Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.

Liquorice-induced sodium retention. Merely an acquired condition of apparent mineralocorticoid excess? A case report.

Excessive ingestion of liquorice may result in sodium retention, hypertension, hypokalemia, and suppression of renin and aldosterone. Similarities between liquorice-induced effects and congenital apparent mineralocorticoid excess have recently been emphasized, as in both conditions, reduced activity of the enzyme 11 beta-hydroxysteroid dehydrogenase type 2 allows cortisol to act as a potent mineralocorticoid. We report a case of generalized edema without any increase in blood pressure, with biochemical and hormonal features of apparent mineralocorticoid excess, in a young woman who had been ingesting substantial amounts of liquorice for several years. Liquorice-induced wide-spread edema without hypertension in our patient, as well as in a few other cases previously reported, and the more common occurrence of edema associated with hypertension challenge the current explanation of liquorice syndrome as a purely acquired apparent mineralocorticoid excess. Indeed, in both congenital apparent and true mineralocorticoid excess, edema is typically absent, as a result of the sodium escape phenomenon. As pressure-natriuresis may be an essential mechanism accounting for the sodium escape phenomenon, some component of liquorice could partially or completely oppose the circulatory response that converts liquorice-induced sodium retention into blood pressure elevation. In patients with unexplained generalized edema and hypokalemia without hypertension, liquorice ingestion should be carefully investigated and the renin-aldosterone system should be assayed.

Expression study on D123 gene product: evidence for high positivity in testis.

A novel 44-kDa gene product (D123) has been proposed as necessary for S-phase entry of the cell cycle: a point mutation resulted in a temperature-sensitive arrest in G1-phase. From human fibrosarcoma cDNA library, we have isolated an identical gene and studied its sequence and mRNA and protein expression. Compared with D123, three nucleotide differences within the human coding sequence, plus others, result in a change of two amino acids. A partial sequence similarity has been found with a yeast gene of unknown function. The protein has several potential phosphorylation sites, is highly hydrophilic, and may be highly structured in alpha-helix. The mRNA is abundantly expressed by a variety of normal and transformed cells and by all tissues examined, being most highly expressed in testis. Specific antibodies, raised against a rhD123 polypeptide, recognize a major 42- to 44-kDa molecule in crude extract of various human cell lines. Immunohistochemistry reveals that D123 protein is not homogeneously expressed: it is detected, often in granular vescicles, in the cytoplasm of some epithelial, stromal, and sperm cells and in varicosities lining nervous fibers, while it appears to be absent in nuclei, endothelial, and smooth muscle cells. The precise link between cytoplasmic occurrence of D123 and cell cycle progression still remains to be clarified.

Transient expression of type IV collagenolytic metalloproteinase by human mononuclear phagocytes.

A type IV collagenolytic metalloproteinase secreted by human monocytes/macrophages has been isolated and characterized. Monocytes isolated from peripheral blood and cultured in vitro exhibited a high type IV collagenolytic activity during the first and second day, but such activity declined markedly over subsequent days. Type IV collagenolytic activity was also transiently elaborated by macrophages isolated from (a) bronchioalveolar lavage of patients with pulmonary sarcoidosis, (b) primary human colostrum, and (c) peritoneal lavage of a patient with peritonitis. In contrast, macrophages isolated from the bronchioalveolar lavage of normal individuals, or from noninflammatory peritoneal fluids, failed to exhibit type IV collagenolytic activity. A type IV collagenolytic neutral proteinase was purified from macrophages isolated from inflammatory peritoneal fluid. The proteinase has a mass of 67 kDa on gel electrophoresis and is not altered in its migration under reducing conditions. It produces a characteristic 1/4-3/4 cleavage of type IV collagen, and its activity is abolished by treatment with EDTA but not phenylmethanesulfonyl fluoride. The isoelectric pH of the proteinase is 5.2 as judged by two-dimensional gel electrophoresis. The amino acid composition of the proteinase was notable for a high content of serine, glutamic acid, glycine, and alanine and no detectable hydroxyproline, cysteine, or methionine residues. The carbohydrate content of the proteinase was 11.2%, and galactose was the most abundant monosaccharide (8.7%) released following acid hydrolysis, followed by glucose (1.3%), mannose (1.2%), and trace amounts of fucose and galactosamine. Such a type IV collagenolytic protease may play an important role during the traversal of the vascular basement membrane by extravasating monocytes. The biochemical characteristics and biologic function of the macrophage proteinase may be similar or identical to the type IV collagenolytic proteinase identified in metastatic tumor cells.

Supraventricular tachycardia emergencies: diagnosis and management.

A variety of acute supraventricular tachycardias may be encountered. In many instances the therapies for these rhythm disturbances overlap, but a rational approach to individual disturbances should be based on an understanding of the anatomy and physiology involved in the individual dysrhythmia. Numerous investigative approaches are underway at present, especially with regard to interruption of arrhythmia pathways by electroshock therapy or surgical therapy. In addition, pacing overdrive may be very effective, especially in patients with reentrant arrhythmias.