Nelson J. Gurll

A familial visceral myopathy with external ophthalmoplegia and autosomal recessive transmission

A new visceral myopathy family was identified. The disease in this family is transmitted by an autosomal recessive gene. Only 3 patients were identified from approximately 1500 family members. All 3 patients are the products of intermarriage. The patients had gastric atony, dilatation of the entire small bowel, and multiple diverticula throughout. Pathology of the jejunum showed fibrosis and degeneration, mainly of the longitudinal muscle layer, indistinguishable from that of previously reported families. Two of the patients also had ptosis and external ophthalmoplegia. Jejunal manometric studies were performed on the probands asymptomatic mother and five siblings. All had normal esophageal manometric studies and upper gastrointestinal x-rays. The mother and three siblings had abnormal jejunal manometric studies characterized by the absence of phase 1 in some of the migrating motor complexes and increased motility indices in phase 2. We conclude that familial visceral myopathy can be transmitted by an autosomal recessive gene, and that jejunal manometry is a sensitive technique to identify asymptomatic heterozygotes.

Evidence for a role of endorphins in the cardiovascular pathophysiology of primate shock.

Using the opiate receptor antagonist naloxone, we tested the hypothesis that endorphins act on opiate receptors to cause cardiovascular depression in primate shock. Mean arterial pressure (MAP), cardiac output, and left ventricular contractility (LV dP/dtmax) were measured in 34 anesthetized cynomolgus monkeys. Hemorrhagic shock was induced by bleeding into a heparinized reservoir to achieve (t = 0) and maintain MAP at 45 mm Hg. At t = 60 min, the reservoir was clamped and the animals were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 5) or 0.9% NaCl as a control (n = 5). There were no significant differences in the cardiovascular responses to naloxone and saline when acid-base balance and core body temperature were not controlled. Pressor responses to naloxone, however, were present in proportion to arterial pH and body temperature. When these factors were controlled, naloxone (n = 6) significantly increased MAP and LV dP/dtmax by 48% and 83%, respectively, whereas saline (n = 6) had no significant effect. Blood was reinfused at t = 120 min, and survival rate at 72 h was significantly (p = .01) higher with naloxone (3/6) than saline controls (0/6). In the endotoxic shock model, cynomolgus monkeys were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 6) or 0.9% NaCl (n = 6) when MAP reached 75 mm Hg or its nadir 60 to 90 min after Escherichia coli endotoxin, 5 mg/kg iv. Naloxone significantly increased MAP and LV dP/dtmax by 24% and 22%, respectively, whereas saline had no effect. Survival rate at 48 h was significantly (p = .01) higher with naloxone (6/6) than saline (1/6). Plasma beta-endorphin and beta-lipotropin concentrations rose three to five-fold in both shock models and were not affected by treatment. We conclude that endorphins are activated in primate shock and act on opiate receptors to contribute to the cardiovascular depression found with hemorrhage and endotoxemia.

Tc-99m MIBI scintigraphic detection of metastatic insular thyroid carcinoma.

Thallium-201 and, recently, Tc-99m MIBI have been used in conjunction with I-131 scintigraphy for follow-up of patients with well-differentiated thyroid cancer. Insular carcinoma of the thyroid is a fairly aggressive thyroid neoplasm that is believed to arise from follicular cells and usually concentrates I-131. The authors report a patient with recurrent insular thyroid carcinoma in whom bilateral adrenal and lung metastatic lesions developed 3 years after ablative I-131 therapy for cervical lymph node and skeletal metastases. Tc-99m MIBI planar and SPECT images demonstrated these new lesions better than pretherapy I-131 scintigraphy and affords an imaging technique for post-I-131 therapy follow-up that does not require withholding thyroid hormone suppression.

