Usher syndrome (USH) affects an estimated 1/16,000 to 1/50,000 people worldwide and has been reported to underlie a majority of deaf-blindness. There are three generally accepted clinical subtypes of Usher syndrome, which is a recessively inherited neurosensory disorder. Usher syndrome type 1 is characterized by profound congenital deafness, retinitis pigmentosa and vestibular abnormalities in humans. Seven USH1 loci have been mapped and genes for five of them have been identified. Mutations in CDH23, the gene encoding cadherin 23, were found in both USH1D and DFNB12 patients. Missense mutations of CDH23 also cause nonsyndromic recessive deafness, while more severe mutations (truncating mutations and some missense mutations) are associated with an USH1D phenotype. Protein truncating mutations in the gene encoding protocadherin 15 (PCDH15) cause Usher syndrome type 1 (USH1F) while less disabling mutant alleles of PCDH15 are associated with nonsyndromic recessive hearing loss (DFNB23). This suggests that the retina is somehow resistant to the effects of altered or reduced levels of protocadherin 15 due to particular missense mutations, which nevertheless cause profound deafness. In the waltzer (v) and Ames waltzer (av) mouse, recessive mutations of Cdh23 and Pcdh15, respectively, are associated with profound deafness and circling behavior, but not retinal degeneration. In this study of Pcdh15av-5J mice and mice either double heterozygous or double homozygous for the Cdh23v-6J and Pcdh15av-Jfb alleles, we extended the characterization of the auditory phenotype and initiated a study of the retinal phenotype of these mice. We have shown that two alleles of young Ames waltzer mice have (Pcdh15av-5Jfb, Pcdh15av-5J ) have significantly reduced electroretinogram (ERG) potentials and provide evidence suggesting that splice variants of Pcdh15 may compensate for the mutant allele in the eye but not in the ear. Furthermore, we show that there are no obvious genetic interactions between the Cdh23v-6J and Pcdh15av-Jfb alleles using double heterozygous as well as double homozygous mice / acase@tulane.edu

Skin biopsies of early cutaneous lesions (7 months or less of evolution) caused by Leishmania braziliensis panamensis were obtained from 31 male patients from the Pacific Coast of Colombia. Using a panel of monoclonal antibodies and an avidin-biotin-peroxidase complex, the frozen biopsies were characterized immunohistologically. Lymphocytes and other mononuclear cells were phenotypically identified and quantitated based on differentiation antigens and activation markers; amastigotes were localized, and histopathologic changes were described. Data on the systemic immune response of the patients was obtained through measurement of cutaneous delayed hypersensitivity (Montenegro reaction), lymphocyte blastogenesis assays, and titration of anti-Leishmania antibodies. Diverse histopathological changes were seen; a pathognomonic histological pattern was not evident. Infiltrates consisted of variable numbers of lymphocytes, plasma cells, and macrophages. Of these cells, T and B lymphocytes had a non-random vertical distribution in the dermis. T cell activation detected as IL-2 and IL-2 receptor expression was evident in a small percentage of lymphocytes in the majority (74%) of the biopsies. Although not statistically significant, the physical presence of amastigotes in certain areas coincided with lymphocytic infiltrates. Multiple regression analysis showed statistically significant association between total T lymphocytes, T helper, and T suppresso cells; T suppressor lymphocytes and plasma cells; T helper lymphocytes and macrophages; and plasma cells and the observation of amastigotes. Even though heterogeneity of the immunohistological characteristics was manifested at various microanatomical levels by the magnitude and type of cellular infiltrates, the detectable presence of amastigotes and the histopathological changes, statistically significant relationships could be predictive of the outcome of infection with respect to the response to treatment, recurrent disease and the development of acquired resistance. This information on early lesions caused by L. b. panamensis is expected to be useful in understanding the host response with respect to the spectrum of diseases caused by the Leishmania braziliensis species complex / acase@tulane.edu

