding (HR: 0.906; P = .018). Significant weight loss (≥10%) during VAD support was achieved only by a small proportion (18.6%) of patients with BMI ≥ 35 kg/m2. Significant weight loss rates observed in obese patients with VAD implantation as destination and bridge to transplant strategy were comparable. Obese patients with significant weight loss were more likely to undergo cardiac transplantation. Weight loss worsened bleeding risk without altering risk for infection, cardiac arrhythmia, and device complications. CONCLUSIONS: Obesity alone should not be considered a contraindication for VAD therapy in contemporary era. Given durability of heart transplantation, strategies should be developed to promote weight loss, which occurs infrequently in obese patients. Impact of weight loss on clinical outcome of obese patients warrants further investigation.

Safety of Anteromedial Portals in Elbow Arthroscopy: A Systematic Review of Cadaveric Studies.

PURPOSE: To systematically review available literature comparing location and safety of 2 common anteromedial portals with nearby neurovascular structures in cadaveric models and to determine the correct positioning and preparation of the joint before elbow arthroscopy. METHODS: The review was devised in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inclusion criteria consisted of original, cadaveric studies performed by experienced surgeons on male or female elbows evaluating anteromedial portal placement with regard to proximity of the arthroscope to neurovascular structures. Exclusion criteria consisted of case reports, clinical series, non-English language studies, and noncadaveric studies. Statistical analysis was done to measure reviewer reliability after scoring of each study. RESULTS: During screening, 2,596 studies were identified, and 10 studies met final inclusion as original, cadaveric investigations of anteromedial portal proximity to neurovascular structures. The difference in distance between proximal and distal portals was <1 mm for the brachial artery and <1.5 mm for the medial antebrachial cutaneous nerve, whereas the ulnar nerve was 4.17 mm further from the distal portal and the median nerve was 5.07 mm further from the proximal portal. Joint distension increased the distances of neurovascular structures to portal sites, with the exception of the ulnar nerve in distal portals. Elbow flexion to 90° increased distances of all neurovascular structures to portal sites. CONCLUSION: The results show that the proximal anteromedial portal puts fewer structures at risk compared with the distal portal. Elbows in 90° flexion with joint distension carry a lower risk for neurovascular injury during portal placement. These findings suggest the proximal anteromedial portal to be the safer technique in anteromedial arthroscopy of the elbow. CLINICAL RELEVANCE: Discrepancies in placement of portals have existed in the literature, indicating differing safety margins regarding surrounding neurovascular anatomy. The present study aims to link together the literature-based evidence to describe the safest anteromedial portal variation.

Memory Self-Efficacy and Beliefs about Memory and Aging in Oldest-Old Adults in the Louisiana Healthy Aging Study (LHAS).

Background/Study Context. Adaptation to normative age-related declines in memory is an important but understudied aspect of successful aging. The purpose of the present study was to shed new light on memory self-efficacy and beliefs about memory and aging as two integral aspects of adult cognition with relevance to successful aging. METHODS: Young (19 to 27 years) and community-dwelling older adults (60 to 94 years) from the Louisiana Healthy Aging Study (LHAS) completed an adapted Memory Functioning Questionnaire (MFQ) which includes a memory self-efficacy subscale, the Memory Controllability Inventory (MCI), and the Aging Concerns Scale (ACS). RESULTS: Nonagenarians' self-reported memory and beliefs about memory and aging were of central interest. We compared their responses to three younger reference groups to examine hypothesized differences in self-reported memory and beliefs about memory and aging in very late life. Results yielded age effects for most of the MFQ and MCI subscales demonstrating more positive subjective views about memory functioning and control over memory for the young adults. Correlation and regression analyses were conducted to isolate factors that may be associated with memory self-efficacy. Age, symptoms of depression, and memory control beliefs accounted for approximately half of the variance in memory self-efficacy ratings. CONCLUSION: These data indicate that although memory self-efficacy may be age sensitive, we detected no differences in subjective views across the three older groups. Implications for cognitive adaptability and successful aging are considered.

Pre-pregnancy cardiovascular risk factors and racial disparities in birth outcomes: the Bogalusa Heart Study.

