Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system

Thyroid hormone receptors (TRs) modulate various physiological functions in many organ systems. The TR alpha and TR beta isoforms are products of 2 distinct genes, and the beta 1 and beta 2 isoforms are splice variants of the same gene. Whereas TR alpha 1 and TR beta 1 are widely expressed, expression of the TR beta 2 isoform is mainly limited to the pituitary, triiodothyronine-responsive TRH neurons, the developing inner ear, and the retina. Mice with targeted disruption of the entire TR beta locus (TR beta-null) exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss. To clarify the contribution of the TR beta 2 isoform to the function of the endocrine and auditory systems in vivo, we have generated mice with targeted disruption of the TR beta 2 isoform. TR beta 2-null mice have preserved expression of the TR alpha and TR beta 1 isoforms. They develop a similar degree of central resistance to thyroid hormone as TR beta-null mice, indicating the important role of TR beta 2 in the regulation of the hypothalamic-pituitary-thyroid axis. Growth hormone gene expression is marginally reduced. In contrast, TR beta 2-null mice exhibit no evidence of hearing impairment, indicating that TR beta 1 and TR beta 2 subserve divergent roles in the regulation of auditory function.     

Inhibition of polymorphonuclear leukocyte chemotaxis byα-macrofetoprotein,an acute-phase reactant of the rat

-Macrofetoprotein (_MFP) is a normal fetal plasma constituent in the rat, with very low plasma levels in the adult phase but rising sharply after injury. This fetal acute-phase protein is a strong inhibitor of inflammatory edema. Fetal inflammatory reactions show diminished exudation, but also impaired emigration of polymorph nuclear cells (PMNs). Therefore we studied the effect of (_MFP on chemotaxis of PMN in vitro and in vivo. In vitro experiments showed a strong inhibitory effect on casein-induced leukotaxis (Boyden technique) with a clear dose-effect relationship. In vivo with glycogen-induced pleurisy and peritonitis, high (_MFP levels are accompanied by diminished PMN emigration and vice versa. The significance of these findings is discussed in relation to fetal pathology and also as a model showing the modulating effects of acute-phase proteins on the inflammatory reaction induced by tissue injury.     

At what age could screening for familial retinoblastoma be stopped? A register based study 1945-98

AIM: To evaluate until what age children in families with retinoblastoma should be screened. METHODS: A register based cohort (n= 685) study of Dutch retinoblastoma patients (1945-1998). The records of all familial hereditary retinoblastoma patients from 1945 were reviewed and the age at diagnosis and either they were screened from birth determined. RESULTS: 75 patients had the familial hereditary form of retinoblastoma. The mean age at diagnosis in patients with fundus screening (n=50) from birth on was 4.9 months (median 1.9 months; range 1 day to 48 months). Thus, 4 years was the latest onset of familial retinoblastoma properly evaluated from birth. This mean age was significantly different (p<0.0001) from the mean age at diagnosis in patients without fundus screening (n=25) from birth (mean 17.2 months; median 10.0 months; range 1.5-63.0 months). CONCLUSIONS: Ophthalmological screening of children and sibs at risk for familial hereditary retinoblastoma is recommended until the age of 4 years in order to detect retinoblastoma as early as possible.     

HIV-2-infected individuals with undetectable plasma viremia carry replication-competent virus in peripheral blood lymphocytes

Using an optimized HIV co-culture protocol it was possible to isolate infectious HIV-2 variants from 6 HIV-2-infected individuals who had undetectable plasma viremia and maintained high CD4 T-cell numbers for prolonged periods. This shows for the first time that HIV-2-infected individuals with no demonstrable in vivo virus production carry replication-competent virus in peripheral blood mononuclear cells (PBMCs). The frequency of PBMCs with infectious virus was low, ranging from 0.01-0.9 infectious units per million (IUPM) CD4 T cells with a median value of 0.2 IUPM. In comparison, viremic HIV-2-infected individuals had a 2-log higher median infectious load (36 IUPM, range 1-673; P = 0.003). HIV-2 infectious load correlated with CD4 counts (rs = -0.88, P < 0.0001). The low infectious load in aviremic HIV-2-infected persons is reminiscent of what has been observed for HIV-1 infection controlled by highly active antiretroviral therapy.     

Renal disorders in rheumatoid arthritis

Renal disorders are a frequent cause of death in patients with rheumatoid arthritis (RA), but are less apparent in living RA patients. In part, this may be because of insensitive screening methods. In this review, some of the relations among renal pathology, renal function, and antirheumatic therapy are clarified. A classification of renal disorders according to etiology is proposed. Two categories of disorders are distinguished: those related to RA and its complications, and those related to drug therapy. The disorders belonging to these categories are reviewed. Finally, a case is made for the existence of a third category, "RA nephropathy." It is hypothesized that this mild and nonspecific nephropathy is the result of cumulative minor insults caused by the disease and its therapy. The presence of such a "subclinical" nephropathy would explain the greater sensitivity of RA patients to other renal insults, and the high prevalence of renal failure at death.