During the 1990s, the Dominican Republic experienced economic growth which reached a high of 6% per year by 2000. At the same time, malaria incidence dramatically increased, rising two- to three-fold in different parts of the country. This paper examines the relationship between development and malaria vis-a-vis the dynamics of social and environmental change in a southeastern province of the Dominican Republic over the last decade. Two distinct approaches to development serve as the departure point for this exploration. Socio-environmental factors including land use and the extent of land cover change associated with sugarcane monoculture and tourism are explored in relation to malaria distribution by using remotely-sensed data and GIS techniques. Analyses are conducted using statistical and geo-spatial methods, and interpreted through a qualitative framework. The process of developing tourism, specifically the construction that serves as a precursor, introduces factors that heighten the malaria risk to the surrounding populations without providing resources to mitigate the threat. Malaria dynamics in and around resort communities show two marked trends. During the initial construction phase, malaria cases peak. These peaks are quickly controlled and overall vulnerability to malaria declines for those within the resort communities, but malaria does not end. The risk is pushed to proximal communities. These communities lack the resources to respond to the malaria danger, and thus prove highly vulnerable to sustained transmission. The hazard stems from environmental and social change. In contrast, risk in the agriculturally-based communities has changed little over the course of ten years. These populations are less vulnerable to malaria than communities which are near tourist facilities. The most vulnerable communities, however, consist of migrant laborers found in both agricultural and tourist settings. These pockets of vulnerability are created largely through social inequity. This analysis is undertaken with an end goal being the formulation of policy to address immediate and long-term vulnerabilities / acase@tulane.edu

Zoonotic filarial infections have been reported from most parts of the world. However, the range of species involved, host-parasite interactions and morphologic criteria for the specific identification of the species is still poorly known and understood. Species of Dirofilaria are the most common agents of human infection and the most studied group of zoonotic filariae. Several other groups, including species of Brugia and Onchocerca are being reported with increasing frequency. Loaina uniformis, a common parasite of rabbits in the southeastern United States, represents yet another species recovered from human tissues, although extremely rare. This parasite is of additional interest because its apparent morphologic and possible biologic similarity to Loa loa a common filaria of humans in West and Central Africa. The present study was undertaken to characterize the morphologic features of Loaina uniformis to enable its recognition when encountered in human tissues. This objective additionally permitted comparison of L. uniformis to Loa loa at both, gross and microscopic levels to determine, to whatever extent possible, the relationship of the two parasites. L. uniformis adult worms both living and dead were collected from the tissues of the natural host, the rabbit Sylvilagus floridanus. These were processed for gross examination and histologic study by light microscopy of serially sectioned material. Detailed microscopic observations were recorded for worms of both sexes and full anatomic characterizations were prepared. Emphasis was placed on the structure of the body and detailed features of the cuticle, hypodermis and musculature. The structural features of the digestive and reproductive systems as well as their arrangement within the pseudocoelom have been characterized. Observations indicate that L. uniformis can be distinguished from all other known species of zoonotic filariae available for study on the basis of their microanatomical features. Equivalent material of L. Loa obtained from experimental definitive hosts was compared with L. uniformis. The anatomical features of L. uniformis and L. loa are similar in many respects and they share many biological features suggesting that they are taxonomically closely related / acase@tulane.edu

