bluuebunny/crossref_metadata_2025 huggingface dataset:
Consumer involvement in consent document development: a multicenter cluster randomized trial to assess study participants' understanding
Authors: Guarino Peter , Elbourne Diana , Carpenter James , Peduzzi Peter
Published: February 2006

Background Despite widespread agreement on the importance of informed consent in clinical research, uncertainty remains about the adequacy of current consent procedures and documentation.

Methods The objective of the study was to compare an informed consent document developed by a consumer group of potential study participants to one developed by the study investigators. The study was a cluster randomized, controlled study embedded in a ‘parent’ randomized controlled trial of 1092 participants with Gulf War veterans’ illnesses recruited in 1999–2000 at 20 US medical centers. Centers were randomized to the investigator-developed or participant-developed consent document. The primary outcome measure was an Informed Consent Questionnaire-4 (ICQ-4), a validated four-item scale measuring self-reported participant understanding scored from 0 to 1. Secondary outcomes included the Client Satisfaction Questionnaire-8 and measures of study refusal and adherence to the parent trial protocol.

Results There were no significant differences between consent documents on the ICQ-4 score overall or at any of the time points. Mean (95% CI) treatment differences ranged from 0.020 (0.015, 0.055) (better understanding) at entry to 0.021 (0.054, 0.012) (worse understanding) at three-months for the participant versus the investigator document group. There were also no significant differences in satisfaction, adherence to the protocol, or in the proportion of patients who refused to participate in the trial.

Limitations The consumer group may not have been representative of the study participants and they did not suggest dramatic changes to the consent document. The outcome assessment questionnaire was not validated prior to the trial's initiation.

Conclusions Consumer modification of the consent document did not lead to either benefit or harm in understanding, satisfaction, or study refusal and adherence rates. This study did demonstrate, however, that embedding consent studies in a clinical trial is feasible and can address important questions about informed consent without disrupting the primary study.
The continual reassessment method for dose-finding studies: a tutorial
Authors: Garrett-Mayer Elizabeth
Published: February 2006

The Continual Reassessment Method (CRM), along with other adaptive dose-finding study designs, has gained popularity since its proposal by O'Quigley. Several of the reasons it has been embraced by clinical trialists is that it tends to incur fewer toxic events, and more accurately estimate the maximum tolerated dose as compared to the standard Phase I dose escalation designs. Many variations have been published and discussed in the statistical literature, but there has not been as much practical advice for choosing design parameters and implementing the CRM. As a result, the CRM has not been as widely utilized as it could be for dose-finding studies. The goal of this paper is to provide a tutorial for those unfamiliar with the CRM who are either statisticians considering using the CRM for the first time, or investigators with some statistical background. This paper presents the original CRM, and then some of its modified versions. It also explains the specifications that define a CRM design, along with simulated examples of CRMs and standard designs, for illustration.
Estimation of the average causal effect among subgroups defined by post-treatment variables
Authors: Matsuyama Yutaka , Morita Satoshi
Published: February 2006

Background In clinical trials, when comparing treatments in a subgroup of patients defined by an event that occurred after randomization is required, the standard estimator that adjusts for the post-treatment variable does not have a causal interpretation.

Purpose To address this problem, we formulate clinically relevant causal estimands using the principal stratification framework developed by Frangakis and Rubin [3], and propose a new estimation method for the principal causal effect.

Methods We consider the comparison of the duration of response among patients who responded to chemotherapy in a cancer clinical trial. Our goal is to estimate the local average treatment effect, that is, the treatment difference among patients who would have responded to either treatment. In order to identify this estimand, we make the assumption that the value of the counterfactual indicator of response is independent of both the actual response status and the outcome variable of interest conditional on the covariates. The proposed estimator is a weighted average of the standard estimators for responders where weights are the probability that the response would have occurred had the patient received the other treatment.

Results The proposed method is applied to data from a randomized phase III clinical trial in patients with advanced non-small-cell lung cancer. The average difference for the duration of response among responders estimated by the proposed method and the standard one was 16.1 (days) and 9.5 (days), respectively. We also evaluate the performance of the proposed method through simulation studies, which showed that the proposed estimator was unbiased, while the standard one was largely biased.

Conclusions We have developed an estimation method for the local average treatment effect. For any type of outcome variables, our estimator can be easily constructed and can be interpreted as the treatment effect among patients who would have had the event in either treatment group.
Hormonal Regulation of Male Reproductive Tract Development
Authors: VERMA‐KURVARI SUNITA , NEF SERGE , PARADA LUIS F.
Published: February 2006

Abstract: We have employed gene knockout technology in mice to probe gene function in various stages of mouse male sexual differentiation. Insulin‐like factor (Insl3) is prominently expressed in Leydig cells. Mutation of this gene leads to fully penetrant cryptorchidism. Single mutation in each of the three known insulin family receptor tyrosine kinases alone has limited effects on sexual differentiation; however, compound mutations result in formation of ovotestes, and triple mutations cause male‐to‐female sexual reversal. The implications of our mouse models are discussed.
Transgenic Rescue of SF‐1‐Null Mice
Authors: KARPOVA TATIANA , MARAN R. R. M. , PRESLEY JEREMY , SCHERRER SERGE P. , TEJADA LOVELLA , HECKERT LESLIE L.
Published: February 2006

