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Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias

Mon, 03/23/2015 - 2:58pm

BACKGROUND: Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects.

OBJECTIVE: We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families.

METHODS: We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA.

RESULTS: Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA.

CONCLUSIONS: We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA. Mosby, Inc. All rights reserved.

Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-gamma responses before antiretroviral therapy but not higher T-cell responses during therapy

Mon, 03/23/2015 - 2:58pm

BACKGROUND: Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART).

METHODS: Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and -induced production of interferon-gamma (IFN-gamma), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients.

RESULTS: Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-gamma production in 24-hour cultures pre-cART and 4 weeks post-cART (P = .0437 and .0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P = .0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P = .0053, .0436 and .0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART.

CONCLUSION: Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-gamma production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.

A rare presentation of hypertrophic olivary degeneration secondary to primary central nervous system lymphoma

Mon, 03/23/2015 - 2:58pm

Case report: A 71-year-old man presented with a 2-week history of nausea, vomiting, unsteady gait, and diplopia.

Targeted expression of human folylpolyglutamate synthase for selective enhancement of methotrexate chemotherapy in osteosarcoma cells

Mon, 03/23/2015 - 2:58pm

The antifolate methotrexate (MTX) is an important chemotherapeutic agent for treatment of osteosarcoma. This drug is converted intracellularly into polyglutamate derivates by the enzyme folylpolyglutamate synthase (FPGS). MTX polyglutamates show an enhanced and prolonged cytotoxicity in comparison to the monoglutamate. In the present study, we proved the hypothesis that transfer of the human fpgs gene into osteosarcoma cells may augment their MTX sensitivity. For this purpose, we employed the human osteocalcin (OC) promoter, which had shown marked osteosarcoma specificity in promoter studies using different luciferase assays in osteosarcoma and non-osteosarcoma cell lines. A recombinant lentiviral vector was generated with the OC promoter driving the expression of fpgs and the gene for enhanced green fluorescent protein (egfp), which was linked to fpgs by an internal ribosomal entry site (IRES). As the vector backbone contained only a self-inactivating viral LTR promoter, any interference of the OC promoter by unspecific promoter elements was excluded. We tested the expression of FPGS and enhanced green fluorescent protein (EGFP) after lentiviral transduction in various osteosarcoma cell lines (human MG-63 cells and TM 791 cells; rat osteosarcoma (ROS) 17/2.8 cells) and non-osteogenic tumor cell lines (293T human embryonic kidney cells, HeLa human cervix carcinoma cells). EGFP expression and MTX sensitivity were assessed in comparison with non-transduced controls. Whereas the OC promoter failed to enhance MTX sensitivity via FPGS expression in non-osteogenic tumor cell lines, the OC promoter mediated a markedly increased MTX cytotoxicity in all osteosarcoma cell lines after lentiviral transduction. The present chemotherapy-enhancing gene therapy system may have great potential to overcome in future MTX resistance in human osteosarcomas.

A small jab - a big effect: nonspecific immunomodulation by vaccines

Mon, 03/23/2015 - 2:58pm

Recent epidemiological studies have shown that, in addition to disease-specific effects, vaccines against infectious diseases have nonspecific effects on the ability of the immune system to handle other pathogens. For instance, in randomized trials tuberculosis and measles vaccines are associated with a substantial reduction in overall child mortality, which cannot be explained by prevention of the target disease. New research suggests that the nonspecific effects of vaccines are related to cross-reactivity of the adaptive immune system with unrelated pathogens, and to training of the innate immune system through epigenetic reprogramming. Hence, epidemiological findings are backed by immunological data. This generates a new understanding of the immune system and about how it can be modulated by vaccines to impact the general resistance to disease.

Accuracy of Dietary Reference Intakes for determining energy requirements in girls

Mon, 03/23/2015 - 2:58pm

BACKGROUND: The most recent Dietary Reference Intakes (DRIs) (2002) for energy were based on pooled data from convenience samples of individuals with energy expenditure determined by using doubly labeled water (DLW). To our knowledge, the accuracy of these intake estimates has not been assessed in children.

OBJECTIVE: We assessed the accuracy of DRI prediction equations for determining daily energy needs in girls by comparing the individual-level prediction of estimated energy requirements with the measured value of total energy expenditure (TEE) from DLW, which is considered the gold standard.

