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The effect of the menstrual cycle on fluid balance during physical work in the heat when fluids are freely available is unknown. This study demonstrates that fluid balance is not modified in women across three distinct phases of the menstrual cycle during physical work in the heat These results indicate that when women have free access to cool fluid during physical work in the heat, they respond similarly across all three phases to maintain fluid homeostasis across the menstrual cycle.

Baranauskas, Marissa N., Timothy J. Fulton, Alyce D. Fly, Bruce J. Martin, Timothy D. Mickleborough, and Robert F. Chapman. High intraindividual variability in the response of serum erythropoietin to multiple simulated altitude exposures.

Baranauskas, Marissa N., Joseph Powell, Alyce D. Fly, Bruce J. Martin, Timothy D. Mickleborough, Hunter L. Paris, and Robert F. Chapman. Influence of zinc on the acute changes in erythropoietin and proinflammatory cytokines with hypoxia.

INTRODUCTION: An adequate increase in minute ventilation to defend arterial oxyhemoglobin saturation (SpO(2)) during hypoxic exercise is commonly viewed as an important factor contributing to large inter-individual variations in the degree of exercise performance impairment in hypoxia. Although the hypoxic ventilatory response (HVR) could provide insight into the underpinnings of such impairments, it is typically measured at rest under isocapnic conditions. Thus, we aimed to determine whether 1) HVR at rest and during exercise are similar and 2) exercise HVR is related to the degree of impairment in cycling time trial (TT) performance from normoxia to acute hypoxia (ΔTT). METHODS: Sixteen endurance-trained men (V̇O(2peak), 62.5 ± 5.8 mL·kg(−1)·min(−1)) performed two poikilocapnic HVR tests: one during seated rest (HVR(REST)) and another during submaximal cycling (HVR(EX)). On two separate visits, subjects (n = 12) performed a 10-km cycling TT while breathing either room air (F(i)O(2) = 0.21) or hypoxic gas mixture (F(i)O(2) = 0.16) in a randomized order. RESULTS: HVR(EX) was significantly (P < 0.001) greater than HVR(REST) (1.52 ± 0.47 and 0.22 ± 0.13 L·min(−1)·%SpO(−1)(2), respectively), and these measures were not correlated (r = −0.16, P = 0.57). ΔTT was not correlated with HVR(REST) (P = 0.70) or HVR(EX) (P = 0.54), but differences in ventilation and end-tidal CO(2) between hypoxic and normoxic TT and the ventilatory equivalent for CO(2) during normoxic TT explained ~85% of the variance in performance impairment in acute hypoxia (P < 0.01). CONCLUSION: We conclude that 1) HVR is not an appropriate measure to predict the exercise ventilatory response or performance impairments in acute hypoxia and 2) an adequate and metabolically matched increase in exercise ventilation, but not the gain in the ventilatory response to hypoxia, is essential for mitigating hypoxia-induced impairments in endurance cycling performance.

Objective: Blood flow to the brain is extremely sensitive to changes in PCO2. While animal studies show a similar potent PCO2 dependence in retinal and choroidal vessels, the PCO2-retinal blood flow relationship has never been adequately studied in humans. Methods: Video scanning laser ophthalmoscopy after fluorescein angiography was used to analyze retinal arterial and capillary blood velocity under conditions of mild hypercapnia and hypocapnia. Control conditions (end-tidal PCO2 = 38.3 ± 0.4 mmHg) were contrasted with hyperventilation-induced hypocapnia (PCO2 = 34.0 ± 0.4 mmHg) and hypercapnia (PCO2 = 42.3 ± 0.5 mmHg) created by PCO2 addition to inspired gas. Results: Both larger vessel and macular capillary blood velocity was dependent upon PCO2: arteriovenous passage time fell as PCP2 rose, and both mean arterial dye velocity and capillary blood velocity rose as PCO2 rose (all p< 0.05). These changes in flow velocity occurred despite unchanged heart rate, arterial systolic and diastolic blood pressure, intraocular pressure, and calculated ocular perfusion pressure. Contrast sensitivity was also unchanged by PCO2 variation. Conclusions: The human retinal circulation, like the whole cerebral circulation, may be strongly dependent upon PCO2 in a manner that is unrelated to perfusion pressure and apparently outside strict autoregulatory controls.

The topic of psychoactive drugs is one of inherent interest to college students. We used this insight to design and implement a multidisciplinary undergraduate course with psychoactive drugs as the central theme. The Medical Science of Psychoactive Drugs examines the biological mechanisms underlying all major effects of psychoactive drugs, including the effects on the brain and other organs and tissues. Physiological principles, molecular mechanisms, and genetic factors involved in drug-induced therapeutic and adverse effects are emphasized. The course is open to undergraduate students at all levels and carries no prerequisites, and enrollment is limited to ∼50 students. Major teaching modes include lecture, short homework papers on topics related to the previous class meeting, small-group discussions at several points during each class, and whole class discussions. Because of the diversity of students' knowledge of basic science, we employ a variety of methods designed to help students grasp the necessary scientific concepts. Our methods are intended to be inquiry based and highly interactive. Our goals are 1) to foster the development of an organized knowledge base about psychoactive drugs that will have practical applicability in the daily lives of the students; 2) to promote the rational application of this knowledge in thinking about current medical, social, legal, and ethical issues involving psychoactive drugs; and 3) to cultivate science literacy, critical thinking, and communication skills among students.