Abstract: Steroidogenic factor 1 (SF‐1, Nr5a1, and Ad4bp) is an orphan nuclear receptor required for adrenal and gonad development and endocrine regulation. To extend our understanding of SF‐1 function and the mechanisms controlling its expression, a transgenic rescue strategy was employed to locate important transcriptional control regions and to reveal functional roles of the protein. A rat yeast artificial chromosome containing Ftz‐F1, the gene encoding SF‐1, was used to generate mice with different transgenes that varied in size. Rat SF‐1 mRNA expression was assayed to assess each transgene's targeting ability. SF‐1‐deficient/transgene‐positive (SF‐1−/−; tg/+) “rescue” mice were then generated and the animals' developmental and reproductive status was evaluated. The results identified differences in expression patterns and rescue abilities that provided insight into SF‐1 transcriptional control and function. Comparing transgene maps and mRNA profiles placed critical transcriptional elements for pituitary and hypothalamic expression to a region 3′ to intron 4, whereas examination of rescued mice revealed that an ∼153‐kb region of the Ftz‐F1 locus recapitulates most or all activity ascribed to the endogenous allele. A second line of rescued mice was hypomorphic, with males showing defects in androgen‐dependent tissues due to abnormal Leydig cell differentiation. Histological analysis of embryonic (e14.5) and adult testes from these mice implicated SF‐1 in roles that are distinct in fetal and adult Leydig cells.
Estrogens in Testis Biology
Authors: SIERENS JAYNE E. , SNEDDON SHARON F. , COLLINS FRANCES , MILLAR MICHAEL R. , SAUNDERS PHILIPPA T. K.
Published: February 2006

Abstract:Levels of estrogen within the male reproductive tract are higher than in the general circulation and the aromatase enzyme is expressed in the adult testis. Estrogens such as estradiol (E2) modify cell function by binding to high‐affinity estrogen receptors (ER). Two subtypes (ERα and ERβ) have been identified. Studies in animals have shown that over‐ or underexposure to estrogens can have an impact on testis function. For example, mice with targeted disruption of the aromatasecyp19gene become infertile because round spermatids fail to differentiate normally. In rodents, ERα is expressed in Leydig cells; ERα mRNA and protein are not detectable in testes from humans or primates. High levels of expression of ERα occur in the efferent ductules in rodents, primates, and the human. ERβ protein has been immunolocalized to all somatic cells and to some germ cells in these same species. Messenger RNAs for splice variant isoforms of human ERβ are expressed in human testes. Homologues of the ERβ2 variant have been cloned from primates; this isoform does not exist in rodents and does not bind E2. Full‐length ERβ protein (ERβ1) and ERβ2 have differential patterns of expression in human testes. In conclusion, although estogens are synthesized in the testis and it has been suggested that E2 may function as a germ cell survival factor, the mechanisms by which estrogens influence male fertility remain uncertain and rodents may be poor models in which to examine this.
Determining Structure and Function of Steroid Dehydrogenase Enzymes by Sequence Analysis, Homology Modeling, and Rational Mutational Analysis
Authors: DUAX WILLIAM L. , THOMAS JAMES , PLETNEV VLADIMIR , ADDLAGATTA ANTHONY , HUETHER ROBERT , HABEGGER LUKAS , WEEKS CHARLES M.
Published: February 2006

Abstract: The short‐chain oxidoreductase (SCOR) family of enzymes includes over 6,000 members identified in sequenced genomes. Of these enzymes, ∼300 have been characterized functionally, and the three‐dimensional crystal structures of ∼40 have been reported. Since some SCOR enzymes are steroid dehydrogenases involved in hypertension, diabetes, breast cancer, and polycystic kidney disease, it is important to characterize the other members of the family for which the biological functions are currently unknown and to determine their three‐dimensional structure and mechanism of action. Although the SCOR family appears to have only a single fully conserved residue, it was possible, using bioinformatics methods, to determine characteristic fingerprints composed of 30‐40 residues that are conserved at the 70% or greater level in SCOR subgroups. These fingerprints permit reliable prediction of several important structure‐function features including cofactor preference, catalytic residues, and substrate specificity. Human type 1 3β‐hydroxysteroid dehydrogenase isomerase (3β‐HSDI) has 30% sequence identity with a human UDP galactose 4‐epimerase (UDPGE), a SCOR family enzyme for which an X‐ray structure has been reported. Both UDPGE and 3‐HSDI appear to trace their origins back to bacterial 3α,20β‐HSD. Combining three‐dimensional structural information and sequence data on the 3α,20β‐HSD, UDPGE, and 3β‐HSDI subfamilies with mutational analysis, we were able to identify the residues critical to the dehydrogenase function of 3‐HSDI. We also identified the residues most probably responsible for the isomerase activity of 3β‐HSDI. We test our predictions by specific mutations based on sequence analysis and our structure‐based model.
The mRNA Encoding τCstF‐64 Is Expressed Ubiquitously in Mouse Tissues
Authors: HUBER ZANE , MONAREZ ROBERTO R. , DASS BRINDA , MacDONALD CLINTON C.
Published: February 2006