The interaction of corticosteroids and naloxone in canine hemorrhagic shock

Abstract β-Endorphin is released concomitantly with adrenocorticotropin from the pituitary following stress and, during hemorrhagic shock, can alter cardiovascular hemodynamics. In 41 anesthetized dogs, we assessed the combined effects of pituitary suppression with dexamethasone (D) or methylprednisolone (M) and opiate receptor blockade with naloxone (N) during hemorrhagic shock. We found that N alone was the most effective treatment in improving arterial pressure, cardiac output, and left ventricular contractility and resulted in the best survival. D and M alone were little better than saline. When combined with N, D and M were better than saline but not as good as N alone. This attenuation of the N effect may be due to corticosteroid: suppression of β-endorphin and ACTH release from the pituitary; alterations in opiate metabolism; or changes in opiate receptor availability.

High-dose, short-term local urokinase for clearing femoral thrombi by vasodilation and thrombolysis

Abstract 1. 1. Intra-arterial infusion of urokinase results in a sustained increase in femoral arterial blood flow which is dose- and preparation-related. 2. 2. This vasodilation is separable from the fibrinolytic activity of urokinase since the latter but not the former is attenuated by inhibition of plasminogen activation. 3. 3. Intra-arterial infusion of urokinase induces a local fibrinolytic state which is more effective than systemic administration in achieving thrombolysis. 4. 4. Similar doses are required for vasodilation and local fibrinolysis-thrombolysis, thus suggesting the clinical use of intra-arterial urokinase in thrombotic occlusions of the femoral artery.

Effects of TRH in Circulatory Shock and Central Nervous System Ischemia

bNeuropharmacology Branch Department of Medical Neurosciences Division of Neuropsychiatry Walter Reed Army Institute of Reseurch Washington, DC 20307-5100 dResearch Institute of Surgery Chongquing, Sichuan Province, Peoples Republic of China eDepartment of Surgery University of South Florida, College of Medicine Tampa, Florida 33612 fDepartment of Surgery University of Iowa College of Medicine Iowa City, Iowa 52242

Thyrotropin releasing hormone: effects in monkeys and dogs subjected to experimental circulatory shock

We tested the hypothesis that thyrotropin releasing hormone (TRH) would improve cardiovascular function and survival in circulatory shock by opposing the adverse effects of endogenous opioids and other pathophysiologic mediators. Cynomolgus monkeys and mongrel dogs were anesthetized and catheterized to measure mean arterial pressure (MAP) and left ventricular contractility (LV dp/dtmax). Hemorrhagic shock was induced by bleeding into a reservoir to achieve and maintain MAP at 45 mm Hg for one hour. Endotoxic shock was produced by the iv injection of an LD80 dose of Escherichia coli lipopolysaccharide endotoxin (3 mg/kg in dogs and 5 mg/kg in monkeys). Animals were treated iv with either TRH (2 mg/kg plus 2 mg/kg X h) or equivolume saline. TRH significantly increased MAP and LV dp/dtmax in primate hemorrhagic and endotoxic shock. In primate hemorrhagic shock, TRH significantly (p = .02) improved survival (alive/total = 4/5 vs. 0/5). However, TRH had no effect on survival in endotoxemic primates. In contrast, TRH treatment in dogs produced only a transient hemodynamic response after endotoxemia and no significant hemodynamic effect after acute hemorrhage (even at twice the TRH dose). TRH did not affect survival in either dog model of circulatory shock. Based on extensive evidence with the opiate receptor antagonist naloxone in other studies, endogenous opioids play a role in the cardiovascular depression in primate and canine circulatory shock. From these studies with TRH, we conclude that TRH is relatively ineffective in canine circulatory shock, and physiologic antagonism of the adverse effects of opioids and other cardiodepressant substances by TRH administration may prove to be a useful alternative treatment of primate hemorrhagic shock.

Autonomic effects of central injections of D-Ala2-Met-enkephalinamide (DAME) in the conscious monkey.

