A novel missense mutation in human TTF-2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis.

BACKGROUND: Thyroid dysgenesis is the most frequent cause of congenital hypothyroidism (CH), and its genetic basis is largely unknown. Hitherto, two mutations in the human thyroid transcription factor 2 (TTF-2) gene have been described in unrelated cases of CH with cleft palate, spiky hair, variable choanal atresia, and complete thyroid agenesis. Here, we describe a novel TTF-2 mutation in a female child resulting in syndromic CH in the absence of thyroid agenesis. RESULTS: The index case is homozygous for an arginine to cysteine mutation (R102C) of a highly conserved residue within the forkhead, DNA binding domain of TTF-2. Her consanguineous, heterozygous parents are unaffected, and the mutation was not detected in 100 control chromosomes. Consonant with its location, the R102C mutant TTF-2 protein showed loss of DNA binding and was transcriptionally inactive. CH in the proposita was associated with cleft palate, spiky hair, and bilateral choanal atresia. However, radiological studies showed the presence of thyroid tissue in a eutopic location. CONCLUSION: Our findings indicate that human thyroid development can occur despite loss of TTF-2 function and suggest that TTF-2 gene defects should also be considered in cases of syndromic CH without total athyreosis.

Elevated plasma adiponectin in humans with genetically defective insulin receptors.

CONTEXT: Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity. OBJECTIVE: The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance. DESIGN/SETTING: This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States. PARTICIPANTS: Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls. OUTCOME MEASURES: Fasting plasma insulin, adiponectin, and leptin were measured. RESULTS: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6-36.6 (normal adult range for body mass index 20 kg/m(2) = 3-19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12-11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0-16: normal adult range for body mass index of < 25 kg/m(2) = 2.4-24.4 (female) and 0.4-8.3 ng/ml (male)]. CONCLUSIONS: We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.

Cimetidine therapy in nonsteroidal anti-inflammatory drug gastropathy. Double-blind long-term evaluation.

To assess the efficacy of cimetidine in treating and preventing gastric mucosal lesions associated with nonsteroidal anti-inflammatory drug (NSAID) therapy (NSAID gastropathy), we endoscopically studied 104 patients taking NSAIDs for a variety of rheumatic diseases. Fifty-six percent (22/43) of patients randomized to cimetidine 300 mg four times a day and 52% (22/42) of those randomized to placebo showed progression of endoscopic lesions during the eight-week short-term phase. Thirty-nine patients whose endoscopic lesions improved were then randomized to a ten-month maintenance regimen of either cimetidine 400 mg at bedtime or placebo. Fifty percent (7/14) of placebo-treated and 42% (5/12) of cimetidine-treated patients showed progression of lesions during the maintenance phase. The failure of cimetidine to offer any significant benefit under these protocol conditions reflects the fundamental difference in pathophysiologic features between classic acid-mediated ulcer disease and NSAID gastropathy.

Bronchial reactivity of healthy subjects: 18-20 h postexposure to ozone.

Exposure of humans to ambient levels of ozone (O(3)) causes inflammatory changes within lung tissues. These changes have been reported for the "initial" (1- to 3-h) and "late" (18- to 20-h) postexposure periods. We hypothesized that at the late period, when protein and cellular markers of inflammation at the airway surface remain abnormal and the integrity of the epithelial barrier is compromised, bronchial reactivity would be increased. To test this, we measured airway responsiveness to cumulative doses of methacholine (MCh) aerosol in healthy subjects 19+/-1 h after a single exposure to O(3) (130 min at ambient levels between 120 and 240 parts/billion and alternate periods of rest and moderate exercise) or filtered air. Exposures were conducted at two temperatures: mild (22 degrees C) and moderate (30 degrees C). At the late period, bronchial reactivity to MCh increased, i.e., interpolated dose of MCh leading to a 50% fall in specific airway conductance (PC(50)) was less after O(3) than after filtered air. PC(50) for O(3) at 22 degrees C was 27 mg/ml (20% less than the PC(50) after filtered air), and for O(3) at 30 degrees C it was 19 mg/ml (70% less than the PC(50) after filtered air). The forced expiratory volume in 1 s (FEV(1)) at the late time point after O(3) was slightly but significantly reduced (2.3%) from the preexposure level. There was no relationship found between the functional changes observed early after exposure to O(3) and subsequent changes in bronchial reactivity or FEV(1) at the late time point. These results suggest that bronchial reactivity is significantly altered approximately 1 day after O(3); this injury may contribute to the respiratory morbidity that is observed 1-2 days after an episode of ambient air pollution.