Abstract: Polyadenylation is a process of endonucleolytic cleavage of the mRNA, followed by addition of up to 250 adenosine residues to the 3′ end of the mRNA. Polyadenylation is essential for eukaryotic mRNA expression, and CstF‐64 is a subunit of the CstF polyadenylation factor that is required for accurate polyadenylation. We discovered that there are two forms of the CstF‐64 protein in mammalian male germ cells, one of which (CstF‐64) is expressed in all tissues, the other of which (τCstF‐64) is expressed only in male germ cells and in brain (albeit at significantly lower levels in the brain). Therefore, we were surprised to find that, using reverse transcription‐PCR, cDNA cloning, and RNA blot analyses, τCstF‐64 mRNA was expressed at higher levels in brain than in testis. Also, τCstF‐64 mRNA was expressed at lower but detectable levels in all tissues tested, including epididymis, heart, kidney, liver, lung, muscle, ovary, spleen, thymus, and uterus. These results suggest the hypothesis that τCstF‐64 mRNA is regulated at the translational or post‐translational level.
Drivers of Germ Cell Maturation
Authors: LOVELAND K. L. , HOGARTH C. , MENDIS S. , EFTHYMIADIS A. , LY J. , ITMAN C. , MEACHEM S. , BROWN C. W. , JANS D. A.
Published: February 2006

Abstract: Spermatogenesis requires progression of germ line stem cells through a precisely ordered differentiation pathway to form spermatozoa. Diverse and dynamic signals from the transforming growth factor‐β (TGF‐β) superfamily influence many stages of germ cell development. For example, interactions between several TGF‐β superfamily ligands (bone morphogenetic proteins, activin, and glial‐derived neurotrophic growth factor [GDNF]) appear to govern the onset of spermatogenesis, and we are exploring how germ cells interpret these competing signals. We examined the in vivo impact of activin on testis development using two mouse models, the inhba−/− mouse (which lacks the gene encoding the activin A subunit and dies at birth) and BK mice, with inhbb (encoding the activin βB subunit) replacing inhba (which survive to adulthood and show delayed fertility onset in males). Distinct effects on Sertoli cell and germ cell populations during fetal and early postnatal development were measured. We recognize that specific proteins, including downstream targets of TGF‐β signals, such as Smads, must move into the nucleus to implement the gene transcription changes required for development. We hypothesized that changes at the level of cellular nuclear transport machinery may be required to mediate this. Examination of proteins involved in classical nuclear import, the importins, revealed that each importin has a developmentally regulated expression pattern in male germ cells. Because each importin binds a selected range of cargo proteins and mediates their nucleocytoplasmic passage, our findings suggest that each importin ferries cargo required for discrete stages of spermatogenesis.
Sperm Chemotaxis: A Primer
Authors: HILDEBRAND E. , KAUPP U. B.
Published: February 2006

Abstract: Sperm become attracted by chemical substances that are released from the outer coating of the egg, a process called chemotaxis. In this paper the cellular pathway and the motor response during chemotaxis of sperm from sea urchin and starfish are briefly outlined.
Epigenetic Regulation of Testis‐Specific Gene Expression
Authors: McCARREY JOHN R. , GEYER CHRISTOPHER B. , YOSHIOKA HIROTAKA
Published: February 2006

Abstract: Cellular differentiation is mediated by differential gene expression. The cells of the testis are no exception. Indeed, recent studies based on microarray and expressed sequence tag analyses have revealed dynamic changes in gene expression during spermatogenesis. The autosomal phosphoglycerate kinase gene Pgk2 is an example of a gene that is tightly regulated during spermatogenesis, with transcription initiating in primary spermatocytes and ceasing in postmeiotic spermatids. Our studies show that this tissue‐specific transcription is regulated at multiple levels, including binding of ubiquitous and testis‐specific transcription factors, reconfiguration of nucleosomes, decondensation of chromatin, modifications of specific residues in histones, and demethylation of DNA. Our ability to isolate relatively pure populations of different spermatogenic cell types has allowed us to determine the order of these events that lead up to initiation of transcription of the Pgk2 gene. By examining similar parameters in transgenic mice carrying various portions of Pgk2 regulatory sequence, we have localized specific signals responsible for each of these regulatory events. Together these results demonstrate that activation of testis‐specific transcription of the Pgk2 gene involves a multifaceted, ordered cascade of epigenetic events that potentiates this locus in preparation for the initiation of transcription.
Nonmelanoma Skin and Mucosal Cancers After Hematopoietic Cell Transplantation
Authors: Leisenring Wendy , Friedman Debra L. , Flowers Mary E.D. , Schwartz Jeffrey L. , Deeg H. Joachim
Published: February 2006

Purpose

To evaluate the incidence of and risk factors for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in survivors of hematopoietic cell transplantation (HCT).

