Is paromomycin an effective and safe treatment against cutaneous leishmaniasis? A meta-analysis of 14 randomized controlled trials.

BACKGROUND: High cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26-1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54-0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56-1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV. CONCLUSIONS/SIGNIFICANCE: Topical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.

Congential syphilis in Harris County, Texas, 1993--1996

The specific aims of this study were to: (1) To determine the incidence of congenital syphilis (CS) for the 1993-96 birth cohorts in Houston/Harris County, based on the newly revised 1989 CS surveillance definition in Houston/Harris County, Texas; (2) To study the distribution of selected variables listed in the Centers for Disease Control and Prevention (CDC) Congenital Syphilis Case Investigation and Report Form for the reported cases of CS; (3) To ascertain the relationships of maternal demographic factors, geographic distribution, and provision and utilization of prenatal care, associated with reported congenital syphilis delivery.^ This was a descriptive study analyzing reported cases of congenital syphilis in Houston/Harris, County, TX during the years 1993-96 using the data recorded on the CDC's Congenital Syphilis Case Investigation and Report forms. The population included infants delivered during 1993-96 who were diagnosed with congenital syphilis, using the revised 1990 criteria of the CDC. This study examined the risk factors associated with the occurrence of congenital syphilis in Harris County where the prevalence of maternal syphilis infection (13.7/100,000/1995) is high. (Abstract shortened by UMI.) ^

Cutaneous malignant melanoma: A study of skin cancer in the United States from 1973--1997

Cutaneous malignant melanoma (CMM) is the cancer of the melanocytes, the cells that produce the pigment melanin, and is an aggressive skin cancer that is most prevalent in the white population. Although most cases of malignant melanoma are white, black and other non-white populations also develop this disease. However, the etiologic factors involved in the development of melanoma in these lower-risk populations are not well known. Generally, survival rates of malignant melanoma have been found to be lower in blacks than for whites with similar stage of disease at diagnosis. ^ This study presents an analysis of the differences in survival between black and white cases with malignant melanoma of the skin as the only or first primary cancer, found in the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) cancer registry from 1973 to 1997. A total of 54,193 cases of CMM were diagnosed in black and white patients between 1973 and 1997. Black patients tended to be older, with a mean age of 64.46 years, compared to 53.14 years for white patients. Eighty-nine percent of patients were diagnosed with CMM as the only cancer. (Abstract shortened by UMI.)^

The role of endogenous IFN-beta in cutaneous melanoma: Consequences of epidermal hyperplasia

The purpose of this study was to characterize epidermal hyperplasia overlying malignant melanoma, to determine the mitogenic factor responsible for the induction of this hyperplasia and to investigate its biological consequence. Whether increased keratinocyte proliferation overlying melanoma is due to production of growth factors by the tumor cells or to other mechanisms is unknown. Epidermal hyperplasia overlying human melanoma was found overlying thick (>4.0mm), but not thin (<1.0mm) tumors. Immunostaining of the sections for growth factors related to angiogenesis revealed that epidermal hyperplasia was associated with loss of IFN-β production by the keratinocytes directly overlying the tumors. Since previous studies from our laboratory have demonstrated that exogenous administration of IFN-β negatively regulates angiogenesis, we hypothesize that tumors are able to produce growth factors which stimulate the proliferation of cells in the surrounding tissues. This hyperplasia leads to a decrease in the endogenous negative regulator of angiogenesis, IFN-β. ^ The human melanoma cell line, DM-4 and several of its clones were studied to identify the mitogenic factor for keratinocytes. The expression of TGF-α directly correlated with epidermal hyperplasia in the DM-4 clones. A375SM, a human melanoma cell line that produces high levels of TGF-α, was transfected with a plasmid encoding full-length antisense TGF-α. The parental and transfected cells were implanted intradermally into nude mice. The extent of epidermal hyperplasia directly correlated with expression of TGF-α and decreased production of IFN-β, hence, increased angiogenesis. ^ In the next set of experiments, we determined the role of IFN-β on angiogenesis, tumor growth and metastasis of skin tumors. Transgenic mice containing a functional mutation in the receptor for IFN α/β were obtained. A375SM melanoma cells were implanted both s.c. and i.v. into IFN α/βR −/− mice. Tumors in the IFN α/β R −/− mice exhibited increased angiogenesis and metastasis. IFN α/βR −/− mice were exposed to chronic UV irradiation. Autochthonous tumors developed earlier in the transgenic mice than the wild-type mice. ^ Collectively, the data show that TGF-α produced by tumor cells induces proliferation of keratinocytes, leading to epidermal hyperplasia overlying malignant melanoma associated with loss of IFN-β and enhanced angiogenesis, tumorigenicity and metastasis. ^