DESIGN: In this cross-sectional analysis, we measured the resting metabolic rate (RMR) by using indirect calorimetry and TEE by using DLW in 161 nonobese premenarcheal girls aged 8-12 y. The activity factor TEE/RMR was used to categorize the physical activity level used in DRI equations.

RESULTS: We observed a strong linear relation between TEE by using DLW and estimated energy requirements predicted from DRI equations (Pearson's r = 0.78, P < 0.0001, R(2) = 0. 61). The DRI-predicted energy requirements underestimated measured TEE by ~120 kcal on average. The overall mean (+/-SD) error in the sample was -121.3 +/- 163.9 kcal. The average (+/-SD) percentage error in the sample was -5.8 +/- 7.9%. Seventy percent of participants had predicted TEE values < /=10% of measured TEE.

CONCLUSIONS: DRI equations for girls predict well for the group. The use of these equations for individuals may result in the underestimation of energy requirements for a significant percentage of girls.

Post-translational modification by cysteine protects Cu/Zn-superoxide dismutase from oxidative damage

Mon, 03/23/2015 - 2:58pm

Reactive oxygen species (ROS) are cytotoxic. To remove ROS, cells have developed ROS-specific defense mechanisms, including the enzyme Cu/Zn superoxide dismutase (SOD1), which catalyzes the disproportionation of superoxide anions into molecular oxygen and hydrogen peroxide. Although hydrogen peroxide is less reactive than superoxide, it is still capable of oxidizing, unfolding, and inactivating SOD1, at least in vitro. To explore the relevance of post-translational modification (PTM) of SOD1, including peroxide-related modifications, SOD1 was purified from postmortem human nervous tissue. As much as half of all purified SOD1 protein contained non-native post-translational modifications (PTMs), the most prevalent modifications being cysteinylation and peroxide-related oxidations. Many PTMs targeted a single reactive SOD1 cysteine, Cys111. An intriguing observation was that unlike native SOD1, cysteinylated SOD1 was not oxidized. To further characterize how cysteinylation may protect SOD1 from oxidation, cysteine-modified SOD1 was prepared in vitro and exposed to peroxide. Cysteinylation conferred nearly complete protection from peroxide-induced oxidation of SOD1. Moreover, SOD1 that has been cysteinylated and peroxide oxidized in vitro comprised a set of PTMs that bear a striking resemblance to the myriad of PTMs observed in SOD1 purified from human tissue.

Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury

Mon, 03/23/2015 - 2:58pm

BACKGROUND and AIMS: Heat shock protein 90 (hsp90) is an emerging therapeutic target in chronic liver diseases. Hsp90 plays an important role in liver immune cell activation; however its role in alcoholic liver disease (ALD) remains elusive. Here we hypothesize that hsp90 is crucial in alcohol induced steatosis and pro-inflammatory cytokine production. To test this hypothesis, we employed a pharmacological inhibitor of hsp90, 17-DMAG (17-Dimethylamino-ethylamino-17-demethoxygeldanamycin) in an in vivo mouse model of acute and chronic alcoholic liver injury.

METHODS: C57BL/6 mice were given either a single dose of ethanol via oral gavage (acute) or chronically fed alcohol for 2 weeks followed by oral gavage (chronic-binge). 17-DMAG was administered during or at the end of feeding. Liver injury parameters, inflammatory cytokines and lipid metabolism genes were analysed.

RESULTS: Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevented but also alleviated alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis showed that 17-DMAG decreased alcohol mediated oxidative stress, reduced serum endotoxin, decreased inflammatory cells, and diminished sensitization of liver macrophages to LPS, resulting in downregulation of CD14, NFkappaB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreased fatty acid synthesis genes via reduced nuclear SREBP-1 and favoured fatty acid oxidation genes via PPARalpha.

CONCLUSIONS: Inhibition of hsp90 decreased alcohol induced steatosis and pro-inflammatory cytokines and inhibited alcoholic liver injury. Hsp90 is therefore relevant in human alcoholic cirrhosis and a promising therapeutic target in ALD. Elsevier B.V. All rights reserved.

Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies

Mon, 03/23/2015 - 2:58pm

Post-transplant lymphoproliferative diseases (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that complicate solid organ or hematopoietic transplantation. Risk factors for PTLD include viral infections, degree of immunosuppression, recipient age and race, allograft type, and host genetic variations. Clinically, extra-nodal disease is common including 10-15 % presenting with central nervous system (CNS) disease. Most PTLD cases are B cell (5-10 % T/NK cell or Hodgkin lymphoma), while over one-third are EBV-negative. World Health Organization (WHO) diagnostic categories are: early lesions, polymorphic, and monomorphic PTLD; although in practice, a clear separation is not always possible. Therapeutically, reduction in immunosuppression remains a mainstay, and recent data has documented the importance of rituximab +/- combination chemotherapy. Therapy for primary CNS PTLD should be managed according to immunocompetent CNS paradigms. Finally, novel treatment strategies for PTLD have emerged, including adoptive immunotherapy and rational targeted therapeutics (e.g., anti-CD30 based therapy and downstream signaling pathways of latent membrane protein-2A).

Role of Astrocytes in Sculpting Neuronal Circuits in the Drosophila CNS: A Dissertation

Sun, 03/22/2015 - 10:26pm

The nervous system is composed of neurons and glia. Glial cells have been neglected and thought to have only a supportive role in the nervous system, even though ~60% of the mammalian brain is composed of glia. Yet, in recent years, it has been shown that glial cells have several important functions during the development, maintenance and function of the nervous system. Glial cells regulate both pre and post mitotic neuronal survival during normal development and maintenance of the nervous system as well as after injury, are necessary for axon guidance, proper axon fasciculation, and myelination during development, promote synapse formation, regulate ion balance in the extracellular space, are required for normal synaptic function, and have immune functions in the brain. Although glia have crucial roles in nervous system development and function, there are still much unknown about the underlying molecular mechanisms in glial development, function and glial-neuronal communication.

Drosophila offers great opportunity to study glial biology, with its simple yet sophisticated and stereotypic nervous system. Glial cells in flies show great complexity similar to the mammalian nervous system, and many cellular and molecular functions are conserved between flies and mammals. In this study, I use Drosophila as a model organism to study the function of one subtype of glia: astrocytes. The role of astrocytes in synapse formation, function and maintenance has been a focus of study. However, their role in engulfment and clearance of neuronal debris during development remains unexplored.

I generated a driver line that enables the study of astrocytes in Drosophila.In chapter two of this thesis, I characterize astrocytes during metamorphosis, when extensive neuronal remodeling takes place. I found that astrocytes turn into phagocytes in a cell-autonomous, steroid-dependent manner, by upregulating the phagocytic receptor Draper and forming acidic phagolysosomal structures. I show that astrocytes clear neuronal debris during nervous system remodeling and that this is a novel function for astrocytes during the development of nervous system. I analyzed two different neuronal populations: MB γ neurons that prune their neurites and vCrz+ neurons that undergo apoptosis. I discovered that MB γ axons are engulfed by astrocytes using the Draper and Crk/Mbc/dCed-12 pathways in a partially redundant way. Interestingly, Draper is required for clearance of vCrz+ cell bodies, while Crk/Mbc/dCed-12, but not Draper, are required for clearance of vCrz+ neurites. Surprisingly, I also found that loss of Draper delayed vCrz+ neurite degeneration, suggesting that glia facilitate neurite destruction through engulfment signaling.

Taken together, my work identifies a novel function for astrocytes in the clearance of synaptic and neuronal debris during developmental remodeling of the nervous system. Additionally, I show that Crk/Mbc/dCed-12 act as a new glial signaling pathway required for pruning, and surprisingly, that glia use different engulfment pathways to clear neuronal debris generated by cell death versus local pruning.

Activity Regulates Neuronal Connectivity and Function in the C. elegans Motor Circuit: A Dissertation

Sun, 03/22/2015 - 10:26pm

Activity plays diverse roles in shaping neuronal development and function. These roles range from aiding in synaptic refinement to triggering cell death during traumatic brain injury. Though the importance of activity-dependent mechanisms is widely recognized, the genetic underpinnings of these processes have not been fully described. In this thesis, I use the motor circuit of Caenorhabditis elegans as a model system to explore the functional and morphological consequences of modulating neuronal activity.

First, I used a gain-of-function ionotropic receptor to hyperactivate motor neurons and asked how increased excitation affects neuronal function. Through this work, I identified a cell death pathway triggered by excess activation of motor neurons. I also showed that suppression of cell body death failed to block motor axon destabilization, providing evidence that death of the cell body and of motor axons can be genetically separated.

