Distribution of North Pacific right whales (Eubalaena japonica) as shown by 19th and 20th century whaling catch and sighting records

North Pacific right whales (Eubalaena japonica) were extensively exploited in the 19th century, and their recovery was further retarded (severely so in the eastern population) by illegal Soviet catches in the 20th century, primarily in the 1960s. Monthly plots of right whale sightings and catches from both the 19th and 20th centuries are provided, using data summarized by Scarff (1991, from the whale charts of Matthew Fontaine Maury) and Brownell et al. (2001), respectively. Right whales had an extensive offshore distribution in the 19th century, and were common in areas (such as the Gulf of Alaska and Sea of Japan) where few or no right whales occur today. Seasonal movements of right whales are apparent in the data, although to some extent these reflect survey and whaling effort. That said, these seasonal movements indicate a general northward migration in spring from lower latitudes, and major concentrations above 40°N in summer. Sightings diminished and occurred further south in autumn, and few animals were recorded anywhere in winter. These north-south migratory movements support the hypothesis of two largely discrete populations of right whales in the eastern and western North Pacific. Overall, these analyses confirm that the size and range of the right whale population is now considerably diminished in the North Pacific relative to the situation during the peak period of whaling for this species in the 19th century. For management purposes, new surveys are urgently required to establish the present distribution of this species; existing data suggest that the Bering Sea, the Gulf of Alaska, the Okhotsk Sea, the Kuril Islands and the coast of Kamchatka are the areas with the greatest likelihood of finding right whales today.

Determining spatial and temporal scales for management: lessons from whaling

Selection of the appropriate management unit is critical to the conservation of animal populations. Defining such units depends upon knowledge of population structure and upon the timescale being considered. Here, we examine the trajectory of eleven subpopulations of five species of baleen whales to investigate temporal and spatial scales in management. These subpopulations were all extirpated by commercial whaling, and no recovery or repopulation has occurred since. In these cases, time elapsed since commercial extinction ranges from four decades to almost four centuries. We propose that these subpopulations did not recover either because cultural memory of the habitat has been lost, because widespread whaling among adjacent stocks eliminated these as sources for repopulation, and/or because segregation following exploitation produced the abandonment of certain areas. Spatial scales associated with the extirpated subpopulations are frequently smaller than those typically employed in management. Overall, the evidence indicates that: (1) the time frame for management should be at most decadal in scope (i.e., <100 yr) and based on both genetic and nongenetic evidence of population substructure, and (2) at least some stocks should be defined on a smaller spatial scale than they currently are.

DESIGN AND ANALYSIS OF MULTIFUNCTIONAL ROBOT FOR NOTES

The elimination of all external incisions is an important step in reducing the invasiveness of surgical procedures. Natural Orifice Translumenal Endoscopic Surgery (NOTES) is an incision-less surgery and provides explicit benefits such as reducing patient trauma and shortening recovery time. However, technological difficulties impede the widespread utilization of the NOTES method. A novel robotic tool has been developed, which makes NOTES procedures feasible by using multiple interchangeable tool tips. The robotic tool has the capability of entering the body cavity through an orifice or a single incision using a flexible articulated positioning mechanism and once inserted is not constrained by incisions, allowing for visualization and manipulations throughout the cavity. Multiple interchangeable tool tips of the robotic device initially consist of three end effectors: a grasper, scissors, and an atraumatic Babcock clamp. The tool changer is capable of selecting and switching between the three tools depending on the surgical task using a miniature mechanism driven by micro-motors. The robotic tool is remotely controlled through a joystick and computer interface. In this thesis, the following aspects of this robotic tool will be detailed. The first-generation robot is designed as a conceptual model for implementing a novel mechanism of switching, advancing, and controlling the tool tips using two micro-motors. It is believed that this mechanism achieves a reduction in cumbersome instrument exchanges and can reduce overall procedure time and the risk of inadvertent tissue trauma during exchanges with a natural orifice approach. Also, placing actuators directly at the surgical site enables the robot to generate sufficient force to operate effectively. Mounting the multifunctional robot on the distal end of an articulating tube provides freedom from restriction on the robot kinematics and helps solve some of the difficulties otherwise faced during surgery using NOTES or related approaches. The second-generation multifunctional robot is then introduced in which the overall size is reduced and two arms provide 2 additional degrees of freedom, resulting in feasibility of insertion through the esophagus and increased dexterity. Improvements are necessary in future iterations of the multifunctional robot; however, the work presented is a proof of concept for NOTES robots capable of abdominal surgical interventions.

