Semipermeable species boundaries create opportunities for gene flow and adaptive potential.

Hybridisation and gene flow can have both deleterious and adaptive consequences for natural populations and species. To better understand the extent of hybridisation in nature and the balance between its beneficial and deleterious outcomes in a changing environment, information on naturally hybridising nonmodel organisms is needed. This requires the characterisation of the structure and extent of natural hybrid zones. Here, we study natural populations of five keystone mound-building wood ant species in the Formica rufa group across Finland. No genomic studies across the species group exist, and the extent of hybridisation and genomic differentiation in sympatry is unknown. Combining genome-wide and morphological data, we demonstrate more extensive hybridisation than was previously detected between all five species in Finland. Specifically, we reveal a mosaic hybrid zone between Formica aquilonia, F. rufa and F. polyctena, comprising further generation hybrid populations. Despite this, we find that F. rufa, F. aquilonia, F. lugubris and F. pratensis form distinct gene pools in Finland. We also find that hybrids occupy warmer microhabitats than the nonadmixed populations of cold-adapted F. aquilonia, and suggest that warm winters and springs, in particular, may benefit hybrids over F. aquilonia, the most abundant F. rufa group species in Finland. In summary, our results indicate that extensive hybridisation may create adaptive potential that could promote wood ant persistence in a changing climate. Additionally, they highlight the potentially significant ecological and evolutionary consequences of extensive mosaic hybrid zones, within which independent hybrid populations face an array of ecological and intrinsic selection pressures.

[Morphological changes in rabbit cornea after implantation of a new keratoprosthesis supporting plate]. / Morfologicheskie izmeneniya rogovitsy krolika pri implantatsii novoi modeli opornoi plastinki keratoproteza.

PURPOSE: To evaluate biocompatibility of the new keratoprosthesis supporting plates (KSP) in rabbits in vivo. MATERIAL AND METHODS: The study included 15 chinchilla rabbits. In the first group (5 rabbit eyes) KSP made of hydrophobic acryl with square penetrating holes of 220×220 micron (model 1) were inserted into rabbits' corneas. In the second group (5 eyes), KSP made of hydrophobic acryl were used that had trapezoidal fenestrations with size (from 170×130 micron to 180×70 microns) gradually changing from periphery to the center of KSP (model 2). The control group rabbits (5 eyes) had 1/2 of Fyodorov-Zuev KSP made of titanium implanted. All animals were observed for up to 3 months with biomicroscopy and optical coherence tomography of the anterior segment. The animals were then euthanized and had their corneo-scleral discs excised and then examined with optical microscopy and scanning electron microscopy (SEM). RESULTS: After 3 months, there was only one case of KSP protrusion in the first group. In the second group, thinning of the corneal layers above the central part of KSP occurred in one case. The presence of polymer KSP (of both models) in the corneal stroma was found not to cause formation of rough fibrotic tissue. At the same time, adhered cellular and fibrous elements were discovered on the surface and inside the holes of the polymer KSP, while on the surface of the titanium plate cellular elements were absent. CONCLUSION: Supporting plates made of hydrophobic acrylic material can potentially serve as a foundation for the new keratoprosthesis design.

Long-term self-renewal of postnatal muscle-derived stem cells.

The ability to undergo self-renewal is a defining characteristic of stem cells. Self-replenishing activity sustains tissue homeostasis and regeneration. In addition, stem cell therapy strategies require a heightened understanding of the basis of the self-renewal process to enable researchers and clinicians to obtain sufficient numbers of undifferentiated stem cells for cell and gene therapy. Here, we used postnatal muscle-derived stem cells to test the basic biological assumption of unlimited stem cell replication. Muscle-derived stem cells (MDSCs) expanded for 300 population doublings (PDs) showed no indication of replicative senescence. MDSCs preserved their phenotype (ScaI+/CD34+/desmin(low)) for 200 PDs and were capable of serial transplantation into the skeletal muscle of mdx mice, which model Duchenne muscular dystrophy. MDSCs expanded to this level exhibited high skeletal muscle regeneration comparable with that exhibited by minimally expanded cells. Expansion beyond 200 PDs resulted in lower muscle regeneration, loss of CD34 expression, loss of myogenic activity, and increased growth on soft agar, suggestive of inevitable cell aging attributable to expansion and possible transformation of the MDSCs. Although these results raise questions as to whether cellular transformations derive from cell culturing or provide evidence of cancer stem cells, they establish the remarkable long-term self-renewal and regeneration capacity of postnatal MDSCs.

