l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents.

OBJECTIVE: High-protein diets (HPDs) are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which HPDs exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may have a role in appetite regulation and satiety. We investigated the effects of l-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents. METHODS: We investigated the effects of the aromatic amino-acid and calcium-sensing receptor (CaSR) agonist l-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal (GI) hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral l-Phe administration on glucose tolerance in rats. RESULTS: Oral administration of l-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal l-Phe also reduced food intake in rats. l-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal l-Phe in rats, and l-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade. CONCLUSIONS: l-Phe reduced food intake, stimulated GLP-1 and PYY release, and reduced plasma ghrelin in rodents. Our data provide evidence that the anorectic effects of l-Phe are mediated via the CaSR, and suggest that l-Phe and the CaSR system in the GI tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.

A review of the relationship between patent foramen ovale and type II decompression sickness.

The significance of patent foramen ovale (PFO) in the pathophysiology of Type II decompression sickness (DCS) remains controversial. PFOs are common, occurring in approximately one quarter of the normal population, thus making right-to-left shunting of venous gas emboli (VGE) a theoretical concern in both hyper- and hypobaric situations. Despite this high prevalence of PFO in the general population, and the relatively common occurrence of venous gas bubbles in diving and altitude exposures, the incidence of Type II DCS in diving or with altitude is remarkably low. Although the literature supports a relationship between the presence and size of PFO and cryptogenic stroke, and an increased relative risk of Type II DCS with a PFO in divers, the absolute increase in risk accrued is small. Hence, the value of screening is also controversial. This paper presents a summary of the literature on PFOs and DCS in animals, and in human altitude and diving, focusing on the latter; as well the analogous literature on cryptogenic stroke. The results of an examination of the literature on detection of, screening for, and treatment of PFOs is also presented.

Exercise rhabdomyolysis in military aircrew: two cases and a review of aeromedical disposition.

INTRODUCTION: Exercise rhabdomyolysis (ER) is a rare, sometimes catastrophic condition where muscle fibers breakdown in response to exertion and release their breakdown products into the circulation. While ER was brought to the medical community's attention largely through reports from military training establishments we are unaware of ER having resulted from the activities of military aircrew. This paper reports two cases of ER in military aircrew and discusses the condition and the approaches taken in determining their future aeromedical disposition. CASE REPORTS: Rhabdomyolysis occurred in two military pilots as a result of their aircrew duties. One, an experienced pilot, suffered rhabdomyolysis as a result of centrifuge based G-training, while the other, a cadet in training, suffered rhabdomyolysis precipitated by exertion during moderately warm weather. Further investigation revealed the second case to also have the Malignant Hyperthermia Trait. AEROMEDICAL DISPOSTION: After wide consultation and lengthy deliberations both of these aircrew were returned to their full previous flying status. No further complications or recurrences have occurred.

Granisetron shows no pro-arrhythmic effect in normal subjects during or after exercise in a hot environment.

BACKGROUND: 5-HT3 receptor antagonists are being evaluated as possible agents to prevent nausea and vomiting associated with radiation exposure in a non-clinical military setting. Because of concern about potential cardiovascular toxicity and the observation that certain developmental 5-HT3 antagonists produced undesirable effects, all drugs in this class are being carefully scrutinized for possible adverse cardiac effects. METHOD: In this study, nine subjects underwent ambulatory ECG monitoring for an average of 21.6 h after a 2-mg oral dose of granisetron or placebo in a double-blind crossover protocol. Monitoring included a 3-h period of submaximal exercise in a 40 degrees C environment. RESULTS: Although isolated ventricular and supraventricular ectopic activity, sinus bradycardia, and pauses were found, there were no sustained arrhythmias observed in either the placebo or granisetron conditions. CONCLUSION: Although the generalizability of this study is limited by the small number of subjects, these observations add to the body of evidence confirming the lack of cardiovascular toxicity of granisetron.

Diabetes mellitus in aircrew--type I diabetes in a pilot.

Diabetes mellitus had traditionally been considered disqualifying for flying duties. Increasingly, our understanding of both Type I and Type II diabetes permits identification of subgroups of diabetics with an acceptable aeromedical risk. A case is presented of a Canadian Forces pilot with Type I diabetes who continues on restricted flying duties. The pathophysiology of Type I and Type II diabetes is discussed, as well as aeromedical considerations for returning a diabetic to flying status. Within an envelope of defined geographic and operational flying limitations, diabetic aircrew may be safely and usefully returned to restricted flying duties.

