Supramedullary modulation of sympathetic vasomotor function

1. Supramedullary structures including the ventral medial prefrontal cortex (MPFC) and the midbrain cuneiform nucleus (CnF) project directly and indirectly to premotor sympatho-excitatory neurons of the rostral ventrolateral medulla (RVLM) that are critically involved in the generation of sympathetic vasomotor tone. 2. Electrophysiological studies have demonstrated that activation of depressor sites within the MPFC is associated with splanchnic sympathetic vasomotor inhibition and inhibition of the activity of RVLM sympathoexcitatory neurons. 3. Antidromic mapping and anatomical studies support the notion that a relay in the nucleus tractus solitarius is involved in the cardiovascular response to MPFC stimulation. 4. The midbrain CnF, which lies adjacent to the midbrain periaqueductal grey, is a sympathoexcitatory region of the midbrain reticular formation. Sympathoexcitatory responses evoked from the CnF are associated with short-latency excitation of RVLM neurons. 5. Cuneiform nucleus stimulation induces the expression of mRNA for the immediate early genes c-fos and NGFI-A in mid-brain, pontine and hypothalamic structures. 6. The MPFC and CnF are supramedullary structures with opposing modulatory influences on sympathetic vasomotor drive, whose roles in cardiovascular control mechanisms warrant further investigation.     

Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis

OBJECTIVE: The structure of the collagen scar during healing of a myocardial infarction is a determinant of the function of the remodeled tissue. We hypothesize that the passive deformations of both scar and normal tissue are related to the underlying collagen uncoiling as the tissue stretches, and that the unloaded tortuosity of the collagen may be a determinant of tissue stiffness at low ventricular pressure. Hence collagen uncoiling and tissue strain were measured during passive loading in normal tissue, and in healing infarct tissue. METHODS: Left ventricles of rats were infarcted by ligation of the left anterior descending artery for 2 weeks. Surface strains were measured during passive inflation in the scar region in one set of excised hearts, and other arrested hearts were fixed at different ventricular pressures, after which collagen tortuosity was measured in the infarcted and normal tissue. RESULTS: Passive loading strains were smaller in the scar in both the fiber and cross-fiber directions. Tortuosity decreased with load in normal and infarcted tissue, with fibrils tending to straighten more in the scar tissue at higher pressures (1.056 +/- 0.009 vs. 1.024 +/- 0.009 at P = 20 mmHg) with similar tortuosities at zero pressure (1.110 +/- 0.012 vs. 1.098 +/- 0.019). The decrease in tortuosity with strain was greater for the infarcted tissue. CONCLUSIONS: The greater stiffness of infarcted tissue at low pressure is not due to 'straightened' collagen fibers, and there may be a different three-dimensional structure of infarct vs. normal coiled collagen fibers which can affect the material properties of these tissues.     

Laboratory studies in cross-species lung transplantation

The lack of sufficient suitable human donor lungs for the many patients requiring pulmonary transplantation as life-saving therapy for end-stage lung diseases has generated extensive interest in cross-species lung transplantation. Ethical concerns and those of animal rights advocates have prompted studies of nonprimate species as potential solid organ donors for humans. This paper provides an overview of some of the laboratory studies of cross-species pulmonary transplantation performed over the past 20 years and focuses, in particular, on more recent work (from our laboratory and others) in the area of porcine-to-primate pulmonary xenotransplantation.     

Oncological outcomes of operative treatment of subcutaneous soft-tissue sarcomas of the extremities

We reviewed the cases of sixty-two patients who had had a subcutaneous sarcoma to determine the effect of tumor and treatment-related variables on the rates of survival and local recurrence. Fifty-nine (95 per cent) of the patients had had an operation at another hospital before being referred to us. Twenty-nine (47 per cent) of the sixty-two tumors were high-grade, forty-two (68 per cent) were small (five centimeters or less), and thirty (48 per cent) were malignant fibrous histiocytomas. We followed a treatment strategy that consisted of repeat excision with the goal of obtaining wide margins. Excluding thirteen patients who had had a palpable local recurrence at the time of presentation, twenty (49 per cent) of forty-one patients who had had a marginal excision at another hospital had microscopic residual tumor on repeat excision. At a median of fifty-six months after the repeat excision, fifty (81 per cent) of the sixty-two patients had been continuously disease-free, one had no evidence of disease, eight had died of the disease, and three had died of other causes. The five-year rate of disease-free survival was 85 per cent (fifty-three of sixty-two patients). There were three local recurrences, all in patients who had had a marginal resection. No recurrences were noted in patients who had had a wide local excision of the tumor or of the previous operative field. Multivariate analysis revealed that a large tumor (greater than five centimeters), a marginal excision, and adjuvant radiation therapy were associated with a worse prognosis. Excellent rates of survival for patients who have a subcutaneous sarcoma, including those who have a large or high-grade tumor and those who have residual tumor following a previous operation, can be obtained with carefully planned operative treatment alone. We recommend operative excision or repeat excision with wide margins because of the high prevalence of residual tumor. Size is the most important tumor-related factor, and the operative margin is the most important treatment-related factor. The additional value of adjuvant radiation therapy remains unproved.     

