Calbindins decreased after space flight

Exposure of the body to microgravity during space flight causes a series of well-documented changes in Ca²⁺ metabolism, yet the cellular and molecular mechanisms leading to these changes are poorly understood. Calbindins, vitamin D-dependent Ca²⁺ binding proteins, are believed to have a significant role in maintaining cellular Ca²⁺ homeostasis. In this study, we used biochemical and immunocytochemical approaches to analyze the expression of calbinding-D_28k and calbindin-D_9k in kidneys, small intestine, and pancreas of rats flown for 9 d aboard the space shuttle. The effects of microgravity on calbindins in rats from space were compared with synchronous Animal Enclosure Module controls, modeled weightlessness animals (tail suspension), and their controls. Exposure to microgravity resulted in a significant and sustained decrease in calbindin-D_28k content in the kidney and calbinding-D_9k in the small intestine of flight animals, as measured by enzyme-linked immunosorbent assay (ELISA). Modeled weightlessness animals exhibited a similar decrease in calbindins by ELISA. Immunocytochemistry (ICC) in combination with quantitative computer image analysis was used to measurein situ the expression of calbindins in the kidney and the small intestine, and the expression of insulin in pancreas. There was a large decrease of immunoreactivity in renal distal tubular cell-associated calbindin-D_28k and in intestinal absorptive cell-associated calbindin-D_9k of space flight and modeled weightlessness animals compared with matched controls. No consistent difference in pancreatic insulin immunoreactivity between space flight, modeled weightlessness, and controls was observed. Regression analysis of results obtained by quantitative ICC and ELISA for space flight, modeled weightlessness animals, and their controls demonstrated a significant correlation. These findings after a short-term exposure to microgravity or modeled weightlessness suggest that a decreased expression of calbindins may contribute to the disorders of Ca²⁺ metabolism induced by space flight.     

Cardiovascular function and basics of physiology in microgravity

Space exploration is a dream of mankind. However, this intriguing environment is not without risks. Life, and the human body, has developed all over evolution in the constant presence of gravity, especially from the moment on when living creatures left the ocean. When this gravitational force is no longer acting on the body, drastic changes occur. Some of these changes occur immediately, others progress only slowly. In the past 40 years of human space flight (first orbital flight by Yuri Gagarin on 12 April, 1961) several hazards for the human body have been identified. Bone mineral density is lost, muscle atrophy and cardiovascular deconditioning occur; pulmonary function, fluid regulating systems of the body, the sensory and the balance system are all disturbed by the lack of gravity. These changes in human physiology have to be reversed again when astronauts return to earth. This can cause adaptation problems, especially after long-duration space flights. Also the reaction of human physiology to radiation in space poses a huge risk at this moment. In this review the accent will be on cardiovascular function in space: how normal function is modified to reach a new equilibrium in space after short- and long-duration exposure to microgravity. In order to make long-duration space flight possible the mechanisms of this physiological adaptation must be understood to full extent. Only with this knowledge, effective countermeasures can be developed.     

Effects of exposure to space flight on endocrine regulations in experimental animals

This minireview summarizes the results of the observations on changes in endocrine functions of rats exposed to space flights for various periods. The results found after space flights are compared with those obtained from rats in acute or repeated restrain stress. A slight increase of plasma catecholamine levels was observed in rats after space flight of longer duration (>14 days), but no changes in catecholamine content in the activity of catecholamine synthesizing enzymes were noted in adrenal medulla and in hypothalamus. The norepinephrine content was, however, decreased in several nuclei selected from hypothalamus of flight rats. Plasma corticosterone levels were increased after space flight and morphological examination of pituitary showed elevated activity of corticotrophs. However, the plasma levels of ACTH were not increased in rats 6 hours after space flight. These changes in plasma hormone levels affected the activity of enzymes involved in metabolism of amino acids in liver and lipolysis in adipose tissue. The plasma levels of testosterone and triiodothyronine were diminished after space flight suggesting the suppression of the thyroid and gonadal activity. Increase of plasma insulin and glucose levels were found in rats after space flight, but the glucagon values were not changed. Comparing these results from flight rats with the animals exposed to acute or repeated stress indicate that long stay in microgravity do not represent very intensive stressogenic stimulus for adrenocortical and sympatho-adrenomedullar systems, and hormone alterations observed after space flight may be due to acute gravitational stress resulting from a return to Earth gravity. Therefore further studies including the inflight animal experiments on a board of International Space Station are necessary for elucidation of the effects of microgravity on endocrine functions.     

