Activity of the notch-signalling pathway in circulating human chronic lymphocytic leukaemia cells.

Dysregulation of the Notch-pathway has been implicated in the pathogenesis of chronic lymphocytic leukaemia (B-CLL). We characterized the mRNA expression of Notch pathway elements in circulating normal B- and B-CLL cells, and compared expression profiles with clinical and prognostic data. Similar expression profiles were found in normal B-cells and B-CLL cells, however, most B-CLL samples showed lower Hairy/Enhancer of Split-1 expression than normal B-cells, which suggests that the pathway is not over-activated in B-CLL. The expression of Notch-pathway genes did not correlate with other prognostic factors of B-CLL. The importance of Notch-signalling in CLL cells in lymphatic tissue microenvironments remains to be determined.

The acid-labile subunit of the serum insulin-like growth factor-binding protein complexes. Structural determination by molecular modeling and electron microscopy.

The acid-labile subunit (ALS) is a glycosylated 85-kDa member of the leucine-rich repeat (LRR) protein superfamily and circulates in ternary complexes with the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). These complexes are thought to regulate the serum IGFs by restricting IGF movement out of the circulation. However, little is known about how ALS binds to IGFBP-3 or -5, which link the IGFs to ALS. To investigate potential sites of interaction, the ALS structure has been modeled with the crystal structure of the LRR protein porcine ribonuclease inhibitor as a template. ALS is predicted to be a donut-shaped molecule with an internal diameter of 1.7 nm, an external diameter of 7.2 nm, and a thickness of 3.6 nm. These dimensions are supported by rotary shadowing electron microscopy of ALS. The internal face is lined with a substantial region of electronegative surface potential that could interact with the positively charged region on IGFBP-3 known to be involved in ALS binding. The model also predicts that three potential N-linked oligosaccharide sites within the LRR domain are clustered together, which may be important in light of recent studies showing ALS glycan involvement in complex formation with IGFBP-3.

[Effectiveness of pinaverium bromide therapy on colonic motility disorders in irritable bowel syndrome]. / A pinaverium bromid hatása a vastagbél motilitási zavarára irritábilis bél szindrómában.

The special patterns of the slow wave activity in irrittable bowel syndrome by means of surface electromyography were examined and the effect of pinaverium bromide on the symptoms and on the colonic motility in this disease was estimated. Twenty two patients with irritable bowel syndrome and 7 healthy controls were selected to the study. The clinical symptoms were abdominal pain and bloating in all patients, constipation in 9, and diarrhoea in 6 cases. Surface electromyography was carried out before and on the 14th day of the treatment with pinaverium bromide (50 mg t. i. d). The colonic motility was analysed in a 2 hour fasting and a 2 hour postprandial period following a standard (800 kCal) meal. The slow wave frequency of 0.01-0.04 Hz were selected and analysed. The mean frequency of activity peaks (n/10 min) and power-index (area under curve, microV 10 min) were measured. For statistical analysis Student's t-test was applied. Electromyogram of patients with irritable bowel syndrome showed a significant increase of the measured colonic motility parameters both in fasting and postprandial states. Fourteen days of pinaverium bromide treatment was able to significantly reduce the intensity of the colonic motor activity. Administration of pinaverium bromide completely released in 6 and significantly improved the abdominal pain in other 12 patients, while the bloating disappeared in 12 and was significantly improved in 5 from 22 patients. Pinaverium bromide was able to normalise the stool frequency: the weekly number of stools was decreased from 16 to 7 in the patients complaining diarrhoea ant it was increased from 2 to 6 in the patients with constipation.

N-Linked glycosylation and sialylation of the acid-labile subunit. Role in complex formation with insulin-like growth factor (IGF)-binding protein-3 and the IGFs.

Over 75% of the circulating insulin-like growth factors (IGF-I and -II) are bound in 140-kDa ternary complexes with IGF-binding protein-3 (IGFBP-3) and the 84-86-kDa acid-labile subunit (ALS), a glycoprotein containing 20 kDa of carbohydrate. The ternary complexes regulate IGF availability to the tissues. Since interactions of glycoproteins can be influenced by their glycan moieties, this study aimed to determine the role of ALS glycosylation in ternary complex formation. Complete deglycosylation abolished the ability of ALS to associate with IGFBP-3. To examine this further, seven recombinant ALS mutants each lacking one of the seven glycan attachment sites were expressed in CHO cells. All the mutants bound IGFBP-3, demonstrating that this interaction is not dependent on any single glycan chain. Enzymatic desialylation of ALS caused a shift in isoelectric point from 4.5 toward 7, demonstrating a substantial contribution of anionic charge by sialic acid. Ionic interactions are known to be involved in the association between ALS and IGFBP-3. Desialylation reduced the affinity of ALS for IGFBP-3. IGF complexes by 50-80%. Since serum protein glycosylation is often modified in disease states, the dependence of IGF ternary complex formation on the glycosylation state of ALS suggests a novel mechanism for regulation of IGF bioavailability.

[Diagnostic problems of Wilson disease]. / A Wilson-kór diagnosztikájának problémái.

A family (three siblings) of Wilson's-disease is described. The authors review the pathogenesis, diagnostics, pathology and treatment of Wilson's-disease. The diagnostic difficulties are emphasised. The variety of liver lesions are demonstrated in the different grades of the disease. The importance of the early diagnosis is stressed.

A novel human cDNA highly homologous to the fish hormone stanniocalcin.

Stanniocalcin is a glycoprotein hormone previously considered present only in bony fish where it is secreted by the corpuscles of Stannius, endocrine organs involved in Ca2+ homeostasis. In fish, stanniocalcin was thought to be an adaptation for Ca2+ regulation in aquatic environments, and its effects include inhibition of gill Ca2+ transport. We have obtained a human cDNA clone coding for a protein highly homologous to fish stanniocalcin. The mRNA is expressed in many human tissues, with the highest levels in ovary, prostate and thyroid. In vitro human cell culture studies show that the mRNA is positively regulated by extracellular Ca2+ in the medium. We conclude that a human protein similar to the fish hormone is expressed in multiple tissues rather than by a specialized endocrine organ.

Unhealthy health care costs.

The private sector has implemented many cost containment measures in efforts to control rising health care costs. However, these measures have not controlled costs in the long run, and can be expected not to succeed as long as business cannot control factors within the health care system which affect costs. Controlling private sector health care costs requires constraints on cost shifting which necessitates a unified financing system with expenditure limits. A unified financing system will involve a partnership between the public and private sectors.