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.^

Contributions to midwifery, and diseases of women and children : with a report on the progress of obstetrics, and uterine and infantile pathology in 1858 /

Mode of access: Internet.

Natural history study of arthrogryposis multiplex congenita, amyoplasia type

Arthrogryposis or Arthrogrypsosis Multiplex Congenita (AMC) are terms used to describe the clinical finding of multiple congenital contractures. There are more than 300 distinct disorders associated with arthrogryposis. Amyoplasia is the most common type of arthrogryposis and is often referred to as the “classic” type. There is no known cause of amyoplasia and no risk factors have been identified. Moreover, there is no established diagnostic criteria, which has led to inconsistency and confusion in the medical literature. The purpose of this study was to describe the natural history of amyoplasia, to determine if there are any identifiable risk factors and develop a list of diagnostic criteria. A retrospective chart review of 59 children with arthrogryposis ascertained at the Shriners Hospitals for Children in Houston, Texas was performed and included the following information: prenatal, birth, and family histories, and phenotypic descriptions. Forty-four children were identified with amyoplasia and 15 children with other multiple congenital contractures and other anomalies (MCC) were used as a comparison group. With the exception of abnormal amniotic fluid levels during pregnancy, there were no significant demographic or prenatal risk factors identified. However, we found common features that discriminate amyoplasia from other types of arthrogryposis and developed a diagnostic checklist. This checklist can be used as diagnostic criteria for discriminating amyoplasia from isolated and multiple contracture conditions.

Evaluation of Recurrence Risks for Left-Sided Cardiac Lesions

It is widely accepted that hypoplastic left heart syndrome (HLHS), aortic valve stenosis with or without bicuspid aortic valve (AS/BAV) and coarctation of the aorta (CoA) occur in families more commonly with each other than with any other congenital heart defect (CHD). Genetic counseling for CHDs is currently based on empiric risk estimates derived from data collected on all types of CHDs between 1968 and 1990. Additionally, for the specific group of defects described above, termed left-sided lesions, estimates are available for sibling recurrence. Utilizing family history data from 757 probands recruited between 1997 and 2007 from The Children’s Hospital of Philadelphia, this study reassessed the pre/recurrence risks for LSLs specifically. Sibling pre/recurrence risks for HLHS (5.5%, 95% CI: 3.1%-8.9%), CoA (4.0%, 95% CI: 2.1%-6.7%), and AS/BAV (6.0%, 95% CI: 3.3%-9.8%) were higher than currently quoted risks based on sibling data for individual LSLs. Additionally, the prevalence of BAV in 202, apparently unaffected, parents of 134 probands was assessed by echocardiography. BAV, which occurs at a frequency of 1% in the general population, was found to occur in approximately 10% of parents of LSL probands. Lastly, among affected first-degree relative pairs (i.e. siblings, parent-offspring), the majority (65%-70%) were both affected with a LSL. Defect specific concordance rates were highest for AS/BAV. Together, these findings suggest that over the past 20 years with changing diagnostic capabilities and environmental/maternal conditions (e.g. folic acid fortification, increased maternal diabetes and obesity) recurrence risks may have increased, as compared to current LSL specific risk estimates. Based on these risk estimate increases and prior studies, a protocol for screening first-degree relatives of LSL probands should be devised.

STIMULATION THROUGH TLR4 INCREASES FVIII INHIBITOR FORMATION IN A MOUSE MODEL OF HEMOPHILIA A

Hemophilia A is a clotting disorder caused by functional factor VIII (FVIII) deficiency. About 25% of patients treated with therapeutic recombinant FVIII develop antibodies (inhibitors) that render subsequent FVIII treatments ineffective. The immune mechanisms of inhibitor formation are not entirely understood, but circumstantial evidence indicates a role for increased inflammatory response, possibly via stimulation of Toll-like receptors (TLRs), at the time of FVIII immunization. I hypothesized that stimulation through TLR4 in conjunction with FVIII treatments would increase the formation of FVIII inhibitors. To test this hypothesis, FVIII K.O. mice were injected with recombinant human FVIII with or without concomitant doses of TLR4 agonist (lipopoysaccharide; LPS). The addition of LPS combined with FVIII significantly increased the rate and the production of anti-FVIII IgG antibodies and neutralizing FVIII inhibitors. In the spleen, repeated in vivo TLR4 stimulation with LPS increased the relative percentage of macrophages and dendritic cells (DCs) over the course of 4 injections. However, repeated in vivo FVIII stimulation significantly increased the density of TLR4 expressed on the surface of all spleen antigen presenting cells (APCs). Culture of splenocytes isolated from mice revealed that the combined stimulation of LPS and FVIII also synergistically increased early secretion of the inflammatory cytokines IL-6, TNF-α, and IL-10, which was not maintained throughout the course of the repeated injections. While cytokine secretion was relatively unchanged in response to FVIII re-stimulation in culture, LPS re-stimulation in culture induced increased and prolonged inflammatory cytokine secretion. Re-stimulation with both LPS and FVIII induced cytokine secretion similar to LPS stimulation alone. Interestingly, long term treatment of mice with LPS alone resulted in splenocytes that showed reduced response to FVIII in culture. Together these results indicated that creating a pro-inflammatory environment through the combined stimulation of chronic, low-dose LPS and FVIII changed not only the populations but also the repertoire of APCs in the spleen, triggering the increased production of FVIII inhibitors. These results suggested an anti-inflammatory regimen should be instituted for all hemophilia A patients to reduce or delay the formation of FVIII inhibitors during replacement therapy.