BACKGROUND: Racial disparities in birth outcomes are mirrored in cardiovascular health. Recently there have been calls for more attention to preconception and interconceptional health in order to improve birth outcomes, including as a strategy to reduce black-white disparities. METHODS: As part of a larger study of cardiovascular and reproductive health ("Bogalusa Babies"), female participants were linked to their children's birth certificates for Louisiana, Mississippi, and Texas births from 1982 to 2009. Three thousand and ninety-five women were linked to birth certificate data. Birth outcomes were defined as low birthweight (LBW) birthweight < 2500 g; preterm birth (PTB), > 3 weeks early; small for gestational age (SGA), <10th percentile for gestational age (percentiles based on study population); large for gestational age (LGA) >90th percentile for gestational age]. Cardiovascular measures (blood pressure, lipids, glucose, insulin) at the visit closest in time but prior to the pregnancy was examined as predictors of birth outcomes using logistic models adjusted for covariates. RESULTS: Only a few cardiovascular risk factors were associated with birth outcomes. Triglycerides were associated with higher risk of LBW among whites (aOR 1.05, 95% 1.01-1.10). Higher glucose was associated with a reduction in risk of SGA for black women (aOR 0.85, 95% CI 0.76-0.95), but not whites (p for interaction = 0.02). Clear racial disparities were found, but they were reduced modestly (LBW/SGA) or not at all (PTB/LGA) after CVD risk factors were adjusted for. CONCLUSIONS: This analysis does not provide evidence for preconception cardiovascular risk being a strong contributor to racial disparities.

Aging is associated with impaired angiogenesis, but normal microvascular network structure, in the rat mesentery.

A big problem associated with aging is thought to be impaired microvascular growth or angiogenesis. However, to link the evidence for impaired angiogenesis to microvascular dysfunction in aged tissues, we must compare adult vs. aged microvascular networks in unstimulated scenarios. The objective of this study was to test the hypothesis that aged microvascular networks are characterized by both fewer vessels and the impaired ability to undergo angiogenesis. Mesentery tissues from adult (9-mo) and aged (24-mo) male Fischer 344 rats were harvested and immunolabeled for platelet/endothelial cell adhesion molecule (an endothelial cell marker) according to two scenarios: unstimulated and stimulated. For unstimulated groups, tissues harvested from adult and aged rats were compared. For stimulated groups, tissues were harvested 3 or 10 days after compound 48/80-induced mast cell degranulation stimulation. Unstimulated aged microvascular networks displayed larger mean vascular area per tissue area compared with the unstimulated adult networks. The lack of a decrease in vessel density was supported at the gene expression level with RNA-Seq analysis and with comparison of vessel densities in soleus muscle. Following stimulation, capillary sprouting and vessel density were impaired in aged networks at 3 and 10 days, respectively. Our results suggest that aging associated with impaired angiogenesis mechanisms might not influence normal microvascular function, since unstimulated aged microvascular networks can display a "normal adult-like" vessel density and architecture. NEW & NOTEWORTHY: Using a multidimensional approach, we present evidence supporting that aged microvascular networks display vessel density and patterning similar to adult networks despite also being characterized by a decreased capacity to undergo angiogenesis. Thus, vessel loss is not necessarily a characteristic of aging.

A Comparison of 4 Analgesic Regimens for Acute Postoperative Pain Control in Breast Augmentation Patients.

PURPOSE: Patients undergoing breast augmentation are treated with multiple combinations of medications for pain control including ketorolac, liposomal bupivacaine, bupivacaine, and intravenous and oral narcotics. There is no current consensus on the optimal combination; therefore, all are used at the discretion of the surgeon. METHODS: This was a single-center, retrospective study. The total number of patients included was 132. Comparisons were made between 4 groups: bupivacaine only (B); bupivacaine and liposomal bupivacaine (BL); bupivacaine and liposomal bupivacaine plus intraoperative ketorolac (BLKi); and bupivacaine and liposomal bupivacaine plus postoperative ketorolac (BLKp). Average pain scores immediately postoperative and before discharge were recorded and correlated to percentage of patients who received narcotic in the post-anesthesia care unit (PACU). Additional end points noted were side effects including nausea and time spent in PACU postoperatively. RESULTS: Those receiving intraoperative ketorolac had the lowest pain on discharge (P < 0.0001) and the lowest percentage of patients receiving narcotics (P = 0.009) out of all 4 groups. There was no significant difference between the 4 groups in terms of time spent in PACU, pain immediately after the procedure, or amount of antiemetic given. No bleeding complications were noted for those who did or did not receive ketorolac. CONCLUSIONS: When given options for pain control in breast augmentation, intraoperative ketorolac should be considered, because its inclusion was significant in decreasing use of narcotics and pain upon discharge. Addition of other costly drugs such as liposomal bupivacaine may not provide additional benefit in the immediate postoperative setting for procedures with a short recovery period such as breast augmentation.