Aim: Normal pressure glaucoma (NPG) patients exhibit prolonged retinal arteriovenous passage times in fluorescein angiography and colour Doppler imaging suggests increased resistance downstream from the central retinal and posterior ciliary arteries. The aim of the study was to elucidate the morphological source of decreased perfusion and increased resistance of the ocular circulation in NPG. Methods: Retinal arteriovenous passage time (AVP) and peripapillary arterial and venous diameters were measured in digital scanning laser fluorescein angiograms. For estimation of retinal capillary density the area of the foveal avascular zone (FAZ) and the perifoveal intercapillary area (PIA) was quantified. 36 patients with NPG (mean age 57 (SD 13) years) and 21 healthy subjects (mean age 51 (13) years) were enrolled in the comparative study. Results: In NPG patients the AVP (2.55 (1.1) seconds) was significantly prolonged (p

Addition of dorzolamide to timolol in primary open-angle glaucoma shows augmented reduction of intraocular pressure. It is unknown as yet if addition of dorzolamide will alter hemodynamics.Fifteen patients with primary open-angle glaucoma were placed on a medication-dependent 1-week to 4-week washout that included maintenance on timolol. After washout, baseline measurements were taken (timolol). They were studied after a month on timolol or dorzolamide-timolol (Cosopt; Merck, Inc, Whitehouse Station, New Jersey), with the second drug preceded by another month of timolol maintenance and second baseline measurements. At each visit, visual function, intraocular pressure, and ocular hemodynamics were monitored, including indocyanine green and fluorescein angiography and color Doppler imaging.Cosopt significantly reduced intraocular pressure (14.7 to 13.4 mm Hg, P.05) and increased arteriovenous passage time (superior temporal artery) of fluorescein dye (2.13 to 1.76 seconds, P =.01) but had no effect on visual function.When compared with timolol in primary open-angle glaucoma, Cosopt augments ocular tension reduction and reduces the amount of time required for blood to pass through the superior retinal vasculature.

Factors other than intraocular pressure (IOP) elevation must be involved in initiation and progression of glaucoma. An additional element in disease causation may be ischemia in the retina and optic nerve head. Ischemic damage to neurons in the CNS is similar mechanistically and histopathologically to changes seen in glaucoma. Further, glaucoma patients with normal IOP show clear evidence for cerebral and ocular ischemia. Aging and atherosclerosis reduce the ability of the eye to autoregulate blood flow when ocular perfusion pressure changes: the dependence of blood flow on perfusion pressure links ischemia to IOP. Consequently, neuroprotective treatments for glaucoma should be designed to both reduce IOP and improve ocular nutrient delivery.

Purpose: Scanning laser ophthalmoscopy is capable of producing high-resolution fluorescein angiograms. Measurements of capillary blood velocities in the fovea are well established. In this study, we used an identical technique to measure particle velocities in the superficial layers of the optic nerve head. We compared these data with simultaneous velocity measurements in the retinal and macular vasculature. Methods: Fluorescein angiograms were performed in 30 subjects (12 men, 18 women; mean age, 26 years; standard deviation [SD], 3 years). Off-line, the velocities of hypofluorescent particles through the microvasculature of epipapillary and macular vessels were measured by image-processing techniques. We also assessed the arteriovenous passage (AVP) time of the fluorescein dye front. Results: Epipapillary blood velocities ranged from 2.7 to 6.5 mm/sec (mean, 4.0 mm/sec; SD, 0.99 mm/sec) and differed significantly from macular capillary blood velocities (MCBVs), which ranged from 1.67 to 3.31 mm/sec (mean, 2.53 mm/sec; SD, 0.34 mm/sec). The AVP time in all subjects was 1.74 ± 0.5 sec (mean ± SD) and correlated with the MCBV (P Conclusions: The scanning laser methodology, adapted to objectively assess velocities in the epipapillary vasculature, shows that these measurements are neither correlated with velocities in the perifoveal network, nor inversely correlated with overall retinal transit time. Epipapillary blood velocities were found to be substantially higher than those measured in macular capillaries. This result might be explained by the different anatomy of epipapillary vessels compared with macular capillaries.

PURPOSE Topical beta-blockers are the most common treatment for ocular hypertension in glaucoma, but their ocular hemodynamic effects are not well known. We investigated the acute effects of betaxolol (beta-1 selective antagonist), levobunolol (non-selective antagonist with active polar metabolite), and timolol (non-selective antagonist) on retinal and superficial optic nerve head circulation. METHODS Intraocular pressure (IOP), heart rate, blood pressure, and retinal circulation were evaluated in 12 healthy subjects (6F/6M; mean age=24+/-2 years) before and two hours after instillation of each drug on separate occasions at least two weeks apart. Macular capillary blood velocity (MCBV), epipapillary blood velocities (EBV), arteriovenous passage (AVP) times, and arterial and venous diameters were measured by digital image analysis of scanning laser fluorescein angiograms. RESULTS All drugs significantly (p

Purpose To investigate ocular hemodynamic and visual function changes in patients with normal-tension glaucoma after treatment with a calcium channel blocker (nifedipine). Methods In 21 patients with normal-tension glaucoma, color Doppler imaging of the ophthalmic, central retinal, and short posterior ciliary arteries was carried out after a 4-week washout of prior drug treatment and again after 6 months of treatment with nifedipine (30 mg per day). Visual field sensitivity, spatial contrast sensitivity, and intraocular pressure were also recorded. Results Three subjects experienced intolerable side effects from the drug and were removed from the study. In two other patients, visual function was substantially reduced after 4 months of treatment; nifedipine was discontinued. In the remaining 16 subjects, mean intraocular pressure, retrobulbar hemodynamics, visual field mean sensitivity, and contrast sensitivity at 3, 12, and 18 cycles per degree (cpd), respectively, were unchanged after nifedipine treatment. Contrast sensitivity at 6 cpd, however, improved after drug treatment ( P = .004). Individuals with the greatest improvements in contrast sensitivity at 6 cpd showed the largest increases in ophthalmic arterial peak systolic velocity ( r = .57; P = .02) and end-diastolic velocity ( r = .65; P = .001). Conclusion Nifedipine fails to provide uniform visual function or retrobulbar hemodynamic responses in patients with normal-tension glaucoma. Those patients who do show improved visual function also show improved indices of retrobulbar perfusion.