The C-terminal region of the major outer sheath protein of Treponema denticola inhibits neutrophil chemotaxis.

Treponema denticola is an oral spirochete strongly associated with severe periodontal disease. A prominent virulence factor, the major outer sheath protein (Msp), disorients neutrophil chemotaxis by altering the cellular phosphoinositide balance, leading to impairment of downstream chemotactic events including actin rearrangement, Rac1 activation, and Akt activation in response to chemoattractant stimulation. The specific regions of Msp responsible for interactions with neutrophils remain unknown. In this study, we investigated the inhibitory effect of truncated Msp regions on neutrophil chemotaxis and associated signaling pathways. Murine neutrophils were treated with recombinant protein truncations followed by assessment of chemotaxis and associated signal pathway activation. Chemotaxis assays indicate sequences within the C-terminal region; particularly the first 130 amino acids, have the strongest inhibitory effect on neutrophil chemotaxis. Neutrophils incubated with the C-terminal region protein also demonstrated the greatest inhibition of Rac1 activation, increased phosphoinositide phosphatase activity, and decreased Akt activation; orchestrating impairment of chemotaxis. Furthermore, incubation with antibodies specific to only the C-terminal region blocked the Msp-induced inhibition of chemotaxis and denaturing the protein restored Rac1 activation. Msp from the strain OTK, with numerous amino acid substitutions throughout the polypeptide, including the C-terminal region compared with strain 35405, showed increased ability to impair neutrophil chemotaxis. Collectively, these results indicate that the C-terminal region of Msp is the most potent region to modulate neutrophil chemotactic signaling and that specific sequences and structures are likely to be required. Knowledge of how spirochetes dampen the neutrophil response is limited and Msp may represent a novel therapeutic target for periodontal disease.

Prevalence of mitochondrial DNA haplogroups in an Australian population.

Mitochondrial DNA (mtDNA) haplogroups are 'neutral polymorphisms' in the mtDNA genome, which have accumulated and persisted along maternal lineages as the human population has migrated worldwide. Three ethnically distinct lineages of human mtDNA populations have been identified: European, characterized by nine haplogroups H, I, J, K, T, U, V, W and X; African, characterized by superhaplogroup L and Asian, characterized by superhaplogroup M. We studied the prevalence of mtDNA haplogroups in participants of the Blue Mountains Eye Study, a large population-based survey of vision conducted between 1991 and 2000 of non-institutionalized permanent residents aged 49 years or older from two suburban postcode areas, west of Sydney, Australia. Total DNA isolated from either hair follicles or blood was available for 3377 of the 3509 participants (96.2%) to determine mtDNA haplogroups by polymerase chain reaction/restriction fragment length polymorphism analysis. Approximately 94.2% of samples could be assigned to one of the nine major European haplogroups, whereas a further 1.2% included the African (L) and Asian (M) superhaplogroups. The five principal haplogroups represented were H (42.9%), U (14.1%), J (10.7%), T (9.2%) and K (8.1%), which together included 85% of this population.

Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis.

Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (P<0.001). Among the 78 patients (53.4%) in the ruxolitinib arm who achieved ⩾35% reductions in spleen volume at any time, the probability of maintaining response was 0.48 (95% confidence interval (CI), 0.35-0.60) at 5 years (median, 3.2 years). Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with ruxolitinib compared with BAT by intent-to-treat analysis (hazard ratio (HR)=0.67; 95% CI, 0.44-1.02; P=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18-1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits.

Sampling Methods for Detection and Monitoring of the Asian Citrus Psyllid (Hemiptera: Psyllidae).