Intestinal microbiota in metabolic diseases

The trillions of bacterial cells that colonize the mammalian digestive tract influence both host physiology and the fate of dietary compounds. Gnotobionts and fecal transplantation have been instrumental in revealing the causal role of intestinal bacteria in energy homeostasis and metabolic dysfunctions such as type-2 diabetes. However, the exact contribution of gut bacterial metabolism to host energy balance is still unclear and knowledge about underlying molecular mechanisms is scant. We have previously characterized cecal bacterial community functions and host responses in diet-induced obese mice using omics approaches. Based on these studies, we here discuss issues on the relevance of mouse models, give evidence that the metabolism of cholesterol-derived compounds by gut bacteria is of particular importance in the context of metabolic disorders and that dominant species of the family Coriobacteriaceae are good models to study these functions.     

Plasma and blood volume in space

Body fluid regulation is affected by gravity. The primary mechanisms of the etiology of hypovolemia found in simulation studies on earth and after space flight are different. The increased diuresis after increase of central blood volume postulated by Henry Gauer could not be found. Based on recent findings, new hypotheses about fluid volume regulation during space flight have emerged. The reduced blood volume in space is the result of 1) a negative balance of decreased fluid intake and smaller reduction of urine output; 2) fast fluid shifts from the intravascular to interstitial space as the result of lower transmural pressure after reduced compression of all tissue by gravitational forces especially of the thorax cage; and 3) fluid shifts from intravascular to muscle interstitial space because of less muscle tone required to maintain body posture. Additionally, loss of erythrocytes reduces blood volume. The attenuated diuresis during space flight can be explained by increased retention after stress-mediated sympathetic activation during initial phase of space flight, stimulation caused by reduced red cell mass, and activation after fast blood volume contraction. Additionally, the relation between plasma osmolarity and vasopressin release might be disturbed in microgravity.     

Intestinal Permeability in Long-Term Follow-up of Patients with Celiac Disease on a Gluten-Free Diet

Intestinal permeability is frequently abnormal in patients with celiac disease. The long-term effect of a gluten-free diet on intestinal permeability and the correlation of intestinal permeability with a gluten-free diet are not known. The objectives of this study were to determine the responses of intestinal permeability and antibody testing to gluten free diet and the degree of correlation of these measurements with gluten ingestion. In this prospective study, patients with celiac disease were divided into three groups based on length of time on a gluten-free diet: Group A, < 1 month; Group B, 1 month–1 year; Group C, > 1 year. Patients in Groups B and C were tested at baseline and at 4–12 weeks later for the following: lactulose/mannitol intestinal permeability, endomysial antibody, and 3-day food record. Permeability tests were also performed in Group A and control subjects. Intestinal permeability was elevated in newly diagnosed celiac disease and in individuals on a gluten-free diet for less than 1 year. Intestinal permeability was normal in 80% at visit 1 and 87% at visit 2 in individuals with celiac disease on a gluten-free diet for more than a year. Trace gluten ingestion was associated with increased intestinal permeability on visit 2 (P = 0.0480). The sensitivity of detecting gluten ingestion as measured by a 3-day food record was higher for permeability testing (29 and 36%) compared with endomysial antibody testing (18 and 18%) for visits 1 and 2, respectively. Intestinal permeability normalizes in the majority of individuals with celiac disease on a gluten-free diet. Gluten ingestion as measured by a 3-day food record correlates with intestinal permeability measurements. The role of permeability testing in the follow-up of patients with celiac disease warrants further investigation.     

External biliary drainage plus bile acid feeding is not equal to internal drainage in preserving the cellular immunity following prolonged obstructive jaundice

This study investigates the importance of intestinal bile flow in cellular immunity. Sprague-Dawley rats undergoing bile duct ligation (BDL) and sham ceiliotomy (Sham) for 14 and 21 days were investigated. Experimental animals following BDL were further divided into an external drainage (ED) group, an ED group with rat chow mixed with 2:2:1 cholic acid, chenodeoxycholic acid, and deoxycholic acid ( ED + BF), and an internal drainage (ID) group. Fourteen days later, they were killed and analyzed for spleen lymphocytic [³H] thymidine uptake (LHU) under mitogen stimulation with phytohemagglutinin, blood biochemistry, hemogram, and liver pathology. In the 14-day BDL experiment, LHU and serum albumin level were decreased in the BDL group (P < 0.05). After drainage, they were not significantly different among sham, ED, ED + BF, and ID groups. In the 21-day BDL experiment, the red cell volume was decreased (P < 0.05). After drainage, the ED, ED + BF, and ID groups still had a significantly lower LHU than the sham group (P < 0.05). However, the ID group had higher LHU than the ED and ED + BF groups (P < 0.05). The ED + BF group had a slightly higher LHU than the ED group but not statistically significant. Liver pathology returned to normal after drainage in the 14-day BDL model. In contrast, the 21-day BDL group had prominent periportal necrosis and developed periportal fibrosis after drainage. The present study reveals the duration of BDL determines the severity of hepatic damage. In the 14-day BDL groups, all kinds of drainage completely reverse the impaired liver function and cellular immunity. In the 21-day BDL group, 14-day drainage is inadequate for recovery because irreversible pathological changes are found. The reversal of cellular immunity in ID is better and faster, because it provides a better hepatic functional, nutritional, and hematological recovery besides the presence of primarily secreted bile acids.     