Secondly, I removed excitatory drive from a simple neural circuit and asked how loss of excitatory activity alters circuit development and function. I identified excitatory motor neurons as master regulators of inhibitory synaptic connectivity. Additionally, I was able to identify previously undescribed activity-dependent mechanisms for regulating inhibitory synapses in both developing and mature neural circuits.

Finally, I show data to implicate the highly conserved genes neurexin and neuroligin in determining inhibitory synapse connectivity. Collectively this work has lent insight into activity-dependent mechanisms in place to regulate neuronal development and function, a core function of neurobiology that is relevant to the study of a wide range of neurological disorders.

Caspase-8 and RIP Kinases Regulate Bacteria-Induced Innate Immune Responses and Cell Death: A Dissertation

Sun, 03/22/2015 - 10:26pm

Yersinia pestis (Y. pestis), as the causative agent of plague, has caused deaths estimated to more than 200 million people in three historical plague pandemics, including the infamous Black Death in medieval Europe. Although infection with Yersinia pestis can mostly be limited by antibiotics and only 2000-5000 cases are observed worldwide each year, this bacterium is still a concern for bioterrorism and recognized as a category A select agent by the Centers for Disease Control and Prevention (CDC). The investigation into the host-pathogen interactions during Y. pestis infection is important to advance and broaden our knowledge about plague pathogenesis for the development of better vaccines and treatments.

Y. pestis is an expert at evading innate immune surveillance through multiple strategies, several mediated by its type three secretion system (T3SS). It is known that the bacterium induces rapid and robust cell death in host macrophages and dendritic cells. Although the T3SS effector YopJ has been determined to be the factor inducing cytotoxicity, the specific host cellular pathways which are targeted by YopJ and responsible for cell death remain poorly defined. This thesis research has established the critical roles of caspase-8 and RIP kinases in Y. pestis-induced macrophage cell death. Y. pestis-induced cytotoxicity is completely inhibited in RIP1-/- or RIP3-/-caspase-8-/- macrophages or by specific chemical inhibitors. Strikingly, this work also indicates that macrophages deficient in either RIP1, or caspase-8 and RIP3, have significantly reduced infection-induced production of IL-1β, IL-18, TNFα and IL-6 cytokines; impaired activation of NF-κB signaling pathway and greatly compromised caspase-1 processing; all of which are critical for innate immune responses and contribute to fight against pathogen infection. Y. pestis infection causes severe and often rapid fatal disease before the development of adaptive immunity to the V bacterium, thus the innate immune responses are critical to control Y. pestis infection. Our group has previously established the important roles of key molecules of the innate immune system: TLR4, MyD88, NLRP12, NLRP3, IL-18 and IL-1β, in host responses against Y. pestis and attenuated strains. Yersinia has proven to be a good model for evaluating the innate immune responses during bacterial infection. Using this model, the role of caspase-8 and RIP3 in counteracting bacterial infection has been determined in this thesis work. Mice deficient in caspase-8 and RIP3 are very susceptible to Y. pestis infection and display reduced levels of pro-inflammatory cytokines in spleen and serum, and decreased myeloid cell death. Thus, both in vitro and in vivo results indicate that caspase-8 and RIP kinases are key regulators of macrophage cell death, NF-κB and caspase-1 activation in Yersinia infection. This thesis work defines novel roles for caspase-8 and RIP kinases as the central components in innate immune responses against Y. pestis infection, and provides further insights to the host-pathogen interaction during bacterial challenge.

Putting the Pieces Together: Exons and piRNAs: A Dissertation

Sun, 03/22/2015 - 10:26pm

Analysis of gene expression has undergone a technological revolution. What was impossible 6 years ago is now routine. High-throughput DNA sequencing machines capable of generating hundreds of millions of reads allow, indeed force, a major revision toward the study of the genome’s functional output—the transcriptome. This thesis examines the history of DNA sequencing, measurement of gene expression by sequencing, isoform complexity driven by alternative splicing and mammalian piRNA precursor biogenesis. Examination of these topics is framed around development of a novel RNA-templated DNA-DNA ligation assay (SeqZip) that allows for efficient analysis of abundant, complex, and functional long RNAs. The discussion focuses on the future of transcriptome analysis, development and applications of SeqZip, and challenges presented to biomedical researchers by extremely large and rich datasets.