Patients and Methods

The impact of patient-, disease-, treatment-, and toxicity-related factors on risk of BCC and SCC was determined in a retrospective cohort study of 4,810 patients who received allogeneic HCT and who survived for at least 100 days.

Results

Among allogeneic HCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n = 158; SCC, n = 95). Twenty-year cumulative incidences of BCC and SCC were 6.5% and 3.4%, respectively. Total-body irradiation was a significant risk factor for BCC (P = .003), most strongly among patients younger than 18 years old at HCT (P = .02, interaction). Light-skinned patients had an increased risk of BCC (P = .01). Acute graft-versus-host disease (GVHD) increased the risk of SCC (P = .02), whereas chronic GVHD increased the risk of both BCC (P = .01) and SCC (P < .001).

Conclusion

This analysis suggests that immutable factors, such as age and complexion, have a significant impact on BCC and SCC. However, specific treatment (radiotherapy) and transplantation complications (GVHD) may modify that risk. These additional risk factors suggest the contribution of immunologic mechanism DNA and tissue repair in the development of BCC and SCC. We confirm previous reports that exposure to ionizing radiation increases the risk of BCC but not SCC. Survivors of HCT should be monitored for the development of BCC and SCC and use preventive strategies.
Prospective Study of Wide Excision Alone for Ductal Carcinoma in Situ of the Breast
Authors: Wong Julia S. , Kaelin Carolyn M. , Troyan Susan L. , Gadd Michele A. , Gelman Rebecca , Lester Susan C. , Schnitt Stuart J. , Sgroi Dennis C. , Silver Barbara J. , Harris Jay R. , Smith Barbara L.
Published: February 2006

Purpose

It has been hypothesized that wide excision alone with margins ≥ 1 cm may be adequate treatment for small, grade 1 or 2 ductal carcinoma in situ (DCIS). To test this hypothesis, we conducted a prospective, single-arm trial.

Methods

Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of ≤ 2.5 cm treated with wide excision with final margins of ≥ 1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The accrual goal was 200 patients.

Results

In July 2002, the study closed to accrual at 158 patients because the number of local recurrences met the predetermined stopping rules. The median age was 51 and the median follow-up time was 40 months. Thirteen patients developed local recurrence as the first site of treatment failure 7 to 63 months after study entry. The rate of ipsilateral local recurrence as first site of treatment failure was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive disease. Twelve recurrences were detected mammographically and one was palpable. Ten were in the same quadrant as the initial DCIS and three were elsewhere within the ipsilateral breast. No patient had positive axillary nodes at recurrence or subsequent metastatic disease.

Conclusion

Despite margins of ≥ 1 cm, the local recurrence rate is substantial when patients with small, grade 1 or 2 DCIS are treated with wide excision alone. This risk should be considered in assessing the possible use of radiation therapy with or without tamoxifen in these patients.
Natriuretic Peptides, Their Receptors, and Cyclic Guanosine Monophosphate-Dependent Signaling Functions
Authors: Potter Lincoln R. , Abbey-Hosch Sarah , Dickey Deborah M.
Published: February 2006

Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.
Long-Term Corticosteroid Replacement and Bone Mineral Density in Adult Women with Classical Congenital Adrenal Hyperplasia
Authors: King Jeremy A. , Wisniewski Amy B. , Bankowski Brandon J. , Carson Kathryn A. , Zacur Howard A. , Migeon Claude J.
Published: February 2006

Context: Concern has been raised regarding the potential impact of chronic glucocorticoid therapy on the bone mineral density (BMD) of patients with congenital adrenal hyperplasia (CAH).

Objective: The purpose of this investigation was to assess the impact of chronic glucocorticoid replacement in adult women with classical CAH.

Patients and Design: We used dual energy x-ray absorptiometry to evaluate lumbar spine and whole body BMD in 11 women with salt-losing (SL) CAH and 15 with the simple virilizing form. Physical characteristics and serum hormone concentrations were also measured. Results were compared with those of unaffected sisters of CAH patients (n = 9).

Main Outcome Measure: BMD was the main outcome measure.

Results: Osteopenia was noted in 45% of SL CAH patients, 13% of patients with the simple virilizing form, and 11% of controls. Lumbar spine and whole body BMDs of CAH subjects were lower than those of controls (P < 0.05). Compared with CAH subjects with normal BMD, those with osteopenia had reduced serum levels of dehydroepiandrosterone sulfate and dehydroepiandrosterone. Adrenal androgen levels were particularly suppressed among postmenopausal women receiving glucocorticoid replacement.

Conclusions: Adult women with classical CAH treated with long-term glucocorticoids are at risk for decreased BMD, especially those with the SL form. Oversuppression of adrenal androgens is associated with increased risk for bone loss in this population.
Low Sex Hormone-Binding Globulin, Total Testosterone, and Symptomatic Androgen Deficiency Are Associated with Development of the Metabolic Syndrome in Nonobese Men
Authors: Kupelian Varant , Page Stephanie T. , Araujo Andre B. , Travison Thomas G. , Bremner William J. , McKinlay John B.
Published: February 2006

Background: The metabolic syndrome (MetS), characterized by central obesity, lipid and insulin dysregulation, and hypertension, is a precursor state for cardiovascular disease. The purpose of this analysis was to determine whether low serum sex hormone levels or clinical androgen deficiency (AD) predict the development of MetS.