The purpose of this prospective cohort study was to assess the effects of partner notification for human immunodeficiency virus (HIV) infection on partnerships and behaviors, and to compare these changes to the effects of partner notification for syphilis. Persons who received partner notification for HIV or syphilis in the New Orleans metropolitan area were eligible to participate. Participants were enrolled in the study at the time of partner notification, and follow-up data were collected at three and six months after partner notification. A behavioral questionnaire was administered in a face-to-face interview at each visit. The main outcomes of interest included the status of partnerships at follow-up (dissolution/continuation) and changes in high-risk behaviors including abstinence, frequency of unprotected vaginal or anal intercourse, condom use at last sexual act, and consistent condom use. The formation of new partnerships after partner notification was also described. Descriptive analyses were stratified by the infection status of the participant and the concordance status of the partnership, and generalized estimating equations were used in the modeling A total of 112 individuals with 159 partnerships were included in the analysis. The study sample was predominantly African-American, heterosexual, and of low socioeconomic class. At the end of the 6-month follow-up period, 73% of HIV concordant, 56% of HIV discordant, and 75% of syphilis partnerships had dissolved. After adjusting for confounding, HIV concordant partnerships were 2.6 times (95% CI = 0.7--9.7) more likely to dissolve than syphilis partnerships, and there was no difference in the likelihood of dissolution between HIV discordant and syphilis partnerships (OR = 0.9, 95% CI = 0.33.8). Both HIV concordant and discordant partnerships that did not dissolve were more likely than syphilis partnerships to reduce the frequency of unprotected sexual acts and to increase condom use. HIV index cases formed 8 new partnerships during the follow-up period, and 7 of these new partnerships were discordant. The rate of new partner acquisition among HIV index cases in the follow-up period was 4.4 per 100 person-months, which was comparable to the baseline rate of 3.5 per 100 person-months (p > 0.90) The results of this study suggest that positive changes occur after partner notification for HIV. The reduction in the number of sexual partners and the decreases in high-risk behaviors are likely to result in lower rates of HIV transmission. Despite these beneficial effects, the greater likelihood of dissolution among HIV concordant partnerships and the formation of new discordant partnerships by HIV index cases after partner notification may promote the spread of HIV in the community. Though these negative effects may not be directly attributable to partner notification, their occurrence could diminish the positive effect that partner notification has on reducing the spread of HIV Partner notification remains an important public health intervention for counseling at-risk individuals, providing HIV testing to people who do not know their serostatus, and identifying infected persons who can be referred for treatment. The benefits of HIV partner notification most likely outweigh the potentially negative consequences, though such outcomes are not negligible and should be addressed during the partner notification process and in future research studies / acase@tulane.edu

Compromised renal perfusion results in the development of hypertension through the activation of the renin-angiotensin system. The model utilized in these experiments, the two-kidney, one-clip (2K1C) Goldblatt rat, uniquely permits the simultaneous examination of the response of the clipped kidney to impaired blood flow and the effects of hypertension, and of the stimulated levels of angiotensin II (Ang II) on the contralateral kidney. Although not the initial causative factor, the otherwise normal contralateral kidney plays a permissive role in the development of hypertension These investigations delineated the singular role of elevated circulating Ang II levels on the contralateral kidney in the pathogenesis of 2K1C hypertension. By infusing exogenous Ang II via an osmotic minipump, the clipped kidney was supplanted as the source of elevated circulating Ang II levels. Plasma Ang II levels observed in the 2K1C rats during the developmental phase of hypertension were simulated by the exogenous subcutaneous administration of Ang II at 40 ng/min and resulted in a comparable blood pressure profile and systemic Ang II levels, demonstrating that similar levels of circulating Ang II result in a similar blood pressure response The data further demonstrate that the elevated levels of circulating Ang II result in an increase in the intrarenal Ang II content, despite marked suppression of intrarenal and plasma renin, and support the hypothesis that enhanced endogenous Ang II generation occurs de novo via a renin-independent, positive amplification mechanism and may involve other enzymes known to metabolize angiotensinogen to angiotensin in the kidney Renal function studies did not demonstrate significant differences in renal hemodynamic or excretory parameters, despite differences in blood pressure and intrarenal Ang II levels. The acute administration of losartan caused a reduction in blood pressure without significant differences in renal function These data support the hypothesis that the development of 2K1C hypertension is an Ang II-dependent phenomenon inducing the contralateral kidney to increase local Ang II content. Augmented intrarenal Ang II, via intracellular sequestration or from a renin-independent positive amplification mechanism, along with an inappropriate renal functional response may participate as a sustained hypertensinogenic stimulus / acase@tulane.edu

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Since early in the HIV epidemic, a wide variety of studies have provided evidence linking HIV infection with other sexually transmitted diseases. Both the number of studies performed and the consistency of the observed associations suggest that ulcerative and perhaps non-ulcerative STD facilitate HIV transmission. Relatively few well-designed studies have demonstrated these associations in US populations, particularly in predominantly heterosexual populations. This investigation examined behavioral and biological risk factors for HIV seroconversion in patients attending a New Orleans STD clinic between January 1990 and April 1998. A retrospective cohort was constructed using computerized medical records containing client demographics, STD diagnosis information and behavioral risk information. Multivariate Cox regression analysis was used to identify risk factors for HIV seroconversion among clients repeatedly HIV tested, while controlling for the effects of behavioral risks. STD exposure status was permitted to change over the follow-up period, allowing the effect of the timing of STD in relation to HIV seroconversion to be examined. In overall multivariate models, having a recent syphilis or GUD diagnosis was associated with roughly four and five-fold increases in risk of seroconversion in males and females, respectively. Among males with no history of GUD or syphilis, a recent gonorrhea diagnosis was associated with more than a two-fold increase of risk of seroconversion. Among males with a history of GUD or syphilis, those with recent ulcerative STD diagnoses were twice as likely to seroconvert than those with no recent diagnosis. This study suggests that both ulcerative and non-ulcerative STD may be associated with increased risk of HIV transmission and therefore that comprehensive STD control programs may be particularly effective tools for HIV prevention / acase@tulane.edu

