Antihypertensive therapy in type 2 diabetes mellitus

Fifty-seven patients with failed sclerotherapy received a mesocaval interposition shunt with an externally supported, ringed polytetrafluoroethylene prosthesis of either 10 or 12 mm diameter. Thirty-one patients had Child-Pugh grade A disease and 26 grade B; all had a liver volume of 1000-2500 ml. Follow-up ranged from 16 months to 6 years 3 months. Three patients (5 per cent) died in the postoperative period. There were two postoperative recurrences of variceal haemorrhage and one recurrent bleed in the second year after surgery. The cumulative shunt patency rate was 95 per cent and the incidence of encephalopathy 9 per cent; the latter was successfully managed by protein restriction and/or lactulose therapy. The actuarial survival rate for the whole group at 6 years was 78 per cent, for those with Child-Pugh grade A 88 per cent and for grade B 67 per cent. Small-lumen mesocaval interposition shunting achieves portal decompression, preserves hepatopetal flow, has a low incidence of shunt thrombosis, prevents recurrent variceal bleeding and is not associated with significant postoperative encephalopathy.     

Cellular thiols as a determinant of responsiveness to menadione in cardiomyocytes

The role of intracellular thiols in menadione-mediated toxicity was studied in neonatal rat cardiomyocytes. The sensitivity of cardiomyocytes to menadione was greater than that of skeletal muscle cells and 3T3 fibroblasts. Before cell degeneration, menadione induced marked depletion of intracellular thiols and an increase of oxidized glutathione. The sensitivity of these cells to menadione correlated with the level of depletion of intracellular thiols. After incubation of cardiomyocytes with menadione, glutathione reductase activity was inhibited and lipid peroxidation was increased. Both dicumarol (an inhibitor of DT-diaphorase) and diethyldithiocarbamate (an inhibitor of superoxide dismutase) enhanced the capacity of menadione to induce cellular damage and to cause depletion of intracellular glutathione. Decreasing intracellular glutathione by pretreatment of cells with N-ethylmaleimide or buthionine sulphoximine also increased menadione-induced cell degeneration. Preincubation with cysteine or dithiothreitol suppressed the capacity of menadione to damage the cells. Menadione-induced lipid peroxidation was also suppressed by the same treatment. These results show that the oxidative stress induced by menadione in cardiomyocytes results in the depletion of glutathione and protein thiols. Both DT-diaphorase and superoxide dismutase can protect cells from the toxicity of menadione. Cellular thiols are determinants of the responsiveness to menadione.     

Persistent pulmonary hypertension of the neonate and asymmetric growth restriction

OBJECTIVE: To evaluate the possible associations between persistent pulmonary hypertension of the neonate, need for extra-corporeal membranous oxygenation, small for gestational age (SGA), and low ponderal index for gestational age in infants with persistent pulmonary hypertension of the neonate and in matched controls. METHODS: Eighty-six infants with persistent pulmonary hypertension of the neonate delivered from 1991 to 1994 at our hospital were matched with 430 contemporaneous control singleton neonates. Birth weight and ponderal indices (100 x weight/length3) less than the tenth percentile for gestational age and gender were defined as SGA and low ponderal index, respectively. We assessed associations between these markers, the presence of persistent pulmonary hypertension of the neonate, and the need for extracorporeal membranous oxygenation. RESULTS: Low ponderal index was associated with persistent pulmonary hypertension of the neonate (odds ratio [OR] 5.4), whereas SGA was not. Low ponderal index (OR 4.0) was an independent correlate of persistent pulmonary hypertension of the neonate after adjustment with logistic regression for 5-minute Apgar scores less than 7, umbilical arterial pH less than 7.10, and presence of meconium. Low ponderal index was associated with need for extracorporeal membranous oxygenation in neonates with persistent pulmonary hypertension (P < .001). CONCLUSION: Fetal developmental events may significantly affect neonatal pulmonary status. Diminished neonatal nutritional status, as measured by low ponderal index for gestational age, is associated with increased risk of persistent pulmonary hypertension of the neonate and severity of the disease process.     

