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To test the hypothesis that altitude exposure increases glucose utilization and that this increment is mediated by a beta-adrenergic mechanism, the effects of hypobaric hypoxia and beta-blockade on glucose rates of appearance (Ra), disappearance (Rd), oxidation (Rox), and leg uptake [G = 2(arteriovenous glucose difference)(1 - leg blood flow)] were measured during rest and a given submaximal exercise task. We studied six healthy beta-blocked (beta) men [26.7 +/- 1.2 (SE) yr, 74.0 +/- 6.6 kg] and five matched controls (C; 26 +/- 1.2 yr, 69.3 +/- 2.6 kg) in energy and nitrogen balance during rest and leg cycle-ergometer exercise at sea level, on acute altitude exposure to 4,300 m (barometric pressure = 463 Torr), and after 3 wk of habituation. Subjects received a primed continuous infusion of [6,6-2H]- and [1-13C]glucose, rested for = or = 90 min, and then immediately exercised for 45 min at 89 W, which elicited 49% of sea-level peak O2 consumption (VO2peak; 65% of altitude VO2peak). At sea level, resting Ra was 1.47 +/- 0.19 and 1.66 +/- 0.16 mg x kg-1 x min-1 for C and beta, respectively, and increased to 3.04 +/- 0.25 and 3.56 +/- 0.27 mg x kg-1 x min-1, respectively, during exercise. Thus glucose Ra was significantly increased by beta-blockade during rest and exercise at sea level. At sea level, beta-blockade increased leg G, which accounted for 49 and 69% of glucose disposal during exercise in C and beta, respectively. On acute altitude exposure, glucose Ra rose significantly during rest and exercise relative to sea level, whereas blockade continued to augment this increment. During exercise on acute exposure, G increased more than at sea level and accounted for a greater percentage (80 and 97%, respectively) of Rd in C and beta during exercise. Similarly, Rox values, particularly during exercise, were increased significantly at altitude relative to sea level, and beta-blockade potentiated this effect. During a given submaximal exercise task after acclimatization, glucose Ra, Rox, and G were increased relative to sea level, but these increments were less than those in response to exercise measured on acute exposure. We conclude that altitude exposure increases glucose use during rest and a given submaximal exercise bout and beta-blockade exaggerates the response.

Abstract Differences in cation transport have been observed between African Americans and whites. These differences may underlie the increased predisposition of African Americans to essential hypertension. To further explore these racial differences, we used platelets as a cellular model for calcium regulation. We measured 45 Ca fluxes in platelets from 21 African American and 25 white men. Additionally, using fura 2, we measured cytosolic free calcium levels in resting platelets and platelets treated with ouabain and thrombin. Platelet 45 Ca uptake was described by two exchangeable pools: a small, rapidly exchangeable pool and a larger, slowly exchangeable pool. Both pools were larger in platelets from African Americans than from whites (263 versus 185 pmol per 1×10 8 platelets for the rapidly exchangeable pool, P 8 platelets for the slowly exchangeable pool, P 45 Ca washout was described by a rapidly exchangeable pool and a static pool. The former was also higher in platelets from African Americans than from whites (246 versus 202 pmol per 1×10 8 platelets, P P =.033). Platelets from African Americans demonstrate higher intracellular calcium stores than platelets from whites. This racial difference could explain the sensitivity of African Americans to vasoactive agents acting through calcium mobilization from intracellular stores and cytosolic calcium.

The clearance of urea, creatinine, amino acids, vancomycin, and phenytoin was measured in vivo in a small animal model during continuous venovenous (CVV) hemofiltration, CVV hemodiafiltration, and CVV hemodialysis using a 0.25 m2 polysulfone hemofilter. Six domestic piglets (weighing 6-11.8 kg) each received 1 hr of all three techniques in random order. Blood flow was 50 ml/min. During CVV hemofiltration, filtrate production was 500 ml/hr and dialysate flow was zero. During CVV hemodiafiltration, filtrate production was 250 ml/hr and dialysate flow was 250 ml/hr. During CVV hemodialysis, net filtrate production was zero and dialysate flow was 500 ml/hr. The ratio of concentration of solute in filter effluent to concentration in whole plasma was derived for each solute during each of the three techniques. Mean (SD) effluent:plasma ratio for urea during CVV hemofiltration was 0.957 (0.038), CVV hemodiafiltration 0.876 (0.109), and CVV hemodialysis 0.754 (0.123); creatinine 0.942 (0.05), 0.934 (0.056), and 0.814 (0.057); amino acids 0.996 (0.344), 0.904 (0.196), and 0.778 (0.18). For small unbound solutes, there is a decrease in clearance of 6% from CVV hemofiltration to CVV hemodiafiltration and a further decrease of 14% from hemodiafiltration to hemodialysis. The effluent:plasma ratio for vancomycin during CVV hemofiltration was 0.739 (0.082), CVV hemodiafiltration 0.643(0.063), and CVV hemodialysis 0.509 (0.081), corresponding to a decrease of 30% from CVV hemofiltration to CVV hemodialysis. The effluent:plasma ratio for phenytoin was 0.302 (0.028) during CVV hemofiltration and was not significantly different during CVV hemodiafiltration or CVV hemodialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk identification during the early design phases of complex systems is commonly implemented but often fails to result in the identification of events and circumstances that truly challenge project performance. Inefficiencies in cost and schedule estimation are usually held accountable for cost and schedule overruns, but the true root cause is often the realization of programmatic risks. A deeper understanding of frequent risk identification trends and biases pervasive during space system design and development is needed, for it would lead to improved execution of existing identification processes and methods.