The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama is a key pest of citrus due to its role as vector of citrus greening disease or "huanglongbing." ACP monitoring is considered an indispensable tool for management of vector and disease. In the present study, datasets collected between 2009 and 2013 from 245 citrus blocks were used to evaluate precision, sensitivity for detection, and efficiency of five sampling methods. The number of samples needed to reach a 0.25 standard error-mean ratio was estimated using Taylor's power law and used to compare precision among sampling methods. Comparison of detection sensitivity and time expenditure (cost) between stem-tap and other sampling methodologies conducted consecutively at the same location were also assessed. Stem-tap sampling was the most efficient sampling method when ACP densities were moderate to high and served as the basis for comparison with all other methods. Protocols that grouped trees near randomly selected locations across the block were more efficient than sampling trees at random across the block. Sweep net sampling was similar to stem-taps in number of captures per sampled unit, but less precise at any ACP density. Yellow sticky traps were 14 times more sensitive than stem-taps but much more time consuming and thus less efficient except at very low population densities. Visual sampling was efficient for detecting and monitoring ACP at low densities. Suction sampling was time consuming and taxing but the most sensitive of all methods for detection of sparse populations. This information can be used to optimize ACP monitoring efforts.

Estrogen receptor immunoreactivity in the adult primate brain: neuronal distribution and association with p75, trkA, and choline acetyltransferase.

The neuroactive steroid hormone, estrogen, has been implicated in both the prevention and treatment of Alzheimer's disease. Interactions between estrogen and neurotrophic systems may partially explain the beneficial effects of estrogen therapy. Previous studies have identified estrogen binding sites colocalized with neurotrophin-related proteins and mRNA within the rodent brain. Extending these studies to a model more relevant to human systems, we have mapped the distribution of estrogen receptor alpha (ER-alpha)-immunoreactive neurons in adult nonhuman primate brains. In addition, we used double-label immunohistochemistry to examine colocalization of ER-alpha with the low- and high-affinity neurotrophin receptors, p75 and trkA, and with the cholinergic marker choline acetyltransferase. Large numbers of ER-alpha-immunoreactive cells were detected in several amygdaloid and hypothalamic nuclei. ER-alpha-labeled cells were also found in the lateral septum, nucleus of the stria terminals, subfornical organ, and periaqueductal gray. Only rare, scattered ER-alpha-immunoreactive cells were noted in the cholinergic basal forebrain. In contrast to rodents, no cells exhibited ER-alpha and p75 or ER-alpha and trkA double-labeling. However, ER-labeled neurons in the amygdala, a region containing putative nerve growth factor-producing cells and exhibiting a role in memory, were densely and specifically invested with cholinergic terminals projecting from the basal forebrain. Estrogen-labeled neurons were also present in the lateral septal nucleus, a system that receives hippocampal inputs and projects to the neurotrophin-sensitive medial septum. Thus, interactions between neurotrophin-sensitive neurons and ER-bearing neurons exist in the primate brain, providing a potential paracrine basis for estrogen-state modulation of vulnerability to Alzheimer's disease.

Enhancement of iron excretion via monoanionic 3-hydroxypyrid-4-ones.

The ability of 3-hydroxypyrid-4-ones bearing either a carboxylic acid or sulfonic acid group to mobilize iron into the bile and urine of normal rats has been examined and compared with that produced by 1,2-dimethyl-3-hydroxypyrid-4-one (L1). The compounds tested were 3-hydroxy-1-methyl-4-oxopyridine-6-carboxylic acid and 1-[3-hydroxy-6-(hydroxymethyl)-4-oxopyridyl]-2-ethanesulfonic acid, whose synthesis, biological activity, and X-ray crystallographic properties are described. Although estimates of activity, based on polarity and membrane permeability, predict such compounds to be ineffective, they were found to have an iron-mobilizing ability similar to that of the compounds which do not bear any charge at physiological pH when given parenterally. When given orally, the 3-hydroxypyrid-4-one containing a carboxylate group enhanced the urinary excretion of iron, while the sulfonate analog did not substantially increase the excretion of iron in the urine relative to the controls. The results obtained here suggest that the previous emphasis on the preparation of 3-hydroxypyrid-4-ones that are electrically neutral at physiological pH is unnecessarily restrictive and that the presence of an appropriate group bearing a single negative charge is consistent with a high level of activity. It is proposed that such negatively charged molecules may gain access to the interior of cells in both the kidney and the liver via monoanionic transport systems. Such compounds may prove to be less toxic than the neutral 3-hydroxypyrid-4-ones.