AIM/BACKGROUND—In diabetic eye disease the factors leading to compromised circulation and the resulting loss of visual function are poorly understood. Although retinal circulation has been widely investigated, it accounts for only a fraction of total eye blood flow. Blood flow was investigated in the larger vessels feeding the eye in patients with early diabetic retinopathy. METHODS—Eleven patients with early diabetes with minimal or no retinopathy and 11 healthy controls were evaluated for retrobulbar blood flow velocity using colour Doppler imaging for the ophthalmic and central retinal arteries. Patients and subjects were tested while breathing room air and again under conditions of isocapnic hyperoxia. RESULTS—Hyperoxia induced a significant change in the central retinal artery end diastolic velocity (EDV) (p = 0.008) and resistance index (RI) (p = 0.032) in normal subjects, but not in diabetic patients. Consequently, during hyperoxia, the diabetic patients were significantly higher for EDV (p = 0.006) and significantly lower for RI (p = 0.002) compared with normal controls. Hyperoxia caused no significant change in either group in the ophthalmic artery; nevertheless, under isocapnic hyperoxia conditions the diabetic patients had lower peak systolic velocity (p = 0.05) and lower RI (p = 0.05) than normal subjects. CONCLUSIONS—Imposition of isocapnic hyperoxia produces significant differences in the ophthalmic and central retinal artery blood flow velocities in diabetic patients with early disease when compared with normal subjects. These results demonstrate that diabetic patients with minimal or no retinopathy suffer from irregular ocular vascular function in the major vessels feeding the eye.

AIMS/BACKGROUND: Mechanical and vascular factors may both contribute to glaucoma. This study investigated the relation of mechanical to vascular factors by examining how acute IOP elevation altered flow velocities in the central retinal and ophthalmic arteries. METHODS: IOP was elevated from a baseline near 14 to approximately 45 mm Hg using suction ophthalmodynamometry. During recovery from scleral suction, IOP fell to near 8 mm Hg. At each IOP, peak systolic and end diastolic velocities (PSV and EDV) were measured in the central retinal and ophthalmic arteries using colour Doppler imaging (Siemens Quantum 2000). Eleven healthy people served as subjects. RESULTS: Acute elevation in IOP had no effect upon PSV, EDV, or the derived resistance index in the ophthalmic artery: flow velocities in this vessel were identical at IOP of 8 mm Hg or 45 mm Hg. In contrast, in the central retinal artery, PSV and EDV fell, and the resistance index rose, in steady progression as IOP was acutely elevated (each p < 0.01). At IOP of 45 mm Hg, EDV was virtually absent and the resistance index was very nearly 1.0. CONCLUSION: Ophthalmic arterial haemodynamics are unrelated to acute fluctuations of the IOP over a wide range, suggesting that ocular hypertension itself cannot induce vascular dysfunction in this artery. In contrast, flow velocities in the central retinal artery were highly IOP dependent, implying that haemodynamic and mechanical factors are closely linked in this vascular bed.

Purpose β-Adrenergic blocking drugs lower intraocular pressure. The question of whether these drugs also alter, either directly or indirectly, orbital hemodynamics is potentially of great importance for patients with normal-tension glaucoma who may have some degree of reversible vasospasm. Methods We compared the effect of selective (betaxolol) and nonselective (timolol) β-adrenergic blocking drugs on flow velocities (as determined by color Doppler imaging) in orbital vessels in 13 patients with normal-tension glaucoma (mean age, 62 ± 3 years; mean intraocular pressure, 15 ± 2 mm Hg). A one-month drug treatment double-masked crossover design, with a three-week washout before each drug, was used. Results Neither drug changed peak systolic velocity in any of the four vessels studied (ophthalmic, nasal and temporal posterior ciliary, and central retinal arteries). Additionally, timolol did not alter end-diastolic velocity or resistance index (defined as [peak systolic velocity minus end-diastolic velocity] divided by peak systolic velocity) in any of the vessels measured. In contrast, betaxolol tended to increase end-diastolic velocity and to decrease resistance index: the four-vessel average end-diastolic velocity increased 30% (P = .08), and the four-vessel average resistance index decreased significantly (P = .04). These reductions in resistance index occurred despite that betaxolol, in contrast to timolol, did not significantly decrease intraocular pressure. Conclusions These results suggest that, in patients with normal-tension glaucoma, selective β-adrenergic blockade (betaxolol) may have ocular vasorelaxant effects independent of any influence on intraocular pressure, whereas nonselective blockade (timolol) lowers intraocular pressure without apparently altering orbital hemodynamics.

Regular physical activity provokes numerous adaptations in the gastrointestinal tract and liver. It has been suggested that these changes may alter the pharmacokinetics of drugs in humans. We addressed this suggestion by measuring paracetamol pharmacokinetics in a group of healthy young males chosen to represent the widest possible range of habitual physical activity and food intake. Daily caloric intake in the 19 men, obtained from 3-day dietary records, ranged from 1680 to 5110 kcal (21 to 66 kcal/kg). Each volunteer ingested paracetamol 1000mg in the fasted, resting state in the morning; antecubital venous blood samples were analysed for the parent compound and its glucuronide and sulfate conjugates by high-performance liquid chromatography for 6 subsequent hours. We found no evidence that paracetamol pharmacokinetics vary with physical activity or with caloric intake: (a) for the parent compound, there was no correlation in maximum blood concentrations, half-life, total clearance, or area under the curve with individual caloric intake, and (b) when volunteers were divided a priori into more active and less active groups, or a posteriori into higher and lower calorie consumers (a 70% difference in daily caloric intake), these groups had identical plasma disappearance curves for paracetamol itself and for both of its metabolites. We conclude that the enormous variation among humans in long term physical activity and food intake fails to alter any aspect of the appearance or disappearance of paracetamol from blood.

A total synthesis of the novel antifungal substance myxothiazol 1 isolated from the myxobacterium Myxococcus fulvus is described. The synthesis is based on elaboration of the S-E,E -diene thioamide 1 5 and the 2 R S , 3 S R amide aldehyde 2 5 as key intermediates, followed by conversion of 1 5 into the bis -thiazole 1 9 and a final Wittig coupling reaction between 2 5 and the salt 2 0 c leading to 7 S ,18 S R , 19 R S myxothiazol.