Echocardiographic and color flow Doppler findings in military pilot applicants.

This report details the findings of 1476 Canadian Forces pilot candidates screened with echocardiography and Doppler. All candidates had previously been medically screened at a recruiting center. We found 115 (7.8%) to have disqualifying findings. Mitral valve prolapse (MVP) was the most common (4.8%). Other abnormalities included aortic regurgitation (2.3%), bicuspid aortic valve (0.9%), left ventricular hypertrophy, asymmetric septal hypertrophy, and atrial septal defect (< 0.05%). Of the 71 candidates found to have mitral valve prolapse, 40 had positive clinical findings on careful auscultation. Echocardiography is a safe, cost-effective tool for screening candidates for military pilot training. Normative data on this population agree well with published norms.

The effect of captopril on +Gz tolerance of normotensives.

Recently, there has been considerable interest in whether angiotensin converting enzyme inhibitors can be used to treat hypertensive pilots without compromising their operational effectiveness. This study was undertaken to evaluate the possible effects of captopril on tolerance to +Gz, of relevance in tactical fighter operations. A counterbalanced double blind crossover protocol was used to administer 25 mg of captopril or placebo twice daily in identical capsules to seven fit, normotensive individuals from the DCIEM acceleration research panel. The five males and two females took each course of capsules for 4 d prior to G-tolerance assessment and waited 1 week for drug wash-out after assessment on their first condition prior to commencement of the second course of capsules. The subjects did not wear G-suits. Standard ASCC gradual onset runs, relaxed and with a straining maneuver, and rapid onset runs were used to assess G tolerance. The group G tolerances are listed as mean +/- S.E.M.: during relaxed gradual onset runs (GOR) 3.96 +/- 0.14 on placebo and 3.61 +/- 0.10 on captopril (p = 0.02, paired t-test). Corresponding results for relaxed rapid onset runs (ROR) were 3.36 +/- 0.17 on placebo and 3.33 +/- 0.18 on captopril (p = 0.21, Wilcoxon signed ranks test). The straining tolerances during GOR runs were 7.21 +/- 0.23 on placebo and 6.83 +/- 0.25 while on captopril (p = 0.05, paired t-test). Given the relatively low dosage and the significant compromise of Gz-tolerance on both relaxed and straining GOR runs, caution is recommended in using captopril to treat hypertensive fighter aircrew.(ABSTRACT TRUNCATED AT 250 WORDS)

Permanent grounding and flying restrictions in Canadian Forces pilots: a 10-year review.

The medical files were reviewed of all Canadian Forces pilots in whom a permanent change in flying category was recommended during the period 1 January 1978 through 31 December 1987. In an average pilot population of 2,697 pilots, 60 permanent groundings (2.2 per thousand) and 209 permanent operational flying restrictions (7.7 per thousand) were assigned among 258 pilots. Coronary heart disease was the most common cause for permanent grounding (25% of total), followed by neurologic disorders including migraine (22% of total), other cardiovascular disorders, including mitral valve prolapse and arrhythmias (17%), and psychiatric problems (12%). Refractive errors were the most common basis for an operational flying restriction (25%), followed by orthopedic disorders (17%), mainly low back pain. The relevance of these observations is discussed in terms of medical selection and surveillance procedures.

Cases from the aerospace medicine residents' teaching file. Case #26. A fighter pilot with a single left frontal lobe infarction and probable mitral valve prolapse and supraventricular arrhythmias.

A fighter pilot with a single left frontal lobe infarction and probable mitral valve prolapse and supraventricular arrhythmias is presented. He was found unfit for flying duties as a fighter pilot, but because of his experience and expertise he was restricted to flying with a qualified copilot in aircraft other than fighters, with regular aeromedical followup.

Closed versus open kinematic chain measurements of subtalar joint eversion: implications for clinical practice.

