Alternate pathways of thyroid hormone metabolism.

The major thyroid hormone (TH) secreted by the thyroid gland is thyroxine (T(4)). Triiodothyronine (T(3)), formed chiefly by deiodination of T(4), is the active hormone at the nuclear receptor, and it is generally accepted that deiodination is the major pathway regulating T(3) bioavailability in mammalian tissues. The alternate pathways, sulfation and glucuronidation of the phenolic hydroxyl group of iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage provide additional mechanisms for regulating the supply of active hormone. Sulfation may play a general role in regulation of iodothyronine metabolism, since sulfation of T(4) and T(3) markedly accelerates deiodination to the inactive metabolites, reverse triiodothyronine (rT(3)) and T(2). Sulfoconjugation is prominent during intrauterine development, particularly in the precocial species in the last trimester including humans and sheep, where it may serve both to regulate the supply of T(3), via sulfation followed by deiodination, and to facilitate maternal-fetal exchange of sulfated iodothyronines (e.g., 3,3'-diiodothyronine sulfate [T(2)S]). The resulting low serum T(3) may be important for normal fetal development in the late gestation. The possibility that T(2)S or its derivative, transferred from the fetus and appearing in maternal serum or urine, can serve as a marker of fetal thyroid function is being studied. Glucuronidation of TH often precedes biliary-fecal excretion of hormone. In rats, stimulation of glucuronidation by various drugs and toxins may lead to lower T(4) and T(3) levels, provocation of thyrotropin (TSH) secretion, and goiter. In man, drug induced stimulation of glucuronidation is limited to T(4), and does not usually compromise normal thyroid function. However, in hypothyroid subjects, higher doses of TH may be required to maintain euthyroidism when these drugs are given. In addition, glucuronidates and sulfated iodothyronines can be hydrolyzed to their precursors in gastrointestinal tract and various tissues. Thus, these conjugates can serve as a reservoir for biologically active iodothyronines (e.g., T(4), T(3), or T(2)). The acetic acid derivatives of T(4), tetrac and triac, are minor products in normal thyroid physiology. However, triac has a different pattern of receptor affinity than T(3), binding preferentially to the beta receptor. This makes it useful in the treatment of the syndrome of resistance to thyroid hormone action, where the typical mutation affects only the beta receptor. Thus, adequate binding to certain mutated beta receptors can be achieved without excessive stimulation of alpha receptors, which predominate in the heart. Ether link cleavage of TH is also a minor pathway in normal subjects. However, this pathway may become important during infections, when augmented TH breakdown by ether-link cleavage (ELC) may assist in bactericidal activity. There is a recent claim that decarboxylated derivates of thyronines, that is, monoiodothyronamine (T(1)am) and thyronamine (T(0)am), may be biologically important and have actions different from those of TH. Further information on these interesting derivatives is awaited.     

Vertical reduction mammaplasty utilizing the superomedial pedicle: is it really for everyone?

Background: Classically, the vertical-style reduction mammaplasty utilizing a superomedial pedicle has been limited to smaller reductions secondary to concerns for poor wound healing and nipple necrosis. Objectives: The authors reviewed a large cohort of patients who underwent a vertical-style superomedial pedicle reduction mammaplasty in an attempt to demonstrate its safety and efficacy in treating symptomatic macromastia. Methods: A retrospective review was performed of 290 patients (558 breasts) who underwent a vertical-style superomedial pedicle reduction mammaplasty. All procedures were conducted by one of 4 plastic surgeons over 6 years (JDR, MAA, DLV, DRA). Results: The average resection weight was 551.7 g (range, 176-1827 g), with 4.6% of resections greater than 1000 g. A majority of patients (55.2%) concomitantly underwent liposuction of the breast. The total complication rate was 22.7%, with superficial dehiscence (8.8%) and hypertrophic scarring (8.8%) comprising the majority. Nipple sensory changes occurred in 1.6% of breasts, with no episodes of nipple necrosis. The revision rate was 2.2%. Patients with complications had significantly higher resection volumes and nipple-to-fold distances (P = .014 and .010, respectively). Conclusions: The vertical-style superomedial pedicle reduction mammaplasty is safe and effective for a wide range of symptomatic macromastia. The nipple-areola complex can be safely transposed, even in patients with larger degrees of macromastia, with no episodes of nipple necrosis. The adjunctive use of liposuction should be considered safe. Last, revision rates were low, correlating with a high level of patient satisfaction.     

Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen alpha-chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for 2 mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Coexpression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant beta chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation.     

Change in Visceral Adiposity Independently Predicts a Greater Risk of Developing Type 2 Diabetes Over 10 Years in Japanese Americans

OBJECTIVE

—Visceral adiposity is an important risk factor for cardiovascular disease and type 2 diabetes. We sought to determine whether change in intraabdominal fat area (IAF) over time predicts subsequent development of diabetes.

RESEARCH DESIGN AND METHODS

—We followed up 436 nondiabetic Japanese-American subjects (mean age 51.9 years, mean BMI 24.2 kg/m², 54% male) for development of diabetes. We fit a logistic regression model to examine the association over a 10-year follow-up between change in IAF at 5-year follow-up and other fat areas (measured by computed tomography) and development of incident diabetes, adjusted for age, sex, family history of diabetes in a first-degree relative, second-generation versus third-generation Japanese American (Nisei vs. Sansei), baseline IAF, BMI, weight change over time, smoking status, physical activity level, and subcutaneous fat (SCF) depot areas.