Interventions for the primary prevention of work-related carpal tunnel syndrome.

OBJECTIVE: To evaluate interventions for the primary prevention of work-related carpal tunnel syndrome (CTS). SELECTION CRITERIA: Studies had to include an engineering, administrative, personal, or multiple component intervention applied to a working or working-age population. All study designs that included comparison data were considered. Outcome measures included the incidence, symptoms, or risk factors for CTS, or a work-related musculoskeletal disorder of the upper extremity that included CTS in the definition. RESULTS: Twenty-four studies met our inclusion criteria. Engineering interventions included alternative keyboards, computer mouse designs and wrist supports, keyboard support systems, and tool redesign. Personal interventions included ergonomics training, splint wearing, electromyographic biofeedback, and on-the-job exercise programs. Multiple component interventions (e.g., ergonomic programs) included workstation redesign, establishment of an ergonomics task force, job rotation, ergonomics training, and restricted duty provisions. Multiple component programs were associated with reduced incidence rates of CTS, but the results are inconclusive because they did not adequately control for potential confounders. Several engineering interventions positively influenced risk factors associated with CTS, but the evaluations did not measure disease incidence. None of the personal interventions alone was associated with significant changes in symptoms or risk factors. All of the studies had important methodologic limitations that may affect the validity of the results. CONCLUSIONS: While results from several studies suggest that multiple component ergonomics programs, alternative keyboard supports, and mouse and tool redesign may be beneficial, none of the studies conclusively demonstrates that the interventions would result in the primary prevention of carpal tunnel syndrome in a working population. Given the societal impact of CTS, the growing number of commercial remedies, and their lack of demonstrated effec- tiveness, the need for more rigorous and long-term evaluation of interventions is clear. Fund- ing for intervention research should prioritize randomized controlled trials that include: (1) adequate sample size, (2) adjustment for relevant confounding variables, (3) isolation of speci- fic program elements, and (4) measurement of long-term primary outcomes such as the inci- dence of CTS, and secondary outcomes such as employment status and cost.

MR imaging of the brain in patients with migraine headaches.

Forty-one patients with migraine headaches were referred for MR imaging of the brain. Intermediate and T2-weighted images were obtained to determine the frequency of areas of high intensity within the white matter. The average age of these patients was 29.8 years; only five were over 40 years old. Each patient was evaluated in the axial plane with long TR/short and long TE images. Twenty-three patients also had T1-weighted short TR/short TE MR scans; enhancement with gadopentetate dimeglumine was used in three patients. Intracranial abnormalities were seen in only six patients: foci or white matter high intensity on intermediate and T2-weighted images in five and a venous angioma in one. Prior studies have indicated that parenchymal brain abnormalities may be found in up to 46% of patients with migraines. The current study demonstrated parenchymal brain lesions in only 12%. This study suggests that the frequency of foci of high intensity seen on long TR sequences in the migraine patient is much lower than previously reported, especially in patients under 40 years old (5.5% in our series).

Artificial intelligence and Bayesian decision theory in the prediction of chemical carcinogens.

Two procedures for predicting the carcinogenicity of chemicals are described. One of these (CASE) is a self-learning artificial intelligence system that automatically recognizes activating and/or deactivating structural subunits of candidate chemicals and uses this to determine the probability that the test chemical is or is not a carcinogen. If the chemical is predicted to be carcinogen, CASE also projects its probable potency. The second procedure (CPBS) uses Bayesian decision theory to predict the potential carcinogenicity of chemicals based upon the results of batteries of short-term assays. CPBS is useful even if the test results are mixed (i.e. both positive and negative responses are obtained in different genotoxic assays). CPBS can also be used to identify highly predictive as well as cost-effective batteries of assays. For illustrative purposes the ability of CASE and CPBS to predict the carcinogenicity of a carcinogenic and a non-carcinogenic polycyclic aromatic hydrocarbon is shown. The potential for using the two methods in tandem to increase reliability and decrease cost is presented.

Clinical evaluation of 58 organolead manufacturing workers.

Fifty-eight workers were evaluated at a university-based occupational health clinic for potential health effects related to organic and inorganic lead exposures. The clinical evaluation included a history, physical, and laboratory examination, and in a subset of workers, neurobehavioral tests and nerve conduction studies. Workers reported symptoms that predominantly involved the central and peripheral nervous systems. Findings for which no alternative medical explanations could be found included neurobehavioral abnormalities (18 of 39 workers) and sensorimotor polyneuropathies (11 of 31 workers). The clinical presentation and evaluation of workers exposed to organic lead are discussed.

