Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities

Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (Pi) cotransporter that is expressed in the proximal tubule where the bulk of filtered Pi is reabsorbed. Mice deficient in the Npt2 gene were generated by targeted mutagenesis to define the role of Npt2 in the overall maintenance of Pi homeostasis, determine its impact on skeletal development, and clarify its relationship to autosomal disorders of renal Pi reabsorption in humans. Homozygous mutants (Npt2(-/-)) exhibit increased urinary Pi excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal Pi reabsorption. However, unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia. At weaning, Npt2(-/-) mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual overcompensation of the skeletal phenotype. Our findings demonstrate that Npt2 is a major regulator of Pi homeostasis and necessary for normal skeletal development.     

High iron intake depresses hepatic copper content in goats

Earlier studies with ruminants point to a depressant effect of dietary iron on the copper status. To verify this we determined hepatic copper concentrations in dry, non-pregnant goats subjected to a 56 x 56-days cross-over trial with adequate copper rations containing either 269 or 2380 mg iron/kg dry matter. High iron intake reduced the group mean plasma copper (by 18%) and caeruloplasmin activity (by 13%) and produced a significant decrease (27%) in hepatic copper concentrations. Hepatic iron concentrations were raised (by 56%) after feeding the high iron ration. It is concluded that high dietary levels of iron, within the range of their fluctuation in silage and forage, can impair the copper status of ruminants, especially when concurrent intakes of copper are low.     

G alphas-induced neurodegeneration in Caenorhabditis elegans

We describe a genetic model for neurodegeneration in the nematode Caenorhabditis elegans. Constitutive activation of the GTP-binding protein Galphas induces neurodegeneration. Neuron loss occurs in two phases whereby affected cells undergo a swelling response in young larvae and subsequently die sometime during larval development. Different neural cell types vary greatly in their susceptibility to Galphas-induced cytotoxicity, ranging from 0 to 88% of cells affected. Mutations that prevent programmed cell death do not prevent Galphas-induced killing, suggesting that these deaths do not occur by apoptosis. Mutations in three genes protect against Galphas-induced cell deaths. The acy-1 gene is absolutely required for neurodegeneration, and the predicted ACY-1 protein is highly similar (40% identical) to mammalian adenylyl cyclases. Thus, Gs-induced neurodegeneration is mediated by the second messenger cAMP. Mutations in the unc-36 and eat-4 genes are partially neuroprotective, which indicates that endogenous signaling modulates the severity of the neurotoxic effects of Galphas. These experiments define an intracellular signaling cascade that triggers a necrotic form of neurodegeneration.     

Thyroxine 5'-deiodination mediates norepinephrine-induced lipogenesis in dispersed brown adipocytes

In euthyroid rats, maximal sympathetic nervous system stimulation (e.g. during cold exposure) results in a 3- to 4-fold increase in brown adipose tissue lipogenesis, a response that is blunted in hypothyroid rats. To further investigate this phenomenon, the role of local type II 5'-deiodinase (5'-DII) was studied in freshly isolated brown adipocytes. In a typical experiment, 1.5 x 10(6) cells were incubated for up to 48 h in a water-saturated 5% CO2-95% O2 atmosphere. After incubation with medium alone or with different concentrations of T4, T3, and/or norepinephrine (NE), lipogenesis was studied by measuring 1) the rate of fatty acid synthesis as reflected by 3H2O incorporation into lipids and 2) the activity of key rate-limiting enzymes, i.e. acetyl coenzyme A carboxylase and malic enzyme, and the results are reported in terms of DNA content per tube. Lipogenesis decreased progressively over time (approximately 40%) when no additions were made to the incubation medium. T4 or T3 partially prevented that inhibition at physiological concentrations (65 x 10[-9] and 0.77 x 10[-9] M, respectively), whereas a receptor-saturating concentration of T3, (154 x 10[-9] M) doubled the lipogenesis rate. The addition of 10(-6) M NE inhibited lipogenesis acutely (approximately 50% by 12 h) and was followed by a progressive stimulation that reached approximately 2-fold by 48 h, but only in the presence of T4. Furthermore, NE did not attenuate T3 (154 x 10[-9] M)-induced lipogenesis. Both the inhibition and the stimulation of lipogenesis caused by NE showed a strong dose-response relationship within the range of 10(-11)-10(-5) M. The role of local 5'-DII was further tested by incubating brown adipocytes with 10(-6) M NE and T4 (65 x 10[-9] M) in the presence of 100 microM iopanoic acid, a potent inhibitor of 5'-DII. Although iopanoic acid did not affect the T3 stimulation of lipogenesis, it did block the approximately 2-fold stimulation of lipogenesis triggered by NE in the presence of T4, confirming the mediation of 5'-DII in this process. In conclusion, lipogenesis in brown adipose tissue is under complex hormonal control, with key roles played by NE, thyroid hormones, and local 5'-DII. As in other tissues, NE-generated signals acutely (12 h) inhibited lipogenesis. However, the presence of the 5'-DII generated enough T3 to stimulate lipogenesis and gradually reverse the short-lived NE-induced inhibition, leading to the 2- to 3-fold response observed at later time points.     