Mobilization of iron by chiral and achiral anionic 3-hydroxypyrid-4-ones.

In the search for 3-hydroxypyrid-4-ones with enhanced iron-mobilizing ability, seven chiral, anionic amino acid derivatives of maltol (3-hydroxy-2-methyl-4-pyrone) have been synthesized, utilizing L-methionine, L-serine, L-leucine, L-phenylalanine, L-glutamic acid, and the D- and L-isomers of alanine. Two achiral, aromatic compounds were also synthesized and compared with the phenylalanine derivative. The biliary iron excretion following iv injection and the urinary iron excretion following po administration were measured using female Sprague-Dawley rats and compared to that of the standard, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). While none of the compounds was as effective as L1 in enhancing the urinary excretion of iron, all monoanionic chelators increased excretion relative to the controls. All monoanionic compounds were at least equivalent to L1 in enhancing the biliary excretion of iron, with the methionine, leucine, and benzoate derivatives surpassing the standard and the other aromatic compounds also showing strong activity. The dianionic glutamate derivative showed low activity relative to the controls for both urinary and biliary iron excretion. No significant difference in iron excretion was observed due to variation in chirality; molecular weight and the number of negative charges appeared to have the greatest influence on the ability of the various derivatives to enhance iron excretion. In order to evaluate the relative purity of the stereoisomers, the alanine derivatives were analyzed by circular dichroism. Further characterization was provided by UV/vis spectroscopy for all compounds and X-ray crystallography for the novel dianionic derivative.

Structure-activity relationships among dithiocarbamate antidotes for acute cadmium chloride intoxication.

Eight sodium dithiocarbamates (NaS2CNR1R2) have been examined as antidotes for acute cadmium intoxication. While all of them possess an ability to increase survival when given to mice 2 hr after a lethal (greater than 99%) intraperitoneal injection of 10 mg/kg of CdCl2 X 2.5H2O, their effects on the organ distribution of cadmium vary considerably. It has been possible to show that the accumulation of cadmium in the brain and kidney as well as the survival rates can be correlated with a numerical measure of the polarity of the groups R1 and R2. Each factor has a different dependence on the polarity, but it is possible to construct a composite factor for antidotal efficacy which incorporates survival rate, brain cadmium levels and kidney cadmium levels. The factor constructed here exhibits an optimal value approximately in the middle of the polarity range studied. Compounds which have R1 = -CH2CH1OH and R2 = -CH2CH2OH, or -CH3 or -C2H5 appear to be the most effective antidotes of the compounds examined.

Structural factors in the in vivo chelate mobilization of aged cadmium deposits.

The role of structural factors in determining the relative efficacy of dithiocarbamates as chelating agents for the in vivo mobilization of aged cadmium deposits is examined for 23 newly synthesized compounds of this type. The critical feature in determining the efficacy of the compounds in mobilizing intracellular cadmium is the balance between hydrophobic and hydrophilic groups. This balance also governs the other properties of these compounds such as the organ specificity of action and the relative propensity to carry cadmium to the brain. The transport of cadmium to the brain by dithiocarbamate can be greatly reduced by the incorporation of appropriate hydrophilic groups that prevent the formation of lipid-soluble cadmium complexes that pass readily into the brain. If the chelating agents carry an additional ionic charge, their ability to pass through cellular membranes and react with intracellular deposits of cadmium is significantly reduced, with other structural factors being equal. The structural features that optimize mobilization of cadmium from the kidney do not appear to be identical with those that optimize its mobilization from the liver. The correlation of cadmiummobilizing properties of these chelating agents with the sum of the Hansch pi constants for the parts of the molecular structures other than the dithiocarbamate grouping (sigma pi) is reasonably good for the removal of renal cadmium by derivatives of D-glucamine and D-xylamine. Another aspect of the molecular structure that appears to play a role is the presence of uncharged polar groups having the ability to form hydrogen bonds. The relevance of these factors in designing chelating agents to enhance the excretion of other toxic metals from their intracellular sites is discussed.

Monoisoamyl meso-2,3-dimercaptosuccinate as a delayed treatment for mercury removal in rats.

Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) was found to be superior to meso-2,3-dimercaptosuccinic acid (DMSA) in decreasing the body burden of 203Hg in rats under conditions of early treatment. In this experiment Mi-ADMS was used as late treatment for mercury removal. Albino rats aged 6 weeks and 7-day-old sucklings received a single intraperitoneal injection of 203Hg (as nitrate). Two weeks later they were treated with DMSA or Mi-ADMS (0.25 mmole/kg bw) on two consecutive days. The radioactivity in the carcass (whole body after removal of the gastrointestinal tract), liver, kidneys and brain was determined by solid crystal gamma scintillation counting six days after chelation therapy administration (3 weeks after 203Hg application). Both chelators reduced the body burden of mercury compared to controls. The effect of Mi-ADMS was superior to DMSA treatment in older rats for decreasing carcass and kidney retention, and in suckling rats for decreasing carcass, liver, and kidney retention. They were equally effective in decreasing brain retention in older rats and had no effect on brain retention in sucklings. The efficiency of Mi-ADMS in reducing the body burden of mercury was generally higher than the efficiency of the DMSA treatment. Therefore, Mi-ADMS deserves further attention as a late treatment for mercury removal.

Immunologic, morphologic and chromosomal characterization of a cell line (TC78) established from a child with acute lymphoblastic leukemia.

We characterized a cell line established from bone marrow cells from a child with acute lymphoblastic leukemia. This cell line, TC78, had lymphoblastic morphology and was cytoplasmic peroxidase and esterase negative. The cells did not have T- or B-cell properties such as E- or EAC-rosette forming ability, reactivity with monoclonal T-cell or B2 antibodies, or immunoglobulin synthesis. We concluded that TC78 was a pre-pre B-cell line based on the following monoclonal antibody staining pattern: BA-1+, BA-2+, cALLa+, Ia+, 2H7+ and OKB2+. Growth in 'Dickie' culture and reactivity with 1G10 myeloid antibody suggested coexpression of lymphoid and myeloid characteristics. However, 1G10 expression proved dependent on culture conditions, illustrating one caveat in application of monoclonal antibodies in lineage determination.

4,6-dibenzamidopyrazolo[3,4-d]pyrimidine is a highly selective inhibitor of cytomegalovirus adsorption to cells.

The heterocycle, 4,6-dibenzamidopyrazolo[3,4-d]pyrimidine (DBAPP), inhibited cytopathology induced by human, mouse, and vervet monkey cytomegaloviruses (CMV) in vitro at 0.2 to 0.5 microM, but did not inhibit cell replication at less than or equal to 30 microM. Herpes simplex viruses were unaffected by the inhibitor. The antiviral agent ganciclovir was effective against these CMVs at 3-10 microM in parallel assays. DBAPP and ganciclovir were synergistic inhibitors when used in combination. The heterocycle was only active if applied to cells before virus replication, indicating that it inhibited virus adsorption. Cells pre-treated 1 h with 30 microM DBAPP, then extensively rinsed, were resistant to infection by mouse CMV even 3 days after removal of the inhibitor. Human and monkey CMVs were able to infect cells and replicate within 24 h of drug removal. When virus and DBAPP were combined together then dialyzed to remove the compound, mouse CMV infectivity was decreased 1.7 logs, whereas human CMV and monkey CMV infectivity titers were relatively unaffected. Treatment of mice with DBAPP twice a day for 7 days starting 6 h after mouse CMV inoculation caused a moderate increase in number of survivors at 30 mg/kg. Cell to cell spread of the virus may account for poor efficacy of the compound when added after virus infection. DBAPP may serve as a tool to explore aspects of CMV adsorption or to characterize the cellular component of the CMV receptor.

Paramagnetic NMR contrast agents. Development and evaluation.