Evaluating the Utility of Clinical Criteria for the Identification of Lynch Syndrome among Endometrial Cancer Patients

Background: Lynch Syndrome (LS) is a familial cancer syndrome with a high prevalence of colorectal and endometrial carcinomas among affected family members. Clinical criteria, developed from information obtained from familial colorectal cancer registries, have been generated to identify individuals at elevated risk for having LS. In 2007, the Society of Gynecologic Oncology (SGO) codified criteria to assist in identifying women presenting with gynecologic cancers at elevated risk for having LS. These criteria have not been validated in a population-based setting. Materials and Methods: We retrospectively identified 412, unselected endometrial cancer cases. Clinical and pathologic information were obtained from the electronic medical record, and all tumors were tested for expression of the DNA mismatch repair proteins through immunohistochemistry. Tumors exhibiting loss of MSH2, MSH6 and PMS2 were designated as probable Lynch Syndrome (PLS). For tumors exhibiting immunohistochemical loss of MLH1, we used the PCR-based MLH1 methylation assay to delineate PLS tumors from sporadic tumors. Samples lacking methylation of the MLH1 promoter were also designated as PLS. The sensitivity and specificity for SGO criteria for detecting PLS tumors was calculated. We compared clinical and pathologic features of sporadic tumors and PLS tumors. A simplified cost-effectiveness analysis was also performed comparing the direct costs of utilizing SGO criteria vs. universal tumor testing. Results: In our cohort, 43/408 (10.5%) of endometrial carcinomas were designated as PLS. The sensitivity and specificity of SGO criteria to identify PLS cases were 32.7 and 77%, respectively. Multivariate analysis of clinical and pathologic parameters failed to identify statistically significant differences between sporadic and PLS tumors with the exception of tumors arising from the lower uterine segment. These tumors were more likely to occur in PLS tumors. Cost-effectiveness analysis showed clinical criteria and universal testing strategies cost $6,235.27/PLS case identified and $5,970.38/PLS case identified, respectively. Conclusions: SGO 5-10% criteria successfully identify PLS cases among women who are young or have significant family history of LS related tumors. However, a larger proportion of PLS cases occurring at older ages with less significant family history are not detected by this screening strategy. Compared to SGO clinical criteria, universal tumor testing is a cost effective strategy to identify women presenting with endometrial cancer who are at elevated risk for having LS.