A total synthesis of the novel antifungal substance myxothiazol 1 isolated from the myxobacterium Myxococcus fulvus is described. The synthesis is based on elaboration of the S-E,E -diene thioamide 1 5 and the 2 R S , 3 S R amide aldehyde 2 5 as key intermediates, followed by conversion of 1 5 into the bis -thiazole 1 9 and a final Wittig coupling reaction between 2 5 and the salt 2 0 c leading to 7 S ,18 S R , 19 R S myxothiazol.

Although chronic physical activity by humans can raise energy requirements and energy intake severalfold above sedentary levels, whether these increases alter digestive strategy remains unknown. To investigate this possibility, food passage rate (mouth-to-large intestinal lactulose transit) and absorption (xylose) were compared in a cross section of young men chosen to represent a wide range of daily physical activity and food intake. In 20 men (energy intake 1,272-5,342 kcal/day), resting mouth-to-cecum transit was faster in high caloric consumers (r = -0.69, P less than 0.01). In contrast, xylose absorption (n = 26; measured either as urinary xylose excretion or integrated breath H2 production from the sugar) was unrelated to food intake. Dietary fiber intake was uncorrelated with energy intake. This apparent human digestive strategy of rapid transit across the gut absorptive surface, without a sacrifice in absorption, parallels the adaptations made by several animal species similarly faced with increased energy demand at constant fiber intake. We therefore conclude that the hyperphagia of chronic exercise in humans may be linked with significant gastrointestinal adaptations.

Fever, exercise, and exposure to a hot environment can all cause symptoms of gastrointestinal dysfunction as they elevate body temperature. Nonetheless, the link between hyperthermia per se and these symptoms is unknown. To test the functional significance of increased body temperature, we investigated the influence of substantial passive hyperthermia on orocecal transit in 12 young, healthy men. Transit time was determined by a consistent rise in H2 concentration in a rebreathing apparatus after oral ingestion of 0.7 g lactulose/kg body weight. Lactulose was given in combination with a 350-ml liquid meal (360 kcal). After raising core temperature in warm water to 38.3 degrees C, orocecal transit time was identical to control (90 +/- 13 min at 38.3 degrees C, 92 +/- 13 min at 37.1 degrees C). While hyperthermia did elevate heart rate and minute ventilation, serum motilin, gastrin, and cortisol were similar in the two conditions. The failure of a passive core temperature rise to alter mouth-to-cecum transit suggests that this aspect of alimentary function is independent of body temperature.

Little is known of the influence of exercise on movement of ingested food through the alimentary tract or of the association of several gastrointestinal hormones with transit rate in exercise. In this study, orocecal transit during mild exercise was measured in 21 women by detecting a rise in expired H2 after ingestion of 20 g lactulose in a 350-ml (360 kcal) liquid meal. Motilin, gastrin, and cortisol were measured in peripheral venous blood when, as evidenced by a breath H2 rise, the first portion of the meal arrived at the cecum. Comparison was made between seated rest and a treadmill walk at 5.6 km/h up a 2% grade. The walk predictably elevated heart rate, O2 uptake, and rectal temperature and also reduced transit time from 98 min at rest to 75 min during exercise (P less than 0.001). Faster transit in exercise was associated with a significant rise in cortisol, while gastrin and motilin levels were both unchanged. In conclusion, in women mild concurrent exercise accelerates orocecal transit rate of at least the first portion of nonabsorbable carbohydrate in a liquid meal. Although the mechanism for the effect remains unknown, it may be secondary to some aspect of the stress response to physical activity.

Convergent total syntheses of myxothiazols A and Z are described. The syntheses are based on elaboration of the (S)-E,E-diene thioamide 22, conversion of 22 into the bis-thiazole 27 and Wittig reactions between 27c and the aldehyde 30. The substituted beta-methoxyacrylate aldehyde 30 was produced via an Evans asymmetric aldol protocol or via the 2H-pyran-2-one 31. An E-selective Wittig reaction between the ylide derived from the phosphonium salt 27c and the (+)-aldehyde 30 led to (+)-myxothiazol Z (1b), and a corresponding reaction with the (+/-)-acrylamide aldehyde 44 gave (+/-)-myxothiazol A (1a). Complementary studies led to synthesis of the ester 47b, corresponding to myxothiazol R and myxothiazol S.

The metabolic syndrome, a cluster of factors linked to obesity that contribute to risk for atherosclerosis and Type 2 diabetes, may affect 20–25% of the adults in the United States. We designed a medical physiology laboratory to evaluate and discuss the physiological and nutritional principles involved in the metabolic syndrome. The five criteria used to diagnose this syndrome (fasting blood triglycerides, high-density lipoprotein cholesterol, and glucose, blood pressure, central obesity) were measured by students on each other either previously or during this exercise. In addition, to illustrate nutritional factors involved in causation and treatment of the metabolic syndrome, a meal was provided during the laboratory. Class members were randomized to groups allowed ad libitum meal composition, or constrained to the National Cholesterol Education Program Step I or Step II diets. The composition of the diet (including saturated fat, cholesterol, dietary fiber, and carbohydrate content) was discussed in the context of blood cholesterol, triglyceride, and glucose levels. This laboratory allows a comprehensive analysis of the physiological and nutritional factors involved in the development of the metabolic syndrome.

Purpose: To review the role of ocular perfusion in the pathophysiology of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the industrialized world. Methods: Medline search of the literature published in English or with English abstracts from 1966 to 2000 was performed using various combinations of relevant key words. Results: Vascular defects have been identified in both nonexudative and exudative AMD patients using fluorescein angiographic methods, laser Doppler flowmetry, indocyanine green angiography, and color Doppler imaging. Conclusion: Although these studies lend some support to the vascular pathogenesis of AMD, it is not possible to determine if the choroidal perfusion abnormalities play a causative role in nonexudative AMD, if they are simply an association with another primary alteration, such as a primary RPE defect or a genetic defect at the photoreceptor level, or if they are more strongly associated with one particular form of this heterogeneous disease. Further study is warranted.