Atrial fibrillation (AF) progression to a more sustained form is associated with increased morbidities and mortality. The specific aims of the present study were to identify risk factors of AF progression and the effect of management approaches on AF progression in the RecordAF-U.S. cohort. The

The adaptive responses of the cardiovascular system to altitude appear to be dominated by increased sympathetic neural activity. We investigated the combined roles of the sympathetic and parasympathetic nervous systems (SNS and PNS, respectively) in the early (days 4–5) and subsequent (days 11–12) phases of acclimatization on Pike's Peak, CO (4,300 m), by spectral analysis of heart rate variability. Male subjects were randomly assigned to groups receiving oral propranolol (240 mg/day; n = 6) or a matched placebo (n = 3). On ascent to altitude, the high-frequency, fractal, and total spectral powers were reduced in the placebo group during days 4–5 and 11–12. At altitude during days 4–5, all three placebo group subjects increased SNS and decreased PNS activities compared with at sea level, and during days 11–12 SNS decreased and PNS increased compared with days 4–5. Relative to the placebo group, propranolol caused lengthening of the R-R interval; increases in high-frequency power, total spectral power, and the PNS indicator; and a decrease in the SNS indicator. Total spectral power tended to decrease at altitude, but there were no effects of altitude on PNS and SNS indicators in the propranolol group. The data from the placebo and propranolol groups suggest that both the PNS and SNS are involved in the elevated heart rate during the early phase of altitude acclimatization. Changes in heart rate variability during days 11–12 at altitude must be considered in light of the possible reductions in sympathetic receptor number noted in previous studies.

Regulation of cytosolic Ca2+ and cytosolic Na+ is critical for lymphocyte cation homeostasis and function. To examine the influence of cytosolic Na+ on Ca2+ regulation in human peripheral blood lymphocytes, Ca2+ entry and cytosolic Ca2+ (measured with fura-2) were monitored in cells in which cytosolic Na+ was increased and/or the Na+ gradient was decreased by reduction of external Na+ concentration. Ouabain-treated cells (0.1 mM for 30 min at 37 degrees C), suspended in Na(+)-free medium, showed a 30-65% increase in Ca2+ uptake compared to cells in 140 mM Na+ medium. Enhanced Ca2+ influx was entirely dependent on ouabain pretreatment and reversal of the Na+ gradient. Na pump inhibition or Na ionophore addition and subsequent exposure to Na(+)-free medium resulted in a sustained elevation of cytosolic Ca2+. As preincubation of cells in Ca(2+)-free medium further enhanced the ouabain-dependent increase in cytosolic Ca2+, the effects of the microsomal Ca(2+)-ATPase inhibitor thapsigargin on Ca2+ influx and cytosolic Ca2+ were studied. Thapsigargin stimulated Ca2+ entry following ouabain pretreatment and reversal of the Na+ gradient; the effects of thapsigargin were retained in the presence of LaCl3, a potent inhibitor of store-dependent calcium influx pathways. These results show lymphocytes demonstrate Na+/Ca2+ exchange activity and suggest the Na+/Ca2+ exchanger modulates cytosolic Ca2+ following intracellular Ca2+ store depletion.