Paramagnetic ions could be theoretically used as NMR contrast agents because of their effect upon T1. However, the toxicity of these ions prevents their application. By the formation of appropriate chemical complexes with these ions, the toxicity of these agents can be substantially reduced while maintaining the paramagnetic effect. Two potential NMR contrast agents, one for oral use and one for intravenous administration, were developed and evaluated both in vitro and in vivo. The effect upon T1 in vitro of these paramagnetic compounds was determined using a JEOL FX-90Q NMR spectrometer. These agents were evaluated in vivo in dogs with a Technicare 0.3 tesla superconducting magnet system and in rabbits with the Aberdeen 0.04 tesla resistive NMR imager. Using calculated T1 NMR images, a nontoxic dose of gadolinium oxalate provided visualization of the gastrointestinal tract. Intravenous administration of chromium EDTA provided enhancement of the kidneys, ureters, and bladder, thereby potentially allowing for the evaluation of renal function with magnetic resonance imaging. Stable paramagnetic complexes can serve as effective, nontoxic, oral and intravenous NMR contrast agents.

Evaluation of preserved bovine tendon xenografts: a histological, biomechanical and clinical study.

Glutaraldehyde treated bovine tendon xenografts have been introduced into clinical trials as human knee ligament replacements recently, following animal experiments. This paper reports a further clinical study in which complications arose from implant debris. A laboratory study showed that the implants were not absorbed or integrated into the tissues of the host animals, as had been claimed by the originators. Mechanical tests of tendon reconstructions showed that the implants were not functional. It was concluded that this material is not suitable for clinical use within the knee joint as a cruciate ligament prosthesis.

Spaceflight alters autonomic regulation of arterial pressure in humans.

Spaceflight is associated with decreased orthostatic tolerance after landing. Short-duration spaceflight (4-5 days) impairs one neural mechanism: the carotid baroreceptor-cardiac reflex. To understand the effects of longer-duration spaceflight on baroreflex function, we measured R-R interval power spectra, antecubital vein plasma catecholamine levels, carotid baroreceptor-cardiac reflex responses, responses to Valsalva maneuvers, and orthostatic tolerance in 16 astronauts before and after shuttle missions lasting 8-14 days. We found the following changes between preflight and landing day: 1) orthostatic tolerance decreased; 2) R-R interval spectral power in the 0.05 to 0.15-Hz band increased; 3) plasma norepinephrine and epinephrine levels increased; 4) the slope, range, and operational point of the carotid baroreceptor cardiac reflex response decreased; and 5) blood pressure and heart rate responses to Valsalva maneuvers were altered. Autonomic changes persisted for several days after landing. These results provide further evidence of functionally relevant reductions in parasympathetic and increases in sympathetic influences on arterial pressure control after spaceflight.

Short-duration spaceflight impairs human carotid baroreceptor-cardiac reflex responses.

Orthostatic intolerance is a predictable but poorly understood consequence of space travel. Because arterial baroreceptors modulate abrupt pressure transients, we tested the hypothesis that spaceflight impairs baroreflex mechanisms. We studied vagally mediated carotid baroreceptor-cardiac reflex responses (provoked by neck pressure changes) in the supine position and heart rate and blood pressure in the supine and standing positions in 16 astronauts before and after 4- to 5-day Space Shuttle missions. On landing day, resting R-R intervals and standard deviations, and the slope, range, and position of operational points on the carotid transmural pressure-sinus node response relation were all reduced relative to preflight. Stand tests on landing day revealed two separate groups (one maintained standing arterial pressure better) that were separated by preflight slopes, operational points, and supine and standing R-R intervals and by preflight-to-postflight changes in standing pressures, body weights, and operational points. Our results suggest that short-duration spaceflight leads to significant reductions in vagal control of the sinus node that may contribute to, but do not account completely for, orthostatic intolerance.

Microgravity decreases heart rate and arterial pressure in humans.

Spaceflight causes adaptive changes in cardiovascular physiology, such as postflight orthostatic intolerance, that can have deleterious effects on astronauts. In-flight cardiovascular data are difficult to obtain, and results have been inconsistent. To determine normative in-flight changes in Shuttle astronauts, we measured heart rate, arterial pressure, and cardiac rhythm disturbances for 24-h periods before, during, and after spaceflight on Shuttle astronauts performing their normal routines. We found that heart rate, diastolic pressure, variability of heart rate and diastolic pressure, and premature ventricular contractions all were significantly reduced in flight. Systolic pressure and premature atrial contractions also tended to be reduced in flight. These data constitute the first systematic evaluation of in-flight changes in basic cardiovascular variables in Shuttle astronauts and suggest that a microgravity environment itself does not present a chronic stress to the cardiovascular system.