Regulation of Cell Calcium and Role of Plasma Membrane Calcium ATPases.

The plasma membrane Ca2+ ATPase (PMCA pump) is a member of the superfamily of P-type pumps. It has 10 transmembrane helices and 2 cytosolic loops, one of which contains the catalytic center. Its most distinctive feature is a C-terminal tail that contains most of the regulatory sites including that for calmodulin. The pump is also regulated by acidic phospholipids, kinases, a dimerization process, and numerous protein interactors. In mammals, four genes code for the four basic isoforms. Isoform complexity is increased by alternative splicing of primary transcripts. Pumps 2 and 3 are expressed preferentially in the nervous system. The pumps coexist with more powerful systems that clear Ca2+ from the bulk cytosol: their role is thus the regulation of Ca2+ in selected subplasma membrane microdomains, where a number of important Ca2+-dependent enzymes interact with them. Malfunctions of the pump lead to disease phenotypes that affect the nervous system preferentially.

Reduced mitochondrial Ca(2+) transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase.

Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear- and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A>G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca(2+) homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A>G cells. This is due to a specific downregulation of mitochondrial Ca(2+) uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca(2+) homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient.

Fatal tubular nephropathy following an overdose of theophylline in an infant.

A case of fatal acute intoxication in a 4-month and 20-day-old male infant from an overdose of theophylline (Paidomal) drops retard is described. Apart from the usual symptoms caused by theophylline overdose, severe obstructive tubular nephropathy was also observed.

A survey of the use and educational value of the hospital formularly manual.

The medical and nursing staffs of two affiliated hospitals were surveyed on their frequency and purpose of use of their hospital's formulary manual. A numerical rating of the perceived educational value of the manuals was also requested. Twenty-two per cent (141/650) of those surveyed completed their questionnaires. Ninety-six per cent of the respondents indicated use of the formulary manuals at least once a month; 62% used the manuals at least once a week. The frequency and character of use of various sections of the formulary manuals are presented. The perceived educational value of the manuals was rated 3 or greater on a scale of 1 (no value) to 5 (greatest value) by 80% of the respondents. The hospitals' formulary manuals are frequently referred to for various types of drug information. The professional staffs perceive the formulary manuals to be educationally valuable sources of drug information. Reasons for the low rate of response to the survey are presented. A plan of how to increase the response rate in a planned future survey is also presented.