Phosphorus utilization by corn as affected by green manure, nitrogen and phosphorus fertilizers

The objective of this work was to evaluate the utilization by corn plants of P from triple superphosphate fertilizer labeled with P-32 (P-32-TSP), and of P from soil as affected by N rates and by the green manures (GM) sunn hemp (Crotalaria juncea) and millet (Pennisetum glaucum). The experiment was carried out using pots filled with 5 kg Oxisol (Rhodic Hapludox). A completely randomized design was used, in a 4x4x2 factorial arrangement, with four replicates. The treatments were: four P rates as TSP (0, 0.175, 0.350, and 0.700 g P per pot); four N rates as urea (0, 0.75, 1.50, and 2.25 g N per pot); and sunn hemp or millet as green manure. The additions of N and P by the GM were taken into account. After grain physiologic maturation, corn dry matter, P contents, accumulated P, and P recovery in the different treatments were measured. P-32-TSP recovery by corn increased with N increasing rates, and decreased with increasing rates of P-32-TSP. The mineral fertilizer provides most of the accumulated P by corn plants. The recovery of P-32-TSP by corn was 13.12% in average. The green manure species influence the assimilation of P-32-TSP by the plants.

Physiological responses and rate of perceived exertion in Brazilian jiu-jitsu athletes

In this study, the physiological responses and rate of perceived exertion in Brazilian jiu-jitsu fighters submitted to a combat simulation were investigated. Venous blood samples and heart rate were taken from twelve male Brazilian jiu-jitsu athletes (27.1+/-2.7 yrs, 75.4+/-8.8 kg, 174.9+/-4.4 cm, 9.2+/-2.4% fat), at rest, after a warm-up (ten minutes), immediately after the fight simulation (seven minutes) and after recovery (fourteen minutes). After the combat the rate of perceived exertion was collected. The combat of the Brazilian jiu-jitsu fighters did not change blood concentrations of glucose, triglycerides, total cholesterol, low density lipoprotein and very low density lipoprotein, ureia and ammonia. However, blood levels of high density lipoprotein were significantly higher post-fight (before: 43.0+/-6.9 mg/dL, after: 45.1+/-8.0 mg/dL) and stayed at high levels during the recovery period (43.6+/-8.1 mg/dL) compared to the rest values (40.0+/-6.6 mg/dL). The fight did not cause changes in the concentrations of the cell damage markers of creatine kinase, aspartate aminotransferase and creatinine. However, blood concentrations of the alanine aminotransferase (before: 16.1+/-7.1 U/L, after: 18.6+/-7.1 U/L) and lactate dehydrogenase (before: 491.5+/-177.6 U/L, after: 542.6+/-141.4 U/L) enzymes were elevated after the fight. Heart rate (before: 122+/-25 bpm, after: 165+/-17 bpm) and lactate (before: 2.5+/-1.2 mmol/L, after: 11.9+/-5.8 mmol/L) increased significantly with the completion of combat. Despite this, the athletes rated the fight as being light or somewhat hard (12+/-2). These results showed that muscle glycogen is not the only substrate used in Brazilian jiu-jitsu fights, since there are indications of activation of the glycolytic, lipolytic and proteolytic pathways. Furthermore, the athletes rated the combats as being light or somewhat hard although muscle damage markers were generated.

