Imported cases and minimum temperature drive dengue transmission in Guangzhou, China: evidence from ARIMAX model.

Dengue is the fastest spreading mosquito-transmitted disease in the world. In China, Guangzhou City is believed to be the most important epicenter of dengue outbreaks although the transmission patterns are still poorly understood. We developed an autoregressive integrated moving average model incorporating external regressors to examine the association between the monthly number of locally acquired dengue infections and imported cases, mosquito densities, temperature and precipitation in Guangzhou. In multivariate analysis, imported cases and minimum temperature (both at lag 0) were both associated with the number of locally acquired infections (P < 0.05). This multivariate model performed best, featuring the lowest fitting root mean squared error (RMSE) (0.7520), AIC (393.7854) and test RMSE (0.6445), as well as the best effect in model validation for testing outbreak with a sensitivity of 1.0000, a specificity of 0.7368 and a consistency rate of 0.7917. Our findings suggest that imported cases and minimum temperature are two key determinants of dengue local transmission in Guangzhou. The modelling method can be used to predict dengue transmission in non-endemic countries and to inform dengue prevention and control strategies.

Assessment of the Physiological Adaptations to Chronic Hypoxemia in Eisenmenger Syndrome.

OBJECTIVE: Eisenmenger syndrome is characterized by severe and lifelong hypoxemia and pulmonary hypertension. Despite this, patients do surprisingly well and report a reasonable quality of life. The aim of this study was to investigate whether these patients undergo adaptation of their skeletal and cardiac muscle energy metabolism which would help explain this paradox. DESIGN AND SETTING: Ten patients with Eisenmenger syndrome and eight age- and sex-matched healthy volunteers underwent symptom-limited treadmill cardiopulmonary exercise testing, transthoracic echocardiography and (31) P magnetic resonance spectroscopy of cardiac and skeletal muscle. Five subjects from each group also underwent near infrared spectroscopy to assess muscle oxygenation. RESULTS: Despite having a significantly lower peak VO2 , patients with Eisenmenger syndrome have a similar skeletal muscle phosphocreatine (PCr) recovery, a measure of oxidative capacity, when compared to healthy controls (34.9 s ± 2.9 s vs. 35.2 s ± 1.7 s, P = .9). Furthermore their intracellular pH falls to similar levels during exercise suggesting they are not reliant on early anaerobic metabolism (0.3 ± 0.06 vs. 0.28 ± 0.04, P = .7). While their right ventricular systolic function remained good, the Eisenmenger group had a lower cardiac PCr/ATP ratio compared to the control group (1.55 ± 0.10 vs. 2.17 ± 0.15, P < .05). CONCLUSIONS: These results show that adult patients with Eisenmenger syndrome have undergone beneficial physiological adaptations of both skeletal and cardiac muscle. This may, in part, explain their surprisingly good survival despite a lifetime of severe hypoxemia and adverse cardiopulmonary hemodynamics.

Hypoxia is an effective stimulus for vesicular release of ATP from human umbilical vein endothelial cells.

INTRODUCTION: Hypoxia induces dilatation of the umbilical vein by releasing autocoids from endothelium; prostaglandins (PGs), adenosine and nitric oxide (NO) have been implicated. ATP is vasoactive, thus we tested whether hypoxia releases ATP from primary Human Umbilical Vein Endothelial Cells (HUVEC). METHODS: HUVEC were grown on inserts under no-flow conditions. ATP was assayed by luciferin-luciferase and visualised by quinacrine labeling. Intracellular Ca(2+) ([Ca(2+)]i) was imaged with Fura-2. RESULTS: ATP release occurred constitutively and was increased by hypoxia (PO2: 150-8 mmHg), ∼10-fold more from apical, than basolateral surface. Constitutive ATP release was decreased, while hypoxia-induced release was abolished by brefeldin or monensin A, inhibitors of vesicular transport, and LY294002 or Y27632, inhibitors of phosphoinositide 3-kinases (PI3K) and Rho-associated protein kinase (ROCK). ATP release was unaffected by NO donor, but increased by calcium ionophore, by >60-fold from apical, but <25% from basolateral surface. Hypoxia induced a small increase in [Ca(2+)]i compared with ATP (10 µM); hypoxia inhibited the ATP response. Quinacrine-ATP fluorescent loci in the perinuclear space, were diminished by hypoxia and monensin, whereas brefeldin A increased fluorescence intensity, consistent with inhibition of anterograde transport. DISCUSSION: Hypoxia within the physiological range releases ATP from HUVEC, particularly from apical/adluminal surfaces by exocytosis, via an increase in [Ca(2+)]i, PI3K and ROCK, independently of NO. We propose that hypoxia releases ATP at concentrations sufficient to induce umbilical vein dilation via PGs and NO and improve fetal blood flow, but curbs amplification of ATP release by autocrine actions of ATP, so limiting its pro-inflammatory effects.