The sympathoadrenal system plays a major role in adjustments to both short- and long-term high-altitude exposure. Thus, this study investigated catecholamine responses in blood, urine, and muscle during 3 weeks' exposure to 4,300 m in control and beta-blocked subjects. Eleven healthy, sea level (SL)-resident men (aged 26 +/- 1 years) were studied under resting conditions at SL and on arrival and during 21 days at 4,300 m (Pikes Peak). Six subjects received 240 mg/d propranolol, and five were administered a placebo. Compared with SL values (38.7 +/- 4.3 v 32.4 +/- 2.8 micrograms/d for control and beta-blocked, respectively), urinary norepinephrine (NE) excretion increased significantly during altitude exposure, reaching peak values on days 6 to 7 (105.5 +/- 16.1 v 88.4 +/- 12.3 micrograms/d, respectively). Furthermore, resting arterial NE levels (increases 87%), as well as net NE release (decreases 219%) across the leg, both increased during acclimatization, indicating elevated sympathetic activity. Systemic vascular resistance and arterial pressures increased with time at altitude and correlated with NE measurements. Resting heart rates increased initially and then declined steadily after day 4 at altitude in both groups of subjects. Urinary epinephrine (EPI) excretion increased with initial exposure as compared with SL values (5.1 +/- 0.8 to 6.6 +/- 0.7 micrograms/d for control, 4.5 +/- 0.5 to 5.2 +/- 1.3 micrograms/d for beta-blocked); however, no consistent pattern was observed for the following 20 days at altitude. Arterial EPI increased upon acute exposure, but declined after 21 days' acclimatization. No changes in dopamine excretion were observed with beta-blockade or altitude exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Residence at high altitude has been associated with elevation in systemic arterial blood pressure, but the time course has been little studied and the mechanism is unknown. Because plasma epinephrine (E) and norepinephrine (NE) also increase at altitude, we hypothesized that heightened sympathoadrenal activity may cause increased arterial pressure. We measured ambulatory blood pressure by cuff monitor in relation to 24-h urinary excretion of E and NE at sea level and during 3 wk of residence at 4,300 m (Pikes Peak, CO) in 11 healthy men. In five subjects taking placebo, arterial pressure progressively increased at 4,300 m from 82 +/- 1 (SE) mmHg at sea level to 88 +/- 3 on day 2, 91 +/- 3 on day 8, and 97 +/- 6 on day 17. In six subjects, propranolol (240 mg/day) decreased pressure from 85 +/- 4 to 77 +/- 1 mmHg at sea level but did not prevent sustained increase in pressure at 4,300 m (84 +/- 1, 81 +/- 1, and 85 +/- 3 mmHg on days 2, 8, and 17, respectively). Compared with the placebo group, blood pressure did not increase further over the initial elevation observed on day 2 in the propranolol group. There was interindividual variability in the blood pressure responses in both groups, with some subjects demonstrating a more marked increase in blood pressure. Urinary excretion of NE increased concomitantly with pressure at altitude in both groups, with a greater rise in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the extent to which epinephrine influences blood lactate adjustments to exercise during both acute (AC) and chronic (CH) high-altitude exposure. Eleven male sea level residents were divided into a control group (n = 5) receiving a placebo or a drug group (n = 6) receiving 240 mg/day of propranolol. All subjects were studied at rest and during 45 min of submaximal exercise (approximately 50% of sea level maximal O2 uptake) at sea level (SL) and within 4 h of exposure to and after 3 wk residence at 4,300 m (summit of Pikes Peak). Blood samples were collected from the femoral artery for epinephrine and lactate concentration. Exercising blood lactate concentration was significantly different across all altitude conditions such that AC > CH > SL (P < 0.05). For a given arterial O2 saturation, mean exercising blood lactates were lower for the beta-blocked group compared with controls; however, both groups demonstrated similar patterns across all conditions. Epinephrine levels during exercise followed a similar pattern to that of lactate, averaging 0.67, 0.43, and 0.29 ng/ml for AC, CH, and SL, respectively. The correlation between lactate and epinephrine was 0.93 and 0.84 for control and beta-blocked subjects, respectively. Whereas during exercise epinephrine was consistently higher for the beta-blocked group than controls, this difference was only significant during CH exposure. The epinephrine response was related to the extent of hypoxia in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolegomena to a History of Islamicate Manichaeism provides an annotated anthology of primary sources highlighting Manichaeism, a dualist religion emerging in Mesopotamia in the third century and which spread rapidly throughout the Roman and Sasanian empires until it was violently suppressed by both polities. It nevertheless continued to flourish – largely clandestinely – in the Near East, Central Asia, and China until it finally disappeared at the beginning of the seventeenth century. This book translates and assesses the importance of a number of Arabic, Persian, Syriac, and even Hebrew language testimonies for a better understanding of the cultural importance of what many scholars characterize as the first ‘world religion’.

The rapid increase in genomic and genome-scale data is resulting in unprecedented levels of discrete sequence data available for phylogenetic analyses. Major analytical impasses exist, however, prior to analyzing these data with existing phylogenetic software. Obstacles include the management of large data sets without standardized naming conventions, identification and filtering of orthologous clusters of proteins or genes, and the assembly of alignments of orthologous sequence data into individual and concatenated super alignments. Here we report the production of an automated pipeline, Hal that produces multiple alignments and trees from genomic data. These alignments can be produced by a choice of four alignment programs and analyzed by a variety of phylogenetic programs. In short, the Hal pipeline connects the programs BLASTP, MCL, user specified alignment programs, GBlocks, ProtTest and user specified phylogenetic programs to produce species trees. The script is available at sourceforge (http://sourceforge.net/projects/bio-hal/). The results from an example analysis of Kingdom Fungi are briefly discussed.