Effects of caffeine on glucose tolerance: a placebo-controlled study

BACKGROUND: Leishmaniasis recidiva cutis (LRC) is rare in New World leishmaniasis. Only seven cases have been reported so far. MATERIALS AND METHODS: Four cases are reported here. Parasite diagnosis was performed by classical methods of touch preparations, histopathologic sections, and cultures. In addition, the detection of parasite DNA by the polymerase chain reaction (PCR) was performed in all cases. RESULTS: Parasites were detected by at least one of the classical methods in all primary lesions; however, only the PCR was positive in the recidivant lesions. DISCUSSION: LRC cases most likely represent a reactivation of an initial infection, probably due to the persistence of parasites in scarred tissue. Although lupoid leishmaniasis (LL) has been used as a synonym of LRC, a clear difference between LRC and LL can be defined as LL is the initial clinical presentation while LRC is a recurrent lesion. CONCLUSIONS: The results indicate that it is not appropriate to use these two denominations as synonyms. The designation of LRC should be maintained in order to define recidives occurring at the border of an old scar of cutaneous leishmaniasis, avoiding the confusion with the lupoid form of the disease.     

Effect of E. coli endotoxin on auto-/paracrine function and endothelial cell loss of donor corneas in organ culture

A review of the 1995 and past American Dental Association studies on the distribution of dentists provides specific information on the evolving numbers of endodontists at the national, regional, and state levels. Despite an increase in numbers of endodontists, major differences continue in practitioner-to-population ratios in different geographic areas.     

Comparison of cognitive function in human and non-human primates

Fundamental to any comparative study of cognitive function in monkey and man is the demonstration of behavioral homology, viz. that the same cognitive function is being studied in both species. This paper considers a variety of psychological issues that need to be taken into account when attempting to demonstrate behavioural homology. Examples are taken from studies of attentional set-shifting, discrimination reversal learning, spatial working memory and episodic memory. Whilst highlighting the pitfalls to be avoided in the future, these examples also demonstrate the enormous contribution that such studies have had to our understanding of the functions of the temporal lobes and frontal lobes. Moreover, they also illustrate the enormous potential in defining the cognitive functions and dysfunctions of the prefronto-striatal circuitry which underlie so many neurodegenerative and neuropsychiatric disorders.     

Primary fallopian tube cancer: a review of the literature

BACKGROUND: We conducted a population-based case-control study to describe the relationship between occupational exposure to estrogenic chemicals and the occurrence of breast cancer in Cape Cod, Massachusetts. METHODS: Incident cases of breast cancer (n = 261) diagnosed from 1983 through 1986 and controls (n = 753) were interviewed to gather information on breast cancer risk factors and all full-time jobs held since age 18. Blinded exposure assessments were employed using the data from the NIOSH National Occupational Exposure Survey, chemical production and usage information, and the expert judgement of a certified industrial hygienist. RESULTS: Overall, 29.5% of cases and 32.5% of controls had probable occupational exposure to one or more xenoestrogens. Probable exposure to nonylphenol (21.5% of cases, 21.4% of controls), butyl benzyl phthalate (10.0% of cases, 13.2% of controls), BHA (7.3% of cases, 9.6% of controls), bisphenol A (9.6% of cases, 11.6% of controls), and 4-tert-butylphenol (2.7% of cases and 5.3% of controls) were relatively commons, while probable exposure to the other xenestrogens was rare. Only PCBs and 4-octylphenol were associated with moderate increase in the odds of breast cancer (PCBs: 5 exposed cases and 6 exposed controls, adjust odds ratio: 3.2, 95% CI = 0.8-12.2, and 4-octylphenol: 6 exposed cases and 5 exposed controls, adjusted odds ratio: 2.9, 95% CI = 10.8).