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.     

Transluminal angioplasty of the vertebral and basilar artery

Transluminal angioplasty of brachiocephalic vessels for atherosclerotic lesions is now being performed in selected cases. We have thus far treated 17 cases of vertebral artery stenosis and one case of basilar artery stenosis by intravascular balloon dilatation techniques. Clinical presenting symptoms included vertebral basilar insufficiency, repeated transient ischemic attacks (TIAs), and multiple strokes. We performed successful transluminal angioplasty in 16 patients with marked narrowing (greater than 70%) of the dominant vertebral artery from atherosclerosis. One patient with basilar artery stenosis with tandem atherosclerotic lesions was also treated by angioplasty techniques. Repeat angiography at 3- to 12-month intervals has revealed continued patency at the angioplasty site. Complications occurred in our one patient with basilar artery angioplasty, who suffered a brainstem infarction after treatment, and in one patient who had a TIA after bilateral vertebral artery angioplasty. Two other patients had residual vertebral stenosis but remained asymptomatic after the procedure. All other patients who had successful dilatation were asymptomatic at 6 months to 2 years (mean, 15 months) of follow-up. These initial studies indicate that vertebral artery angioplasty may be effective for treating high-grade atherosclerotic lesions and for improving blood flow to the posterior circulation. Angioplasty of the basilar artery is technically more difficult and has a higher degree of risk because of the many perforating branches supplying the brainstem.     

Carotid cavernous fistulae: indications for urgent treatment

Angiographic and clinical data from 155 patients with carotid cavernous fistulae were retrospectively reviewed to determine angiographic features associated with increased risk of morbidity and mortality. These features included presence of a pseudoaneurysm, large varix of the cavernous sinus, venous drainage to cortical veins, and thrombosis of venous outflow pathways distant from the fistula. Clinical signs and symptoms that characterized a hazardous carotid cavernous fistula included increased intracranial pressure, rapidly progressive proptosis, diminished visual acuity, hemorrhage, and transient ischemic attacks. Cortical venous drainage from the carotid cavernous fistula is secondary to occlusion or absence of the normal venous outflow pathways and is associated with signs and symptoms of increased intracranial pressure and an increased risk of intraparenchymal hemorrhage. Angiographic demonstration of a cavernous sinus varix, with extension of the sinus into the subarachnoid space, is associated with an increased risk of fatal subarachnoid hemorrhage. Identification of these high-risk features provides a basis for making decisions about treatment.     

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.