Indigestible cellulose and lignin in determining feces production and apparent digestibility in horses

Four crossbred geldings were used in a randomized blocks experimental design. The objective was to study the use of the internal markers indigestible cellulose (iCEL) and indigestible lignin (iLIG), obtained in situ (cattle) or in vivo (equine) to predict nutrient apparent digestibility in horses. Treatments consisted of different methodologies to determine digestibility: direct method with total feces collection (TC), and indirect method using internal markers iCEL and iLIG obtained either by in situ incubation in bovine rumen or in vivo (IV) using the mobile nylon bag (MNB) technique in horses. Feces production was 2.80 kg in DM, and average recovery rate (p > 0.05) was 101%. Nutrient digestibility coefficient (p > 0.05) estimates were adequately predicted by iCEL and iLIG, obtained in situ or in vivo, with average values of 52.63, 54.17, 64.90, 43.73 and 98.28% for dry matter, organic matter, crude protein, neutral detergent fiber and starch, respectively. It can be concluded that iCEL and iLIG may be obtained in vivo by MNB in horses consuming a forage-concentrate diet, to predict nutrient digestibility coefficients.

Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats

High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threonine kinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-α (TNFα) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNFα-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-κB (Iκβ) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation.

The use of remote sensing imagery for monitoring recovery in the aftermath of a natural disaster: the Hurricane Katrina Case

Although Recovery is often defined as the less studied and documented phase of the Emergency Management Cycle, a wide literature is available for describing characteristics and sub-phases of this process. Previous works do not allow to gain an overall perspective because of a lack of systematic consistent monitoring of recovery utilizing advanced technologies such as remote sensing and GIS technologies. Taking into consideration the key role of Remote Sensing in Response and Damage Assessment, this thesis is aimed to verify the appropriateness of such advanced monitoring techniques to detect recovery advancements over time, with close attention to the main characteristics of the study event: Hurricane Katrina storm surge. Based on multi-source, multi-sensor and multi-temporal data, the post-Katrina recovery was analysed using both a qualitative and a quantitative approach. The first phase was dedicated to the investigation of the relation between urban types, damage and recovery state, referring to geographical and technological parameters. Damage and recovery scales were proposed to review critical observations on remarkable surge- induced effects on various typologies of structures, analyzed at a per-building level. This wide-ranging investigation allowed a new understanding of the distinctive features of the recovery process. A quantitative analysis was employed to develop methodological procedures suited to recognize and monitor distribution, timing and characteristics of recovery activities in the study area. Promising results, gained by applying supervised classification algorithms to detect localization and distribution of blue tarp, have proved that this methodology may help the analyst in the detection and monitoring of recovery activities in areas that have been affected by medium damage. The study found that Mahalanobis Distance was the classifier which provided the most accurate results, in localising blue roofs with 93.7% of blue roof classified correctly and a producer accuracy of 70%. It was seen to be the classifier least sensitive to spectral signature alteration. The application of the dissimilarity textural classification to satellite imagery has demonstrated the suitability of this technique for the detection of debris distribution and for the monitoring of demolition and reconstruction activities in the study area. Linking these geographically extensive techniques with expert per-building interpretation of advanced-technology ground surveys provides a multi-faceted view of the physical recovery process. Remote sensing and GIS technologies combined to advanced ground survey approach provides extremely valuable capability in Recovery activities monitoring and may constitute a technical basis to lead aid organization and local government in the Recovery management.

Development of the optimal estimation method for inversion of stratospheric emission spectra and validation of HNO3 profiles