Effect of Foliarly Applied Spirotetramat on Reproduction of Heterodera avenae on Wheat Roots.

The cereal cyst nematode, Heterodera avenae, has the potential to reduce yields of cereal crops in the Pacific Northwest. Spirotetramat (Movento) is a foliar-applied insecticide with ambimobile translocation that reduces fecundity of sucking insects which feed on roots as well as foliage. Spirotetramat (88 g/ha) was applied to foliage during 2010 in two wheat fields infested by H. avenae near St. Anthony, ID and Palouse, WA. In Idaho, two applications at 2-week intervals during late spring to plants already exhibiting swollen white females reduced the postharvest density of H. avenae eggs plus juveniles by 35% (P = 0.03) compared to the nontreated control. In Washington, a single application before white females became apparent reduced the nematode density by 78% (P = 0.01). Grain yields and test weights were not significantly affected by application of spirotetramat at either location. In addition, symptomatic plants from the Idaho field were transplanted into greenhouse pots and treated with spirotetramat. One application (110 g/ha) reduced numbers of eggs plus juveniles/plant by 78% (P = 0.02). Spirotetramat effectively reduced H. avenae populations and warrants further evaluation as a substitute for crop rotations or long fallow periods that reduce nematode population densities in infested fields.

Rehabilitation and transition after lung transplantation in children.

We describe the key components of an outpatient pediatric recovery and rehabilitation program set up within the adult lung transplant service at the Alfred Hospital, Melbourne. Following discharge, pediatric lung transplant recipients and their families participated in an intensive 3-month outpatient rehabilitation program. Weekly sessions included education regarding transplant issues, physiotherapy, and occupational therapy sessions. The overall aim of the program was to comprehensively address physical rehabilitation and psychosocial and educational needs. Sessions tailored to meet the individual needs of the child were presented at an appropriate cognitive level. Education sessions for both the children and parents focused on medications, identification of infection and rejection, nutrition, physiotherapy/rehabilitation, occupational roles and stress management, donor issues, psychosocial readjustment, and transition issues. Physiotherapy included a progressive aerobic and strength training program, postural reeducation, and core stability. We incorporate Age-appropriate play activities: running, dancing, jumping, ball skills, and so on. Occupational therapy sessions addressed the primary roles of patient, students, and player. Transitions such as returning to school, friends, and the community were explored. Issues discussed included adjustment to new health status, strategies to manage side effects of medications, and altered body image issues. Weekly multidisciplinary team meetings were used to discuss and plan the rehabilitation progress. School liaison and visits occurred prior to school commencement with follow-up offered to review the ongoing transition process. Both patients and parents have reported a high level of satisfaction with the rehabilitation program. We plan to formally evaluate the program in the future.

The role of platelet activating factor in a neonatal piglet model of necrotising enterocolitis.

BACKGROUND AND AIMS: Necrotising enterocolitis (NEC) is a potentially devastating disorder of preterm infants but its aetiology remains unclear. The aim of these studies was to develop a neonatal piglet model for NEC and to then use the model to investigate the role of platelet activating factor (PAF) in its pathogenesis. METHODS: Anaesthetised newborn piglets were divided into six groups: (i) controls, and groups subjected to (ii) hypoxia, (iii) lipopolysaccharide (LPS), (iv) hypoxia+LPS, (v) hypoxia+LPS and the PAF antagonist WEB 2170, and (vi) PAF. Arterial blood pressure (ABP), superior mesenteric artery blood flow (MBF), mesenteric vascular conductance (MVC), and arterial blood gases were recorded, and intestinal histology was evaluated. RESULTS: Exposure to LPS, hypoxia+LPS, or PAF all caused haemorrhagic intestinal lesions associated with varying degrees of intestinal injury. PAF caused a significant initial decrease in both MVC and MBF whereas hypoxia+LPS caused a significant late reduction in ABP and MBF with a trend towards a decrease in MVC. The effects of hypoxia+LPS on both haemodynamic changes and intestinal injury were ameliorated by WEB 2170. CONCLUSIONS: Administration of hypoxia and LPS or of PAF in the neonatal piglet induces haemodynamic changes and intestinal lesions that are consistent with NEC. These effects are ameliorated by prior administration of WEB 2170, indicating an important role for PAF in the pathogenesis of NEC.