Case control study identifying the maternal risk factors for congenital syphilis in Texas: 1998--2001

Background. Congenital syphilis (CS) is the oldest recognized congenital infection in the world. CS infection can affect multiple organs and can even cause neonatal death. CS is largely preventable when maternal syphilis is treated in an adequate and timely manner. During the decade of the nineties, rates of CS in Texas have often exceeded the overall US rate. Few studies, with adequate sample sizes, have been conducted to determine the risk factors associated with CS while controlling for factors associated with adult (maternal) syphilis infection. Objective. To determine the current maternal risk factors for CS infection in Texas from 1998–2001. Methods. A total of 1083 women with positive serological tests for syphilis during pregnancy or at delivery were reported to, and assessed by, health department surveillance staff. Mothers delivering infants in Texas between January 1, 1998 and June 30, 2001 comprised the study population. Mothers of infants diagnosed with confirmed or presumptive CS (N = 291) were compared to mothers of infants diagnosed as non-cases (N = 792) to determine the risk factors for vertical transmission (while controlling for risk factors of horizontal transmission). Logistic regression analyses were conducted to determine the associated odds between selected maternal variables and the outcome of CS. Results. Among 291 case infants, 5 (1.7%), 12 (4.1%), 274 (94.2%) were classified as confirmed cases, syphilitic stillbirths, and presumptive cases, respectively. Lack of maternal syphilis treatment was the strongest predictor of CS: odds ratio (OR) = 199.57 (95% CI 83.45–477.25) compared to those receiving treatment before pregnancy, while women treated during their pregnancies were also at increased risk (OR = 6.67, 95% CI 4.01–11.08). Women receiving no prenatal care were more likely (OR = 2.77, 95% CI 1.60–4.79) to have CS infants than those receiving prenatal care. Single women had higher odds (OR = 1.90, 95% CI 1.10–3.26) than ever-married women. African-Americans (OR 0.91, 95% CI 0.37–2.23) and Hispanics (OR = 1.66, 95% CI 0.68–4.05) may be more likely to have a CS infant than non-Hispanic Whites. Conclusions. The burden of CS in Texas can be alleviated through the provision of quality health care services, particularly prenatal care and treatment for sexually transmitted diseases. ^

NRAS and BRAF mutations in primary cutaneous melanoma: A comparison of mutation rates between radial and vertical growth phases in individual tumors

Primary cutaneous melanoma is a cancer arising from melanocytes in the skin. In recent decades the incidence of this malignancy has increased significantly. Mortality rates are high for patients with tumors measuring over a few millimeters in thickness. Response rates to conventional radiation and chemotherapy are very low in patients with metastatic melanoma. New therapies targeting melanoma’s aberrant cell signaling pathways such as the MAP Kinase pathway are being developed. Mutations of NRAS and BRAF genes are quite common in cutaneous melanoma and lead to constitutive activation of the MAP Kinase pathway. This study tests the hypothesis that NRAS and BRAF mutations increase as a tumor progresses from the noninvasive radial growth phase (RGP) to the invasive vertical growth phase (VGP). Laser capture microdissection was used to obtain separate, pure tumor DNA samples from the RGP and VGP of thirty primary cutaneous melanomas. PCR was used to amplify NRAS exon 2 and BRAF exon 15 tumor DNA. The amplified DNA was sequenced and analyzed for mutations. An overall mutation rate of 74% was obtained for the twenty-three melanomas in which there were complete sequence results. With the exception of one melanoma NRAS and BRAF mutations were mutually exclusive. All seven NRAS exon 2 mutations involved codon 61. Three of these melanomas had mutations in both the RGP and VGP. The remaining four tumors were wild type for NRAS exon 2 in the RGP but mutated in the VGP. Of the fifteen BRAF exon 15 mutated melanomas all but one involved codon 600. Twelve of the fifteen BRAF exon 15 mutations were the T1799A type. Nine of the fifteen BRAF mutated tumors had the same mutation in both the RGP and VGP. Five of fifteen melanomas had wild type RGP DNA and BRAF exon 15 mutated VGP DNA. A single melanoma had BRAF exon 15 mutated DNA in the RGP and wild type DNA in the VGP. Overall, these results suggest a trend toward the acquisition of NRAS and BRAF mutations as cutaneous melanomas change from a noninvasive to an invasive, potentially deadly cancer.^