This doctoral thesis focuses on ground-based measurements of stratospheric nitric acid (HNO3)concentrations obtained by means of the Ground-Based Millimeter-wave Spectrometer (GBMS). Pressure broadened HNO3 emission spectra are analyzed using a new inversion algorithm developed as part of this thesis work and the retrieved vertical profiles are extensively compared to satellite-based data. This comparison effort I carried out has a key role in establishing a long-term (1991-2010), global data record of stratospheric HNO3, with an expected impact on studies concerning ozone decline and recovery. The first part of this work is focused on the development of an ad hoc version of the Optimal Estimation Method (Rodgers, 2000) in order to retrieve HNO3 spectra observed by means of GBMS. I also performed a comparison between HNO3 vertical profiles retrieved with the OEM and those obtained with the old iterative Matrix Inversion method. Results show no significant differences in retrieved profiles and error estimates, with the OEM providing however additional information needed to better characterize the retrievals. A final section of this first part of the work is dedicated to a brief review on the application of the OEM to other trace gases observed by GBMS, namely O3 and N2O. The second part of this study deals with the validation of HNO3 profiles obtained with the new inversion method. The first step has been the validation of GBMS measurements of tropospheric opacity, which is a necessary tool in the calibration of any GBMS spectra. This was achieved by means of comparisons among correlative measurements of water vapor column content (or Precipitable Water Vapor, PWV) since, in the spectral region observed by GBMS, the tropospheric opacity is almost entirely due to water vapor absorption. In particular, I compared GBMS PWV measurements collected during the primary field campaign of the ECOWAR project (Bhawar et al., 2008) with simultaneous PWV observations obtained with Vaisala RS92k radiosondes, a Raman lidar, and an IR Fourier transform spectrometer. I found that GBMS PWV measurements are in good agreement with the other three data sets exhibiting a mean difference between observations of ~9%. After this initial validation, GBMS HNO3 retrievals have been compared to two sets of satellite data produced by the two NASA/JPL Microwave Limb Sounder (MLS) experiments (aboard the Upper Atmosphere Research Satellite (UARS) from 1991 to 1999, and on the Earth Observing System (EOS) Aura mission from 2004 to date). This part of my thesis is inserted in GOZCARDS (Global Ozone Chemistry and Related Trace gas Data Records for the Stratosphere), a multi-year project, aimed at developing a long-term data record of stratospheric constituents relevant to the issues of ozone decline and expected recovery. This data record will be based mainly on satellite-derived measurements but ground-based observations will be pivotal for assessing offsets between satellite data sets. Since the GBMS has been operated for more than 15 years, its nitric acid data record offers a unique opportunity for cross-calibrating HNO3 measurements from the two MLS experiments. I compare GBMS HNO3 measurements obtained from the Italian Alpine station of Testa Grigia (45.9° N, 7.7° E, elev. 3500 m), during the period February 2004 - March 2007, and from Thule Air Base, Greenland (76.5°N 68.8°W), during polar winter 2008/09, and Aura MLS observations. A similar intercomparison is made between UARS MLS HNO3 measurements with those carried out from the GBMS at South Pole, Antarctica (90°S), during the most part of 1993 and 1995. I assess systematic differences between GBMS and both UARS and Aura HNO3 data sets at seven potential temperature levels. Results show that, except for measurements carried out at Thule, ground based and satellite data sets are consistent within the errors, at all potential temperature levels.

Consequences of DNA damage for gene transcription : direct effects of modified nucleobases and the role of base excision repair = Folgen von DNA-Schäden für die Gentranskription