Methods: Data were obtained from the Massachusetts Male Aging Study, a population-based prospective cohort of 1709 men observed at three time points (T1, 1987–1989; T2, 1995–1997; T3, 2002–2004). MetS was defined using a modification of the ATP III guidelines. Clinical AD was defined using a combination of testosterone levels and clinical signs and symptoms. The association between MetS and sex hormone levels or clinical AD was assessed using relative risks (RR), and 95% confidence intervals (95% CI) were estimated using Poisson regression models.

Results: Analysis was conducted in 950 men without MetS at T1. Lower levels of total testosterone and SHBG were predictive of MetS, particularly among men with a body mass index (BMI) below 25 kg/m2 with adjusted RRs for a decrease in 1 sd of 1.41 (95% CI, 1.06–1.87) and 1.65 (95% CI, 1.12–2.42). Results were similar for the AD and MetS association, with RRs of 2.51 (95% CI, 1.12–5.65) among men with a BMI less than 25 compared with an RR of 1.22 (95% CI, 0.66–2.24) in men with a BMI of 25 or greater.

Conclusions: Low serum SHBG, low total testosterone, and clinical AD are associated with increased risk of developing MetS over time, particularly in nonoverweight, middle-aged men (BMI, <25). Together, these results suggest that low SHBG and/or AD may provide early warning signs for cardiovascular risk and an opportunity for early intervention in nonobese men.
Aromatase Inhibitors for Ovulation Induction
Authors: Casper Robert F. , Mitwally Mohamed F. M.
Published: February 2006

Context: For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction.

Evidence Acquisition: We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine.

Evidence Synthesis: Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders.

Conclusions: Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking.
A Comparison of Short-Term Changes in Health-Related Quality of Life in Thyroid Carcinoma Patients Undergoing Diagnostic Evaluation with Recombinant Human Thyrotropin Compared with Thyroid Hormone Withdrawal
Authors: Schroeder Pamela R. , Haugen Bryan R. , Pacini Furio , Reiners Christoph , Schlumberger Martin , Sherman Steven I. , Cooper David S. , Schuff Kathryn G. , Braverman Lewis E. , Skarulis Monica C. , Davies Terry F. , Mazzaferri Ernest L. , Daniels Gilbert H. , Ross Douglas S. , Luster Markus , Samuels Mary H. , Weintraub Bruce D. , Ridgway E. Chester , Ladenson Paul W.
Published: February 2006

Context: Thyroid carcinoma requires lifelong monitoring with serum thyroglobulin, radioactive iodine whole body scanning, and other imaging modalities. Levothyroxine (l-T4) withdrawal for thyroglobulin measurement and whole body scanning increases these tests’ sensitivities but causes hypothyroidism. Recombinant human TSH (rhTSH) enables testing without l-T4 withdrawal.

Objective: Our objective was to examine the impact of short-term hypothyroidism on the health-related quality of life (HRQOL) of patients after rhTSH vs.l-T4 withdrawal.

Design, Setting, and Patients: In this multicenter study, the SF-36 Health Survey was administered to 228 patients at three time points: on l-T4, after rhTSH, and after l-T4 withdrawal.

Interventions: Interventions included administration of rhTSH on l-T4 and withdrawal from thyroid hormone.

Main Outcome Measures: Mean SF-36 scores were compared during the two interventions and with the U.S. general population and patients with heart failure, depression, and migraine headache.

Results: Patients had SF-36 scores at or above the norm for the general U.S. population in six of eight domains at baseline on l-T4 and in seven of eight domains after rhTSH. Patients’ scores declined significantly in all eight domains after l-T4 withdrawal when compared with the other two periods (P < 0.0001). Patients’ HRQOL scores while on l-T4 and after rhTSH were at or above those for patients with heart failure, depression, and migraine in all eight domains. After l-T4 withdrawal, patients’ HRQOL scores were significantly below congestive heart failure, depression, and migraine headache norms in six, three, and six of the eight domains, respectively.

Conclusions: Short-term hypothyroidism after l-T4 withdrawal is associated with a significant decline in quality of life that is abrogated by rhTSH use.
A Novel LHX3 Mutation Presenting as Combined Pituitary Hormonal Deficiency
Authors: Bhangoo Amrit P. S. , Hunter Chad S. , Savage Jesse J. , Anhalt Henry , Pavlakis Steven , Walvoord Emily C. , Ten Svetlana , Rhodes Simon J.
Published: February 2006

Context: LHX3 encodes LIM homeodomain class transcription factors with important roles in pituitary and nervous system development. The only previous report of LHX3 mutations described patients with two types of recessive mutations displaying combined pituitary hormone deficiency coupled with neck rigidity.

Objective: We report a patient presenting a unique phenotype associated with a novel mutation in the LHX3 gene.