A shared genetic mechanism for melanotic encapsulation of CM-Sephadex beads and a malaria parasite, Plasmodium cynomolgi B, in the mosquito, Anopheles gambiae

Dialysis dose and malnutrition have a great impact on the clinical out come of chronic hemodialysis patients. The interrelationships between them, however, remain undefined. Thus, we performed a study to determine the effects of increasing the dialysis dose on serum albumin concentrations and mortality in hemodialysis patients. We examined urea kinetic modeling, biochemical nutritional indices, comorbid conditions, patient survival time, and annual mortality rate. Dialysis dose, measured by Kt/V, significantly increased from 1.3 +/- 0.3 in 1987 to 1.5 +/- 0.4 in 1990 and to 1.7 +/- 0.4 in 1993. Serum albumin level also increased from 3.8 +/- 0.4 g/dL in 1987 to 4.0 +/- 0.4 in 1990 and to 1.7 +/- 0.4 in 1993. In 1993, 76% of patients had Kt/V > or = 1.50 compared with 45% in 1990 and 28% in 1987, whereas 82% of patients had a serum albumin level > or 4.0 g/dL in 1993 compared with 58% in 1990 and 29% in 1987. Protein catabolic rate and hematocrit also increased from 1987 to 1993, but not serum cholesterol or triglyceride. The annual mortality rate declined from 16.1% in 1987 to 13.2% in 1990 and to 8.0% in 1993. The decrease in mortality appeared to be unrelated to differences in patient selection or comorbid conditions. Serum albumin levels, hematocrit, Kt/V, and protein catabolic rate were significantly related to patient survival after age, sex, and diabetic status had been adjusted. Furthermore, there was a positive correlation between Kt/Vs and serum albumin concentration (r = 0.216, P < 0.001). Thus it appears that increasing the dose of dialysis improves serum albumin levels and perhaps survival rate in hemodialysis patients as well.     

Acromioclavicular joint cyst and rotator cuff tear

The role of a depressor factor, atrial natriuretic peptide, in the development of arterial hypertension in adolescents with pubertal hypothalamic syndrome was studied in 52 patients and 13 healthy males aged 13-24 years. The duration of disease was 2-11 years. Radioimmunological methods were used to measure plasma atrial natriuretic peptide, plasma renin activity, and serum aldosterone. Patients with borderline arterial hypertension were found to have a significant reduction in their atrial natriuretic peptide levels, and this correlated directly with the renin-aldosterone system, demonstrating insufficiency of the depressor system in patients with pubertal hypothalamic syndrome and the involvement of atrial natriuretic peptide in the development of arterial hypertension, along with disturbances in the functional relationship between atrial natriuretic peptide and the renin-aldosterone system.     

Postmarketing surveillance: perspectives of a journal editor

In the absence of a systematic monitoring program for drugs newly approved by the Food and Drug Administration (FDA), reports in clinical journals provide a legitimate forum for disseminating information about unexpected pharmacologic events. A journal editor bears the responsibility for publishing educated clinical observations that meet standards of scientific rigor while not giving premature credibility to chance and dubious reports of side effects of new drugs. Often this responsibility involves overcoming the fear of bad publicity and withstanding pressures from pharmaceutical companies to print only positive information about new products. Published preliminary observations may contribute to the problem of product liability, but they also generate testable hypotheses and healthy debate. If hypotheses later prove to be incorrect, they can be refuted by systematic studies and clarified in reviews and editorials. Our goal of effective education will be reached not by self-censorship but by scientific openness.     

A 37-year-old man with multiple somatic complaints

Catecholamines and volume repletion are currently used for the treatment of septic shock. However, the prognosis of patients suffering from this condition is very poor. An overproduction of nitric oxide (NO) seems to be related to the hypotension and tissue damage of endotoxin shock. Thus, treatment with NO synthase inhibitors has been proposed. Using a rat model of septic shock we have studied the effects of noradrenaline or the NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NMMA) on arterial pressure, tissue damage and NO production. Anaesthetized rats treated with Salmonella typhosa showed a decrease in blood pressure accompanied by an increase in the plasma concentration of cytosolic enzymes (transaminases and lactate dehydrogenase, markers of cell disruption) and nitrite plus nitrate (NO2-/NO3-, markers of NO production). A large proportion of these animals (40%) died before the end of the experiment. Co-treatment with noradrenaline resulted in temporary maintenance of arterial pressure followed by a decline, despite the dose being increased progressively. No differences were observed in plasma cytosolic enzymes, NO2-/NO3- or mortality compared with animals treated with lipopolysaccharide (LPS) alone. In contrast, administration of L-NMMA (10 mg kg-1) to septic animals prevented the fall in blood pressure and death caused by endotoxin. This treatment markedly diminished cell disruption, as measured by the plasma levels of necrosis enzymes, and partially, but significantly, reduced the production of NO as assessed by plasma NO2-/NO3-. We conclude that tissue damage in septic shock is related to the overproduction of NO and not exclusively to the hypotension that follows this increased production. Thus, maintenance of blood pressure with catecholamines fails to improve cellular damage. Instead, partial inhibition of NO generation is sufficient to ameliorate the haemodynamic and tissue-damaging effects of septic shock and improves survival in this model of endotoxaemia.     

Transoesophageal echocardiographic assessment of haemodynamic function during laparoscopic cholecystectomy

We have measured cardiovascular changes associated with insufflation of carbon dioxide and the reverse Trendelenburg position during laparoscopic cholecystectomy, using transoesophageal echocardiography in 13 healthy patients. End-tidal carbon dioxide values increased after insufflation of carbon dioxide, with values significantly (P < 0.05) increased after lateral tilt positioning. Creation of a pneumoperitoneum was associated with increases (P < 0.05) in left ventricular end-systolic wall stress, concomitant with increases (P < 0.01) in peak airway pressure and systemic arterial pressure. In addition, left ventricular end-diastolic area decreased (P < 0.05) after reverse Trendelenburg positioning. Left ventricular ejection fraction was maintained throughout the study.