RESULTS

—Cumulative incidence of diabetes was 20.4% at 10 years. Mean change in IAF was 10.9 cm². An increase of 1 SD in IAF was associated with a 1.65-fold increase in the odds of diabetes over 10 years (OR = 1.65, 95% CI 1.21–2.25) after adjusting for the above covariates. This association was also independent of changes in thoracic, thigh, and abdominal SCF, as well as change in weight.

CONCLUSIONS

—We conclude that baseline IAF and accumulation of fat in this area over time are independent predictors of the development of type 2 diabetes in Japanese Americans.Central obesity is well established as an independent risk factor for type 2 diabetes. This association is strong and has been demonstrated in cross-sectional and longitudinal analyses with a number of different metrics, including surface measurements such as waist circumference and waist-to-hip ratio in a variety of populations (1,2), and imaging of the visceral fat depot. A higher risk of incident type 2 diabetes over 5 to 10 years of follow-up was associated with larger baseline visceral fat area measured using single-slice computed tomography (CT) scans in Japanese Americans (3).The association between change in regional or overall adiposity and risk of diabetes is less clear with a smaller number of investigations reported and inconsistent results. Several investigations document a higher prevalence of diabetes with greater duration of overweight or obesity (4), and an obesity-years metric was recently proposed to refer to this phenomenon (5) in relation to mortality. Measurements at baseline may reflect size of adipose depots over a number of years, whereas recent change in depot size might be expected to have less influence on health outcomes because of a shorter exposure period. A number of studies have investigated recent weight change in relation to diabetes risk, finding it to be inconsistently associated, whereas baseline adiposity is consistently associated with this outcome (6). Although studies of diabetes risk have been performed in relation to weight change that presumably reflects change in overall adiposity, to our knowledge only one observational study has examined increase in regional adiposity as measured by waist circumference in relation to diabetes risk; that study found an independent association even after adjusting for weight gain (7). To our knowledge, no observational research has examined whether increase in size of a directly measured fat depot (visceral or otherwise) is associated with diabetes risk. In a substudy of the Diabetes Prevention Program (a randomized trial of diabetes prevention in persons identified as being at high risk for this outcome based on elevated levels of fasting and 2-h plasma glucose), diabetes risk was assessed in relation to a decrease in CT-measured fat depots over a brief 1-year period. In that intervention, a decline in body fat depot size over the first year was shown to predict diabetes risk over a subsequent mean 1.5 years of follow-up (8). In addition, a randomized clinical trial in Japanese Americans examined whether lifestyle changes improved measurements of adiposity in individuals with impaired glucose tolerance. In that trial, the treatment arm showed significantly greater reduction in percent body fat, BMI, and CT-measured subcutaneous fat (SCF) depots at six and 24 months, with at least one occurrence of a normal oral glucose tolerance test occurring significantly more frequently in the intervention arm during follow-up. Both treatment arms, however, showed similar decreases in intraabdominal fat area (IAF) (9).Given the paucity of information on the effects of change in size of regional adipose depots in general and the visceral depot in particular in relation to diabetes risk, we investigated the association between 5-year change in CT-measured adipose depots and diabetes occurrence over 10 years in a prospective study of Japanese Americans.     

Effects of combined estrogen and progesterone on brain infarction in reproductively senescent female rats.

Recent data from the Women's Health Initiative have highlighted many fundamental issues about the utility and safety of long-term estrogen use in women. Current hormone replacement therapy for postmenopausal women incorporates progestin with estrogen, but it is uncertain if combined therapy provides major cerebrovascular risks or benefits to these women. No experimental animal stroke studies have examined combined hormone administration. The authors tested the hypothesis that combined hormone treatment reduces ischemic injury in middle-aged female rat brain. Reproductively senescent female rats underwent 2-hour middle cerebral artery occlusion (MCAO) followed by 22 hours reperfusion. Estrogen implants were placed subcutaneously at least 7 days before MCAO, and progesterone intraperitoneal injections were given 30 minutes before MCAO, at initiation, and at 6 hours of reperfusion. Rats received no hormone, a 25-microg estrogen implant, a 25-microg estrogen implant plus 5 mg/kg intraperitoneal progesterone, or 5 mg/kg intraperitoneal progesterone. Cortical, caudoputamen, and total infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis at 22 hours reperfusion. Cortical and total infarct volumes, except in the acute progesterone-treated group, were significantly attenuated in all estrogen-alone and combined hormone-treated groups. There were no significant differences in caudoputamen infarct volumes in all hormone-treated groups as compared with untreated rats. These data have potential clinical implications relative to stroke for postmenopausal women taking combined hormone replacement therapy.     

Availability of School Health Services for Young Children

ABSTRACT: A survey to assess availability of school health services was distributed to 221 directors of Schools of the 21st Century, an educational model that provides integrated services to children and families. Of this distribution, 126 (57%) surveys were returned; 88% of respondents reported they provided some type of school health services for their students; 75% of schools had access to school nursing services, yet only 33% had a school nurse on-site; 50% had less than daily access to a school nurse. Despite a high reported prevalence of physical and mental health problems, other services such as acute care, nutrition counseling, dental screenings, or mental health services were provided less frequently. Barriers perceived as problematic for schools providing health services included inadequate funding, limited parental awareness, and opposition by school or community members. Respondents believed transportation, limited financial resources, and inadequate health insurance were barriers to care for children and families. Among this sample of schools, school health services varied in availability and comprehensiveness. Educators, health providers, and parents must work together to provide improved school health services for children. (J Sch Health. 1997;67(8):327–332)