To determine if spirometric changes reflect early high-altitude pulmonary edema (HAPE) formation, we measured the FVC, FEV 1 , and FEF25–75 serially during the short-term period following simulated altitude exposure (4,400 m) in eight male subjects, four with a history of HAPE and four control subjects who had never experienced HAPE. Three of the four HAPE-susceptible subjects developed acute mountain sickness (AMS), based on their positive Environmental Symptom Questionnaire (AMS-C) scores. Clinical signs and symptoms of mild pulmonary edema developed in two of the three subjects with AMS after 4 h of exposure, which prompted their removal from the chamber. Their spirometry showed small decreases in FVC and greater decreases in FEV 1 and FEF25–75 after arrival at high altitude in the presence of rales or wheezing on clinical examination and normal chest radiographs. One of the two subjects had desaturation (59 percent) and tachycardia during mild exercise, and excessive fatigue and inability to complete the exercise protocol developed in the other at 4 h. The six other subjects had minimal changes in spirometry and did not develop signs of lung edema. Further, we measured each subject's ventilatory response to hypoxia (HVR) prior to decompression to determine whether the HVR would predict the development of altitude illness in susceptible subjects. In contrast to anticipated results, high ventilatory responses to acute hypoxia, supported by increased ventilation during exposure to high altitude, occurred in the two subjects in whom symptoms of HAPE developed. The results confirm that HAPE can occur in susceptible individuals despite the presence of a normal or high ventilatory response to hypoxia.

Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations.

Affordability is a commonly used term that takes on numerous meanings depending on the context used. Within conceptual design of complex systems, the term generally implies comparisons between expected costs and expected resources. This characterization is largely correct, but does not convey the many nuances and considerations that are frequently misunderstood and underappreciated. In the most fundamental sense, affordability and cost directly relate to engineering and programmatic decisions made throughout development programs. Systems engineering texts point out that there is a temporal aspect to this relationship, for decisions made earlier in a program dictate design implications much more so than those made during latter phases. This paper explores affordability engineering and its many sub-disciplines by discussing how it can be considered an additional engineering discipline to be balanced throughout the systems engineering and systems analysis processes. Example methods of multidisciplinary design analysis with affordability as a key driver will be discussed, as will example methods of data visualization, probabilistic analysis, and other ways of relating design decisions to affordability results.

Cerebral blood flow increases with acute exposure to high altitude, but the effect of hypoxia on the cerebral circulation at rest and during exercise appears influenced by the duration of high-altitude exposure. To determine whether internal carotid artery flow velocity increased with exercise in long-term residents of high altitude and whether resting values and the response to exercise differed in lifelong vs. acclimatized newcomer male residents of high altitude, we studied 15 native Tibetan and 11 Han (“Chinese”) 6 +/- 2-yr residents of Lhasa (3,658 m), Tibet Autonomous Region, China. Noninvasive Doppler ultrasound was used to measure internal carotid artery diameter, mean flow velocity, and, in combination, hemoglobin and arterial O2 saturation to assess cerebral O2 delivery. Tibetan and Han groups were similar in body size and resting internal carotid artery diameter, blood pressure, hemoglobin concentration, internal carotid artery mean flow velocity, and calculated cerebral O2 delivery. Submaximal exercise increased internal carotid artery mean flow velocity and cerebral O2 delivery in the Tibetan and Han subjects. At peak exercise, the Tibetans sustained the increase in flow velocity and cerebral O2 delivery, whereas the Hans did not. Across all exercise levels up to and including peak effort, the Tibetans demonstrated a greater increase in internal carotid artery flow velocity and cerebral O2 delivery relative to resting values than did the Hans. The greater cerebral O2 delivery was accompanied by increased peak exercise capacity in the Tibetan compared with the Han group. Our findings suggest that the cerebral blood flow response to exercise is maintained in Tibetan lifelong residents of high altitude.

The hypothesis that high-altitude weight loss can be prevented by increasing energy intake to meet energy requirement was tested in seven men, 23.7 +/- 4.3 (SD) yr, taken to 4,300 m for 21 days. Energy intake required to maintain body weight at sea level was found to be 3,118 +/- 300 kcal/day, as confirmed by nitrogen balance. Basal metabolic rate (BMR), determined by indirect calorimetry, increased 27% on day 2 at altitude and then decreased and reached a plateau at 17% above the sea level BMR by day 10. Energy expended during strenuous activities was 37% lower at altitude than at sea level. Fecal excretion of energy, nitrogen, total fiber, and total volatile fatty acids was not significantly affected by altitude. Energy intake at altitude was adjusted after 1 wk, on the basis of the increased BMR, to 3,452 +/- 452 kcal/day. Mean nitrogen balance at altitude was negative (-0.25 +/- 0.71 g/day) before energy intake was adjusted but rose significantly thereafter (0.20 +/- 0.71 and 0.44 +/- 0.66 g/day during weeks 2 and 3). Mean body weight decreased 2.1 +/- 1.0 kg over the 3 wk of the study, but the rate of weight loss was significantly diminished after the increase in energy intake (201 +/- 75 vs. 72 +/- 48 g/day). Individual regression lines drawn through 7-day segments of body weight showed that in four of seven subjects the slopes of body weight were not significantly different from zero after the 2nd wk. Thus weight loss ceased in four of seven men in whom increased BMR at altitude was compensated with increased energy intake.(ABSTRACT TRUNCATED AT 250 WORDS)