Patient: We report a 6-yr, 9-month-old boy born from a consanguineous relationship who presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency were consistent with hypopituitarism. A rigid cervical spine leading to limited head rotation was noticed on follow-up examination. Magnetic resonance imaging revealed an apparently structurally normal cervical spine and a postcontrast hypointense lesion in the anterior pituitary.

Results: Analysis of the LHX3 gene revealed homozygosity for a novel single-base-pair deletion in exon 2. This mutation leads to a frame shift predicted to result in the production of short, inactive LHX3 proteins. The results of in vitro translation experiments are consistent with this prediction. The parents of the patients are heterozygotes, indicating a recessive mode of action for the deletion allele.

Conclusions: The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation.
Thyroid Morphology and Function in Adults with Untreated Isolated Growth Hormone Deficiency
Authors: Alcântara Marta Regina Silva , Salvatori Roberto , Alcântara Paula Regina Silva , Nóbrega Luciana Michele A. , Campos Vera Simone , Oliveira Elma Cristina O. , Oliveira Marcelo Henrique S. , Souza Anita Hermínia Oliveira , Aguiar-Oliveira Manuel Hermínio
Published: February 2006

Objective: GH influences thyroid function and anatomy. Although goiter is frequent in acromegalic patients, the effects of GH deficiency (GHD) are difficult to assess, because hypopituitaric subjects who lack GH often also have a partial or complete deficit of TSH.

Study Design: We studied thyroid morphology and serum levels of thyroid hormones in adult members of a large Brazilian kindred with untreated isolated GHD due to a homozygous mutation in the GHRH receptor gene (GHRHR; nine men and 15 women; GHD group) and compared them to subjects heterozygous for the same mutation (eight men and 10 women; HET group) and subjects homozygous for the wild-type allele [seven men and 11 women; control (CO) group].

Results: GHD subjects had a smaller thyroid volume (TV) than HET and CO. The TV of the HET group was intermediate between those of the GHD and CO groups. When TV was corrected by body surface area, it remained smaller in the GHD and HET groups than in the CO group, but the difference between GHD and HET groups disappeared. The GHD group had lower serum T3 levels than the CO group and higher free T4 levels than HET and CO groups.

Conclusions: Individuals with severe untreated GHD due to a homozygous GHRHR mutation and heterozygous carriers of the same mutation have smaller TV than normal subjects, suggesting that GH has a permissive role in the growth of the thyroid gland. In addition, GHD subjects have reduced serum total T3 and increased serum free T4, suggesting a reduction in the function of the deiodinase system.
Targeting newly enrolled low-age school children for the control of the intestinal helminth infection in rural Nepal
Authors: Poudyal Amod K , Jimba Masamine , Silwal Ram Chandra , Murakami Izumi , Sherchand Jeevan B , Wakai Susumu
Published: February 2006

This study aims to identify an effective intervention group for the control of the intestinal helminth infection among school-age children in rural Nepal. We examined 1677 stool samples of school-age children from 25 schools and 1014 samples from 25 communities in rural Nepal. We used formalin-ether sedimentation technique for the microscopic examination of the stool samples and identified three major intestinal helminths: Ascariasis lumbricoides, hookworm and Trichuris trichiura.

Our results revealed that the newly enrolled under-6-year-old children at the schools were more widely infected with at least one of the three major helminths than those in the communities (odds ratio [OR] 2.29). We detected a significant difference in the prevalence of A. lumbricoides (OR 1.70), hookworm (OR 2.57) and T.trichiura (OR 3.23) between under-6-year-old children at the schools and those at the communities. The study results suggest that an appropriate deworming programme is needed for the newly enrolled under-6-year-old children in the primary schools in Nepal.
TB treatment outcomes following directly-observed treatment at an urban outpatient specialist TB facility in South Africa
Authors: Kharsany A B M , Connolly C , Olowolagba A , Abdool Karim S S , Abdool Karim Q
Published: February 2006

The treatment of 450 consecutive new patients with pulmonary TB was evaluated to determine outcome following directly-observed treatment. In all, 176 (39.1%) patients were cured, 23 (5.1%) completed treatment, 80 (17.8%) defaulted treatment, 24 (5.3%) died, 54 (12.0%) were lost to follow-up and 93 (20.7%) were transferred out. Increasing age was significant for death. Males were more likely to default and those with negative pretreatment sputum smears and those who were unemployed were more likely to be lost to follow-up. The overall treatment success rate remains low. Our data suggests that greater emphasis is needed to improve TB treatment success.
Ocular leprosy in Nigeria: a survey of an Eku leprosorium
Authors: Waziri-Erameh M J M , Omoti A E
Published: February 2006

To determine the ocular morbidity, visual disability and potential for blindness in leprosy patients recently released from treatment.

In-patients from Eku leprosy settlement were interviewed and examined for ocular disease from leprosy and other causes. They were examined using the Snellen's chart, pentorch, Kowa portable slit-lamp, direct ophthalmoscope and the pulsair non-contact tonometer. The patients were also refracted.