To determine whether dosages of a selective beta-blocking agent (betaxolol) and a topical carbonic anhydrase inhibitor (dorzolamide), sufficient to significantly lower intraocular pressure (IOP), have similar or disparate impact on the retinal and retrobulbar circulation.Counterbalanced crossover, with open-label use of medications.Nine persons with normal-tension glaucoma (NTG).After a 3-week drug washout, NTG patients were studied after 1 month of treatment with either dorzolamide or betaxolol, with determinations of IOP and retinal and retrobulbar hemodynamics.At baseline and after treatment with each drug, retinal arteriovenous passage time was determined by scanning laser ophthalmoscopy after fluorescein dye injection, and flow velocities in the central retinal and ophthalmic arteries were measured with color Doppler ultrasonography imaging.Betaxolol and dorzolamide each lowered IOP significantly, with these changes apparent and maximal after 2 weeks (each P0.05). In contrast, dorzolamide (but not betaxolol) accelerated arteriovenous passage of fluorescein dye in the inferior temporal quadrant of the retina (P0.05). Neither drug affected arteriovenous passage in the superotemporal retina or any aspect of central retinal or ophthalmic artery flow velocity after either 2 or 4 weeks.Although both dorzolamide and betaxolol are effective ocular hypotensive agents and their topical instillation leaves retrobulbar hemodynamics unaltered, dorzolamide alone accelerates inferotemporal retinal dye transit.

PURPOSE: To study ocular perfusion defects in age-related macular degeneration. METHODS: Twenty-five subjects with nonexudative age-related macular degeneration were compared with 25 age-matched control subjects in studies of flow velocities in several retrobulbar vessels. Color Doppler imaging, which was performed by an examiner who was masked to the subjects' assignment to the control or age-related macular degeneration group, measured peak systolic and end diastolic velocity in the ophthalmic, central retinal, and nasal and temporal posterior ciliary arteries of one eye. A resistive index was calculated from the peak systolic and end diastolic velocity. RESULTS: Subjects with nonexudative age-related macular degeneration showed a consistent trend toward lower peak systolic and end-diastolic velocities in the posterior ciliary arteries. For example, in the nasal posterior ciliary artery, the mean end diastolic velocity measured 1.45 ± 0.34 cm per sec in the age-related macular degeneration group compared with 1.96 ± 0.66 cm per sec in the control group, yielding a 26% decrease in the age-related macular degeneration group, which represented the largest difference and was highly statistically significant ( P = .0012). The resistive index was not significantly altered in the nasal or temporal posterior ciliary artery. Subjects with nonexudative age-related macular degeneration did not differ from control subjects in peak systolic velocity, end diastolic velocity, or resistive index in the ophthalmic artery. In the central retinal artery, the end diastolic velocity was lower (1.37 ± 1.95 cm per sec vs 1.95 ± 0.66 cm per sec), whereas the resistive index was higher (0.83 ± 0.05 vs 0.76 ± 0.06 cm per sec), in the age-related macular degeneration group; these results were highly statistically significant ( P = .0007 and P CONCLUSIONS: Retrobulbar vascular changes in nonexudative age-related macular degeneration subjects include reduced flow velocities in the nasal and temporal posterior ciliary arteries. The reduced peak systolic velocity, combined with the reduced end diastolic velocity at a constant resistive index, seen in nonexudative age-related macular degeneration, is consistent with reduced bulk flow in these vessels, suggesting that choroidal perfusion is abnormal in this form of age-related macular degeneration. The changes in the central retinal artery suggest there may be a more generalized perfusion abnormality beyond the choroid in patients with age-related macular degeneration or that the central retinal artery exhibits a secondary autoregulatory response to a primary change elsewhere.

AIMS—To determine if normal tension glaucoma (NTG) patients differ from age matched controls in blood flow to the peripapillary retina, as measured with confocal scanning laser Doppler flowmetry (cSLDF; "Heidelberg retinal flowmetry"). METHODS—12 NTG patients and 12 age matched controls were compared using (a) 10 × 10 pixel boxes (the instrument default sample size), taken from the nasal and temporal peripapillary retina, (b) the average from two of these boxes, and (c) every qualifying pixel within the peripapillary retina. RESULTS—Patients and controls did not differ in blood flow measured using the default sample from a single 10 × 10 pixel box, placed in either the temporal or nasal peripapillary retina, or expressed as the average from these two boxes. However, in histograms using every pixel from the peripapillary retina, NTG patients displayed significantly higher percentages of minimal flow pixels (defined as less than one arbitrary unit of flow: 30% v 19%, p

Glaucoma remains a major eye illness with unknown etiology. Although elevated intraocular pressure is clearly a major risk factor, vascular deficits may contribute to initiation and progression of glaucoma. When intraocular pressure is acutely elevated in healthy individuals, the resistance index (derived from the peak systolic and end-diastolic velocities and an indirect index of vascular resistance distal to the site of measurement) in the central retinal and posterior ciliary arteries increases progressively. This result implies that mechanical and vascular factors may be coupled in such a way that perfusion of the retina and optic nerve head may be influenced by changes in the intraocular pressure. Further, at night, when ophthalmic artery flow velocities fall as arterial blood pressure falls in glaucoma patients, the risk of disease progression may be increased. The constancy of these same flow velocities in age-matched healthy individuals points to a possible vascular autoregulatory defect in glaucoma. In addition, in normal-tension glaucoma, vasodilation (CO2 inhalation) normalizes retrobulbar arterial flow velocities, hinting that some vascular deficits in glaucoma may be reversible. Finally, Ca2+ channel blockade improves contrast sensitivity in patients with normal-tension glaucoma, who also show increased retrobulbar vessel flow velocities, a result suggesting that visual function loss may be linked to ocular ischemia. Emerging evidence points to a role of ischemia in the pathogenesis of glaucoma, suggesting that treatments designed to improve ocular blood flow may benefit glaucoma patients.

