The incorporation of iodine in thyroid hormone may stem from its role as a prehistoric signal of ecologic opportunity: an evolutionary perspective and implications for modern diseases

To optimize fitness under conditions of varying Darwinian opportunity, organisms demonstrate tremendous plasticity in their life-history strategies based on their perception of available resources. Higher-energy environments generally promote more aggressive life-history strategies, such as faster growth, larger adult size, greater genetic variation, shorter lifespan, larger brood sizes, and offspring ratio skewed towards the larger-sized gender. While numerous mechanisms regulate life-history plasticity including genetic imprinting, methylation, and growth factors, evidence suggests that thyroid hormone plays a central role. Given the pivotal adaptive role of thyroid hormone, the teleology of its dependence on dietary iodine for production remains unexplained. We hypothesize that iodine may have emerged as a substrate for production of thyroid hormone in prehistoric ecosystems because the former represented a reliable proxy for ecologic potential that enabled the latter to modulate growth, reproduction, metabolic rate, and lifespan. Such a scenario may have existed in early marine ecosystems where ocean-surface vegetation, which concentrates iodine for its antimicrobial and antioxidant properties, formed the basis of the food chain. Teleologic parallels can be drawn to the food-chain accumulation of antimicrobials that also exhibit antioxidant properties and promote adult size, brood size, and offspring quality by modulating central hormonal axes. As each higher species in the food chain tunes its life-history strategy based on iodine intake, the coupling of this functional role of iodine with its value as a resource signal to the next member of the food-chain may promote runaway evolution. Whereas predators in prehistoric ecosystems successfully tuned their life-history strategy using iodine as a major input, the strategy may prove maladaptive in modern humans for whom the pattern of iodine intake is decoupled from resource availability. Iodine acquired through sodium iodide supplementation may independently contribute to some biologic dysfunctions currently attributed to sodium.     

Gene expression of connective tissue growth factor in adult mouse

The connective tissue growth factor (CTGF) is a well-known fibroblast mitogen and angiogenic factor that plays an important role in bone formation during embryogenesis. In the adult, CTGF is involved in wound healing as well as fibrotic and vascular disease. However, little is known about its physiological functions under non-pathological conditions in the adult organism. Here, we describe the cellular site of the CTGF mRNA expression in adult male and female mice as revealed by in situ hybridization histochemistry. Strong and persistent CTGF gene expression was particularly prominent in the mesenchyme of the cardiovascular system (aorta, auricular tissue, renal glomeruli), the mesenchyme surrounding the ovarian follicles or the testicular tubes in the gonadal tissue, and the subcapsular mesenchyme bordering densely innervated parts of whisker hair vibrissae. CTGF hybridization signals were not observed in the mesenchyme of many other organs including gut, muscle, liver or most parts of the lymphatic tissue. Strong expression was also present in the primary (early) ovarian follicles, the epithelium of the deep uterine glands and on myenteric ganglia neurons. These data suggest a selective and continuous mesenchymal function in the gonads and those tissues attracting very strong vascular supply or peripheral innervation. CTGF may also be involved in the cyclical proliferation of the uterine gland epithelium and in the early stages of follicular maturation, as well as in the neuropeptide regulation in the gut, cardiovascular and renal systems.     

Interaction of Blastomyces dermatitidis, Sporothrix schenckii, and Histoplasma capsulatum with Acanthamoeba castellanii

Several dimorphic fungi are important human pathogens, but the origin and maintenance of virulence in these organisms is enigmatic, since an interaction with a mammalian host is not a requisite for fungal survival. Recently, Cryptococcus neoformans was shown to interact with macrophages, slime molds, and amoebae in a similar manner, suggesting that fungal pathogenic strategies may arise from environmental interactions with phagocytic microorganisms. In this study, we examined the interactions of three dimorphic fungi with the soil amoeba Acanthameobae castellanii. Yeast forms of Blastomyces dermatitidis, Sporothrix schenckii, and Histoplasma capsulatum were each ingested by amoebae and macrophages, and phagocytosis of yeast cells resulted in amoeba death and fungal growth. H. capsulatum conidia were also cytotoxic to amoebae. For each fungal species, exposure of yeast cells to amoebae resulted in an increase in hyphal cells. Exposure of an avirulent laboratory strain of H. capsulatum to A. castellanii selected for, or induced, a phenotype of H. capsulatum that caused a persistent murine lung infection. These results are consistent with the view that soil amoebae may contribute to the selection and maintenance of certain traits in pathogenic dimorphic fungi that confer on these microbes the capacity for virulence in mammals.     

Age-related loss of synaptophysin immunoreactive presynaptic boutons within the hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L transgenic mice

Neuron and synapse loss are important features of the neuropathology of Alzheimer's disease (AD). Recently, we observed substantial age-related hippocampal neuron loss in APP751SL/PS1M146L transgenic mice but not in PS1M146L mice. Here, we investigated APP751SL mice, PS1M146L mice, and APP751SL/PS1M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1-2 (SR) by analyzing densities and numbers of synaptophysin-immunoreactive presynaptic boutons (SIPBs). Wild-type mice, APP751SL mice and PS1M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751SL mice and PS1M146L mice showed age-related SIPB loss within SR. Importantly, APP751SL/PS1M146L) mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular Abeta deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. The observation of age-related SIPB loss within SR of PS1M146L mice supports a role of mutant PS1 in neurodegeneration apart from its contribution to alterations in Abeta generation.     

Physicians' weight loss counseling in two public hospital primary care clinics.