Roles of Na~+/Ca~(2+) exchanger 1 in digestive system physiology and pathophysiology

The Na~+/Ca~(2+) exchanger(NCX) protein family is a part of the cation/Ca~(2+) exchanger superfamily and participates in the regulation of cellular Ca~(2+) homeostasis. NCX1, the most important subtype in the NCX family, is expressed widely in various organs and tissues in mammals and plays an especially important role in the physiological and pathological processes of nerves and the cardiovascular system. In the past few years, the function of NCX1 in the digestive system has received increasing attention; NCX1 not only participates in the healing process of gastric ulcer and gastric mucosal injury but also mediates the development of digestive cancer, acute pancreatitis, and intestinal absorption.This review aims to explore the roles of NCX1 in digestive system physiology and pathophysiology in order to guide clinical treatments.     

On-orbit prospective echocardiography on International Space Station crew

Objectives: A prospective trial of echocardiography was conducted on six crew members onboard the International Space Station. The main objective was to determine the efficacy of remotely guided tele‐echocardiography, including just‐in‐time e‐training methods and determine what is “space normal” echocardiographic data. Methods: Each crew member operator (n = 6) had 2‐hour preflight training. Baseline echocardiographic data were collected 55–167 days preflight. Similar equipment was used in each 60‐minute in‐flight session (mean microgravity exposure – 114 days [34 – 190]). On‐orbit ultrasound (US) operators used an e‐learning system within 24 hours of these sessions. Expert assistance was provided using US video downlink and two‐way voice. Testing was repeated 5–16 days after landing. Separate ANOVA was used on each echocardiographic variable (n = 33). Within each ANOVA, three tests were made: (a) effect of mission phase (preflight, in‐flight, postflight); (b) effect of echo technician (two technicians independently analyzed the data); (c) interaction between mission phase and technician. Results: Eleven rejections of the null hypothesis (mission phase or technician or both had no effect) were found that could be considered for possible follow up. Of these, eight rejections were for significant technician effects, not space flight. Three rejections of the null hypothesis (aortic valve time velocity integral, mitral E‐wave velocity, and heart rate) were attributable to space flight but determine to not be clinically significant. No rejections were due to the interaction between technician and space flight. Conclusion: Thus, we found no consistent clinically significant effects of long‐duration space flight on echocardiographic variables of the given group of subjects. (Echocardiography 2011;28:491‐501)     

Microtubule self-organization is gravity-dependent

Although weightlessness is known to affect living cells, the manner by which this occurs is unknown. Some reaction-diffusion processes have been theoretically predicted as being gravity-dependent. Microtubules, a major constituent of the cellular cytoskeleton, self-organize in vitro by way of reaction-diffusion processes. To investigate how self-organization depends on gravity, microtubules were assembled under low gravity conditions produced during space flight. Contrary to the samples formed on an in-flight 1 x g centrifuge, the samples prepared in microgravity showed almost no self-organization and were locally disordered.     

Effects of Spaceflight and Skeletal Unloading on Bone Fracture Healing

The physiological adaptation of humans to harsh extracorporeal conditions such as those endured during space flight missions is incompletely understood and deserves considerably more attention to better comprehend and prepare space flight personnel for these alterations. Notable and well-documented changes include the loss of musculoskeletal homeostasis and impairment of bone remodeling. These deleterious effects promote loss of bone mass and mineral density and could lead to insufficient reparative processes such as fracture healing. Knowing this, the question arises as to whether extended exposure to space flight would promote altered musculoskeletal physiologies that impinge upon the normal reparative response should a fracture occur during, or some time after, space flight. This review will provide a survey of existing literature concerning fracture healing, as it pertains to space flight and ground-based unloading analogs, as well as introduce experimentally derived mechanistic hypotheses to address the ramifications of space flight on bone fracture healing. Overall, the consensus from this literature concludes that fracture healing is delayed substantially in animals exposed to space flight or unloading. The use of ground-based models of physiological adaptation to microgravity coupled with valuable insights gleaned from actual space flight missions may lead to the development of novel countermeasures that could alleviate deficiencies in musculoskeletal homeostasis and bone remodeling, among other physiological alterations, for use in future long-duration space missions.     

Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans

BACKGROUND & AIMS: No blood marker assessing the functional absorptive bowel length has been identified. Plasma citrulline, a nonprotein amino acid produced by intestinal mucosa, is one candidate. We tested this hypothesis in adult patients with the short-bowel syndrome, whose condition can lead to intestinal failure. METHODS: In 57 patients, after a minimal follow-up of 2 years subsequent to final digestive circuit modification, postabsorptive citrulline concentration was measured and parenteral nutrition dependence was used to define permanent (n = 37) and transient (n = 20) intestinal failure. Absorptive function, studied over a 3-day period, was evaluated by net digestive absorption for protein and fat (n = 51). Relations between quantitative values were assessed by linear regression analysis and cutoff citrulline threshold, for a diagnosis of intestinal failure by linear discriminant analysis. Cox model was used to compare citrulline threshold and anatomic variables of the short bowel as indicators of transient as opposed to permanent intestinal failure. RESULTS: In patients with short-bowel syndrome, citrulline levels were lower than in controls (n = 51): 20 +/- 13 vs. 40 +/- 10 micromol/L (mean +/- SD), respectively (P < 0.001). After multivariate analysis, citrullinemia was correlated to small bowel length (P < 0.0001, r = 0.86) and to net digestive absorption of fat, but to neither body mass index nor creatinine clearance. A 20-micromol/L threshold citrullinemia, (1) classified short bowel patients with permanent intestinal failure with high sensitivity (92%), specificity (90%), positive predictive value (95%), and negative value (86%); and (2) was a more reliable indicator (odds ratio, 20.0; 95% confidence interval, 1.9-206.1) than anatomic variables (odds ratio, 2.9; 95% confidence interval, 0. 5-15.8) to separate transient as opposed to permanent intestinal failure. Conclusions: In patients with short-bowel syndrome, postabsorptive plasma citrulline concentration is a marker of functional absorptive bowel length and, past the 2-year adaptive period, a powerful independent indicator allowing distinction of transient from permanent intestinal failure.     

Spontaneous tumor rupture and surgical prognosis of patients with hepatocellular carcinoma

Abstract

Background. Spontaneous rupture is an uncommon but the most fatal complication of hepatocellular carcinoma (HCC) and is recognized as a risk factor for tumor recurrence. The present study is to investigate the short- and long-term survival of the patients with HCC rupture and evaluate the influence of tumor rupture on patient's survival after hepatic resection. Patients and methods. The clinical data of 101 patients with HCC rupture from 2000 to 2010 were reviewed retrospectively. The management of tumor rupture and clinicopathological parameters affecting 30-day mortality of the patients were recorded and evaluated. Long-term survival of the 41 patients undergoing hepatic resection was compared with 446 patients with non-ruptured HCC at the same time period. Results. The 30-day mortality rate of the 101 patients with HCC rupture was 35.6% and median survival was 79 days. The independent risk factors affecting 30-day mortality were tumor size and blood transfusion quantity. Compared with 446 non-ruptured HCC patients, 41 patients with ruptured HCC undergoing hepatic resection had a similar overall and disease-free survival to 446 without rupture (Log-rank test, p = 0.704 and 0.084, respectively). Multivariate analysis revealed that age, gender, and tumor size were independently significant factors in differentiating tumor rupture from non-rupture. Conclusion. Early mortality of spontaneous rupture of HCC was dependent on preoperational liver function, tumor status, and severity of bleeding. Prolonged survival can be achieved in patients with ruptured HCC after hepatic resection as those without the complication.     

The role of “watch and wait” in intestinal follicular lymphoma in rituximab era

Objective: There is no consensus regarding the best treatment for intestinal follicular lymphoma (FL). We used “watch and wait” for patients with intestinal FL with low-tumor-burden (LTB) criteria and without mass formation causing bowel obstruction. We investigated the overall survival (OS) and time to treatment required (TTR). Methods: Thirty-three intestinal FL patients [clinical stage (CS) I:16, II1:0, II2:7, IV:10; median observation period: 45.5 months, range: 13–110 months] were diagnosed via endoscopy. Detailed clinical and pathological examinations were performed, and neoplastic process behavior was monitored. Results: All of the 33 patients were WHO grade 1. FL lesions in the digestive tract were found frequently in the second–fourth portion of the duodenum in 91% of the patients; 87% of those patients had lesions in a broader area including the small intestine. Two patients had an enlargement of the area of the lesions and a worsening of the macroscopic findings. Three patients had CS progression; however, these remained within the indication for “watch and wait.” Two patients with transformation into diffuse large B-cell lymphoma received rituximab and chemotherapy, which led to complete remission. The OS was 100%. The time to treatment required (TTR) was 49 months in one patient and 37 months in one patient. Conclusion: Intestinal FL in CS I–IV with broad infiltration of the digestive tract meeting the criteria for LTB had a remarkably slow course. This study suggests that “watch and wait” is appropriate for the treatment of LTB intestinal FL even in the era of rituximab.     