Chronic hypoxia induces prolonged angiogenesis in skeletal muscles of rat.

Skeletal muscle capillarity and fibre cross-sectional area were investigated within and between diaphragm (Diaph), extensor digitorum longus (EDL), soleus (SOL) and tibialis anterior (TA) muscles of control and chronic hypoxic (12 % O(2) for 6 weeks) adult male Wistar rats (final body mass approximately 355 g). Cryostat sections were stained for alkaline phosphatase activity to depict all capillaries, and for succinic dehydrogenase to demonstrate regional differences in oxidative capacity within the muscles. Hypoxia-induced angiogenesis occurred in all muscles (P < 0.01), with capillary-to-fibre ratio (C:F) being higher in the more active and oxidative muscles, Diaph (27 %) and SOL (26 %), than phasically active and glycolytic muscles, TA (21 %) and EDL (15 %). Diaph, SOL and EDL maintained fibre size, and hence showed an increased capillary density (CD) and reduced intramuscular diffusion distance (DD), whereas TA showed fibre hypertrophy and maintained CD and DD compared to control muscles. The extent of angiogenesis among different regions of muscle varied so as to suggest that muscle fibre size has an additional influence on capillary growth during chronic systemic hypoxia, which is progressive over an extended period of systemic hypoxia.

Oxygen delivery and oxygen consumption in rat hindlimb during systemic hypoxia: role of adenosine.

1. In anaesthetised rats, the increase in femoral vascular conductance (FVC) evoked by moderate systemic hypoxia is mediated by adenosine acting on A(1) receptors. It is also nitric oxide (NO) dependent: it is attenuated by NO synthase (NOS) inhibition, but restored when baseline FVC is restored by sodium nitroprusside (SNP), a NO donor. However, under these conditions there was in increase in the critical O(2) delivery (D(O2,crit)) at which hindlimb O(2) consumption (V(O2)) becomes directly dependent upon O(2) delivery (D(O2)), indicating that V(O2) is regulated by newly synthesised NO. 2. In the present study, after NOS inhibition, when baseline FVC was restored with SNP infusion, the increases in FVC evoked by breathing 12 and 8 % O(2) were reduced by the A(1) receptor antagonist DPCPX, by 60 and 40 %, respectively (n = 8). The A(2A) receptor antagonist ZM241385 reduced the FVC increase evoked by 12 % O(2) (by 45 %, n = 8), but did not alter that evoked by 8 % O(2). 3. DPCPX also reduced the increases in FVC evoked by graded systemic hypoxia, breathing 14-6 % O(2) and increased D(O2,crit), from 0.64 +/- 0.06 to 0.95 +/- 0.07 ml O(2) min(-1) kg(-1) (control vs. DPCPX). However, ZM241385 (n = 8) had no effect on the FVC increases or on D(O2,crit) (0.70 +/- 0.02 ml O(2) min(-1) kg(-1), n = 8). 4. Thus, the increases in FVC evoked by mild to severe systemic hypoxia are mediated by A(1) receptors. These responses, which are attributable to proximal arteriolar dilatation, help maintain D(O2). Even after NOS inhibition, adenosine still increases FVC via A(2A) (moderate hypoxia only) and A(1) receptors, providing baseline levels of NO are present. Furthermore, adenosine, acting via A(1) receptors, is important in determining D(O2,crit) and therefore in maintaining V(O2). We propose that this is achieved by A(1)-evoked dilatation of terminal arterioles and is mediated by increased synthesis of NO.

Roles of norepinephrine and ATP in sympathetically evoked vasoconstriction in rat tail and hindlimb in vivo.