Subtalar joint (STJ) range of motion is most critical during the support phase of the gait cycle. The purpose of this study was to determine what differences exist between measures of maximal STJ eversion in open chain and closed chain positions. STJ eversion as a component of STJ pronation was measured in nonweightbearing (NWB) and full weightbearing (WB) positions on 17 subjects who had no significant biomechanical or orthopaedic abnormality. STJ WB eversion was significantly greater than NWB passive ROM. These results indicate that accurate assessment of STJ eversion as a component of pronation requires measurement in a functional WB position as well as in a NWB position. Rehabilitation of persons with lower quarter injuries or disabilities require assessment of ROM in WB positions so that a more accurate and complete evaluation can be done allowing the clinician to make an appropriate diagnosis and treatment.J Orthop Sports Phys Ther 1988;9(9):310-314.

Hypoxia-induced vasopressin release and coagulopathy in a normal subject.

Humans exposed to hypoxia usually increase their plasma procoagulant VIII activity (VIII:C) with no change in the concentration of VIII related antigen (VIIIR:Ag). This case report describes an apparently normal subject who developed marked qualitative and quantitative changes in all components of the factor VIII complex while inhaling an 11% oxygen/balance nitrogen gas mixture for 2 h. Blood from fresh venepunctures was drawn at baseline, during and after exposure to hypoxia for the following: a partial thromboplastin time, a prothrombin time, fibrin monomer, factor VIII:C, VIII procoagulant antigen (VIII:CAg); ristocetin cofactor activity (VIIIR:Co); VIII von Willebrand factor (VIII:vWF) multimer pattern; and arginine vasopressin. During hypoxia VIII:C, VIII:CAg, VIIIR:Ag and VIIIR:Co increased 4 to 5 fold; the VIII:vWF multimer pattern showed increasing low molecular weight complexes, fibrin monomer appeared and arginine vasopressin (AVP) levels increased from 5.5 pg . ml-1 to 73.8 pg . ml-1. These changes are compatible with both the release of the VIIIR:Ag by AVP and protease induced fragmentation of the VIII complex.

Effects of exercise on lung lymph flow in sheep and goats during normoxia and hypoxia.

Vigorous exercise causes a marked increase in cardiac output with only a minimal increase in measureable pulmonary vascular pressures. These changes in pulmonary hemodynamics should affect lung water and solute movement. On nine occasions, we measured the effect of normoxic exercise on lung lymph flow in four sheep and two goats with chronic lymph fistulas (wt = 15-25 kg). In addition, lymph flow was also measured on five occasions in sheep during exercise at reduced barometric pressures (430 and 380 mmHg). During normobaria, the animals ran at 3-5 km/h with 0-10% elevation of the treadmill for 15 to 85 min. Exercise on average caused a 100% increase in cardiac output, a 140% increase in lung lymph flow, and a slight but significant reduction in lymph to plasma concentration ratio (l/p) for total protein and albumin (mol wt = 70,000). There was a significant linear correlation between lymph flow and cardiac output (r = 0.87, P less than 0.01). There was no change in l/p for IgG (mol wt = 150,000) or IgM (mol wt = 900,000) and no significant change in mean pulmonary arterial (Ppa) or mean left atrial (Pla) pressures. Transition from normobaria to hypobaria caused an increase in Ppa but no change in Pla, cardiac output, or lymph flow. Exercise during hypobaria caused increases in lymph flow that were qualitatively similar to changes observed during normobaric exercise: there was a 60% increase in cardiac output, a 90% increase in lymph flow, and an 11% reduction in l/p for total protein. There was no change in l/p for albumin, IgG, or IgM, and no further change in Ppa. The increased lymph flow during normoxic and hypobaric exercise is best explained by an increase in pulmonary vascular surface area for fluid and protein exchange. Our results suggest that the normal ovine lung has the potential to nearly triple the amount of perfused microvascular surface area. This speculation is relevant to the interpretation of lymph flow data from other experiments.

Hypoxia alters blood coagulation during acute decompression in humans.