Acute oral water loading transiently elevates intraocular pressure (IOP) via mechanisms that remain unexplained. We tested the possibilities that water drinking might elevate IOP by creating a blood-aqueous osmotic gradient, or that it might instead alter active ion pumping and the formation of aqueous humor.In the first series, 16 young, healthy individuals were studied during dehydration and for 1 hour after rehydration (14 mL H2O/kg body weight). Hematocrit, total plasma osmolality, and plasma colloid osmotic pressure were determined simultaneously with measurements of IOP. In a second series (N = 16), rehydration occurred after pretreatment with either placebo or a topical carbonic anhydrase inhibitor (1 drop 2% dorzolamide in each eye, 12 and 2 hours before oral water loading).In both series, mean IOP increased significantly 15 minutes after water ingestion and remained elevated above baseline for 45 minutes. In contrast, colloid osmotic pressure and hematocrit were unaltered by water drinking, and neither these variables nor total plasma osmolality correlated with IOP. In the second series, pretreatment with dorzolamide reduced baseline IOP, but failed to alter the magnitude or time course of IOP elevations induced by water drinking.Because water drinking failed to create a blood-ocular osmotic pressure gradient, neither vitreous hydration nor increased aqueous ultrafiltration can explain increases in IOP after acute hydration. Because the increase in ocular tension apparently also is independent of active bicarbonate pumping, factors affecting aqueous drainage must explain the water drinking effect.

Medical physiology laboratories, traditionally devoted to animal experimentation, face unprecedented difficulties linked to cost, staffing, instrumentation, and the use of animals. At the same time, laboratory experiences with living creatures play a unique role in medical education. In this article we describe the use of venipuncture and subsequent blood analysis, with medical students serving as both subjects and experimenters, in a sequence of first-year physiology laboratories. These experiments are safe, robust, inexpensive, and time efficient, and they teach the principles of cardiovascular, respiratory, renal, nutritional, and gastrointestinal physiology. In addition, they enhance medical education in several other important dimensions. First, they teach safe venous blood collection and handling, a training appropriate for students at this level. Second, by serving each week as subjects as well as experimenters, students experience aspects of both sides of the doctor-patient relationship. Third, the laboratories can be used to teach fundamentals of research design and analysis. Finally, because blood analysis is central to medicine, and because the student's own blood data are discussed, students are enthusiastic and cooperative, and the clinical relevance of the data is clear.

Blood flow to the retina and optic nerve remains constant over a range of elevated intraocular pressure or mean arterial pressure, independent of sympathetic activation (pressure autoregulation). In addition, increased metabolic activity in these tissues proportionally increases blood flow (metabolic autoregulation). At constant metabolic rate, altered arterial oxygen content reciprocally alters blood flow, leaving total oxygen delivery constant, while blood flow rises and falls with the arterial carbon dioxide tension. These responses are similar to those of the cerebral circulation. However, while aging, atherosclerosis, arterial hypotension, and individual variation may profoundly alter blood flow regulation and predispose to the development of illness, these factors remain largely unexplored.

AIMS—To evaluate factors affecting Heidelberg retinal flowmeter (HRF) measurements of retinal and optic nerve head blood flow in human subjects. METHODS—The angle of incidence between laser beam and fundus, and camera distance from the eye, were evaluated for their effect upon measures of blood volume, velocity, and flow in a single 100 × 100 × 400 µm volume of temporal peripapillary retinal tissue in normal volunteers. Both intra and intersession reproducibility of these measures were studied. Intersession data were obtained by taking one image per week for 4 weeks. Finally, the intersession haemodynamic data were examined in the entire image (640 × 2560 × 400 µm), using histograms of pixel by pixel blood flow. RESULTS—Measures of blood volume, velocity, and flow from a single anatomical site were unaffected by laser beam to fundus angle of incidence (n = 12). As camera distance from the eye was increased (from 2 to 5 to 7 cm), flow measurements showed increasing individual changes, despite unaltered measured vessel lengths and constant overall mean flow (n = 14). The coefficient of variation for two intrasession images of optic nerve head blood flow averaged 7% (n = 20); in contrast, the 4 week intersession coefficient of variation averaged 30% (n = 15). Intersession reproducibility was increased by using flow histograms from the entire image: the coefficients of variation averaged 16% for total flow and 17% for flow in the pixel of median flow. CONCLUSION—HRF measures of flow are independent of the laser beam to fundus angle of the incidence and dependent upon camera distance from the eye. Intersession reproducibility is best using pixel by pixel analysis of the entire image. Keywords: retina; optic nerve head; glaucoma; diabetic retinopathy

Purpose: Topical carbonic anhydrase inhibitors such as dorzolamide have been developed as ocular hypotensive agents devoid of the side effects plaguing their systemic predecessors. We evaluated the influence of dorzolamide on retinal and retrobulbar blood flow markers to determine if the drug has orbital vascular as well as ocular hypotensive effects. Methods: Eleven persons with healthy eyes received either placebo or two drops 2% dorzolamide, 2 h prior to studies conducted in double-masked, counterbalanced fashion. Four retrobulbar vessels (nasal and temporal posterior ciliary, central retinal, and ophthalmic arteries) were analyzed by color Doppler imaging; scanning laser ophthalmoscopy was used to examine retinal and superficial optic nerve head blood linear velocity. Results: Dorzolamide lowered IOP from 15.7 ± 0.7 to 13.7 ± 0.7 mmHg (p < 0.05). The drug also hastened retinal arteriovenous passage of fluorescein dye, and accelerated capillary dye transit in the macula and optic nerve head. The drug, however, left unaltered blood velocity or resistance index in any retrobulbar vessel. Conclusions: Dorzolamide is an effective ocular hypotensive agent that accelerates blood velocity in the retinal and superficial optic nerve head without an apparent effect upon retrobulbar hemodynamics.