The impact of host immunity on oscillating rates of syphilis when gender and race are considered

The rates of syphilis in the United States have increased since the all time low in 2000. In 2003, the rates of syphilis in the United States were 2.5 cases per 100,000. There were 178 reported cases of primary and secondary syphilis (8.9 cases per 100,000) in Houston, Texas, which was a 58.9% increase from 2002. While syphilis can be completely treated now, unlike in times past, it is still a public health concern. The purpose of this study is to examine the possibility of modeling the impact of an immune response in primary and secondary syphilis in 63 major cities across the United States, stratified by gender and racial-ethnic groups. A Fourier analysis will be performed by SAS. Subsequently, this study will compare the results to a similar study of syphilis in 68 US cities, that focused on immune response, however, did not stratified by race and gender. This study will help determine if the oscillating rates of syphilis are due to biological factors of the disease or to behavioral changes in the population. This study will use surveillance data from 63 major cities across the United States. The data will be provided by the Centers of Disease Control. Ultimately, this study will expand the knowledge of the effect of immunity on endemics.^

Sex, drugs, and STIs: Syphilis infection and hepatitis B vaccine compliance among illicit drug users in Houston

Although the association between syphilis infection status and compliance with the hepatitis B virus vaccine has been the focus of investigation, there is a lack of data regarding the association between syphilis infection and HBV vaccine compliance. The author investigated the association between the exposure of syphilis infection and the outcome of HBV vaccine completion, defined as degree of constancy and accuracy with which a patient follows a prescribed regimen. A cohort design was employed using interview and serological data from the Drugs, AIDS, STDs, Hepatitis (DASH) Research Project; analysis was restricted to HIV and HBV seronegative (at baseline), illicit drug users residing in Harris County. Syphilis negative and syphilis positive infection status was determined from the serological data while covariates and outcome information were determined from the DASH Project Questionnaire; enrolled subjects (n=1160) were selected from the data. Association between exposure and outcome was assessed with logistic regression adjusted for data-based confounders. ^ A prevalence of 7% and 71% was found for syphilis and HBV vaccine compliance, respectively. When measuring the actual association between syphilis infection status and HBV vaccine compliance, an odds ratio of 1.49 (95% CI: 0.86, 2.72) was obtained. There was a non-significant association between these two variables. 78% of the study population was syphilis positive and completed the vaccine series compared to 70% of the population that was syphilis negative and received all three doses. This finding confirms that there is a difference between syphilis positive and negative drug users with respect to HBV vaccine compliance. The fact that differences were found in these drug users with respect to vaccine schedule supports the idea that sub-group differences may exist and thus merits further investigation. If these differences are confirmed, it is recommended that STI interventions identify community characteristics of their samples and target populations based on practices specific to that community. ^

Comparison of alternative methods of contact tracing in a syphilis control program