In all, 60 inpatients who were recently released from treatment, comprising 39 men (65%) and 21 women (35%), were examined. Fifty-eight patients (96.67%) had ocular symptoms, the most common being blurred vision in 23 patients (38.33%). Nine patients (15%) were blind. Cataract was the most common cause of blindness occurring in three of the nine patients (33.33%). The most common types of ocular lesions were madarosis (31.67%), lagophthalmos (16.67%) and cataract (16.67%). Potentially blinding conditions due to leprosy were seen in 42 patients (70%).

The incidence of ocular involvement, blindness and potentially blinding conditions are high in leprosy patients recently released from treatment. Regular ophthalmic evaluation and integration into Vision 2020 programmes are recommended.
Haemospermia: an Indian experience
Authors: Pal Dilip Kumar
Published: February 2006

A study of 35 cases of haemospermia over a period of 7 years revealed that infection was the most common cause (40%), and in nine cases (28%) no cause for haemospermia was found. All the cases were screened for genitourinary TB, which was found to be a significant factor (14%) for haemospermia in the Indian context.
The mantoux test: should we change the site?
Authors: Wammanda R D , Gambo M J , Abdulkadir I
Published: February 2006

Recent studies have shown that sunlight-induced immunosuppression negatively alters the skin response to mantoux test. This study aimed to compare the response of the skin to mantoux test over the volar forearm surface, the traditional site, which is exposed to sunlight and the inner thigh, an area which is not. In all, 45 children had the mantoux test administered using 0.1 mL of 5TU purified protein derivative. Reactive induration to the mantoux test was recorded in five of these children. The average induration of the volar surface was 8.2 mm, while that at the inner thigh was 11.6 mm. The results have highlighted the potential of an enhanced mantoux test result, if parts of the body that are not exposed to high doses of ultraviolet light are used as the site for mantoux test.
Relapse in a child with otogenic tetanus
Authors: Sharma A , Kapoor S
Published: February 2006

Otogenic tetanus is common in a developing country like India. However, adequate sedation and elimination of spasms by medical treatment is sufficient in most cases. Once treated, relapses are rare. The authors report a 2-year-old girl who relapsed twice after near complete recovery. This communiqué is intended to highlight that tetanus is still a significant health problem in third-world countries and a relapse after such a dreadful disease is terrifying.
Breast lump as a presentation of a hydatid disease
Authors: Nagpal Vipin , Kohli Kanika , Chowdhary Abhideep , Kumar Ajay , Andley Manoj , Ravi Bina
Published: February 2006

Hydatid disease is a lesion caused by larval form of Echinococcus granulosus and is seen endemically in sheep-rearing countries. Humans are intermediate hosts of this organism. The liver is the first filter that stops about 75% of the embryos and the lungs filter another 10%, leaving only 15% to develop into cysts in other organs of the body.
Wound infection after metronidazole infiltration
Authors: Bhargava Pranshu , Mehrotra Nidhi , Kumar Ajay
Published: February 2006

In state-run hospitals in India, pre-existing malnutrition and anaemia with late presentation, septicaemia and gross peritoneal contamination lead to a very high wound infection rate despite the use of systemic antibiotics. We studied the wound infection rate of subcutaneous infiltration of metronidazole (group B) versus irrigation with saline (group A) in patients undergoing exploratory laprotomy for perforation peritonitis with pyoperitoneum. The study included 30 patients in group A and 30 in group B. In group A 66.6% of the patients developed wound infection, whereas in group B 26.6% only developed wound infection. This difference is found to be statistically significant at a level of P < 0.01. There was no local complication attributable to infiltration of metronidazole in group B. Thus, we concluded that local infiltration of metronidazole at the incision is a safe and effective measure to control wound infection in cases of perforation peritonitis with pyoperitoneum.
Temporal and biological trends in liver cancers at a University hospital in Southwest Nigeria
Authors: Otegbayo J A , Oluwasola O A , Akere A , Ogunbiyi J O
Published: February 2006

The changes in incidence, sex distribution and histological profile of cancers of the liver over two decades at the University College Hospital (UCH), Ibadan, Nigeria, were studied.

There were 1234 cases of liver cancer, consisting of 876 men and 358 women, a men to women ratio of 2.4:1, and peak age incidence was between 40 and 59 years. Hepatocellular carcinoma (HCC) accounted for 92% of all cases; metastatic carcinoma was 1.78%, cholangiocarcinoma 1.2%, while combined HCC and cholangiocarcinoma was 0.24%.
Salmonella paratyphi osteomyelitis and psoas abscess
Authors: Navin Paul , Thambu David S , Venugopal R , Subhash H S , Thomas Kurien
Published: February 2006

Bone and joint infections associated with Salmonella spp account for less than 1% of all Salmonella infections. Most of the isolates are Salmonella typhi. Joint infections with S. paratyphi are uncommon, and there have been only a few reported cases in literature. Psoas abscess caused by S. paratyphi has not been reported previously in the literature. We report a case of S. paratyphi A osteomyelitis and psoas abscess.
A case control study of active genital Chlamydia trachomatis infection among patients with tubal infertility in northern Nigeria
Authors: Tukur J , Shittu S O , Abdul A M
Published: February 2006

