Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure.

BACKGROUND. Endothelin is a family of potent vasoconstrictor peptides of vascular endothelial origin. Although it has been proposed that the vasoconstrictor effects of endothelin are produced at the local vascular level, increased plasma concentration of endothelin has been identified in cardiovascular disorders. METHODS AND RESULTS. We tested whether immunoreactive endothelin-1 could be detected by radioimmunoassay in plasma of congestive heart failure patients and whether levels correlated with hemodynamic characteristics. Twenty congestive heart failure patients (New York Heart Association class II-IV) were sampled in the morning after an overnight fast, before medication. Cardiac index was decreased to 2.14 +/- 0.45 l/m/m2, and pulmonary wedge pressure was increased to 22 +/- 7 mm Hg. The ranges of pulmonary pressures were: systolic, 22-100 mm Hg, mean, 13-61 mm Hg, and diastolic, 8-42 mm Hg. The endothelin-1 level was 9.07 +/- 4.13 pg/ml (range, 4-19 pg/ml), which was increased compared with 12 normals (3.7 +/- 0.6 pg/ml; range, 2.8-4.7 pg/ml); the difference was statistically significant (p less than 0.0001). Endothelin-1 significantly correlated with pulmonary pressures (systolic, r = 0.78; mean, r = 0.80; diastolic, r = 0.77; all p less than 0.003) and pulmonary vascular resistance (r = 0.65, p less than 0.01). Endothelin-1 strongly correlated with the resistance ratio (pulmonary vascular resistance/systemic vascular resistance) (r = 0.88, p less than 0.0001). Stepwise multiple regression analysis confirmed the significance of these observations. CONCLUSIONS. Elevated immunoreactive endothelin-1 specifically correlated with the extent of pulmonary hypertension in congestive heart failure patients. Whether endothelin-1 is a regional mediator of pulmonary hypertension or a marker for its occurrence requires additional evaluation.     

The pharmacokinetics of lignocaine in humans during a computer-controlled infusion.

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer-controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer-controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5 microg/ml were targeted for 15 min at each concentration. A three-compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two-stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three-compartment mammillary model fit to the measured concentration using the pooled data approach were: V(1) = 7.44, V(2) =11.5 and V(3) = 97.71; Cl(1) = 0.585, Cl(2) = 2.23 and Cl(3) =1.64 l/min. Similarly calculated parameters using NONMEM were V(1) = 6.99, V(2) =12.2 and V(3) =1341; Cl(1) = 0.703, Cl(2) =1.24 and Cl(3) =1.49 l/min. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer-controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer-controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long-lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.     

Risk factors of acute pancreatitis]

A total of 689 operative cases of acute necrotic pancreatitis (ANP) were collected from 42 hospitals all over the country by the ANP Cooperative Study Group in the years of 1987 to 1989. General data, laboratory findings, pathology of the pancreas and the type of surgical treatment were analysed according to the outcome of the patient. The results showed that 37% of the cases were related to cholelithiasis, the highest incidence was in age above 60, and female patients were predominant and with higher mortality. Laboratory findings at admission, WBC greater than 20,000/mm3, Hb greater than 15 g%, blood sugar greater than 200 mg%, serum bilirubin greater than 5 mg%, BUN greater than 20 mg%, and serum calcium less than 7 mg% were related to the markedly elevated mortality rate. Operative findings noted in patients with bloody or cloudy peritoneal fluid, necrotic changes up to 75% of the pancreas, more than 2 areas of extrapancreatic involvements and resection of a large portion of the pancreas was found to be necessary were all related to a higher mortality. And emergency operations performed within 24 hours after the onset of the disease was also related with a highest mortality rate.     

Reactivity of hydroxybenzoic acids in the hydrogen-isotope exchange reaction.