In anesthetized rats, we characterized the contributions of norepinephrine (NE) and ATP to changes in tail and hindlimb (femoral) vascular resistances (TVR and FVR, respectively) evoked by three patterns of sympathetic stimulation: 1) couplets (2 impulses at 20 Hz), 2) short trains (20 impulses at 20 Hz), and 3) a natural irregular pattern previously recorded from a sympathetic fiber innervating the rat tail artery. All stimuli evoked greater changes in TVR than FVR. Judging from the effects of the alpha-adrenoceptor antagonist phentolamine, the purinergic receptor antagonist suramin, or alpha,beta-methylene ATP (which desensitizes P2X receptors), we propose that NE has a major role in the constriction evoked by the couplet, as well as by the short train and by the low- and high-frequency components of the natural pattern, but that considerable synergy occurred between the actions of ATP and NE. This contrasts with previous in vitro studies that indicated that ATP dominates vascular responses evoked by sympathetic stimulation with a few impulses at low frequency and that NE dominates responses to longer trains or at high frequencies.

Symptoms of musculoskeletal disorders in stage rally drivers and co-drivers.

BACKGROUND: During stage rallying, musculoskeletal injuries may be provoked by the high magnitude of vibration and shock to which the driver and co-driver are exposed. Drivers and co-drivers experience similar exposure to whole body mechanical shocks and vibration but different exposure to hand/wrist stressors. OBJECTIVES: To investigate by a questionnaire study the prevalence of symptoms of musculoskeletal injuries after rallying in 13 professional and 105 amateur stage rally competitors. METHODS: The self administered questionnaire investigated whole body and hand/wrist symptoms of musculoskeletal injury. It was loosely based on the Nordic design. RESULTS: 91% of participants who competed or tested for more than 10 days a year (n=90) reported discomfort in at least one body area after rallying. Problems in the lumbar spine (70%), cervical spine (54%), shoulders (47%), and thoracic spine (36%) were the most common. There was a higher prevalence of cervical spine discomfort for co-drivers (62%) than for drivers (46%). Conversely, there was higher prevalence of discomfort in the hands and wrists for drivers (32%) than co-drivers (9%). The prevalence of low back pain in rally participants is higher than that generally reported for workers exposed to whole body vibration. The prevalence of discomfort in the hand and wrist for rally drivers is similar to that previously reported for Formula 1 drivers. CONCLUSIONS: Most stage rally drivers and co-drivers report symptoms of musculoskeletal injury. It is logical to relate the high prevalence of symptoms of injury to the extreme environment of the rally car.

Relationship between capillary angiogenesis, fiber type, and fiber size in chronic systemic hypoxia.

Whether chronic hypoxia causes angiogenesis in skeletal muscle is controversial. Male Wistar rats, 5--6 wk of age, were kept at constant 12% O(2) for 3 wk, and frozen sections of their postural soleus (SOL), phasic extensor digitorum longus (EDL), and tibialis anterior (TA) muscles were compared with those of normoxic controls. Capillary supply increased in SOL muscles [capillary-to-fiber ratio (C/F) = 2.55 +/- 0.09 hypoxia vs. 2.17 +/- 0.06 normoxia; capillary density (CD) = 942 +/- 14 hypoxia vs. 832 +/- 20 mm(-2) normoxia, P < 0.01] but not in EDL muscles (C/F = 1.44 +/- 0.04 hypoxia vs. 1.42 +/- 0.04 normoxia; CD = 876 +/- 52 hypoxia vs. 896 +/- 24 mm(-2) normoxia). The predominantly glycolytic cortex of TA muscles showed higher C/F after hypoxia (1.79 +/- 0.09 vs. 1.53 +/- 0.05 normoxia, P < 0.05), whereas the mainly oxidative TA core with smaller fibers showed no change in capillarity. The region of the SOL muscle with large-sized (mean fiber area 2,843 +/- 128 microm(2)) oxidative fibers (90% type I) had a higher C/F (by 30%) and CD (by 25%), whereas there was no angiogenesis in the region with sparse (76%) and smaller-sized (2,200 +/- 85 microm(2)) type I fibers. Thus systemic hypoxia differentially induces angiogenesis between and within hindlimb skeletal muscles, with fiber size contributing either directly (via a metabolic stimulus) or indirectly (via a mechanical stimulus) to the process.

Vasodilatation, oxygen delivery and oxygen consumption in rat hindlimb during systemic hypoxia: roles of nitric oxide.