Single nucleotide polymorphisms linked to mitochondrial uncoupling protein genes UCP2 and UCP3 affect mitochondrial metabolism and healthy aging in female nonagenarians.

Energy expenditure decreases with age, but in the oldest-old, energy demand for maintenance of body functions increases with declining health. Uncoupling proteins have profound impact on mitochondrial metabolic processes; therefore, we focused attention on mitochondrial uncoupling protein genes. Alongside resting metabolic rate (RMR), two SNPs in the promoter region of UCP2 were associated with healthy aging. These SNPs mark potential binding sites for several transcription factors; thus, they may affect expression of the gene. A third SNP in the 3'-UTR of UCP3 interacted with RMR. This UCP3 SNP is known to impact UCP3 expression in tissue culture cells, and it has been associated with body weight and mitochondrial energy metabolism. The significant main effects of the UCP2 SNPs and the interaction effect of the UCP3 SNP were also observed after controlling for fat-free mass (FFM) and physical-activity related energy consumption. The association of UCP2/3 with healthy aging was not found in males. Thus, our study provides evidence that the genetic risk factors for healthy aging differ in males and females, as expected from the differences in the phenotypes associated with healthy aging between the two sexes. It also has implications for how mitochondrial function changes during aging.

Endobronchial Ultrasound-Transbronchial Needle Aspiration of Mediastinal and Hilar Lymphadenopathy Learning Curve.

Endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) has become a widely available tool that allows sampling of mediastinal and hilar lymph nodes with comparable accuracy as compared with the gold standard procedure, mediastinoscopy. The goal of this study was to evaluate the competence accuracy of this technique in academic medical center in patients with and without malignant disease. This was a retrospective chart review of the first 150 patients who underwent EBUS-TBNA at our institution with an operator not previously trained or supervised while performing the procedure. All nondiagnostic results were confirmed with mediastinoscopy. The cumulative sum analysis is a method used to continuously monitor performance against an established standard to attain competence in the procedure performed. Learning curve was assessed using cumulative sum method. Procedures were divided into sextiles (1-25, 26-50, 51-75, 76-100, 101-125, and 126-150). The technique's diagnostic accuracy was calculated for each of the 6 categories and trend toward improved accuracy was assessed using Cochran-Armitage trend test. Operator competency was achieved between 55th and 60th procedures. The diagnostic accuracy increased from 72% to 88% (from the first to third sextile) but remained stable afterwards at 88% (C-A trend test P = 0.091). The overall diagnostic accuracy was 84%. Trainees' learning rate varies while acquiring adequate knowledge. We suggest that a learning curve for each operator be used to assess competence in EBUS-TBNA procedure before physicians perform it without supervision.

Assessing the Immunogenic Response of a Single Center's Pneumococcal Vaccination Protocol in Sickle Cell Disease.

Sickle cell disease (SCD) is the most common inherited hematologic disorder in the United States. Patients with SCD are at increased risk of invasive pneumococcal disease and are reliant on both early penicillin prophylaxis and antipneumococcal vaccination for prevention of infection. Although studies examining vaccine response have demonstrated a drop-off of titer response after 3 years, an optimal vaccination regimen has not been identified. Our study sought to assess the immunogenicity of our center's pneumococcal vaccination strategy, which included Prevnar (PCV-7) (before the introduction of PCV-13) followed by Pneumovax (PPV-23) given routinely at 2 and 5 years of age and then every 5 years thereafter. Our goal was to assess vaccine response in a population of patients with SCD who had received vaccines according to this regimen using multiplex bead analysis. Our study demonstrated a significant percentage of persons with SCD do not maintain a sufficient vaccination response to PPV-23 for 5 years. Our study revealed that only 36% of patients had protective levels of antipneumococcal antibody titers at an average of 37 months after vaccination. Most alarmingly, within the group of patients with subtherapeutic titers, 64% demonstrated vaccine response to <25% of the tested serotypes. These findings were significantly associated with duration of time since last vaccine administration, but the mean age of lack of response was below the 3-year window where vaccine response was previously reported to wane. Our results indicate antipneumococcal immunity may not be optimally maintained using this vaccination strategy in patients with SCD leaving them vulnerable to invasive pneumococcal disease. Many pediatric hematologists stop prophylactic penicillin at 5 years of age making these results alarming. We recommend further investigation into an optimal vaccine schedule and monitoring of antipneumococcal titers in at-risk patients.