The purpose of this study was to compare the relative effectiveness of alternative methods of tracing named contacts of syphilis patients. A total of 236 contacts, identified by patients in two City of Houston Department of Health and Human Services clinics during the period April 1 through July 31, 1987, were studied. After contacts were grouped by sex and age, the proportion brought to examination by each of three methods, and by a combination of methods, was determined for each subgroup.^ The study found that 78.4% of all the 236 named sex contacts reported were located and brought to examination by the various methods of contact tracing and that 21.6% were missed. Of the 185 contacts examined, a combination of methods identified 47.7% of the cases, telephone contact, 28.6%, field contact, 16.9%, and patient referral, 11.8%.^ Of the 236 contacts reported, males made up 56.8% and females 43.2%. Contact tracing was more successful among females, with 81.4% of the 102 named female contacts, as compared to 76.1% of the 134 named male contacts being brought to examination. It is not known whether equal efforts were exerted in the follow-up of both male and female contacts. In both female and male subgroups, a combination of methods brought over 40% of sex contacts to examination. Telephone contact among females yielded 27.7% of the cases and field contact 18.1%, whereas in males, telephone contact identified 29.4% of the cases and field contact 15.7%. Patient referral was the least productive method in both sex groups, locating 12.8% in males as compared to 10.8% in females.^ On an age specific basis, a combination of methods was the most effective method in the 15-39 age group, whereas telephone contact was most effective in the 40-44 age group, and field contact in the 50-54 age group. Of all the methods of contact tracing, patient referral was the least productive in most age groups.^ Future studies of contact tracing should incorporate several important variables which were not examined in this study. ^

A descriptive study of syphilis infection in Houston, Texas, 1999--2008

The rate of syphilis nationally has been on the rise since 2001. Syphilis, if left untreated can facilitate the transmission of HIV infection. An epidemiologic study describing the trends of syphilis is important to the public health community to lay the foundation for the development and implementation of programs to prevent and eliminate syphilis in the United States. ^ The objective of this study was to describe the trends of syphilis among the population in Houston/Harris County, Texas. ^ We reviewed surveillance data that included 11,605 unique cases from the Houston Department of Human and Health Service from 1999 through 2008. The rates were calculated per 100,000 population. ^ We show the prevalence of syphilis at testing (excluding congenital) increased 40% in Houston/Harris County, Texas from 2001 through 2008, and the ratio of syphilis comparing men to women was 2:1. The 18–29 years age group had the highest percentage of cases of syphilis among all age groups in Houston/Harris County. Primary and Secondary (P&S) syphilis, the most infectious stage, had an 85% increase in rate among males from 1999 through 2008. ^ Between 1999 and 2000, 71% of cases were identified through public facilities compared to private facilities. However, after 2001 rates shifted over more to the private facilities. By 2008, private facilities identified 54.7% of cases, compared to 45.3% identified through public facilities. This may be due to an increase among individuals who have a higher socio-economic status with access to health care insurance. ^ In conclusion, syphilis rates from 1999 through 2008 increased among all race ethnicities, age groups, and genders in Houston/Harris County. Blacks still are disproportionally affected by syphilis infections, and for the first time, White males displayed a significant increase in cases among males. It is vital to Houston public health professionals to have improved surveillance techniques to track syphilis trends and engage high risk groups to better understand their risks in hope of treating and preventing syphilis.^

IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE

IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE Publication No.___________ Lisa Harn-Ging Shiue, B.S. Supervisory Professor: Madeleine Duvic, M.D. Extracorporeal photopheresis (ECP) is an effective, low-risk immunomodulating therapy for leukemic cutaneous T cell lymphoma (L-CTCL) and graft versus host disease (GVHD), but whether the mechanism(s) of action in these two diseases is (are) identical or different is unclear. To determine the effects of ECP in vivo, we studied regulatory T cells (T-regs), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) by immunofluorescence flow cytometry in 18 L-CTCL and 11 GVHD patients before and after ECP at Day 2, 1 month, 3 months, and 6 months. In this study, ECP was effective in 12/18 L-CTCL patients with a 66.7% overall response rate (ORR) and 6/11 GVHD patients with a 54.5% ORR. Prior to ECP, the percentages of CD4+Foxp3+ T cells in 9 L-CTCL patients were either lower (L-CTCL-Low, n=2) or higher (L-CTCL-High, n=7) than normal. Five of the 7 GVHD patients had high percentages of CD4+Foxp3+ T cells (GVHD-High). Six of 7 L-CTCL-High patients had >80% CD4+Foxp3+ T cells which were correlated with tumor cells, and were responders. Both L-CTCL-High and GVHD-High patients had decreased percentages of CD4+Foxp3+ and CD4+Foxp3+CD25- T cells after 3 months of treatment. CD4+Foxp3+CD25+ T cells increased in GVHD-High patients but decreased in L-CTCL-High patients after 3 months of ECP. In addition, numbers of CTLs were abnormal. We confirmed that numbers of CTLs were low in L-CTCL patients, but high in GVHD patients prior to ECP. After ECP, CTLs increased after 1 month in 4/6 L-CTCL patients whereas CTLs decreased after 6 months in 3/3 GVHD patients. Myeloid (mDCs) and plasmacytoid DCs (pDCs) were also low at baseline in L-CTCL and GVHD patients confirming the DC defect. After 6 months of ECP, numbers and percentages of mDCs and pDCs increased in L-CTCL and GVHD. MDCs were favorably increased in 8/12 L-CTCL responders whereas pDCs were favorably increased in GVHD patients. These data suggest that ECP is favorably modulating the DC subsets. In L-CTCL patients, the mDCs may orchestrate Th1 cell responses to overcome immune suppression and facilitate disease regression. However, in GVHD patients, ECP is favorably down-regulating the immune system and may be facilitating immune tolerance to auto-or allo-antigens. In both L-CTCL and GVHD patients, DCs are modulated, but the T cell responses orchestrated by the DCs are different, suggesting that ECP modulates depending on the immune milieu. _______________

Examination of synthetic retinoid -induced apoptosis in cutaneous squamous cell carcinomas: Mechanisms and implications for chemoprevention and chemotherapy with retinoids

Non-melanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma (SCC), are the most common neoplasms in the United States with a lifetime risk nearly equal to all other types of cancer combined. Retinoids are naturally occurring and synthetic analogues of vitamin A that bind to nuclear retinoid receptors and modulate gene expression as a means of regulating cell proliferation and differentiation. Retinoids have been employed for many years in the treatment of various cutaneous lesions and for cancer chemoprevention and therapy. The primary drawback limiting the use of retinoids is their toxicity, which is also associated with receptor-gene interactions. In this study, the effects of the synthetic retinoids N-(4-hydroxyphenyl)retinamide (4HPR) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) were examined in cutaneous keratinocytes. Four human cutaneous SCC cell lines were examined along with normal human epidermal keratinocyte (NHEK) cells from two donors. Sensitivity to 4HPR or CD437 alone or in combination with other agents was determined via growth inhibition, cell cycle distributions, or apoptosis induction. Both synthetic retinoids were able to promote apoptosis in SCC cells more effectively than the natural retinoid all-trans retinoic acid. Apoptosis could not be inhibited by nuclear retinoic acid receptor antagonists. In NHEK cells, 4HPR induced apoptosis while CD437 promoted G1 arrest. 4HPR acted as a prooxidant by generating reactive oxygen species (ROS) in SCC and NHEK cells. 4HPR-induced apoptosis in SCC cells could be inhibited or potentiated by manipulating cellular defenses against oxidative stress, indicating an essential role for ROS in 4HPR-induced apoptosis. CD437 promoted apoptosis in SCC cells in S and G2/M phases of the cell cycle within two hours of treatment, and this rapid induction could not be blocked with cycloheximide. This study shows: (1) 4HPR- and CD437-induced apoptosis do not directly involve a traditional retinoid pathway; (2) 4HPR can act as a prooxidant as a means of promoting apoptosis; (3) CD437 induces apoptosis in SCC cells independent of protein synthesis and is potentially less toxic to NHEK cells; and (4) 4HPR and CD437 operate under different mechanisms with respect to apoptosis induction and this may potentially enhance their therapeutic index in vivo. ^