Educating Dental Health Professionals about People with Intellectual and Developmental Disabilities

Fri, 03/20/2015 - 9:01am

Dental schools and dental hygiene programs are required to incorporate specialized training in their programs to serve people with special needs, however people with intellectual and developmental disability (I/DD) continue to experience poor oral health outcomes. Access to clinicians with the desire and skill to care for people with I/DD remains a challenge. There is a need to understand the best approaches to improve access, and to reduce disparity in oral health, for this vulnerable population representing approximately 1-3% of the general population. Researchers are systematically investigating the literature to uncover evidence of effective approaches to improve access and to support good oral health behaviors. These approaches should be integrated into educational curricula.

Overcoming adherence issues and other barriers to optimal care in gout

Thu, 03/19/2015 - 3:27pm

PURPOSE OF REVIEW: This review presents research published over the last year examining use of urate-lowering therapy (ULT) as well as trends over time in adherence to this class of agents. Additionally, it explores factors associated with nonadherence to ULTs for chronic gout and interventions to improve chronic gout management.

RECENT FINDINGS: New literature suggests prescriptions of ULTs for prevalent and incident gout patients remains lower than expected based on the burden of the disease in the population. Overall ULT adherence remains suboptimal, in part related to inadequate patient education and copayment costs; although one study demonstrated improvement in adherence over a 15-year study period. Finally, interventions that include patient education and medication titration based on laboratory results successfully lowered serum urate levels to less than 6 mg/dl in the majority of patients.

SUMMARY: Gout remains a prevalent disease that is poorly managed despite effective treatments. Recent research suggests that ULTs are underutilized and even when prescribed are not well adhered to. Patient-centered interventions that focus on education about pharmacologic therapy and lifestyle modifications with medication titration have resulted in a greater proportion of patients achieving recommended serum urate levels.

Trends and determinants of reproductive health service use among young women in the USA

Thu, 03/19/2015 - 3:27pm

BACKGROUND: This study explores the current patterns of reproductive health service use among young women in the USA and the changing influence of socio-demographic factors on the types of services used over time.

METHODS: The study population, drawn from the two last cycles of the National Survey of Family Growth, consists of women aged 15-24 (n = 2543 in 1995, n = 2157 in 2002). We examined trends in use of 'contraceptive services' and 'other reproductive health services for preventive care' and tested for changes in the patterns of use of these services over time. Logistic regression models were used to further clarify the factors associated with the use of the two types of services in 2002.

RESULTS: Results show no difference in the overall use of reproductive health services in the past year but did reveal changes in the type of service sought. Use of services for contraception increased by 10 percentage points (39.3% in 1995 to 49.7% in 2002, P < 0.001), although the use of other services remained stable (53.2% in 1995, 50.2% in 2002, P = 0.14). The patterns of use varied over time, exhibiting growing social disparities. In 2002, the use of contraceptive services depended on women's age, number of partners, personal and mother's level of education, and menstrual problems. The use of other reproductive health services for preventive care varied across women's socio-economic background.

CONCLUSION: This study demonstrates increasing social differentials in the use of reproductive health services for preventive care among young women in the USA between 1995 and 2002, a finding which calls for careful monitoring in the context of limited resources.

Dermal collagen matrices for ventral hernia repair: comparative analysis in a rat model

Thu, 03/19/2015 - 3:27pm

PURPOSE: The purpose of this study was to compare inflammatory responses, tissue integration, and strength of the acellular dermal collagen matrices AlloDerm((R))* Regenerative Tissue Matrix, Permacol**Surgical Implant (Permacol), and CollaMend*** Implant in a rat model for ventral hernia repair.

METHODS: Rats were randomized into four groups and abdominal wall defects repaired with an inlay graft of AlloDerm, Permacol, or CollaMend. Rats were sacrificed at six time points and the defect area was removed and analyzed for tissue integration and physical strength.

RESULTS: Variable cell infiltration was seen for the three implant groups. At of the all time points examined, cellular infiltration was most rapid in the AlloDerm implants and slowest for CollaMend. At 14 days, significant cell infiltration along with putative blood vessel formation was observed for AlloDerm, while Permacol implants exhibited a moderate level of infiltration. Very few cells penetrated CollaMend implants at 2 weeks. Cells had reached the center of the Permacol implants by 1 month, whereas CollaMend implants were encapsulated with a loose coat of disconnected cells, with very few cells infiltrating past the surface. At 6 months, AlloDerm and Permacol had evidence of cell penetration throughout the implants, while the CollaMend samples exhibited limited infiltration. Animals for each implant developed seromas: AlloDerm 40%, Permacol 33%, and CollaMend 83%. Mechanical testing revealed that AlloDerm at 6 months showed the lowest tensile strength, CollaMend the highest, and Permacol an intermediate level.