La description d'une celebration nommee Fete des premiers fruits de la vigne occupe deux colonnes (XIX 11 - XXI 10) du Rouleau du Temple. Cette fete n'est pas mentionnee dans le calendrier biblique malgre des allusions a des fetes de vendange. A l'aide des elements contenus dans le Rouleau, de fragments de calendriers publies par Milik et des donnees du Livre des Jubiles, on peut reconstituer son evolution a partir d'une fete de vendange celebree le premier jour du premier mois. L'adoption du calendrier babylonien amene a un nouveau decompte des mois du cycle festif. 11 QT s'efforce de situer ces rituels populaires dans un contexte juif en les faisant passer dans l'orbite de la Fete des Semaines

The Na + -Ca 2+ exchange carrier was purified from bovine cardiac tissue by a new procedure which relies principally upon anion-exchange chromatography. The purified protein exhibited two major bands on sodium dodecyl sulfate gels, at 120 and 160 kDa. The relative intensities of the two bands could be altered by variations in the procedures used for preparing the samples for electrophoresis, suggesting that they represent two different conformational states of the same protein. The NH 2 -terminal amino acid sequences of the 120- and 160-kDa bands were identical and agreed closely with a region of the deduced amino acid sequence of the recently cloned canine cardiac exchanger. The NH 2 -terminal sequence was preceded in the deduced sequence by a 32-residue segment that exhibited the characteristics of a signal sequence; the initial amino acid in the NH 2 -terminal sequence followed immediately after the predicted cleavage site for the signal sequence. The Na + -Ca 2+ exchanger appears to be unique among membrane transport carriers in encoding a cleaved signal sequence. The characteristics of the sequences flanking the first putative transmembrane segment of the mature exchanger suggest that the signal sequence is necessary to ensure the correct topological orientation of the exchanger in the membrane.

We hypothesized that the increased exercise arterial lactate concentration on arrival at high altitude and the subsequent decrease with acclimatization were caused by changes in blood lactate flux. Seven healthy men [age 23 +/- 2 (SE) yr, wt 72.2 +/- 1.6 kg] on a controlled diet were studied in the postabsorptive condition at sea level, on acute exposure to 4,300 m, and after 3 wk of acclimatization to 4,300 m. Subjects received a primed-continuous infusion of [6,6–2D]glucose (Brooks et al. J. Appl. Physiol. 70:919–927, 1991) and [3–13C]lactate and rested for a minimum of 90 min followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the sea level peak O2 consumption (VO2peak; 65 +/- 2% of both acute altitude and acclimatization). During rest at sea level, lactate appearance rate (Ra) was 0.52 +/- 0.03 mg.kg-1.min-1; this increased sixfold during exercise to 3.24 +/- 0.19 mg.kg-1.min-1. On acute exposure, resting lactate Ra rose from sea level values to 2.2 +/- 0.2 mg.kg-1.min-1. During exercise on acute exposure, lactate Ra rose to 18.6 +/- 2.9 mg.kg-1.min-1. Resting lactate Ra after acclimatization (1.77 +/- 0.25 mg.kg-1.min-1) was intermediate between sea level and acute exposure values. During exercise after acclimatization, lactate Ra (9.2 +/- 0.7 mg.kg-1.min-1) rose from resting values but was intermediate between sea level and acute exposure values. The increased exercise arterial lactate concentration response on arrival at high altitude and subsequent decrease with acclimatization are due to changes in blood lactate appearance.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the hypothesis that altitude exposure and acclimatization result in increased dependency on blood glucose as a fuel, seven healthy males (23 +/- 2 yr, 72.2 +/- 1.6 kg, mean +/- SE) on a controlled diet were studied in the postabsorptive condition at sea level (SL), on acute altitude exposure to 4,300 m (AA), and after 3 wk of chronic altitude exposure to 4,300 m (CA). Subjects received a primed continuous infusion of [6,6-2D]glucose and rested for a minimum of 90 min, followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the SL maximal O2 consumption (VO2 max; 65 +/- 2% of altitude VO2 max). At SL, resting arterial glucose concentration was 82.4 +/- 3.2 mg/dl and rose significantly to 91.2 +/- 3.2 mg/dl during exercise. Resting glucose appearance rate (Ra) was 1.79 +/- 0.02 mg.kg-1.min-1; this increased significantly during exercise at SL to 3.71 +/- 0.08 mg.kg-1.min-1. On AA, resting arterial glucose concentration (85.8 +/- 4.1 mg/dl) was not different from sea level, but Ra (2.11 +/- 0.14 mg.kg-1.min-1) rose significantly. During exercise on AA, glucose concentration rose to levels seen at SL (91.4 +/- 3.0 mg/dl), but Ra increased more than at SL (to 4.85 +/- 0.15 mg.kg-1.min-1; P less than 0.05). Resting arterial glucose was significantly depressed with CA (70.8 +/- 3.8 mg/dl), but resting Ra increased to 3.59 +/- 0.08 mg.kg-1.min-1, significantly exceeding SL and AA values.(ABSTRACT TRUNCATED AT 250 WORDS)