Programmed Cell Death Genes Are Linked to Elevated Creatine Kinase Levels in Unhealthy Male Nonagenarians.

Declining health in the oldest-old takes an energy toll for the simple maintenance of body functions. The underlying mechanisms, however, differ in males and females. In females, the declines are explained by loss of muscle mass; but this is not the case in males, in whom they are associated with increased levels of circulating creatine kinase. This relationship raises the possibility that muscle damage rather than muscle loss is the cause of the increased energy demands of unhealthy aging in males. We have now examined factors that contribute to the increase in creatine kinase. Much of it (60%) can be explained by a history of cardiac problems and lower kidney function, while being mitigated by moderate physical activity, reinforcing the notion that tissue damage is a likely source. In a search for genetic risk factors associated with elevated creatine kinase, the Ku70 gene XRCC6 and the ceramide synthase gene LASS1 were investigated because of their roles in telomere length and longevity and healthy aging, respectively. Single nucleotide polymorphisms in these two genes were independently associated with creatine kinase levels. The XRCC6 variant was epistatic to one of the LASS1 variants but not to the other. These gene variants have potential regulatory activity. Ku70 is an inhibitor of the proapoptotic Bax, while the product of Lass1, ceramide, operates in both caspase-dependent and -independent pathways of programmed cell death, providing a potential cellular mechanism for the effects of these genes on tissue damage and circulating creatine kinase.

Kinetics of Genetic Variation of the Mycoplasma genitalium MG192 Gene in Experimentally Infected Chimpanzees.

Mycoplasma genitalium, a human pathogen associated with sexually transmitted diseases, is capable of causing chronic infections, though mechanisms for persistence remain unclear. Previous studies have found that variation of the MgPa operon occurs by recombination of repetitive chromosomal sequences (known as MgPars) into the MG191 and MG192 genes carried on this operon, which may lead to antigenic variation and immune evasion. In this study, we determined the kinetics of MG192 sequence variation during the course of experimental infection using archived specimens from two chimpanzees infected with M. genitalium strain G37. The highly variable region of MG192 was amplified by PCR from M. genitalium isolates obtained at various time points postinfection (p.i.). Sequence analysis revealed that MG192 sequence variation began at 5 weeks p.i. With the progression of infection, sequence changes accumulated throughout the MG192 variable region. The presence of MG192 variants at specific time points was confirmed by variant-specific PCR assays and sequence analysis of single-colony cloned M. genitalium organisms. MG192 nucleotide sequence variation correlated with estimated recombination events, predicted amino acid changes, and time of seroconversion, a finding consistent with immune selection of MG192 variants. In addition, we provided evidence that MG192 sequence variation occurred during the process of M. genitalium single-colony cloning. Such spontaneous variation suggests that some MG192 variation is independent of immune selection but may form the basis for subsequent immune selection.

The effect of flow trigger on rapid shallow breathing index measured through the ventilator.