Inhibition of experimental proliferative vitreoretinopathy by retroviral vector-mediated transfer of suicide gene. Can proliferative vitreoretinopathy be a target of gene therapy?

PURPOSE: To determine the potential of somatic gene transfer as a treatment for proliferative vitreoretinopathy (PVR), experimental PVR was induced in rabbits by intraocular injection of fibroblasts bearing the herpes simplex virus thymidine kinase (HStk) gene. These transduced cells should be susceptible to cytotoxicity by exposure to ganciclovir (GCV). MATERIALS AND METHODS: Rabbit fibroblasts were transduced with retroviral vectors bearing an HStk gene. Proliferative vitreoretinopathy was induced by injection of 5 x 10(4) normal or HStk gene-transduced fibroblasts (HStk fibroblasts) into rabbit eyes. Ganciclovir (100 micrograms per eye) or saline was injected into the vitreous on days 0 and 4. Experimental animals were divided into three groups: group A received HStk fibroblasts with GCV; group B, normal fibroblasts with GCV; group C, HStk fibroblasts with saline. Proliferative vitreoretinopathy also was induced in several other groups of eyes, some receiving GCV and different proportions of HStk fibroblasts to normal fibroblasts, others receiving only normal fibroblasts and GCV. The eyes were examined by indirect ophthalmoscopy on days 4, 7, 14, and 28, and PVR was classified into six stages (0-5). RESULTS: Proliferative vitreoretinopathy was induced and progressed over time in each group. On day 28, PVR was most severe in animals in group B (average stage, 4.6) and group C (average stage, 4.4). Proliferative vitreoretinopathy was inhibited in group A (average stage, 1.0). The groups that received mixed injection of HStk fibroblasts and normal fibroblasts had intermediate PVR. Results of histologic study showed no apparent toxic or pathologic reaction in the retinochoroidal tissue of group A animals. CONCLUSIONS: Severity of experimental PVR clearly was reduced by transfer of the HStk gene and administration of GCV. This inhibitory effect also was produced by a combination of 10% HStk fibroblasts and 90% normal fibroblasts, indicating a significant bystander effect. These data suggest the potential of somatic gene therapy for the treatment of PVR.     

Firing rate analysis using decompostion-enhanced spike triggered averaging in the quadriceps femoris

Electromyographic signals detected from the quadriceps femoris during various constant force contractions were decomposed to identify individual motor unit discharges and mean firing rates (FRs). Subject and group mean FRs were calculated for each force level. Mean FR values and FR variability increased with force. Individual, subject, and group mean FRs showed slight increases until 30% of maximum voluntary contraction and larger increases thereafter. Findings are discussed in relation to motor unit recruitment, frequency modulation, and fatigue.     

The induction of cyclooxygenase-2 by interleukin-4 in human umbilical vein endothelial cells: a possible role in regulation of fetal vascular tone

In immunocytes from the mollusc Mytilus galloprovincialis, the major pathway followed by platelet-derived growth factor (PDGF)-AB and transforming growth factor (TGF)-beta1 in provoking the release of norepinephrine, epinephrine and dopamine into cell-free hemolymph (serum) is mediated by a corticotropin-releasing hormone-adrenocorticotropin hormone (CRH-ACTH) biogenic amine axis. This axis not only annulled the inhibiting properties of PDGF-AB, it even reversed the latter's effect, while the inducing effect of TGF-beta1 was amplified. These findings show that non-classical immune-neuroendocrine molecules, such as PDGF-AB and TGF-beta1, are involved in building stress response, using the same conserved mechanisms present from invertebrates to vertebrates.     

