Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure

Heart Failure Reviews - The nitric oxide (NO)–guanylate cyclase (GC)–cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal...     

An alternative mechanism of actions for neuroleptic and antidepressant drugs

It has earlier been proposed by the author that the aetiology of schizophrenic symptomatology may be due to the presence of abnormally connected interhemispheric fibres which link specialised functions in the brains of schizophrenics that are not connected in normal subjects, and that the neuroleptic drugs may produce their action through a local anaesthetic-like effect in suppression of conduction in these fibres. This line of thought has been extended here to consider the possible mechanism of action of the neuroleptic drugs in more detail, as well as that of the tricyclic antidepressant drugs which are derivatives of the phenothiazine group. Pharmacological similarities with the local anaesthetics both structurally and functionally have been considered, as well as the effects that these drug groups may have in common with the lithium salts. It has been suggested that these drugs all produce their primary effect on cell membranes, though not necessarily at the synapse, that the time course of their clinical effect may correlate with their incorporation into various cell membranes within the CNS, and that they may thus bring about a fundamental alteration in cell membrane microstructure. The possible role of electroconvulsive therapy has also been considered. The corollary of this argument is that the affective disorders may be genetically determined diseases of cell membrane microstructure.     

Composite aortic root replacement in acute type A dissection: time to rethink the indications?

OBJECTIVE: The indications for aortic root replacement in acute type A dissection are unclear. We reviewed the immediate and long-term outcome of consecutive patients in a series in which a low-threshold policy of composite aortic root replacement had evolved. METHODS: From a prospectively compiled aortic surgery database, we identified 162 patients who had either supracoronary interposition grafting, Group A (n=89), or composite root replacement, Group B (n=73) for acute type A dissection. Patients receiving total arch replacements were excluded. Operative and clinical details were analyzed and patient survival was compared to an age and gender matched census cohort. Need for reoperation on the proximal or distal aorta was also noted. Follow-up totaled 795.5 patient-years. RESULTS: Hospital mortality rates were identical in both groups (12.3%: 11 deaths in group A; 9 in group B). Chronic pulmonary disease, diabetes, malperfusion, hemodynamic compromise and aortic root dilatation were independent risk factors for hospital death. Actuarial survival estimates at 1, 5 and 10 years were 79% (71-88%), 64% (53-75%), and 55% (41-68%) for group A, and 79% (70-86%), 73% (62-83%), and 65% (52-78%) for group B (P=0.48). Age and operative patency of the ascending false lumen were independent risk factors for death after hospital discharge. Proximal aortic reoperation was required for four patients in group A and none in group B (P=0.085). CONCLUSION: A strategy of replacement rather than repair of the dissected aortic root for specific indications in type A dissection yielded high survival and low proximal reoperation rates. These results support an aggressive policy of composite root replacement in acute type A dissection.     

Genotype/phenotype of familial pancreatic cancer.

It is estimated that 5% to 10% of pancreatic cancer cases are attributable to hereditary factors. We believe that the number of cases that are genetic in etiology are even greater, however, based not on a classic autosomal dominant pattern of inheritance but rather when one takes into account low-penetrant inherited susceptibility factors. There is also a growing recognition that the development of pancreatic cancer in pancreatic cancer-prone families is dependent not only on genetic variables but on nongenetic factors. The aim of this article is to review the challenges in identifying pancreatic cancer-prone families and how environmental factors interact with genetic factors in these families.     

Laparoscopic-assisted bowel surgery

The use of laparoscopic surgical techniques is now being applied to a variety of operations traditionally performed in an open fashion. Twenty patients underwent laparoscopic-guided large and small bowel surgery at our institution from March 1991 to April 1992. The indications for surgery included polyps, obstruction, bleeding, and perforation, and pathologic diagnoses included benign polyps, lipomas, inflammatory bowel disease, perforation of a jejunal diverticulum, colonic arteriovenous malformations, and adenocarcinoma. Mobilization of the colon, ligation of the mesentery, and closure of the mesenteric defect were performed using the laparoscopic equipment. One trocar site was enlarged to 3 cm to deliver the bowel through the abdominal wall. All anastomoses were hand-sewn. Postoperative hospitalization ranged from 2 to 31 days (median, five days). No mortality was noted, and morbidity was 20 percent. We conclude that laparoscopic-guided bowel surgery is technically feasible and should translate into shorter hospitalization and less patient discomfort.     

Eight Days of Cyclosporine Overdose: A Case Report

A 25–year-old woman was admitted to the hospital because of rising trough cyclosporine concentrations thought to be due to self-administration of 4 times the normal dosage of the drug for 8 days. Her symptoms included colicky central abdominal pains and urinary retention; her serum creatinine concentrations were elevated. Whole blood cyclosporine and metabolite concentrations were measured by high-performance liquid chromatography and monoclonal radioimmunoassays. The highest reported trough cyclosporine concentration was 5877 ng/ml, and AM1 (M17) concentration was 3425 ng/ml. A cyclosporine half-life of 91 hours was calculated. Nine days after the agent was discontinued the patient's serum creatinine concentration had returned to normal and her symptoms resolved. Due to the availability of three sizes of cyclosporine capsules, and the need for frequent dosage changes, continued vigilance is necessary to ensure that patients understand their drug regimen.