Beta2-agonists use during pregnancy and the risk of congenital malformations

Selon les lignes directrices de traitement de l'asthme pendant la grossesse, les beta2-agonistes inhalés à courte durée d’action (SABA) sont les médicaments de choix pour tous les types d’asthme [intermittent, persistant, léger, modéré et sévère] comme médicaments de secours rapide et dans la gestion des exacerbations aiguës. D’autre part, les beta2-agonistes inhalés à longue durée d’action (LABA) sont utilisés pour les patients atteints d'asthme persistant, modéré à sévère, qui ne sont pas entièrement contrôlés par des corticostéroïdes inhalés seuls. Malgré que plusieurs études aient examinées l’association entre les LABA, les SABA et les malformations congénitales chez les nouveau-nés, les risques réels restent controversés en raison de résultats contradictoires et des difficultés inhérentes à la réalisation d'études épidémiologiques chez les femmes enceintes. L'objectif de cette étude était d'évaluer l'association entre l'exposition maternelle aux SABA et LABA pendant le premier trimestre de grossesse et le risque de malformations congénitales chez les nouveau-nés de femmes asthmatiques. Une cohorte de grossesses de femmes asthmatiques ayant accouchées entre le 1er janvier 1990 et le 31 décembre 2002 a été formée en croisant trois banques de données administratives de la province de Québec (Canada). Les issues principales de cette étude étaient les malformations congénitales majeures de touts types. Comme issues secondaires, nous avons considéré des malformations congénitales spécifiques. L'exposition principale était la prise de SABA et/ou de LABA au cours du premier trimestre de grossesse. L'exposition secondaire étudiée était le nombre moyen de doses de SABA par semaine au cours du premier trimestre. L'association entre les malformations congénitales et la prise de SABA et de LABA a été évaluée en utilisant des modèles d’équations généralisées (GEE) en ajustant pour plusieurs variables confondantes reliées à la grossesse, l’asthme de la mère et la santé de la mère et du foetus. Dans la cohorte formée de 13 117 grossesses de femmes asthmatiques, nous avons identifié 1 242 enfants avec une malformation congénitale (9,5%), dont 762 avaient une malformation majeure (5,8%). Cinquante-cinq pour cent des femmes ont utilisé des SABA et 1,3% ont utilisé des LABA pendant le premier trimestre. Les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale associée à l'utilisation des SABA et des LABA étaient de 1,0 (0,9-1,2) et 1,3 (0,9-2,1), respectivement. Les résultats correspondants étaient de 0,9 (0,8-1,1) et 1,3 (0,8-2,4) pour les malformations majeures. Concernant le nombre moyen de doses de SABA par semaine, les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale était de 1.1 (1.0-1.3), 1.1 (0.9-1.3), et 0.9 (0.7-1.1) pour les doses >0-3, >3-10, and >10 respectivement. Les résultats correspondants étaient de 1.0 (0.8-1.2), 0.8 (0.7-1.1), et 0.7 (0.5-1.0) pour les malformations majeures. D'autre part, des rapports de cotes (IC à 95%) statistiquement significatifs ont été observés pour les malformations cardiaques (2.4 (1.1-5.1)), les malformations d'organes génitaux (6.8 (2.6-18.1)), et d'autres malformations congénitales (3.4 (1.4 à 8.5)), en association avec les LABA pris pendant le premier trimestre. Notre étude procure des données rassurantes pour l’utilisation des SABA pendant la grossesse, ce qui est en accord avec les lignes directrices de traitement de l’asthme. Toutefois, d'autres études sont nécessaires avant de pouvoir se prononcer sur l’innocuité des LABA pendant la grossesse.

The association method for diagnosis and treatment of congenital aphasia

This paper is a review of congenital aphasia and the introduction of the McGinnis Association Method for diagnosis and rehabilitation.

Iodide Transport Defect: Functional Characterization of a Novel Mutation in the Na(+)/I(-) Symporter 5 `-Untranslated Region in a Patient with Congenital Hypothyroidism

Context: Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD. Objective: Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype. Design: The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed. Results: The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5`-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency. Conclusions: We described a novel mutation in the 5`-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function. (J Clin Endocrinol Metab 96: E1100-E1107, 2011)

Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023). The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger well characterized high-risk cohort.

Granulomatous uveitis and congenital cataract: a rare association

The association of a granulomatous uveitis and congenital cataract and is rarely observed in newborn children. We describe the history of two patients presenting simultaneously with these two features in the absence of a TORCH infection.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

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.) ^

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. ^

The control of hematopoiesis and leukemia: from basic biology to the clinic.

Hematopoiesis gives rise to blood cells of different lineages throughout normal life. Abnormalities in this developmental program lead to blood cell diseases including leukemia. The establishment of a cell culture system for the clonal development of hematopoietic cells made it possible to discover proteins that regulate cell viability, multiplication and differentiation of different hematopoietic cell lineages, and the molecular basis of normal and abnormal blood cell development. These regulators include cytokines now called colony-stimulating factors (CSFs) and interleukins (ILs). There is a network of cytokine interactions, which has positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor (TNF). This multigene cytokine network provides flexibility depending on which part of the network is activated and allows amplification of response to a particular stimulus. Malignancy can be suppressed in certain types of leukemic cells by inducing differentiation with cytokines that regulate normal hematopoiesis or with other compounds that use alternative differentiation pathways. This created the basis for the clinical use of differentiation therapy. The suppression of malignancy by inducing differentiation can bypass genetic abnormalities that give rise to malignancy. Different CSFs and ILs suppress programmed cell death (apoptosis) and induce cell multiplication and differentiation, and these processes of development are separately regulated. The same cytokines suppress apoptosis in normal and leukemic cells, including apoptosis induced by irradiation and cytotoxic cancer chemotherapeutic compounds. An excess of cytokines can increase leukemic cell resistance to cytotoxic therapy. The tumor suppressor gene wild-type p53 induces apoptosis that can also be suppressed by cytokines. The oncogene mutant p53 suppresses apoptosis. Hematopoietic cytokines such as granulocyte CSF are now used clinically to correct defects in hematopoiesis, including repair of chemotherapy-associated suppression of normal hematopoiesis in cancer patients, stimulation of normal granulocyte development in patients with infantile congenital agranulocytosis, and increase of hematopoietic precursors for blood cell transplantation. Treatments that decrease the level of apoptosis-suppressing cytokines and downregulate expression of mutant p53 and other apoptosis suppressing genes in cancer cells could improve cytotoxic cancer therapy. The basic studies on hematopoiesis and leukemia have thus provided new approaches to therapy.