Separate jasmonate-dependent and salicylate-dependent defense-response pathways in Arabidopsis are essential for resistance to distinct microbial pathogens

The endogenous plant hormones salicylic acid (SA) and jasmonic acid (JA), whose levels increase on pathogen infection, activate separate sets of genes encoding antimicrobial proteins in Arabidopsis thaliana. The pathogen-inducible genes PR-1, PR-2, and PR-5 require SA signaling for activation, whereas the plant defensin gene PDF1.2, along with a PR-3 and PR-4 gene, are induced by pathogens via an SA-independent and JA-dependent pathway. An Arabidopsis mutant, coi1, that is affected in the JA-response pathway shows enhanced susceptibility to infection by the fungal pathogens Alternaria brassicicola and Botrytis cinerea but not to Peronospora parasitica, and vice versa for two Arabidopsis genotypes (npr1 and NahG) with a defect in their SA response. Resistance to P. parasitica was boosted by external application of the SA-mimicking compound 2, 6-dichloroisonicotinic acid [Delaney, T., et al. (1994) Science 266, 1247-1250] but not by methyl jasmonate (MeJA), whereas treatment with MeJA but not 2,6-dichloroisonicotinic acid elevated resistance to Alternaria brassicicola. The protective effect of MeJA against A. brassicicola was the result of an endogenous defense response activated in planta and not a direct effect of MeJA on the pathogen, as no protection to A. brassicicola was observed in the coi1 mutant treated with MeJA. These data point to the existence of at least two separate hormone-dependent defense pathways in Arabidopsis that contribute to resistance against distinct microbial pathogens.     

Neurogenic pulmonary edema. Pathogenesis, clinical picture and therapy

Neurogenic pulmonary edema (NPE) is a rare but always life-threatening complication in patients with central nervous system lesions. NPE is evident if patients shortly after cerebral lesions suddenly develop pulmonary edema and other causes of the symptoms, such as aspiration of gastric content, congestive heart failure and direct toxic exposure, are ruled out. METHODS: The current body of literature, partially obtained by computer-guided search (Winspirs) regarding epidemiology, pathophysiology and therapy of NPE was reviewed. Additionally, the case of a patient who developed a sudden pulmonary edema after an episode of tonic-clonic seizures is analyzed. We first provide information about history, definition, incidence and mortality of NPE. Second, a case report of a postictal NPE is presented to illustrate the clinical picture of NPE, and the applied therapeutic strategies are discussed. Third, recent pathophysiologic concepts about symptoms and possible therapeutic principles are reviewed. Fourth, a rational therapeutic plan for the prehospital emergency therapy of NPE is outlined. RESULTS: The different etiologies all have one characteristic feature: an acute emergency which causes increased intracerebral pressure (ICP). NPE is known in patients after cerebral trauma, intracranial hemorrhage, stroke, intracranial tumor or seizures. The incidence is estimated at around 1% after cerebral trauma, at 71% after cerebral hemorrhage and at 2% after seizures. Mortality is appraised to lie between 60 and 100%, independent of etiology. There is a definite pathophysiologic sequence leading to NPE: a central nervous system lesion causes a sudden increase in ICP which triggers an upregulation of sympathetic signal transduction to assure brain perfusion. Increased tonus of venous and arterial vessels and of myocardial function are the immediate consequences. However, if systemic vascular resistance (SVR) increases excessively, left ventricular failure and finally pulmonary edema (NPE) may result. Additionally, the protein-rich edema fluid points to an increased endothelial permeability within the pulmonary circuit. This is thought to be caused by the acute pressure increase and by neurohumoral mechanisms, possibly similar to those described for the systemic inflammatory response syndrome (SIRS). The most important central nervous system structures involved in NPE are the medulla oblongata and the hypothalamus. CONCLUSION: NPE is always a life-threatening symptom after increased ICP, where immediate therapeutic interventions are imperative. A rational therapeutic approach needs to be focused on decreasing ICP as primary goal. Additionally, attempts should be made to optimize body oxygenation, decrease pre- and afterload and increase myocardial contractility. Postictal patients suspicious for incipient ventilation problems must be admitted to hospital for further evaluation.