The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation

By the end of this decade, it has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus. This epidemic of predominantly type 2 diabetes has largely been mediated by our shift toward a more sedentary lifestyle predisposing to obesity and insulin resistance. Affected individuals can also exhibit an array of associated undesirable traits such as hypertension, dyslipidemia, and hypercoagulability, leading to morbidity and mortality from atherosclerotic vascular disease. The coexistence of several of these traits with insulin resistance constitutes the metabolic syndrome. Accordingly, improving insulin sensitivity in this group, and thereby potentially ameliorating the excess vascular risk, is a primary goal of treatment. Recent interest has focused on the thiazolidinediones, a novel class of antidiabetic agents, which act as insulin sensitizers and, therefore, potentially target the underlying metabolic disturbance. These agents are high-affinity ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma, and a large body of in vitro and in vivo data has evolved to support their increasing clinical use. Importantly, clinical and laboratory findings in human subjects harboring natural mutations and polymorphisms within the receptor have provided additional insights. Here, we focus on the consequences of inherited variation in the human peroxisome proliferator-activated receptor gamma gene, linking this receptor to disordered glucose homeostasis, adipogenesis, lipid metabolism, and blood pressure regulation. These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome.     

The clinical and pathophysiologic implications of pain, ST abnormalities, and scintigraphic changes induced during dipyridamole infusion: their relationships to the peripheral hemodynamic response

In order to determine their significance during dipyridamole perfusion scintigraphy, symptomatic, ECG, and scintigraphic findings were related to each other, to the hemodynamic response, and to angiographic findings in 73 consecutive patients having coronary angiography within 3 months of scintigraphy. The group having induced "cardiac" pain differed from the group without induced pain only in their higher incidence of induced ischemic ST changes, the "marked" hemodynamic response, and their lower incidence of an "absent" hemodynamic response (all p less than 0.01). Induced ST depression was found only in patients with coronary disease. In this population, dipyridamole-induced pain was a moderately specific marker and induced ST abnormalities a more highly specific marker for coronary disease. However, both were insensitive for coronary disease diagnosis. If induced pain or ST abnormalities in the presence of significant coronary disease were accepted as indicators of ischemia, then scintigraphic abnormalities appeared to be produced by dipyridamole in roughly equal incidence by ischemic and nonischemic mechanisms. Induced ischemia related frequently to an exaggerated hypotensive response with no change in double product, suggesting its cause to be an induced increase in myocardial oxygen demand. Dipyridamole-induced image defects were noted even in the absence of a peripheral hemodynamic response. This indicates that the peripheral response does not always correlate with its central coronary effect and an absent peripheral hemodynamic response does not necessarily invalidate scintigraphic results.     

The untapped potential of Instagram to facilitate rheumatology academia

Clinical Rheumatology - Instagram allows for graphical and visual information exchange. This paper aims to explore the current landscape of rheumatology on Instagram and analyse the accounts...     

Cost effectiveness of decentralised care model for managing MDR-TB in India

Background

In India, multidrug-resistant tuberculosis (MDR-TB) patients are usually treated in hospitals. Decentralised care model, however, has been suggested as a possible alternative by the World Health Organization (WHO). In the “End TB Strategy”, the WHO highlights, as one of the key targets for 2035, that ‘no TB-affected families should face catastrophic hardship due to the tuberculosis’. Removal of financial barriers to health-care access and mitigation of catastrophic expenditures are therefore considered vital to achieve the universal health coverage (UHC) goal. Since forgoing healthcare due to the financial constraints is a known fact in India, decentralised care as an intervention choice (as against hospital-based care) might enhance equity provided it is an affordable choice. Thus, an economic evaluation was conducted, from the perspective of the national health system in India, to assess the cost-effectiveness of decentralised care compared to centralised care for MDR-TB.

Prenatal diagnosis of thyroid hormone resistance

A 29-yr-old woman with pituitary resistance to thyroid hormones (PRTH) was found to harbor a novel point mutation (T337A) on exon 9 of the thyroid hormone receptor beta (TRbeta) gene. She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3'-triiodothyroacetic acid (TRIAC) until the onset of pregnancy. This therapy was then discontinued in order to prevent TRIAC, a compound that crosses the placental barrier, from exerting adverse effects on normal fetal development. However, as the patient showed a recurrence of thyrotoxic features after TRIAC withdrawal, we sought to verify, by means of genetic analysis and hormone measurements, whether the fetus was also affected by RTH, in order to rapidly reinstitute TRIAC therapy, which could potentially be beneficial to both the mother and fetus. At 17 weeks gestation, fetal DNA was extracted from chorionic villi and was used as a template for PCR and restriction analysis together with direct sequencing of the TRbeta gene. The results indicated that the fetus was also heterozygous for the T337A mutation. Accordingly, TRIAC treatment at a dose of 2.1 mg/day was restarted at 20 weeks gestation. The mother rapidly became euthyroid, and the fetus grew normally up to 24 weeks gestation. At 29 weeks gestation mild growth retardation and fetal goiter were observed, prompting cordocentesis. Circulating fetal TSH was very high (287 mU/L) with a markedly reduced TSH bioactivity (B/I: 1.1 +/- 0.4 vs 12.7 +/- 1.2), while fetal FT4 concentrations were normal (8.7 pmol/L; normal values in age-matched fetuses: 5-22 pmol/L). Fetal FT3 levels were raised (7.1 pmol/L; normal values in age-matched fetuses: <4 pmol/L), as a consequence of 100% cross-reactivity of TRIAC in the FT3 assay method. To reduce the extremely high circulating TSH levels and fetal goiter, the dose of TRIAC was increased to 3.5 mg/day. To monitor the possible intrauterine hypothyroidism, another cordocentesis was performed at 33 weeks gestation, showing that TSH levels were reduced by 50% (from 287 to 144 mU/L). Furthermore, a simultaneous ultrasound examination revealed a clear reduction in fetal goiter. After this latter cordocentesis, acute complications occured, prompting delivery by cesarean section. The female neonate was critically ill, with multiple-organ failure and respiratory distress syndrome. In addition, a small goiter and biochemical features ofhypothyroidism were noted transiently and probably related to the prematurity of the infant. At present, the baby is clinically euthyroid, without goiter, and only exhibits biochemical features of RTH. In summary, although further fetal studies in cases of RTH are necessary to determine whether elevated TSH levels with a markedly reduced bioactivity are a common finding, our data suggest transient biochemical hypothyroidism in RTH during fetal development. Furthermore, we advocate prenatal diagnosis of RTH and adequate treatment of the disease in case of maternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy.     

The mouse Pax21Neu mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney

We describe a new mouse frameshift mutation (Pax2^1Neu) with a 1-bp insertion in the Pax2 gene. This mutation is identical to a previously described mutation in a human family with renal-coloboma syndrome [Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. & Eccles, M. R. (1995) Hum. Mol. Genet. 4, 2183–2184]. Heterozygous mutant mice exhibit defects in the kidney, the optic nerve, and retinal layer of the eye, and in homozygous mutant embryos, development of the optic nerve, metanephric kidney, and ventral regions of the inner ear is severely affected. In addition, we observe a deletion of the cerebellum and the posterior mesencephalon in homozygous mutant embryos demonstrating that, in contrast to mutations in Pax5, which is also expressed early in the mid-hindbrain region, loss of Pax2 gene function alone results in the early loss of the mid-hindbrain region. The mid-hindbrain phenotype is similar to Wnt1 and En1 mutant phenotypes, suggesting the conservation of gene regulatory networks between vertebrates and Drosophila.