• Background: Exercise acutely lowers intraocular pressure (IOP) and raises arterial pressure. We wondered whether the resultant increase in ocular perfusion pressure would alter retinal blood flow. • Methods: To investigate this question, 11 healthy volunteers each performed progressive cycle ergometer exercise until exhaustion was reached in 5–10 min. Immediately after exercise, retinal blood flow and arteriovenous passage time were determined by video fluorescein angiography. Ten other volunteers performed repeated episodes of cycle ergometer exercise at approximately 60% of the maximal aerobic capacity, immediately prior to estimates of macular leukocyte velocity and density via blue-field stimulation. • Results: Progressive exercise lowered IOP and elevated calculated ocular perfusion pressure. Within the retinal circulation, this exercise tended to raise mean dye velocity, as it significantly narrowed the superior temporal artery and vein; as a result, calculated retinal blood flow was unchanged. Simultaneously, retinal arteriovenous passage time was substantially shortened. Blue-field simulation showed that exercise increased macular leukocyte velocity while leaving leukocyte density unchanged. • Conclusions: These results show that the normal retinal hemodynamic response to increases in perfusion pressure on dynamic exercise includes vasoconstriction that normalizes flow and faster capillary and overall retinal blood transit.

AIM: The cause of vascular and visual pathology in diabetic retinopathy remains unknown. If retinal hypoxia plays a role, then early in the course of diabetes 100% oxygen breathing should normalise both contrast sensitivity and retinal blood flow. METHODS: This hypothesis was tested in 12 diabetic patients with minimal retinopathy who, none the less, exhibited reduced contrast sensitivity (p = 0.003 versus 12 age and sex-matched controls) and prolonged retinal arteriovenous dye transit (p = 0.0001 versus controls). RESULTS: Isocapnic hyperoxia failed to alter contrast sensitivity in controls, while it significantly improved contrast sensitivity in patients (at 12 cpd; p = 0.042) to levels indistinguishable from normal. Individual improvement in contrast sensitivity correlated positively with the severity of the initial defect (r = +0.84, p = 0.0008). Hyperoxia also had haemodynamic effects; it slowed retinal arteriovenous passage of fluorescein dye in controls, but did not further slow this transit time in patients. CONCLUSIONS: These results demonstrate the reversibility of early contrast sensitivity deficits in diabetes mellitus, and support the hypothesis that factors linked to tissue hypoxia initiate both visual and vascular dysfunction in diabetic retinopathy.

PURPOSE: Acetazolamide and CO2 are cerebral vasodilators whose specific effects in various brain regions have not been carefully defined. We investigated the effects of these agents in both larger cerebral and smaller, retrobulbar arteries, to compare their general cerebral vasodilatory influence with their specific ocular vascular effects. METHODS: Twelve young adults with healthy eyes were studied under normocapnic and hypercapnic (6% CO2, 94% O2 tanked gas) conditions after receiving either placebo or 1,000 mg acetazolamide (3 h before study). Color Doppler imaging was used to measure peak systolic and end-diastolic velocities (PSV and EDV) in the internal carotid, middle cerebral, ophthalmic, and central retinal arteries under each condition. RESULTS: Acetazolamide and CO2 each lowered intraocular pressure; combining the agents provided no additive ocular hypotensive effect. Hypercapnia or acetazolamide per se failed to alter PSV, EDV, or the derived resistance index [RI; (PSV-EDV)/PSV] in the internal carotid or in either orbital artery. However, when hypercapnia was superimposed upon acetazolamide, the resistance index fell in the internal carotid and central retinal arteries (each p < 0.05). In contrast, the middle cerebral artery was responsive to either vasodilator and to their combination: PSV and EDV rose, and RI fell with each experimental treatment. CONCLUSIONS: In the brain, the middle cerebral artery exhibits substantial dependence of flow velocity on the vasodilators CO2 and acetazolamide. In contrast, the ophthalmic and central retinal arteries appear less responsive. Nonetheless, the combination of carbonic anhydrase inhibition (acetazolamide) with CO2 augmentation did lower vascular resistance distal to the central retinal artery, suggesting that this mechanism vasodilates critical ocular tissues.

Because the protean biological effects of ethanol include acute alterations in both cortical function and circulatory control, we investigated the effect of acute alcohol consumption on retrobulbar hemodynamics and contrast sensitivity in healthy human volunteers.Twelve young adults received orange juice with and without ethanol in a double-masked fashion. The ethanol dose was sufficient to raise blood alcohol to 0.07 +/- 0.003 g/dl. Retrobulbar hemodynamics were assessed at baseline and twice at elevated blood alcohol by color Doppler imaging.Acute elevation of blood alcohol lowered intraocular pressure from 13.0 +/- 0.7 to 10.7 +/- 0.7 mm Hg (p0.05). In contrast, elevated blood alcohol left peak systolic velocity, end-diastolic velocity and the resistance index constant in three retrobulbar arteries (ophthalmic, central retinal and posterior ciliary). For example, in the central retinal artery, peak systolic velocity, end-diastolic velocity and the resistance index averaged 11.0 +/- 1.3 cm/s, 2.8 +/- 0.4 cm/s and 0.75 +/- 0.03 before ethanol, as compared with 10.5 +/- 1.0 cm/s, 2.9 +/- 0.3 cm/s and 0.72 +/- 0.03 after ethanol (all p = NS). Alcohol ingestion also failed to alter either visual acuity or contrast sensitivity, as assessed under both photopic and mesopic conditions.Although ethanol has widespread cognitive and cardiovascular effects, at blood levels near legal definitions of intoxication we found it ineffective in altering either retrobulbar hemodynamics or contrast sensitivity.

The pathogenesis of normal-tension glaucoma remains unknown. Because ocular vasospasm has been proposed as a possible mechanism, we investigated ocular vessel flow velocity in normal-tension glaucoma patients at rest and under treatment with a cerebral vasodilator. Ten normal-tension glaucoma patients and nine age- and gender-matched controls had flow velocity measured in three vessels (ophthalmic artery, central retinal artery, and temporal short posterior ciliary artery) by using color Doppler imaging, under baseline conditions and during carbon dioxide supplementation sufficient to increase end-tidal PCO2 by 15%. Peak systolic and end-diastolic velocities were measured, and the resistance index (peak systolic velocity minus end-diastolic velocity, divided by peak systolic velocity) was calculated. Compared with controls, these normal-tension glaucoma patients had significantly lower end-diastolic velocities (P = .002) and higher resistance indices (P = .007) in the ophthalmic artery at baseline. When PCO2 was increased, control subjects remained unchanged, whereas it increased end-diastolic velocity in patients (P = .003) and abolished the difference in resistance index between the two groups. Patients and control subjects differed little in their baseline or carbon dioxide response velocities or in resistance in the other two vessels. These results indicate that at baseline these normal-tension glaucoma patients may have increased vascular resistance distal to the ophthalmic artery, although this increased resistance cannot be specifically ascribed to the central retinal arterial or to temporal short posterior ciliary arterial vascular beds. The responsiveness of these patients to a cerebral vasodilator (increased PCO2) indicates further that the increased resistance distal to the ophthalmic artery may be the reversible result of vasospasm.