Application of an injury surveillance system to injuries at an industrial facility.

We developed a computerized surveillance database employing the Abbreviated Injury Scale (AIS) and sampled three months of nonfatal injuries at a large industrial facility. Data from 197 injury visits to the plant medical department were collected. With the addition of some new AIS codes for injuries specific to the workplace, most injuries could be coded and severity scores calculated with good interrater reliability. Neither Maximum AIS nor Injury Severity Score (ISS) predicted restricted or lost work time. Because of its ease of automation and reliability, the AIS can serve as a useful tool for occupational injury surveillance, but its current severity scoring system is not predictive of disability.

Vertex hemangioma mimicking an encephalocele.

Most extracranial masses detected prenatally by use of ultrasonography are either encephaloceles or meningoceles. This article describes an extracranial mass detected prenatally that was initially thought to be an encephalocele, but was subsequently found to be a large hemangioma.

Colon carcinoma discovered in an adolescent during inguinal hernia repair.

Colon carcinoma is an unusual tumor during childhood. The authors report a case of metastatic colonic adenocarcinoma diagnosed in a 14-year-old boy during inguinal hernia repair. To the authors' knowledge, this is the first reported case of this rare disease presenting as an inguinal hernia.

Magnetic resonance imaging of Takayasu's aortitis in an infant.

A fusiform aneurysm involving the ascending aorta and aortic arch in an 8-month-old infant was imaged with magnetic resonance. Histologic studies of the excised aneurysm indicated Takayasu's arteritis. Takayasu's arteritis has rarely been reported in infants, and involvement of the ascending aorta and aortic arch is an unusual finding in this age group.

Evaluating occupational health and safety programs in the public sector.

BACKGROUND: Two case studies are presented of public sector occupational health and safety (OHS) program evaluations, one of an occupational medicine and safety program (OMSP), one of an employee assistance and wellness program (EAWP). METHODS: Both audits involved interviews with key personnel, review of written documentation and physical resources, chart audits, and surveys of the programs' stakeholders. RESULTS: Key findings of the OMSP evaluation were that the various functions were substantially hampered by the absence of an integrated information system. Mechanisms for effective coordination, communication, and feedback were also lacking. The EAWP audit concluded that it provided a valuable and needed service. The mission, staff, facilities, and services offered were in line with the needs of the served community. DISCUSSION: Differences between private and public sector OHS program evaluation include programmatic and environmental factors such as resource availability, organizational structure, and accountability. Similarities include trends in both sectors forcing programs to justify themselves in terms of economic benefits to their respective organizations.

Outcome studies in industry: cost-effectiveness of cumulative trauma disorder prevention.

Cost-effectiveness analysis (CEA) is a method for choosing between alternative strategies to achieve a specified outcome in an environment of limited resources. This paper discusses the use of CEA in evaluating prevention strategies in industrial settings, using cumulative trauma disorder (CTD) prevention programs as an example. Methodologic issues in designing studies of cost-effectiveness for preventive interventions are discussed. A decision analysis model of a CTD prevention program is described as a means of studying the program's cost-effectiveness. The relationship between CEA and outcomes research, and the strengths and limitations of CEA in evaluating occupational health prevention programs is considered.

Noninvasive botryoid extension of Wilms' tumor into the bladder.

We present the previously unreported CT appearance of a Wilms' tumor which extended down the ureter and protruded into the bladder as a botryoid mass. The tumor apparently arose from an intralobar nephrogenic rest and demonstrated local invasion into renal sinus vessels and papillae. There was no tumor invasion into the wall of the ureter or bladder, and therefore, the extension into the ureter and bladder did not upstage the tumor. This report adds to the list of differential diagnoses of a botryoid bladder mass in a child and demonstrates yet another unusual manifestation of Wilms' tumor.

Orofacial abscesses of odontogenic origin in the pediatric patient. Report of two cases.

Odontogenic infections rarely spread beyond the periapical space. Occasionally spread of infection into contiguous anatomic areas occurs through bone, fascial or muscular barriers. Two cases of orofacial abscess of odontogenic origin in the pediatric patient are presented, one imaged with CT and the other with MRI. Both abscesses involved the deep and superficial tissues of the face. Additionally, one of the abscesses extended into the orbit and the other involved the preseptal soft tissue. The pathogenesis, mechanism of spread and management of the disease are discussed.