We have investigated the relationship between O2 delivery (DO2) and O2 consumption (VO2) in hindlimb muscle of anaesthetised rats during progressive systemic hypoxia. Since muscle vasodilatation that occurs during hypoxia is nitric oxide (NO) dependent, we examined the effects of the NO synthase (NOS) inhibitor nitro-L-arginine methyl ester (L-NAME). In control rats (n = 8), femoral vascular conductance (FVC) increased at each level of hypoxia. Hindlimb DO2 decreased with the severity of hypoxia, but muscle VO2 was maintained until the critical DO2 value (DO2,crit) was reached at 0.64 +/- 0.06 ml O2 min-1 kg-1; below this VO2 declined linearly with DO2. This is a novel finding for the rat but is comparable to the biphasic relationship seen in the dog. In another group of rats (n = 6), L-NAME caused hindlimb vasoconstriction and attenuated the hypoxia-evoked increases in FVC DO2 was so low after L-NAME administration that VO2 was dependent on DO2 at all levels of hypoxia. In a further group (n = 8), femoral blood flow and DO2 were restored after L-NAME by infusion of the NO donor sodium nitroprusside (20 g x kg(-1) x min(-1). Thereafter, hypoxia-evoked increases in FVC were fully restored. Nevertheless, DO2,crit was increased relative to control (0.96 +/- 0.07 ml O2 min(-1) x kg(-1), P < 0.01). As NOS inhibition limited the ability of muscle to maintain VO2 during hypoxia, we propose that hypoxia-induced dilatation of terminal arterioles, which improves tissue O2 distribution, is mediated by NO. However, since the hypoxia-evoked increase in FVC was blocked by L-NAME but restored by the NO donor, we propose that the dilatation of proximal arterioles is dependent on tonic levels of NO, rather than mediated by NO.

Roles of adenosine and nitric oxide in skeletal muscle in acute and chronic hypoxia.

In experiments on anaesthetised rats, the roles played by adenosine and nitric oxide (NO) were determined in resting skeletal muscle in acute systemic hypoxia and during acclimation to chronic systemic hypoxia. It is concluded that adenosine acting on A1 receptors, at least in part in an NO-dependent manner, plays essential roles in causing the dilation of proximal and terminal arterioles that helps to maintain muscle O2 consumption when O2 delivery is reduced by acute systemic hypoxia. It is proposed that adenosine and NO are similarly responsible for causing the tonic vasodilation that gradually wanes in the first 7 days of chronic hypoxia and that concomitantly, adenosine and hypoxia stimulate VEGF expression, so increasing venular permeability and triggering angiogenesis. By 7 days of chronic hypoxia, arteriolar remodelling is well established and within 18-21 days, substantial capillary angiogenesis alleviates tissue hypoxia. At this time, vasoconstrictor responses to the sympathetic transmitter norepinephrine are reduced, but dilator responses to adenosine released by acute hypoxia are enhanced, as may be explained by increased sensitivity to NO. Thus, preservation of tissue oxygenation is apparently associated with impaired ability to regulate arterial pressure and vulnerability to further hypoxia.

Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro.

Angiogenesis, the development of new blood vessels from an existing vascular bed, is essential for the growth and spread of malignant tumors. Several endogenous angiogenesis inhibitors have been discovered and shown to suppress endothelial cell function in vitro and tumor growth in vivo. Several of these are proteolytic fragments of larger, endogenous proteins. Here we show that a Mr 50,000 polypeptide derived from the plasmin cleavage of fibrinogen, fibrinogen E-fragment, inhibits endothelial cell migration and tubule formation induced by both proangiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in vitro.

Abnormal venous function in patients with homozygous sickle cell (SS) disease and chronic leg ulcers.