High concentrations of cytosolic Na+ions induce the time-dependent formation of an inactive state of the Na+/Ca2+exchanger (NCX), a process known as Na+-dependent inactivation. NCX activity was measured as Ca2+uptake in fura 2-loaded Chinese hamster ovary (CHO) cells expressing the wild-type (WT) NCX or mutants that are hypersensitive (F223E) or resistant (K229Q) to Na+-dependent inactivation. As expected, 1) Na+-dependent inactivation was promoted by high cytosolic Na+concentration, 2) the F223E mutant was more susceptible than the WT exchanger to inactivation, whereas the K229Q mutant was resistant, and 3) inactivation was enhanced by cytosolic acidification. However, in contrast to expectations from excised patch studies, 1) the WT exchanger was resistant to Na+-dependent inactivation unless cytosolic pH was reduced, 2) reducing cellular phosphatidylinositol-4,5-bisphosphate levels did not induce Na+-dependent inactivation in the WT exchanger, 3) Na+-dependent inactivation did not increase the half-maximal cytosolic Ca2+concentration for allosteric Ca2+activation, 4) Na+-dependent inactivation was not reversed by high cytosolic Ca2+concentrations, and 5) Na+-dependent inactivation was partially, but transiently, reversed by an increase in extracellular Ca2+concentration. Thus Na+-dependent inactivation of NCX expressed in CHO cells differs in several respects from the inactivation process measured in excised patches. The refractoriness of the WT exchanger to Na+-dependent inactivation suggests that this type of inactivation is unlikely to be a strong regulator of exchange activity under physiological conditions but would probably act to inhibit NCX-mediated Ca2+influx during ischemia.

Acute renal failure (ARF) occurs in 7% of patients admitted to the intensive care unit (ICU) (1). Previously, mortality exceeded 91%, but with the introduction of dialysis, this quickly fell to approximately 50% (2). Overall mortality for ARF has remained approximately 50%, associated with increasing comorbidity (3).

Persons with chronic mountain sickness (CMS) hypoventilate and are more hypoxemic than normal individuals, but the cause of the hypoventilation is unclear. Studies of 14 patients with CMS and 11 healthy age-matched control subjects residing in Lhasa, Tibet, China (3,658 m) were conducted to test the hypothesis that hypoventilation, blunted hypoxic ventilatory responsiveness (HVR), and hypoxic ventilatory depression of CMS were due to increased endogenous opioid production. Patients with CMS compared with control subjects exhibited hypoventilation (end-tidal carbon dioxide pressure [PETCO2] = 36.6 +/- 1.0 versus 31.5 +/- 0.5 mm Hg, p less than 0.05), lower tidal volume (VT = 0.54 +/- 0.02 versus 0.61 +/- 0.02 ml BTPS, p less than 0.05), blunted HVR (shape parameter A = 17 +/- 8 versus 114 +/- 22 mm Hg/L BTPS/min, p less than 0.05), and a depressant effect of ambient hypoxia on ventilation (delta PETCO2 with acute hyperoxia = -3.5 +/- 0.5 versus -1.0 +/- 0.6 mm Hg, p less than 0.05). Reduced forced expiratory volume in 1 s to vital capacity ratios (FEV1/VC) and a higher proportion of cigarette smokers in the group of patients with CMS compared with control subjects suggested that at least some patients with CMS had mild airway obstructive lung disease. Naloxone infusion (0.14 mg/kg) to six patients with CMS did not change resting VT, PETCO2, HVR, or SaO2.(ABSTRACT TRUNCATED AT 250 WORDS)

For normal anaesthetic practice, monitoring of neuromuscular blockade is best performed by stimulation of the ulnar nerve at the wrist with a peripheral nerve stimulator and evaluation of the response of the thumb. Determination of the initial threshold for stimulation in the awake patient to allow estimation of the current required for supramaximal stimulation is an important set-up procedure to improve accuracy. The degree of paralysis of specific muscle groups such as the diaphragm can be inferred from their sensitivity to neuromuscular blocking agents relative to adductor pollicis. Monitoring with different stimulation patterns allows a wide spectrum of muscle paralyses to be evaluated.

