Introduction to resources in molecular genetics.

Perhaps no other discipline has experienced as dramatic an information explosion in recent years as has the field of molecular genetics. While the flood of scholarly publications stemming from this research has been extensively indexed in MEDLINE, a number of new databases have been developed that provide direct access to the primary sequence data as well as to curated, reference information. A select group of these databases, including NCBI's GenBank, LocusLink, RefSeq, OMIM, and Genes and Disease, is examined. Following a brief description of each database, a proposed instructional program for their integration into an undergraduate genetics course at the University of Vermont is described.

[Non-Hodgkin's lymphoma: unusual testicular localization: case report]. / Lymphome non-hodgkinien: localisation testiculaire inhabituelle: à propos d'un cas.

We report on a 58-year-old man, in whom a clinical suspicion of orchitis of the right testicle was treated with antibiotics. The instored antibiotics failed to improve the clinical condition of orchitis. Previous medical history revealed a gastric lymphoma for which gastrectomy was performed, followed by combination chemotherapy. Therefore testicular biopsies were performed. These biopsies confirmed the diagnosis of testicular localisation of lymphoma. A combination chemotherapy, in association with alpha-Interferon was instaured. One year after instauration of combination therapy, the patient is in complete remission. This unusual localisation of lymphoma is discussed in regard of other cases described in literature.

The plicamycin and hydroxyurea combination chemotherapy for chronic granulocytic leukemia in myeloid transformation.

Between 1987-1988 we treated, in a cooperative study, 13 patients in blast crisis of CGL according to Koller and Miller's regimen. We observed no return to the chronic phase of the disease, while some patients suffered major drug-induced side effects. Six patients in accelerated phase were treated with the same combination therapy. All of them responded with a return to the chronic phase for a median of 4.5 months. In our hands the combination of plicamycin and hydroxyurea was ineffective in patients with CGL in blast crisis. This regimen could deserve further evaluation in patients with CGL in acceleration.

Acute disseminated intravascular coagulation after percutaneous balloon aortic valvuloplasty in a cirrhotic patient.

We report the case of a 71-year-old man presenting a histologically proven liver cirrhosis with compensated disseminated intravascular coagulation and calcified aortic stenosis. This coagulation disorder became clinically and biologically severe during or soon after percutaneous balloon aortic valvuloplasty. In a cirrhotic patient with compensated disseminated intravascular coagulation, the procedure can induce life-threatening bleeding disorders.

Potassium homeostasis in liver cirrhosis.

Extrarenal mechanisms are important in the defense against hyperkalemia. During a potassium load, cellular uptake is essential to avoid severe hyperkalemia. Liver and muscles represent the major buffering system, partially mediated by insulin, in the distribution of potassium between intracellular and extracellular fluids. To study the potential role of the liver, we administered an oral load of potassium (0.75 mEq/kg) to nine male patients with compensated cirrhosis and ten normal subjects of similar age, sex, and weight. Despite identical renal excretion, cirrhotic patients had higher potassium levels two and three hours after oral administration. Moreover, only cirrhotic patients presented a clear-cut increase in serum C-peptide concentration after the potassium load without any change in glucose level. It is likely that, in cirrhosis, liver failure contributes to the decrease in hepatic cellular potassium uptake despite insulin hypersecretion.

Role of vagal neuropathy in the hyponatraemia of alcoholic cirrhosis.

The hyponatraemia common in decompensated cirrhosis arises in part from secretion of antidiuretic hormone attributed to a decrease in effective blood volume. Baroreceptors send inhibitory impulses to the midbrain and hypothalamus through the vagus and glossopharyngeal nerves. Since vagal neuropathy often occurs in chronic alcoholism, this might theoretically contribute to the inappropriate secretion of antidiuretic hormone, which might in turn induce hyponatraemia. In a prospective study including 34 patients with cirrhosis a high incidence of vagal neuropathy was found in the alcoholics (64%) and a clear cut increase in the incidence of hyponatraemia in patients with evidence of vagal damage and ascites (seven of eight patients (88%); p = 0.02). Results of a retrospective study of 64 patients with cirrhosis and ascitic decompensation showed hyponatraemia in 17 (50%) of 34 alcoholics but in only four (13%) of 30 patients with non-alcoholic disease (p = 0.006). Vagal neuropathy in alcoholic cirrhosis may contribute to the low serum sodium concentrations commonly found in these patients.

Hematopoietic inhibitors in chronic renal failure: lack of in vitro specificity.