The present study, carried out in heavily infected communities in northern Cameroon, was designed to determine the prevalence of urinary tract lesions and their association with Schistosoma haematobium (S.h.) infection and to assess the validity functional, parasitologic and bacteriologic parameters in the identification of persons at high risk for these lesions Schistosoma haematobium infection status, morphologic changes in the urinary tract (as detected by ultrasonography), functional and bacteriologic changes in the urine were determined on 980 persons selected randomly after stratification by age, sex and intensity of infection. Inclusion of egg-free controls from a hypoendemic area further facilitated measurement of association of lesions with bilharzial infection Lesions of the lower urinary tract were very frequent in the study population living in hyperendemic communities. Bladder wall hypertrophies (78%), bladder wall irregularities (67%) and bladder wall tumor/s (34%) were observed. History of persistent hematuria, level of current S.h. egg output, and massive proteinuria ($<$99 mg/dl) were the best predictors of these lesions. Large bladder tumors were, however, also strongly associated with excretion of nitrites (bacterial metabolites) in the urine and/or presence of significant bacteriuria. On the other hand, S.h. infection was associated with increased prevalence of positive excretion of urinary nitrites (14% in infected versus 2% in controls) and with increased risk for bacteriuria among children 5-14 year old (8% in infected versus 3% in the controls) Congestion of the upper urinary tract (UUT) was less frequent (4% for Hydroureter and 14% for hydronephrosis) and more confined to bilharzian patients (Less than 1 percent of controls were affected). The group at the highest risk included persons with combined LUT hyperplasia and evidence of bacterial superinfection, for whom prevalence of UUT congestion was more than 10 times higher than in controls Pathologic changes in LUT or UUT were very rare in persons with neither past history of chronic hematuria nor with current S.h. infection, most of whom were found in the control group from the hypoendemic area Observation of circadian variation in both S.h. urinary egg output and related functional changes (hematuria, proteinuria) have lead field investigators to focus their attention on midday voided urine. The present study has shown that testing first morning urine specimens could provide additional information (nitrite and bacteriuria) shown to be of high predictive value for severe uropathies. (Abstract shortened by UMI.) / acase@tulane.edu

Though cholera toxin (CT) and the heat-labile enterotoxin of Escherichia coli (LT) are known to function as mucosal adjuvants, the initiating signals of this phenomenon remain undefined. In this study, human and mouse cell lines were employed to compare the response of intestinal epithelial cells to an array of toxins and toxin mutants with varied activity levels. Activation of the intracellular Akt and ERK pathways are independent of cAMP-inducing abilities of LT-based. Cytokine analyses determined that, in response to active ADP-ribosylating toxins, these epithelial cell lines secrete proteins with various chemokine and cytokine activities, including IL-8 and proinflammatory cytokines such as IL-6. In contrast, levels of these proteins are much reduced when the epithelial cells were treated with inactive mutants or binding subunits alone. Similar patterns were noted in the production of prostaglandins. Furthermore, the mediators studied are elicited not only by the acknowledged intracellular CAMP pathway, but also by activation of the cyclooxygenase pathway within the epithelial cells. We have shown the cyclooxygenase isoform, COX-2, to be responsible for the enterotoxic effect of LT but not the outcome of adjuvanticity. These findings demonstrate the ability of the epithelial cell to respond to ADP-ribosylating toxins in an immune-initating manner and to alter the outcome of this response based on binding or enzymatic activity of the entertoxin / acase@tulane.edu