Fibroblasts adhere to, and readily grow into, fibrin clots that form as a result of the cleavage of fibrinogen by thrombin. Subsequent fibroblast replication is believed to be stimulated by mitogens released by entrapped platelets, such as platelet-derived growth factor. We suggest that the supernatant remaining after the fibrinogen-thrombin reaction could stimulate fibroblast replication, even in the absence of other blood components. To examine this hypothesis we expressed liquid from a fibrin clot and measured its mitogenic activity on human lung fibroblasts, in serum-free conditions, using a colorimetric assay based on uptake and subsequent release of Methylene Blue. The clot supernatant caused a mitogenic response of 51 +/− 6% above control and was equivalent to about half that elicited by medium containing 10% newborn calf serum. On their own, both thrombin and fibrinopeptides A and B (small molecular weight cleavage products released from fibrinogen) showed some mitogenic activity, but there was also activity in higher molecular weight cleavage products, suggesting the presence of uncharacterized mitogens. It is proposed that these agents may play important roles in wound healing and diseases associated with vascular leakage and fibrosis, by stimulating fibroblast replication.

Altitude exposure provides a natural laboratory for the study of the effects of low oxygen (hypoxia). Oxygen is the most necessary of substances in our environment, and without it we become unconscious within seconds. When O2 is available, but in low concentrations, the body has elaborate defense systems and compensatory mechanisms that are progressively called into play as the duration of hypoxia increases. When these mechanisms fail or when they are stretched beyond their capacity, organ malfunction occurs. This chapter will focus primarily on the mechanisms of response to hypoxia and to a lesser extent on the disorders that result when the response is inadequate. For more information the reader is referred to other reviews (Penulosa and Sime, 1971; Reeves, 1973; Reeves and Grover, 1974; Dempsey and Forster, 1982; Winslow and Monge, 1987; Kawashima, 1989; Hackett and Roach, 1990; Weil, 1990; Reeves and Groves et al., 1991; Moore, 1992; Oelz et al, 1992; Honigman, 1993; Ward, 1995).

Exchange activity is regulated principally by cytosolic Na + , Ca 2+ , and PIP2. However, the properties of these modes of regulation that have emerged from excised patch studies appear to be poorly suited to regulating exchange activity on a beat-to-beat basis. Here we summarize recent findings from our lab indicating that (a) allosteric activation by Ca 2+ exhibits hysteresis, (b) elevated concentrations of cytosolic Na+ induce a mode of activity that no longer requires regulatory Ca 2+ activation, and (c) the requirement for PIP2 is reduced or eliminated after allosteric Ca 2+ activation. Our results suggest that exchange activity in cardiac myocytes may be regulated by the time-integral of Ca 2+ transients occurring over multiple beats.

L-type Ca2+ channel activity was measured in L6 cells as nifedipine-sensitive barium (Ba2+; 5 mM) influx in a depolarizing salt solution containing 140 mM KCl. Addition of AVP (arginine-vasopressin) during Ba2+ uptake reduced the rate of Ba2+ influx by 60–100%; this was followed by a gradual restoration of the initial rate of Ba2+ uptake. Blockade of PKC (protein kinase C) by pretreatment with 10 μM bisindolylmaleimide did not affect the initial inhibition of Ba2+ influx, but completely abolished the recovery phase. The effect of AVP was half-maximal at 10 nM AVP and was blocked by the V1a receptor antagonist d-(CH2)5-Tyr(Me)-AVP. Activation of Gαs by isoprenaline or cholera toxin antagonized the actions of AVP on Ba2+ uptake. This protection persisted in the presence of the PKA (protein kinase A) inhibitor KT5720, and was not mimicked by agents that increase cAMP. Inhibition of Ba2+ influx was also elicited by ATP and ET (endothelin 1) with an order of effectiveness ET

Life Cycle Analysis (LCA) is the evaluation of the impacts that design decisions have on a system and provides a framework for identifying and evaluating design benefits and burdens associated with the life cycles of space transportation systems from a "cradle-to-grave" approach. Sometimes called life cycle assessment, life cycle approach, or "cradle to grave analysis", it represents a rapidly emerging family of tools and techniques designed to be a decision support methodology and aid in the development of sustainable systems. The implementation of a Life Cycle Analysis can vary and may take many forms; from global system-level uncertainty-centered analysis to the assessment of individualized discriminatory metrics. This paper will focus on a proven LCA methodology developed by the Systems Analysis and Concepts Directorate (SACD) at NASA Langley Research Center to quantify and assess key LCA discriminatory metrics, in particular affordability, reliability, maintainability, and operability. This paper will address issues inherent in Life Cycle Analysis including direct impacts, such as system development cost and crew safety, as well as indirect impacts, which often take the form of coupled metrics (i.e., the cost of system unreliability). Since LCA deals with the analysis of space vehicle system conceptual designs, it is imperative to stress that the goal of LCA is not to arrive at the answer but, rather, to provide important inputs to a broader strategic planning process, allowing the managers to make risk-informed decisions, and increase the likelihood of meeting mission success criteria.