BACKGROUND: The rapid shallow breathing index (RSBI) has the best predictive value to assess readiness for weaning from mechanical ventilation. At many institutions, this index is conveniently measured without disconnecting the patient from the ventilator, but this method may be inaccurate. Because modern ventilators have a base flow in the flow trigger mode that may provide a substantial help to the patient, we hypothesized that the RSBI is significantly decreased when measured through the ventilator with flow trigger even without continuous positive airway pressure (CPAP) and pressure support (PS). METHODS: The RSBI was calculated using the values of minute ventilation and respiratory rate obtained either through the digital display of the ventilator or from a digital ventilometer. The RSBI was measured using 3 different methods: method 1, CPAP and PS both 0 cm H2O with flow trigger; method 2, CPAP and PS both 0 cm H2O without flow trigger; and method 3, using digital ventilometer. RESULTS: A total of 165 measurements per method were obtained in 80 adult patients in the medical intensive care unit (MICU). The RSBI (breaths/min/L) values were 70.2 ± 26.5 with method 1, 85.4 ± 30.3 with method 2, and 80.1 ± 30.3 with method 3. The RSBI was significantly decreased using mechanical ventilation with flow trigger as compared with mechanical ventilation without flow trigger (P < .0001) or digital ventilometer (P < .0001). When method 1 was compared with methods 2 and 3, the RSBI decreased by 17% and 12%, respectively. CONCLUSIONS: The RSBI measurement is significantly decreased by the base flow delivered through modern ventilators in the flow trigger mode. If RSBI is measured through the ventilator in the flow trigger mode, the difference should be considered when using RSBI to assess readiness for weaning from mechanical ventilation.

Extensive variation and rapid shift of the MG192 sequence in Mycoplasma genitalium strains from patients with chronic infection.

Mycoplasma genitalium causes persistent urogenital tract infection in humans. Antigenic variation of the protein encoded by the MG192 gene has been proposed as one of the mechanisms for persistence. The aims of this study were to determine MG192 sequence variation in patients with chronic M. genitalium infection and to analyze the sequence structural features of the MG192 gene and its encoded protein. Urogenital specimens were obtained from 13 patients who were followed for 10 days to 14 months. The variable region of the MG192 gene was PCR amplified, subcloned into plasmids, and sequenced. Sequence analysis of 220 plasmid clones yielded 97 unique MG192 variant sequences. MG192 sequence shift was identified between sequential specimens from all but one patient. Despite great variation of the MG192 gene among and within clinical specimens from different patients, MG192 sequences were more related within M. genitalium specimens from an individual patient than between patients. The MG192 variable region consisted of 11 discrete subvariable regions with different degrees of variability. Analysis of the two most variable regions (V4 and V6) in five sequential specimens from one patient showed that sequence changes increased over time and that most sequences were present at only one time point, suggesting immune selection. Topology analysis of the deduced MG192 protein predicted a surface-exposed membrane protein. Extensive variation of the MG192 sequence may not only change the antigenicity of the protein to allow immune evasion but also alter the mobility and adhesion ability of the organism to adapt to diverse host microenvironments, thus facilitating persistent infection.

Interleukin-17 promotes development of castration-resistant prostate cancer potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

BACKGROUND: Interleukin-17 (IL-17) has been demonstrated to promote formation and growth of hormone-naïve prostate adenocarcinoma in mice. IL-17's role in development of castration-resistant prostate cancer is unknown. In the present study, we investigated IL-17's role in castration-resistant prostate cancer in a mouse model. METHODS: IL-17 receptor C (IL-17RC) deficient mice were interbred with Pten conditional mutant mice to produce RC(+) mice that maintained IL-17RC expression and RC(-) mice that were IL-17RC deficient. Male RC(+) and RC(-) mice were Pten-null and were castrated at 16 weeks of age when invasive prostate cancer had already formed. At 30 weeks of age, all male mice were analyzed for the prostate phenotypes. RESULTS: RC(-) mice displayed prostates that were smaller than RC(+) mice. Approximately 23% of prostatic glands in RC(-) mice, in contrast to 65% of prostatic glands in RC(+) mice, developed invasive adenocarcinomas. Compared to castrate RC(+) mice, castrate RC(-) mouse prostate had lower rates of cellular proliferation and higher rates of apoptosis as well as lower levels of MMP7, YBX1, MTA1, and UBE2C proteins. In addition, castrate RC(-) mouse prostate had less angiogenesis, which was associated with decreased levels of COX-2 and VEGF. Moreover, castrate RC(-) mouse prostate had fewer inflammatory cells including lymphocytes, myeloid-derived suppressor cells, and macrophages. CONCLUSIONS: Taken together, our findings suggest that IL-17 promotes development of invasive prostate adenocarcinomas under castrate conditions, potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

Multipotent stromal cells alleviate inflammation, neuropathology, and symptoms associated with globoid cell leukodystrophy in the twitcher mouse.