To assess the potential role of retained inhibitors in the pathogenesis of the anemia of chronic renal failure, we have studied simultaneously the effects of increasing concentrations of normal or uremic sera on the growth of erythroid colonies (from CFU-E), granulocyte-macrophage colonies (from CFU-GM), and megakaryocytic colonies (from CFU-Meg) in mouse marrow cell cultures. As compared to normal human serum, increasing concentrations of uremic sera induced a dose-dependent inhibition in the growth of all colony types. Significant correlations (P less than 0.001) were found between the ability of any individual uremic serum to support CFU-E, CFU-GM, and CFU-Meg growth, and, whenever significant inhibition was seen, all three progenitor types were affected. The inhibitory effect on CFU-E growth was significantly greater (P less than 0.01) in patients with serum creatinine concentrations greater than or equal to 7 mg/dl, but no correlation was found between CFU-E inhibition and hematocrit. Likewise, inhibition of CFU-GM and CFU-Meg growth was not associated with leukopenia or thrombocytopenia, respectively. Sera from patients undergoing chronic intermittent hemodialysis were assayed before and after one hemodialysis session. In each case, the degree of inhibition of CFU-E and CFU-GM growth decreased after hemodialysis, but improvement in CFU-Meg growth was more variable. These data indicate that uremic sera contain dialyzable inhibitors of in vitro hematopoiesis which increase with the severity of renal dysfunction, but these inhibitors lack specificity. If uremic inhibitors of erythropoiesis are of pathophysiologic significance in vivo, there must be unrecognized repair mechanisms for granulopoiesis and thrombopoiesis.

Treatment of hyponatremic cirrhosis with ascites resistant to diuretics by urea.

We have studied the efficacy of urea in the treatment of hyponatremia and hydrosaline retention in cirrhotic patients with ascites resistant to diuretics. In 5 patients with hyponatremia and ascites resistant to a major diuretic treatment (200-400 mg spironolactone combined with 40-160 mg furosemide/day for 4 of them), urea intake (30-90 g/day) induced the following changes: the daily weight changed from a gain of 0.01 +/- 0.06 kg/day to a loss of 1.03 +/- 0.12 kg/day (p less than 0.001) (mean +/- SEM), serum sodium concentration rose from 128 +/- 1.3 to 133 +/- 1.4 mmol/l (p less than 0.01), sodium output increased from 24 +/- 4 to 82.5 +/- 11 mmol/day, diuresis increased from 1.05 +/- 0.10 to 2.24 +/- 0.24 liters/day (p less than 0.01). Despite an important weight loss, the creatinine clearance did not change significantly (53.6 +/- 4.5 ml/min before and 70.0 +/- 8.2 ml/min during urea). In patients responding to classical diuretics, urea as a monotherapy was less effective. From the 6 patients with resistant ascites, only 1 developed prerenal uremia after urea treatment. In order to enhance urea efficacy, it is important to take it together with a long-loop diuretic. Intermittent urea intake seemed to be useful in cirrhotic patients with hyponatremia associated with ascites resistant to diuretics and with low or normal blood urea concentrations.

Platelet-derived growth factor enhances in vitro erythropoiesis via stimulation of mesenchymal cells.

The growth of erythroid colonies (from erythroid colony-forming cells) and erythroid bursts (from burst-forming cells [BFU-E]) is enhanced in the presence of serum as compared with plasma. A significant proportion of the enhanced growth is due to the platelet release product, platelet-derived growth factor (PDGF). Colony growth in cultures of whole marrow cells in platelet-poor plasma-derived serum (PDS) and erythropoietin was enhanced in a dose-dependent fashion by increasing concentrations of purified human PDGF with optimal enhancement at 12.5 ng/ml. However, no effect of platelet-release products or PDGF was observed on nonadherent human marrow cells or peripheral blood BFU-E, suggesting that an accessory cell population was required for the effect of PDGF on hematopoietic progenitors. In a two-layer culture system, pure populations of fibroblasts or smooth muscle cells, known to be present in the marrow microenvironment, restored the response of nonadherent marrow cells in the overlayer to PDGF and also conferred responsiveness to peripheral blood BFU-E. Endothelial cells in the two-layer culture system and macrophages, in contrast, lacked the ability to restore the enhancing effect of PDGF. Because other platelet-release mitogenic products are also found in serum, a monospecific anti-PDGF IgG preparation was added to cultures grown in platelet rich plasma-derived serum. Only partial reduction in colony and burst growth was seen, suggesting that other platelet-release products were acting in this system. These results demonstrate that PDGF enhancement of human hematopoietic progenitor cell growth requires mesenchymal cells, and provide an example and mechanism by which growth factors may influence hematopoietic progenitors via cells of the marrow microenvironment.