Chronic leg ulceration is a major cause of morbidity in homozygous sickle cell (SS) disease in Jamaica. These ulcers have features in common with venous ulcers in patients with a normal haemoglobin genotype (AA). Thus we sought to determine whether there is abnormal venous function in the legs of patients with SS disease who have ulcers. Experiments were performed on 15 SS patients with ulcers, and on 15 SS patients and 15 AA subjects with no history of leg ulcers. Changes in venous blood volume of the bottom one-third of the leg induced by venous occlusion and release were studied by air plethysmography, providing indices of segmental venous capacitance (SVC), maximal venous outflow (MVO) and venous emptying time (VET). The changes in volume (ambulatory volume change; AVC) induced by a period of leg exercise were also measured at the ankle (AVCa) and calf (AVCc); venous refilling times at these sites (RTa and RTc respectively) were also measured. Finally, cutaneous red blood cell flux recovery time (FRT) after ankle exercise was assessed by laser Doppler flowmetry. Measurements were also made of haematological variables. SVC, MVO and VET did not differ between the groups, indicating no deep venous obstruction in the SS patients with ulcers. AVCc, AVCa and RTc did not differ among the three subject groups. However, compared with AA subjects, SS patients with ulcers had reduced RTa and FRT. Moreover, RTa and FRT were further shortened in SS patients with ulcers relative to SS patients without ulcers. Since the levels of anaemia were similar in SS patients with and without ulcers, these differences cannot be attributed to differences in arterial flow secondary to anaemia. These results suggest abnormal venous function in SS patients with ulcers, relative to both AA subjects and SS patients without ulcers. We propose that there is incompetence of venous valves draining the ankle region of SS patients with ulcers: the consequent raised venous pressure contributes to the slow healing and, possibly, to the onset of leg ulceration in SS disease.

Adenosine and muscle vasodilatation in acute systemic hypoxia.

Adenosine is released by skeletal and cardiac muscles when their metabolism increases: it serves to couple O2 supply with O2 demand by causing vasodilatation. This review argues that adenosine plays a similar role in skeletal muscle in systemic hypoxia. It accounts for approximately 50% of the increase in muscle vascular conductance and, within muscle, it causes dilatation of individual arterioles, thus maximizing the distribution of O2 and allowing O2 consumption to remain constant when O2 delivery is reduced. In vivo and in vitro studies have indicated that adenosine can induce dilatation in several different ways. This review argues that during systemic hypoxia, adenosine is predominantly released from the endothelium and acts on endothelial A1 receptors to produce dilatation in a nitric oxide (NO)-dependent manner. A1 receptor stimulation increases the synthesis of NO by a process initiated by opening of ATP-sensitive K+ (KATP) channels. Moreover, recent findings suggest that prostaglandins also make a major contribution to the hypoxia-induced dilatation, but that the dilator pathways for adenosine, NO and prostaglandins are interdependent. In addition, adenosine released from the skeletal muscle fibres contributes indirectly to the dilatation by stimulating A1 and A2 receptors on the muscle fibres, opening KATP channels and allowing efflux of K+, which is a vasodilator. Finally, by acting on endothelial A1 receptors, adenosine attenuates the vasoconstrictor effects of constant or bursting patterns of sympathetic activity. This limits the extent to which the sympathetic nervous system can reduce O2 delivery to muscle when it is already compromised by systemic hypoxia.

Quantitative studies of the vasculature of the carotid body in the chronically hypoxic rat.

The carotid bodies of rats made chronically hypoxic by breathing 12% O2 in a normobaric chamber (inspired PO2 91 mmHg) were compared with those of controls. Serial 5-microm sections of the organs were examined using an interactive image analysis system. The total volume of the carotid bodies was increased by 64%. The total vascular volume rose by 103% and was likely due to an increase in size of the large vessels (>12 microm lumen diameter) because the small vessel (5-12 microm lumen diameter) volume did not increase significantly while the small vessel density tended to decrease. The extravascular volume was increased by 57%. Expressed as a percentage of the total volume of the organ, the total vascular volume did not change, but the small vessel volume was significantly decreased from 7.83 to 6.06%. The large vessel volume must therefore have been increased. The proportion occupied by the extravascular volume was virtually unchanged (84 vs 82%). In accordance with these findings, the small vessel endothelial surface area per unit carotid body volume was diminished from 95.2 to 76.5 mm-1, while the extravascular area per small vessel was increased from 493 to 641 microm(2) or by 30%. In conclusion, the enlargement of the carotid body in chronic hypoxia is most likely due to an increase in total vascular volume, mainly involving the "large" vessels, and to an increase in extravascular volume. This is in contrast to our previously published findings indicating that in the spontaneous insulin-dependent diabetic rat the enlargement of the carotid body is due solely to an increase in extravascular volume.

The cutaneous vasoconstrictor response to venous stasis is normal in subjects with primary Raynaud's disease.