The use of naloxone (NAL), an opioid receptor antagonist, has provided indirect evidence that endogenous opioids contribute to cardiovascular depression during shock. To determine if endogenous opioids act centrally to influence cardiovascular function, injections of D-Ala2-Met-enkephalinamide (DAME), a potent Met-enkephalin analog, were made into the 3rd cerebral ventricle (ICV) of 5 conscious cynomulgus monkeys restrained in primate chairs. Systolic blood pressure (SBP) and heart rate (HR) were determined every 10 min during a 30-60 min control period and for up to 5 hr post-injection. Colonic temperature (Tc) was monitored continuously. SBP declined from baseline values with 50 and 100 micrograms (85.2 and 170.4 nM) doses but was significant (p less than 0.001) for only the 100 micrograms dose between 15-125 min post-injection. HR also decreased but did not exhibit any significant variation with time. However, when averaged across time, HR fell significantly (p less than 0.001) from baseline: -9.1 +/- 2.3 and -15.0 +/- 2.1 b/min for 50 and 100 micrograms DAME, respectively. Tc displayed a nonsignificant, delayed (greater than 2 hr) rise in Tc with the 50 micrograms dose, whereas the 100 micrograms dose caused a significant (p less than 0.001) decline in Tc (from 65-125 min post-injection). NAL injected ICV attenuated the effects of DAME but had no effect on SBP, HR or Tc when injected alone. Systemic injection of DAME (300 micrograms) in one monkey produced a transient decline in SBP (26 mmHg within 2 min) which returned to baseline values 4 min post-injection. HR and Tc were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of endotoxemia and fluid expansion on gastric hemodynamics and mucosal permeability in the baboon

Abstract The effects of sublethal intravenous endotoxin on gastric hemodynamics and mucosal ionic permeability were studied in eight adult baboons. Each baboon had construction of an internally drained Heidenhain pouch 2 weeks prior to testing. Ionic fluxes were determined by instillation and recovery of an acid test solution (ATS) containing 80 m M HCI and 80 m M NaCl. Four hours of endotoxemia resulted in significant decreases in cardiac output and mucosal blood flow to about one-half of control values. There was a small but insignificant increase in hydrogen back diffusion from −58 ± 26 to −131 ± 59 μequiv/ 30 min/100 cm 2 and no significant change in sodium flux from + 183 ± 44 μequiv/30 min/100 cm 2 with shock. Endotoxic shock resulted in a significant decrease in the transmucosal electrical PD from 40 ± 3 to 29 ± 4 mV with a significant increase in potassium flux from 6 ± 2 to 11 ± 3 μequiv/ 30 min/100 cm 2 , both indicating mucosal damage. All pouches developed acute superficial erosions. Fluid resuscitation corrected blood flow and cardiac output without significantly changing ionic fluxes or potential difference. In the baboon, endotoxemia and its attendent ischemia in the presence of acid may result in clinically significant stress ulcers without significant increases in gastric mucosal ionic permeability.

Effects of opiate receptor drugs injected intracerebrally into the normovolemic and hypovolemic monkey

Systemic injection of naloxone (NAL), an opioid-receptor antagonist, significantly elevates systolic blood pressure (SBP) in anesthetized hypovolemic monkeys, providing indirect evidence that endogenous opioids contribute to cardiovascular depression during shock. The purpose of this study was to identify specific centrally located opioid receptor sites that participate in SBP regulation under normovolemic and hypovolemic conditions. In 6 monkeys, bilateral guide cannulae were stereotaxically implanted above areas ranging from the diencephalon to the lower medulla. Microinjections (1 microliter) of D- Ala2-Met-enkephalinamide (DAME) (3.4-27.2 nM) into normovolemic unanesthetized monkeys reduced SBP by 10-65 mm Hg in a dose-related fashion. Subsequent injection of NAL (12.2 nM) attenuated this hypotensive response. Heart rate fell 20-40 bpm with DAME, but not in response to dose. In the anesthetized animal rendered hypotensive (SBP = 45 mm Hg) by hemorrhage. NAL injected into predetermined DAME-sensitive sites failed to increase SBP more than 5 mm Hg. Even consecutive injections into multiple sites elevated SBP only 20 mm Hg. We conclude that the centrally located opioid-sensitive sites tested exert only a mild influence in mediating hemorrhagic hypotension.