A case-controlled study of the prevalence of genital Chlamydia trachomatis infection in 120 patients with tubal infertility (study group) and 120 clients of the family planning clinic (control group) attending the Ahmadu Bello University Teaching Hospital, Zaria in northern Nigeria is reported. The prevalence was 38.3%, 95% confidence interval (CI) (29.6-47.6%) in the study group and 13.3%, 95% CI (7.8-20.7%) in the control group. There was a fourfold risk of having genital Chlamydial infection among the cases compared to the controls (odds ratio [OR] = 4.04, 95% CI (2.04 < OR < 8.09). Tubal infertility was found to be significantly associated with genital C. trachomatis infection ( P<0.001). Out of the 58 cases of primary infertility, 22(37.9%) tested positive for genital C. trachomatis compared with 24 of the 62 (38.7%) that had secondary infertility. The infection was not found to be significantly associated with a particular type of infertility (primary or secondary), number of sexual partners or previous sexually transmitted disease ( P<0.05).

There is need for provision of facilities to enable screening for genital C. trachomatis infection in view of its high prevalence in the study population.
Comparison with the Pan Malaria IgG assays for malaria diagnosis and direct microscopy among suspected malaria patients in Sanliurfa
Authors: Ozbilge H , Kurcer M A , Dogan N , Zeyrek F
Published: February 2006

In this study, we evaluated the usage of the Pan Malaria IgG CELISA test in the diagnosis of malarial infections in Siverek-Sanliurfa, Turkey, where malarial infection is endemic and there are minimal health services available. The Pan Malaria IgG CELISA (Cellabs) test, which uses recombinant antigens and detects exposure to all four forms of malaria ( P. falciparum, P. vivax, P. ovale and P. malariae) was used as individuals. Using the consensus microscopy results as the standard, sensitivity of ELISA for detection of any malarial infection in the rural populations was 83%, specificity was 85%. These results show that the performance of ELISA for the detection of any malarial infection is adequate for acute- and post-emergency situations and rural populations when the alternative is just clinical diagnosis.
Immunocytochemical Study of Amelogenin Deposition during the Early Odontogenesis of Molars in Alendronate-treated Newborn Rats
Authors: Massa Luciana F. , Bradaschia-Correa Vivian , Arana-Chavez Victor E.
Published: February 2006

Newborn rats were treated with sodium alendronate to study how enamel is formed and the effect of alendronate during early odontogenesis. Ultrastructural analysis combined with high-resolution immunocytochemistry for amelogenin was carried out. Twelve rats were subjected to daily SC injections of sodium alendronate (2.5 mg/kg/day) for 3 days on their dorsal region, whereas three rats were daily injected with saline solution as a control. Molar tooth germs from 3-day-old rats were fixed under microwave irradiation in 0.1% glutaraldehyde + 4% formaldehyde buffered at pH 7.2 with 0.1 M sodium cacodylate. The specimens were left undecalcified, postfixed with osmium tetroxide, dehydrated, and embedded in LR White resin. Ultrathin sections were incubated with a chicken anti-24-kDa rat amelogenin antibody, a secondary antibody, and finally with a protein A-gold complex. Large patches of amelogenin were present over the unmineralized mantle dentin and at early secretory ameloblasts. At more advanced stages, they were also detected at the enamel matrix, as well as in the mineralized dentin, at the periodontoblastic space of the dentinal tubules, and at the predentin. It is likely that the main effect of alendronate at early stages of odontogenesis is the increase of synthesis/secretion of amelogenin, promoting its deposition within the forming dentin and enamel.
Tissue Expression of the Novel Serine Carboxypeptidase Scpep1
Authors: Lee Ting-Hein D. , Streb Jeffrey W. , Georger Mary A. , Miano Joseph M.
Published: February 2006

We previously identified a novel gene designated retinoid-inducible serine carboxypeptidase (RISC or Scpep1). Here we characterize a polyclonal antibody raised to Scpep1 and assess its localization in mouse cells and tissues. Western blot analysis revealed an immunospecific ∼35-kDa protein corresponding to endogenous Scpep1. This protein is smaller than the predicted ∼51-kDa, suggesting that Scpep1 is proteolytically cleaved to a mature enzyme. Immunohistochemical studies demonstrate Scpep1 expression in embryonic heart and vasculature as well as in adult aortic smooth muscle cells and endothelial cells. Scpep1 displays a broad expression pattern in adult tissues with detectable levels in epithelia of digestive tract and urinary bladder, islet of Langerhans, type II alveolar cells and macrophages of lung, macrophage-like cells of lymph nodes and spleen, Leydig cells of testis, and nerve fibers in brain and ganglia. Consistent with previous mRNA studies in kidney, Scpep1 protein is restricted to proximal convoluted tubular epithelium (PCT). Immunoelectron microscopy shows enriched Scpep1 within lysosomes of the PCT, and immunofluorescence microscopy colocalizes Scpep1 with lysosomal-associated membrane protein-2. These results suggest that Scpep1 is a widely distributed lysosomal protease requiring proteolytic cleavage for activity. The highly specific Scpep1 antibody characterized herein provides a necessary reagent for elucidating Scpep1 function.