In control subjects and in subjects with primary Raynaud's disease, sudden sound or a mild cool stimulus evokes the pattern of alerting response that includes cutaneous vasoconstriction but vasodilatation in forearm muscle. In control subjects, response habituates on repetition of these stimuli both within experimental sessions and over successive days. However, in subjects with primary Raynaud's disease, the cutaneous vasoconstriction and the muscle vasodilatation persist. We have now tested whether a similar disparity exists for the cutaneous vasoconstriction evoked by venous stasis, a response considered to be a veno-arteriolar reflex mediated by sympathetic fibers, but not requiring transmission through the spinal cord. In 10 subjects with primary Raynaud's disease and in 10 matched controls, a sphygmomanometer cuff on the left arm was inflated to 40 mm Hg for 2 minutes, five times on each of three experimental sessions on days 1, 3, and 5. Cutaneous red cell flux (RCF) was recorded from the pulp and dorsum of the left index finger by using a laser Doppler meter; digital vascular conductance (DCVC) was computed as RCF divided by arterial pressure. The first venous stasis, in session 1, evoked a decrease in pulp and dorsum DCVC in the control and primary Raynaud's subjects. There were no differences between the groups in the magnitudes or durations of these responses. Within session 1, the magnitude of the decrease in DCVC diminished on repetition of venous stasis in the dorsum in controls and in the pulp in primary Raynaud's subjects. We propose these effects reflected the similar reductions in baseline DCVC over time; there was no change in the duration of the responses. Repetition of venous stasis had similar effects in both groups of subjects within sessions 2 and 3. Further, judging from the mean of the responses evoked in each Session the decreases evoked in pulp and dorsum DCVC by venous stasis were fully consistent in magnitude and duration over the three sessions in both groups. These results indicate that the direct constrictor influence of sympathetic fibers upon cutaneous blood vessels is similar in magnitude and similarly reproducible in controls and subjects with primary Raynaud's disease. This reinforces our view that the lack of habituation of the cutaneous vasoconstrictor component of the alerting response in subjects with primary Raynaud's disease reflects impairment of the central neural process of habituation, rather than a peripheral phenomenon, and that this lack of habituation predisposes these subjects to vasospasm.

Physiological adjustments and arteriolar remodelling within skeletal muscle during acclimation to chronic hypoxia in the rat.

1. We have investigated the physiological and structural changes that occur in skeletal muscle vasculature during acclimation to chronic hypoxia in rats exposed to 12 % O2 in a hypoxic chamber for 7 or 18 days (7CH and 18CH rats, respectively) and in age-matched normoxic (7N and 18N) rats. 2. Under anaesthesia and breathing 12 % O2, 7CH and 18CH rats had lower arterial blood pressure (ABP) than 7N and 18N rats breathing air, but the haematocrit of the CH rats was increased so that their arterial O2 content equalled that of N rats. Blood flow recorded from the iliac or femoral artery and used to compute muscle vascular conductance (MVC: blood flow/ABP) showed that, in 18CH rats, MVC was comparable with that of 18N rats. 3. Maximal MVC induced by infusion of sodium nitroprusside (SNP) was used as an index of structural vascular conductance and compared with the MVC evoked by acute hypoxia (breathing 8 % O2). Hypoxia induced similar increases in MVC in 7N and 7CH rats and in 18N and 18CH rats, even though N rats were switched from air to 8 % O2 and CH rats were switched from 12 to 8 % O2. The MVCs attained with 8 % O2 and SNP were similar in 7N and 18N rats. However, the MVCs attained with 8 % O2 in 7CH and 18CH rats were only approximately 60 % of those evoked by SNP, while the MVC attained with SNP was greater in 18CH than in 18N rats. 4. Vascular casts of the spinotrapezius muscle analysed ex vivo showed that interbranch intervals along primary, secondary and terminal arterioles (22-50, 13-18 and 7-13 microm diameter, respectively) were 30-50 % shorter in 7CH and 18CH rats than in 7N and 18N rats. Further, the proportions of branches that were of the secondary and terminal arteriolar categories were increased such that the mean diameter of the branches was lower in 7CH than in 7N rats and lower in 18CH than in 18N rats. 5. These results indicate that arteriolar remodelling and angiogenesis occurs in skeletal muscle during acclimation to chronic hypoxia, beginning by the 7th day and progressing at least until the 18th day, so that the number of small arterioles and the functional size of the vascular bed is increased. We propose that these structural and functional changes enhance the ability of skeletal muscle to respond to acute hypoxia by facilitating the increase in vascular conductance, blood flow and thereby the O2 that can be delivered to muscle.