Globoid cell leukodystrophy (GLD) is a common neurodegenerative lysosomal storage disorder caused by a deficiency in galactocerebrosidase (GALC), an enzyme that cleaves galactocerebroside during myelination. Bone marrow transplantation has shown promise when administered to late-onset GLD patients. However, the side effects (e.g., graft vs. host disease), harsh conditioning regimens (e.g., myelosuppression), and variable therapeutic effects make this an unsuitable option for infantile GLD patients. We previously reported modest improvements in the twitcher mouse model of GLD after intracerebroventricular (ICV) injections of a low-dose of multipotent stromal cells (MSCs). Goals of this study were to improve bone marrow-derived MSC (BMSC) therapy for GLD by increasing the cell dosage and comparing cell type (e.g., transduced vs. native), treatment timing (e.g., single vs. weekly), and administration route (e.g., ICV vs. intraperitoneal [IP]). Neonatal twitcher mice received (a) 2 × 10(5) BMSCs by ICV injection, (b) 1 × 10(6) BMSCs by IP injection, (c) weekly IP injections of 1 × 10(6) BMSCs, or (d) 1 × 10(6) lentiviral-transduced BMSCs overexpressing GALC (GALC-BMSC) by IP injection. All treated mice lived longer than untreated mice. However, the mice receiving peripheral MSC therapy had improved motor function (e.g., hind limb strength and rearing ability), twitching symptoms, and weight compared to both the untreated and ICV-treated mice. Inflammatory cell, globoid cell, and apoptotic cell levels in the sciatic nerves were significantly decreased as a result of the GALC-BMSC or weekly IP injections. The results of this study indicate a promising future for peripheral MSC therapy as a noninvasive, adjunct therapy for patients affected with GLD.

A retrospective study to assess the utility of frequent laboratory monitoring of pediatric patients with sickle cell disease on hydroxyurea.

Hydroxyurea (hydroxycarbamide, HU) is currently the only FDA-approved disease-modifying agent for individuals with sickle cell disease. Despite its efficacy in multicentered, randomized, placebo-controlled studies, HU remains highly underutilized among the sickle cell population. Several barriers to the use of HU have been identified including the need for frequent laboratory monitoring and physician visits. This study aimed to better assess the stability of patients' hematologic parameters when compliant with HU therapy to better determine the necessity of frequent routine laboratory monitoring. We conducted a retrospective review of 20 patients taking HU with record of good compliance. The within-subject coefficient of variation was computed as a measure of subject variability to better assess the stability of individual patients' blood counts to evaluate potential hematologic toxicity in subjects taking HU. Results demonstrated that during routine laboratory appointments, individuals' variability was very consistent; therefore assessment of significant change may be more accurately detected by individual symptomatology. Decreasing the stringency of the requirements for routine laboratory monitoring for patients on HU is unlikely to cause physicians to miss critical nadirs in absolute neutrophil count (or other laboratory values) and may lead to improved acceptance and use of this disease-modifying therapy in sickle cell disease.

Resident physicians' opinions and behaviors regarding the use of interpreters in New Orleans.

OBJECTIVES: In academic medical centers, resident physicians are most involved in the care of patients, yet many have little training in the proper use of interpreters in the care of patients with limited English-language proficiency. Residents have cited lack of time and lack of access to trained medical interpreters as barriers to the use of professional interpreter services. The purpose of this study was to examine the usage patterns of interpreters and perceived barriers to using interpreters in New Orleans. METHODS: Subjects included resident physicians training in internal medicine, pediatrics, and combined internal medicine and pediatrics at Tulane University and Louisiana State University in New Orleans. A survey that consisted of demographics, short-answer, and Likert-scale questions regarding attitudes related to the use of interpreters was used as the metric. RESULTS: The overall response rate was 55.5%. A total of 92.4% of subjects surveyed stated that they had used an interpreter during their residency. Telephone services and family members were the most commonly used types of interpreters (41.3% and 30.5%, respectively). Resident physicians were most likely to use interpreter services during their initial history taking as well as at discharge, but use declined throughout patients' hospitalization (P < 0.001). Residents cited lack of availability, lack of time, and lack of knowledge about accessing interpreter services as the major barriers to using interpreters. CONCLUSIONS: Resident physicians training in New Orleans have experience using interpreter services; however, they continue to use untrained interpreters and use varies during the hospital encounter. Targeted training for residents, including interpreter logistics, may help increase the use of interpreters.