CONCLUSIONS: The three biologics exhibited different patterns and rates of cellular and vascular permeation in our rat model. AlloDerm implants exhibited the most rapid and extensive cellular infiltration, followed by Permacol. However, on gross examination, the AlloDerm implants thinned significantly by 6 months. In contrast, the Permacol and CollaMend implants appeared to be largely intact.

Prostate carcinoma and radiation therapy: therapeutic treatment resistance and strategies for targeted therapeutic intervention

Thu, 03/19/2015 - 3:27pm

Adenocarcinoma of the prostate remains a significant public health problem and a prevalent cancer in men. Prostate-specific antigen used as a biomarker has established a clear migration of patients towards earlier-stage disease at presentation. However, in spite of process improvements in traditional therapies including surgery, radiation therapy, and hormone management, there remains a significant cohort of patients with intermediate- to high-risk features for poor outcome in spite of optimal use of traditional management. This paper focuses on future treatment strategies integrating new therapeutic options with traditional management, specifically to pinpoint new radiation therapy strategies.

Low serum zinc levels in an endemic area of visceral leishmaniasis in Bihar, India

Thu, 03/19/2015 - 3:27pm

BACKGROUND and OBJECTIVES: India carries approximately 50 per cent of the global burden of visceral leishmaniasis and majority of patients from the poor, rural communities of Bihar State. Zinc is an essential trace element and its relevance for proper functioning of the entire immune system is already well documented. Though low serum zinc levels have been reported in many parasitic diseases, limited information is available regarding zinc status in human leishmaniasis. We investigated to define the relationship between zinc level in visceral leishmaniasis (VL) patients in endemic and non-endemic regions. METHODS: Venous blood was collected from 88 patients, 16 parasitologically confirmed VL, 35 healthy controls from endemic area (Bihar) and 37 healthy urban controls from non-endemic area, Delhi. In all the three groups, levels of serum albumin, total protein (markers of nutritional status) and zinc were estimated by colorimetric methods. RESULTS: Serum zinc levels were found to be significantly lower (P<0.001) in VL patients than non-endemic controls. The serum zinc levels in VL endemic controls were also significantly lower (P < 0.001) than non- endemic controls, but these values were not statistically significantly different from VL patients. However, all samples from Bihar (VL patients and controls) had lower serum zinc levels than non-endemic controls from Delhi. INTERPRETATION and CONCLUSION: Low serum Zn levels, in healthy subjects from Bihar and more significantly in VL patients of this region, are possibly associated with vulnerability and endemicity of visceral leishmaniasis in the region. Further studies need to be done to assess the role of oral zinc supplementation in better management and prevention of VL, particularly in endemic areas.

Standardizing the method of measuring by echocardiogram the diameter of the ascending aorta in patients with a bicuspid aortic valve

Thu, 03/19/2015 - 3:27pm

Serial echocardiographic follow-up of patients with a bicuspid aortic valve (BAV), in addition to providing assessment of valve dysfunction, can help identify those at risk of aortic complications. However, currently there is no standardized echocardiographic method for measuring the ascending aorta. We examined the echocardiograms of 45 patients with a BAV and 45 matched controls to understand the effects of the measurement location (1, 2, and 3 cm above the sinotubular junction) and the point in the cardiac cycle (end-diastole, mid-systole, and end-systole) at which the ascending aortic measurements are made. A greater length of aorta could be measured in end-systole than in end-diastole, presumably because of aortic recoil. Using the control data for comparison, we found that more dilated ascending aortas were detected by measuring 3 cm above the sinotubular junction in the patients with a BAV (56%) than at 1 cm (42%). The increases in size between 1 and 2 cm were greater than those between 2 and 3 cm. In conclusion, we propose that all transthoracic echocardiograms should include the proximal aorta at least 2 cm and preferably 3 cm above the sinotubular junction and suggest that for standardization and optimal visualization the measurements be done at end-systole in all patients.