The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia.

The arrival of continuous renal replacement therapy (CRRT) has given the intensivist and the intensive care nurse the opportunity to treat acute renal failure (ARF) independently by giving them the necessary technology and taking CRRT away from absolute nephrological control. This structural shift has created a controversy between those countries where control of CRRT has completely shifted to the intensivist and those countries where nephrological input is still dominant. The argument in favor of intensivist-driven CRRT rests upon several observations, including the fact that therapy is continuous, as is the presence of the intensivist in the intensive care unit (ICU). Critically ill patients require rapid changes in treatment that are best directed by physicians who are at the bedside all the time. CRRT must be seen within the totality of patient care, and the intensivist can see the larger picture more accurately. Intensivists are successfully performing more and more procedures that were previously seen as part of other specialties and, last but not least, "closed" models of ICU care appear to work best. Australian intensivists have taken up CRRT from the start and now control it. Patient outcomes under such a system, as reported here, are above average, and confirm the effectiveness of such an approach.

We investigated retrospectively whether the preexistence of inflammation-producing illnesses such as viral respiratory tract infections contributed to the development of high-attitude pulmonary edema in children. We found that the large majority of native low-attitude children, but not adults, who had this form of edema after traveling to high altitude also had evidence of a preexisting illness. We speculate that the release of inflammatory mediators associated with these illnesses may be tolerated at sea level but may predispose children to increased capillary permeability when superimposed on hypoxia and, possibly, cold and exercise.

This is an international consensus statement of an ad hoc committee formed by the International Society for Mountain Medicine (ISMM) at the VI World Congress on Mountain Medicine and High Altitude Physiology (Xining, China; 2004) and represents the committee's interpretation of the current knowledge with regard to the most common chronic and subacute high altitude diseases. It has been developed by medical and scientific authorities from the committee experienced in the recognition and prevention of high altitude diseases and is based mainly on published, peer-reviewed articles. It is intended to include all legitimate criteria for choosing to use a specific method or procedure to diagnose or manage high altitude diseases. However, the ISMM recognizes that specific patient care decisions depend on the different geographic circumstances involved in the development of each chronic high altitude disease. These guidelines are established to inform the medical services on site who are directed to solve high altitude health problems about the definition, diagnosis, treatment, and prevention of the most common chronic high altitude diseases. The health problems associated with life at high altitude are well documented, but health policies and procedures often do not reflect current state-of-the-art knowledge. Most of the cases of high altitude diseases are preventable if on-site personnel identify the condition and implement appropriate care.

** One of the major decisions that will have to be made during the planning stages of lunar or Martian exploration missions deals with what launch system, or combination of launc h systems, should be utilized to deliver mission modules to Low Earth Orbit (LEO) or some other mission waypoint. Such decision is primarily based on affordability, system feasibility, and mission reliability; sound decision should be predicated on a tenuo us balance between these three. A deterministic forecast of mission architectures (launch system selection, flight rate, payload modularity, etc.) will not be adequate since critical events such as catastrophic vehicle losses, ground operation throughput d elays, and automated rendezvous and docking (AR&D) failures cannot be properly addressed. A probabilistic tool, on the other hand, is able to capture the stochastic variability embedded in “real -world” analysis and provide insight into the cost -effectivene ss and consequence of various decision options. A methodology has been developed by the Exploration Concepts Branch (ECB) at NASA Langley Research Center that utilizes a Discrete Event Simulation (DES) model to evaluate the affordability and reliability im pacts of a mission process from launch system ground preparation to on -orbit module assembly and orbit departure burn. The model was developed using Rockwell Software’s Arena, and is a manifest -driven simulator that can provide the decision make r affordability, feasibility, and reliability metrics along with associated uncertainty bounds. Decision points have been included in the model that reflect catastrophic loss of vehicle (LOV) failures during launch, benign launch vehicle failures resulting in failure to deliver payloads to LEO, and individual docking failures of mission modules. Such decision points impact the overall manifest affordability by incurring replacement flights that require both replacement vehicle and replacement payload costs. Various preparation times, such as integration times and pad times, are stochastically addressed using statistical distributions specified on mission manifests. The model is capable of simulating both expendable and reusable launch vehicles, and is also capable of costing flights based on either a “fixed” launch service price type cost or by using processing flow time factors. The feasibility metrics that are generated by the model reflect the various processing times in conjunction with manifest -specified schedules. The metrics are also dependent on allowable on -orbit time for the various mission modules since propellant boil -off and orbital decay could be significant considerations when analyzing mission architectures. The methodol ogy has recently been applied to study the effects of changing exploration