Characterizing the effect of exposure to microgravity on anemia: more space is worse

The effects of space travel have renewed importance with space tourism and plans for long-term missions to the moon and Mars. The study of space anemia is limited by the availability of subjects and extreme conditions. An approach using the accumulated data on human space flight may characterize space anemia. A total of 17 336 hemoglobin (Hb) concentration measures from 721 space missions and controls were used to study acute and long-term effects of duration of exposure to space on Hb decrement. Nearly half of astronauts (48%) landing after long duration missions were anemic. Returning to Earth revealed Hb decrements whose magnitude and time to recover were dependent on exposure to space: −0.61 g/dL (4%), −0.82 g/dL (5%) and −1.66 g/dL (11%) of preflight Hb for mean exposure to space of 5.4, 11.5, and 145 days, respectively. Astronauts returning from a mean 5.4 days in space took 24 days to return to preflight Hb while astronauts 11.5 to 145 days in space took 49 days. Negative effects of microgravity on Hb persisted throughout female and male astronautsʼ terrestrial lives (−0.001 and −0.002 mg/dL Hb respectively) for every day spent in space (both P < .05). The negative effect of exposure to space was not overcome by a statistically significant effect of being an astronaut compared to controls. Exposure to space showed a dose-response relationship with acute and chronic Hb decrements. Space anemia contributes to the deconditioning of astronauts returning to Earth, and needs to be considered for space travel to other planets, space tourism and for the care of bedridden patients who present similar changes as astronauts.     

Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2)

Background and Aim: The major transporter responsible for bile acid uptake from the intestinal lumen is the apical sodium‐dependent bile acid transporter (ASBT, SLC10A2). Analysis of the SLC10A2 gene has identified a variety of sequence variants including coding region single nucleotide polymorphisms (SNPs) that may influence bile acid homeostasis/intestinal function. In this study, we systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity. Methods: Single nucleotide polymorphisms in SLC10A2 from genomic DNA of ethnically‐defined healthy individuals were identified using a polymerase chain reaction (PCR)‐based temperature gradient capillary electrophoresis (TGCE) system. A heterologous gene expression system was used to assess transport activity of SLC10A2 nonsynonymous variants and missense mutations. Total and cell surface protein expression of wild‐type and variant ASBT was assessed by Western blot analysis and immunofluorescence confocal microscopy. Expression of ASBT mRNA and protein was also measured in human intestinal samples. Results: The studies revealed two nonsynonymous SNPs, 292G>A and 431G>A, with partially impaired in vitro taurocholate transport. A novel variant, 790A>G, was also shown to exhibit near complete loss of taurocholate transport, similar to the previously identified ASBT missense mutations. Examination of ASBT protein expression revealed no significant differences in expression or trafficking to the cell surface among variants versus wild‐type ASBT. Analysis of ASBT mRNA and protein expression in human intestinal samples revealed modest intersubject variability. Conclusions: Genome sequencing and in vitro studies reveal the presence of multiple functionally relevant variants in SLC10A2 that may influence bile acid homeostasis and physiology.     

Bile Salt Metabolism:I. The Physiology of Bile Salts

Bile salt metabolism. I. The physiology of bile salts. A. E. Cowen and C. B. Campbell, Aust. N.Z. J. Med., 1977, 7, pp. 579–586. Bile salts are synthesized in the liver from cholesterol, conjugated with glycine or taurine and secreted in bile with cholesterol and lecithin. The molar concentrations of these three lipids determine solubility of cholesterol in bile. Within the gastrointestinal lumen bile salts play an essential role in lipid absorption and fat transport. An efficient entero-hepatic circulation maintains hepatic bile salt secretion and provides a “feed-back” control of bile salt and cholesterol metabolism. Potentially hepatotoxic lithocholic acid formed in the intestinal lumen by bacterial action on chenodeoxycholic acid is sulphated in the liver thus decreasing intestinal reabsorption. The total faecal excretion of bile salts balances hepatic synthesis and represents a major catabo/ic path in cholesterol metabolism.