PURPOSE: Primary care physicians are an important source of information on weight management. Nevertheless, weight loss counseling by these physicians remains inadequate. This study sought to determine physicians' barriers to providing weight loss counseling in a public hospital, patients' recall of physicians' weight loss recommendations, and the influence of physicians' counseling on patients' understanding, motivation, and behavior regarding weight loss. METHOD: In 2001, four focus groups of faculty and residents were held at two primary care clinics affiliated with the Louisiana State University Health Sciences Center-Shreveport to determine the barriers to providing weight loss counseling. Scripted probes were used to uncover consensus norms. In 2001-02, structured exit interviews were conducted with 210 overweight or obese patients recruited from the clinics to determine patients' recall of physicians' weight loss recommendations, and patients' understanding of the relationship between weight and health, and their stages of readiness for weight loss. RESULTS: Physicians identified major barriers to providing weight loss counseling, including insufficient confidence, knowledge, and skills. Obesity was underdocumented as a distinct clinical diagnosis. Only 5% of the patients recalled being given the combined weight loss strategy of diet and exercise. However, patients who recalled being counseled to lose weight were more likely to understand the risks of obesity, the benefits of weight loss, and were at a higher stage of readiness for weight loss. CONCLUSIONS: Physicians' weight loss counseling had a significant effect on patients' understanding of and motivation for weight loss. However, physicians provided insufficient guidance on weight management strategies, possibly because of inadequate counseling skills and confidence.     

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

The Williams-Beuren syndrome (WBS) is a complex developmental disorder with multisystemic manifestations including supravalvular aortic stenosis (SVAS), a so-called elfin face, a hoarse voice, and a specific cognitive phenotype. Most WBS patients have a >1 Mb deletion on one of their chromosomes 7 in q11 but except for elastin, whose haploinsufficiency causes the cardiovascular malformations, it is unknown which genes in the deletion area contribute to the phenotype. We have investigated a family with a cytogenetically balanced translocation t(7;16)(q11.23;q13) in which affected individuals manifested a broad spectrum of clinical phenotypes ranging from a hoarse voice as the only feature to the full WBS phenotype. Molecular cytogenetic and DNA sequence analyses of the translocation breakpoint showed that the cytogenetic rearrangement disrupts the elastin gene locus within intron 5 in the exact same manner in all translocation carriers. The recently described large inversion of the 7q11.23 region was not present in this family. Our data demonstrate that disruption of the elastin gene by a translocation breakpoint may cause classical WBS, atypical WBS, SVAS, or no recognisable phenotype, and provide a clear example for extensive phenotypic variability associated with a position effect in humans.     

GJB2: the spectrum of deafness-causing allele variants and their phenotype

Genetic testing was completed on 1,294 persons with deafness referred to the Molecular Otolaryngology Research Laboratories to establish a diagnosis of DFNB1. Exon 2 of GJB2 was screened for coding sequence allele variants by denaturing high-performance liquid chromatography (DHPLC) complemented by bidirectional sequencing. If two deafness-causing mutations of GJB2 (encoding Connexin 26) were identified, further screening was not performed. If only a single deafness-causing mutation was identified, we screened for the g.1777179_2085947del (hereafter called del(GJB6-D13S1830); GenBank NT_024524.13) and mutations in the noncoding region of GJB2. Phenotype-genotype correlations were evaluated by categorizing mutations as either protein truncating or nontruncating. A total of 205 persons carried two GJB2 exon 2 mutations and were diagnosed as having DFNB1; 100 persons carried only a single deafness-causing allele variant of exon 2. A total of 37 of these persons were c.35delG carriers, and 51 carried other allele variants of GJB2. Persons diagnosed with DFNB1 segregating two truncating/nonsense mutations had a more severe phenotype than persons carrying two missense mutations, with mean hearing impairments being 88 and 37%, respectively (P < 0.05). The number of deaf c.35delG carriers was greater than expected when compared to the c.35delG carrier frequency in normal-hearing controls (P < 0.05), suggesting the existence of at least one other mutation outside the GJB2 coding region that does not complement GJB2 deafness-causing allele variants.     

Cation channels,cell volume and the death of an erythrocyte

Similar to a variety of nucleated cells, human erythrocytes activate a non-selective cation channel upon osmotic cell shrinkage. Further stimuli of channel activation include oxidative stress, energy depletion and extracellular removal of Cl^–. The channel is permeable to Ca²⁺ and opening of the channel increases cytosolic [Ca²⁺]. Intriguing evidence points to a role of this channel in the elimination of erythrocytes by apoptosis. Ca²⁺ entering through the cation channel stimulates a scramblase, leading to breakdown of cell membrane phosphatidylserine asymmetry, and stimulates Ca²⁺-sensitive K⁺ channels, thus leading to KCl loss and (further) cell shrinkage. The breakdown of phosphatidylserine asymmetry is evidenced by annexin binding, a typical feature of apoptotic cells. The effects of osmotic shock, oxidative stress and energy depletion on annexin binding are mimicked by the Ca²⁺ ionophore ionomycin (1 µM) and blunted in the nominal absence of extracellular Ca²⁺. Nevertheless, the residual annexin binding points to additional mechanisms involved in the triggering of the scramblase. The exposure of phosphatidylserine at the extracellular face of the cell membrane stimulates phagocytes to engulf the apoptotic erythrocytes. Thus, sustained activation of the cation channels eventually leads to clearance of affected erythrocytes from peripheral blood. Susceptibility to annexin binding is enhanced in several genetic disorders affecting erythrocyte function, such as thalassaemia, sickle-cell disease and glucose-6-phosphate dehydrogenase deficiency. The enhanced vulnerability presumably contributes to the shortened life span of the affected erythrocytes. Beyond their role in the limitation of erythrocyte survival, cation channels may contribute to the triggering of apoptosis in nucleated cells exposed to osmotic shock and/or oxidative stress.