Hyperoxic-hypercapnic gas mixture (‘carbogen’: 6% CO2-94% O2) is widely used clinically. Its influence on retinal perfusion remains unclear, since past work suggests that high O2 may reduce and high CO2 may increase retinal blood flow. To examine the changes in retinal blood velocity during ‘hyperoxic-hypercapnic’ gax mixture breathing, we quantified retinal blood velocity indices. Twenty-eight healthy subjects were studied using scanning laser video fluorescein angiograms at baseline and after gas inhalation. Retinal arteriovenous passage time and mean arterial dye velocity were measured by means of a digital image processing system. Arterial diameter measurements showed no change (4%) during carbogen breathing. Increased arterial Pco2 and Po2 resulted in small but statistically significant increases in systolic and diastolic blood pressure and heart rate (each c. 8%, p < 0.05), and a dramatic increase in mean dye velocity (27%, p < 0.01), with parallel reduction in arteriovenous passage time (40%, p < 0.01). The substantial acceleration of retinal dye velocity and transit under combined hyperoxia and hypercapnia strongly suggests that this clinically standard gas mixture may indeed improve oxygenation without reducing retinal perfusion.

Retinal blood flow regulation in health remains poorly described. We hypothesized that retinal perfusion is controlled to provide constant O2 delivery to that tissue, and that changes in retinal blood flow in response to chemical stimuli parallel changes in carotid and retrobulbar perfusion. Accordingly, in 11 young adults with normal eye examinations, we measured retinal blood flow indices (via scanning laser ophthalmoscopy [SLO] during fluorescein angiography) and carotid, ophthalmic, and central retinal arterial blood flow indices (via Doppler imaging [CDI]) under control, hypoxic (alveolar PO2 = 55 +/- 3 mmHg) and hyperoxic (alveolar PO2 = 655 +/- 18 mmHg) conditions. The three conditions were counterbalanced in order and isocapnia was maintained in each. Retinal arterial mean dye velocity and arteriovenous passage time, as measured by SLO, were slowed by hyperoxia and accelerated by hypoxia, in rough proportion to the changes in arterial O2 content (+/- 10%; p0.05). In the seven subjects in which relative measurements of retinal arterial diameters were obtained, neither hypoxia nor hyperoxia significantly altered vessel diameter. At the same time, mean retinal capillary transit velocity was independent of PO2, suggesting that, in health, retinal capillaries may be recruited as PO2 falls. O2-induced changes in carotid, ophthalmic, or central retinal arterial blood flow velocities (via CDI) were not found, though a wide coefficient of variation (30% for CDI vs. 14% for SLO) may have contributed to this failure. We conclude that, under isocapnic conditions, retinal perfusion may be regulated to provide constant O2 delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Anecdotes and animal experiments alike suggest that physiological and psychological stress can profoundly alter gastrointestinal function. However, few studies have examined, in humans, real-world stress to see if free-living persons exhibit gut alterations similar to those produced in the laboratory. To investigate this possibility, we studied 16 medical and premedical students during final written examinations. As compared to a control day, the examination created a classic stress response: elevated serum cortisol (16 +/- 1 to 21 +/- 3 micrograms/dl; P < 0.05), ACTH (31 +/- 1 to 33 +/- 1 pg/ml; P < 0.05), heart rate (72 +/- 3 to 79 +/- 3 beats/min; P < 0.05), arterial blood pressure (systolic pressure 106 +/- 2 to 120 +/- 2 torr; P < 0.05; diastolic pressure 72 +/- 2 to 77 +/- 1 torr; P < 0.05), and subjective anxiety (raw score 28 +/- 2 to 47 +/- 3; P < 0.0001). In contrast, subjects displayed identical orocecal liquid transit time (of 0.36 g/kg lactulose in a 240-ml, 250-kcal liquid meal) under control (103 +/- 8 min) and examination conditions (106 +/- 8 min; P = NS). Mean subjective reports of gas, diarrhea, and borborygmi were unchanged on the day of the experiment, although the examination did increase reported abdominal pain (from 0.5 +/- 0.4 to 2.1 +/- 0.5 on a 0-5 analog scale; P < 0.05). We conclude that examination stress in humans can increase gastrointestinal symptoms without altering orocecal transit.

Previous work in our laboratory has found that mild physical activity accelerates mouth-to-large intestinal transit of lactulose in a mixed liquid meal. Because loperamide is commonly used as an antidiarrheal agent, we wondered if it would blunt the orocecal transit acceleration provoked by mild exercise. We investigated this equation in 12 healthy persons by comparing orocolonic liquid transit at rest and in mild exercise. Each subject ingested 8 mg loperamide 1 hr prior to study under both resting and exercise conditions. With loperamide treatment, exercise (walking at 5.6 km/hr) failed to hasten increased H2 excretion (mean transit time 72 +/- 12 min at rest, 90 +/- 15 min in exercise; P = NS). This result contrasts sharply with previously reported controls: loperamide completely abolished exercise-induced orocecal transit acceleration (-23 +/- 5 min in controls; +18 +/- 13 min with loperamide; P0.05). Compared with these same controls, resting transit was not significantly slowed by the drug, while transit in exercise was retarded (64 +/- 5 min in controls, 90 +/- 15 min with loperamide; P = 0.06). Loperamide left unchanged the heart rate and oxygen uptake rises associated with exercise. In summary, by showing that loperamide blocks an exercise effect on the upper gut, these results suggest that the drug might prove effective in treating some gut symptoms induced by physical activity.