The hydrogen-isotope exchange reaction (T-for-H exchange reaction) between tritiated water vapor (HTO vapor) and 3-hydroxy-4-methoxybenzoic acid (and it's analog; 4-hydroxy-3-methoxybenzoic acid) were observed at 50 and 70 degrees C in a gas-solid system to reveal the reactivity of a functional group in an aromatic compound having two substituents in the aromatic ring. Further, it was shown that (a) the reactivity of the compounds used in this work follows the Hammett's rule, and (b) the reactivity of trisubstituted aromatic compound could be analyzed by applying the additive property of the Hammett's rule even if the compound contains a substituent at the ortho-position.     

围产儿与儿童胸腺的病理改变

The most outstanding pathological changes of perinatal babies and children, based on the review of the autopsy files in the 1st Affiliated Hospital of West China University of Medical Sciences, are lymphocytic depletion, and reticuloepithelial cell swelling and/or fusiform malformation in the cortex, while in the medulla apoptosis is more prominent. We suppose that these alterations are due to immaturity of cortical thymocytes, and in the diseased condition, they are easily affected by extraordinary factors, especially the influence of corticosterone inducing acute severe necrosis, so the number of lymphocytes are obviously diminished. But, in the medulla, as intact mature lymphocytes exist, physiological phenomenon such as apoptosis is rather prominent in it. While in the medulla, Hassall's corpuscles have various characteristic changes, such as cornification, calcification, fusion, cystic change and disintegration. Besides, we observed a new alteration in the thymus defined as vacuolization. All the above pathological changes reached the peak in the 28- day group; there after, they might become either worse or better according to the condition of the disease and growth of the body. However, these are still problems to be further studied separately.     

Managing the premenstrual syndrome

The definition, classification, proposed etiologies, diagnosis, and treatment of the premenstrual syndrome (PMS) are discussed, and guidelines for the clinical management of PMS are presented. PMS encompasses a cluster of physical and psychosocial symptoms that recur during each menstrual cycle. Proposed etiologies for the syndrome include a hormonal imbalance between estrogen and progesterone, pyridoxine hydrochloride deficiency, hypoglycemia, excess prostaglandin production, and increased aldosterone concentrations in the luteal phase of the menstrual cycle. Diagnosis of PMS is usually based on a patient's history of recurrent symptoms accompanied by a seven-day, symptom-free period in the first half of the menstrual cycle. Management of PMS is complicated by the difficulty in diagnosing the syndrome and its unclear etiology. If possible, conservative nonpharmacologic treatment should be tried initially; suggested measures include modifications in diet, exercise, substance use, stress factors, rest patterns, and social support. Pharmacologic treatment should be considered when conservative therapies are ineffective or when PMS symptoms are more severe. Although most therapies are empirical, treatment with progesterone, pyridoxine, bromocriptine, or diuretics might prove beneficial. Once the decision is made to initiate drug therapy, the treatment regimen should be individualized and based on the patient's PMS symptom complex. The clinical management of PMS is complicated by the lack of well-designed clinical investigations of proposed treatments. Future research should be directed toward evaluating the efficacy of proposed therapeutic regimens.     

Modulation of high-dose methotrexate toxicity by a non-toxic level of 5-fluorouracil

High-dose methotrexate (MTX) toxicity is reduced by a non-toxic dose of 5-fluorouracil (FU) when these agents are used in combination. Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, hemoglobin, and hematocrit), ileal tissue, body weight, and mean survival were used as parameters to assess toxicity. For all parameters studied, there were no significant differences between the scheduling of MTX (245 mg/kg) after a priming dose of FU (25 mg/kg), simultaneous MTX and FU, FU alone, and control. However, sequential treatment with MTX followed by FU, and MTX alone resulted in: a marked decrease in the hematopoietic parameters; significant morphological changes in ileal tissue; a reduction of body weight; and increased mortality of animals. Hence, this study suggests that FU, a cytotoxic agent, may protect against MTX toxicity and improve its therapeutic index when FU administration precedes MTX or when these agents are given simultaneously.