Acute decompression is associated with a shortening of the activated partial thromboplastin time (aPTT). This study was performed to examine whether this change in aPTT results from hypoxia or hypobaria. We exposed healthy adults on three separate occasions to 2 h of 1) hypoxic hypobaria (410 Torr, n = 5), 2) hypoxic normobaria (fractional inspired O2 tension = 0.11, n = 4), or 3) normoxic hypobaria (410 Torr breathing supplemental O2, n = 5). The aPTT shortened during hypoxic hypobaria and hypoxic normobaria (P less than 0.05) but was unchanged during normoxic hypobaria. The prothrombin and thrombin times, hematocrit, and concentrations of fibrinogen, total plasma protein, and fibrinogen-fibrin fragment E were unchanged. During hypoxic hypobaria biologic levels of prekallikrein, high-molecular-weight kininogen, and factors XII, XI, X, VII, V, and II were unchanged, but procoagulant VIII (VIII:C) increased 50% without an increase in VIII-related antigen levels (VIIIR:Ag). Fibrin monomer was not detected in any group. In one subject who became ill after 1.5 h of hypoxic normobaria aPTT shortened by 10 s; the platelet count decreased by 93,000/mm3; VIII:C increased fivefold, but VIIIR:Ag only increased three-fold. We conclude that it is the hypoxia which shortens aPTT during acute decompression to 410 Torr and speculate that it results from an increase in plasma VIII:C-like activity.

Hypobaric hypoxia does not affect lung fluid or protein exchange in awake adult sheep at rest.

We measured pulmonary artery (Ppa) and left atrial (Pla) pressures, lung lymph flow, and lymph/plasma protein concentrations in four adult sheep at a barometric pressure of 380 Torr (1 Torr = 133.322 Pa) for 22 h. Hypobaric hypoxia caused an immediate increase in Ppa from 20 to 39 Torr. There was no significant change in Pla, lymph flow, or lymph protein concentrations. We conclude that hypobaric hypoxia does not affect lung fluid or protein exchange in awake adult sheep at rest.

High-altitude retinopathy.

Thirty-nine healthy subjects were examined before and after a stay at 5,360 m by ophthalmoscopy and by retinal photography. Twenty of them were also tested for visual acuity, scotomata, and capillary leakage. Vascular engorgement and tortuosity and disc hyperemia were seen in all subjects at altitude and are a "normal" response to hypoxia. Twenty-two (56%) of the subjects had retinal hemorrhages and one showed "cotton-wool spots". These changes are abnormal reactions and are considered high-altitude retinopathy. After maximal exertion on a cycle ergometer, fresh hemorrhages were observed in seven of 34 subjects. The incidence of hemorrhage associated with exercise was significantly greater than predicted. Fluorescein leakage was noted after exercise in eight of 20 persons tested and was associated with exercise-induced hemorrhages. Two persons developed premacular hemorrhages.

Altered stability and integration frequency of a F' factor in RNA polymerase mutants of Escherichia coli.

A number of spontaneous rifampicin-resistant (Rifr) mutants were isolated from a strain of E. coli having a deletion in the lac proA proB region of the chromosome. The stability of a F'lac proA proB episome in these mutants was determined by their sensitivity to acridine orange curing and the frequency of spontaneous loss of episomes. The Rifr mutants can be divided into three classes based on their ability to maintain the F'lac pro episome. Class I mutants (25% of the total Rifr mutants) showed high degree of spontaneous episome loss and high sensitivity to acridine orange curing. Class II mutants (55% of the total Rifr mutants), like the parent strains, showed intermediate sensitivity to acridine orange curing. Class III mutants (21% of the total Rifr mutants) showed high resistance to acridine orange curing and low frequency of spontaneous episome loss. Three-fourths of the Class II mutants were found to be Hfr as shown by their lack of the F'lac pro DNA band on agarose gel together with their ability to mobilize chromosomal markers in mating. Representative Rifr mutants from each class were selected and the Rifr mutants from each class were selected and the Rifr mutations were mapped within the proB gene for the beta beta' operon by P1 transduction. These results indicate that RNA polymerase, or the beta subunit of RNA polymerase, plays an important role in maintaining the F' lac pro episome and in the integration of the F' lac pro episome where no extensive sequence homology is involved.

Retinal studies at 446 torr in a hypobaric chamber.

This study was designed to see if retinal haemorrhage occurred after 24 h of decompression to a pressure of 446 torr. Four subjects were studied after 24 h of decompression and had retinal photography and fluorescein angiography performed at rest and following maximum exercise. No haemorrhages or fluorescein leakage was noted, even though the subjects experienced typical symptoms of acute mountain sickness and showed an increase in lung density-consistent with subclinical pulmonary edema. We conclude that 24 h exposure to 446 torr with a period of maximal exercise is an inadequate stress, either in time and/or degree, of hypoxia to produce retinal haemorrhage or leakage, as measured by flourescein.