Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

When acral malignant melanoma facades as diabetic foot!

An 85-year-old Indian man presented with non-healing foot ulcer over the left heel. There was initial response to wound size with standard treatment including offloading, debridement and antibiotic therapy. However, subsequently, there was no progress noted. Incidentally, two small black spots in the wound bed raised the suspicion of melanoma. Incisional biopsy confirmed acral lentiginous melanoma (ALM). The final diagnosis was ALM coexisting with diabetic foot ulcer (DFU). The wound was treated by surgical resection and flap reconstruction that resulted in complete healing. Fourteen months after the initial intervention, the patient developed a new lump and ulceration around the previous wound bed. This turned out to be recurrent disease with distant metastasis. The patient died eventually with palliative support. Through this case, we would like to highlight the importance of early biopsy and intervention in DFU especially for those wounds with atypical presentation or refractory to standard treatment.

Effect of a serotonin reuptake inhibitor on irritability, apathy, and psychotic symptoms in patients with Alzheimer's disease.

OBJECTIVE: To ascertain the impact of treatment with citalopram on irritability, apathy, delusions, and hallucinations in nondepressed behaviorally disturbed Alzheimer's disease (AD) patients. METHOD: This was a retrospective analysis of data from the 36-week Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease in which patients with probable AD (diagnosed according to criteria of the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association [NINCDS/ADRDA]) were treated in a naturalistic manner. Scores were compared on the irritability, apathy, delusions, and hallucinations subscales of the Neuropsychiatric Inventory. The trial was conducted between April 2001 and November 2004. RESULTS: Of the 421 patients enrolled, 44 were started on placebo and were later randomly assigned to citalopram treatment. There were data available for 34 subjects who took placebo for at least 14 days. In this group, there was a 60% reduction in irritability and apathy scores, no effect on scores for delusions, and a clinically insignificant drop in scores for hallucinations. CONCLUSIONS: The use of citalopram was associated with greatly reduced irritability without sedation in a group of behaviorally disturbed patients with AD.

Present and prospective clinical therapeutic regimens for Alzheimer's disease.

Alzheimer's disease (AD) is an incurable neurodegenerative disorder that produces cognitive impairments that increase in severity as the disease progresses. The clinical symptoms are related to the presence of neuritic plaques and neurofibrillary tangles in the cerebral cortex which represent the pathophysiological hallmarks of AD. The debilitating nature of the disease can result in clinical burden for the patient, emotional strain for those that care for patients with Alzheimer's, and significant financial burden to society. The goals of current treatments, such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist, are to reduce the severity or slow the progression of cognitive symptoms. Although these treatments have demonstrated modest clinical benefit, they are unable to prevent, prohibit, or reverse the underlying pathophysiology of AD. Considerable progress has been made toward the development of disease-modifying treatments. Treatments currently under development mainly target the production, aggregation, and removal of existing amyloid beta-peptide aggregates which are believed to instigate the overall development of the neuropathology. Additional strategies that target tau pathology are being studied to promote neural protection against AD pathology. The current research has continued to expand our knowledge toward the development of disease modifying Alzheimer's therapies; however, no specific treatment strategy capable of demonstrating empirical efficacy and safety has yet to emerge.