The presence of damaged nucleobases in DNA can negatively influence transcription of genes. One of the mechanisms by which DNA damage interferes with reading of genetic information is a direct blockage of the elongating RNA polymerase complexes – an effect well described for bulky adducts induced by several chemical substances and UV-irradiation. However, other mechanisms must exist as well because many of the endogenously occurring non-bulky DNA base modifications have transcription-inhibitory properties in cells, whilstrnnot constituting a roadblock for RNA polymerases under cell free conditions. The inhibition of transcription by non-blocking DNA damage was investigated in this work by employing the reporter gene-based assays. Comparison between various types of DNA damage (UV-induced pyrimidine photoproducts, oxidative purine modifications induced by photosensitisation, defined synthetic modified bases such as 8-oxoguanine and uracil, and sequence-specific single-strand breaks) showed that distinct mechanisms of inhibition of transcription can be engaged, and that DNA repair can influence transcription of the affectedrngenes in several different ways.rnQuantitative expression analyses of reporter genes damaged either by the exposure of cells to UV or delivered into cells by transient transfection supported the earlier evidence that transcription arrest at the damage sites is the major mechanism for the inhibition of transcription by this kind of DNA lesions and that recovery of transcription requires a functional nucleotide excision repair gene Csb (ERCC6) in mouse cells. In contrast, oxidisedrnpurines generated by photosensitisation do not cause transcriptional blockage by a direct mechanism, but rather lead to transcriptional repression of the damaged gene which is associated with altered histone acetylation in the promoter region. The whole chain of events leading to transcriptional silencing in response to DNA damage remains to be uncovered. Yet, the data presented here identify repair-induced single-strand breaks – which arise from excision of damaged bases by the DNA repair glycosylases or endonucleases – as arnputative initiatory factor in this process. Such an indirect mechanism was supported by requirement of the 8-oxoguanine DNA glycosylase (OGG1) for the inhibition of transcription by synthetic 8-oxodG incorporated into a reporter gene and by the delays observed for the inhibition of transcription caused by structurally unrelated base modifications (8-oxoguanine and uracil). It is thereby hypothesized that excision of the modified bases could be a generalrnmechanism for inhibition of transcription by DNA damage which is processed by the base excision repair (BER) pathway. Further gene expression analyses of plasmids containing single-strand breaks or abasic sites in the transcribed sequences revealed strong transcription inhibitory potentials of these lesions, in agreement with the presumption that BER intermediates are largely responsible for the observed effects. Experiments with synthetic base modifications positioned within the defined DNA sequences showed thatrninhibition of transcription did not require the localisation of the lesion in the transcribed DNA strand; therefore the damage sensing mechanism has to be different from the direct encounters of transcribing RNA polymerase complexes with DNA damage.rnAltogether, this work provides new evidence that processing of various DNA basernmodifications by BER can perturb transcription of damaged genes by triggering a gene silencing mechanism. As gene expression can be influenced even by a single DNA damage event, this mechanism could have relevance for the endogenous DNA damage induced in cells under normal physiological conditions, with a possible link to gene silencing in general.

[Drug therapy of acute and chronic abdominal pain]

For drug therapy a differentiation of acute and chronic pain is essential. In emergency situations of acute abdominal pain a fast diagnosis is mandatory. Analgesia should be provided as soon as possible. The different groups of analgesics should be used according to their known effects, side effects and contraindications. Postoperative pain after abdominal surgery has to be considered as a special condition of acute abdominal pain. Main treatment options are non opioid analgesics and opioids. Opioids can be administered intravenously via patient controlled analgesia (PCA) devices. In major abdominal surgery neuroaxial analgesia, preferentially administered via an epidural catheter provides excellent pain relief with positive impact on gastrointestinal motility and patients' recovery. Because of difficulties to allocate chronic abdominal pain to a specific organ, causal treatment often turns out to be difficult. Peripheral and central sensitization, as well as an alteration of the endogenous pain modulation comes to the fore in these chronic pain conditions. Co-analgesics like anticonvulsants and antidepressants are utilized to reduce sensitization and improve the endogenous pain modulating system. Non drug approaches and alternative treatment options might be useful. In contrast, orally or transcutaneously administered opioids are the principal corner stone for the treatment of cancer pain.

Comparison of the effects of racemic ketamine and S-ketamine for anesthesia in Rheem gazelles (Gazella subgutturosa marica) and Subgutturosa gazelles (Gazella subgutturosa subgutturosa)

OBJECTIVE: To evaluate effects of racemic ketamine and S-ketamine in gazelles. ANIMALS: 21 male gazelles (10 Rheem gazelles [Gazella subgutturosa marica] and 11 Subgutturosa gazelles [Gazella subgutturosa subgutturosa]), 6 to 67 months old and weighing (mean+/-SD) 19 +/- 3 kg. PROCEDURES: In a randomized, blinded crossover study, a combination of medetomidine (80 mug/kg) with racemic ketamine (5 mg/kg) or S-ketamine (3 mg/kg) was administered i.m.. Heart rate, blood pressure, respiratory rate, rectal temperature, and oxygen saturation (determined by means of pulse oximetry) were measured. An evaluator timed and scored induction of, maintenance of, and recovery from anesthesia. Medetomidine was reversed with atipamezole. The alternate combination was used after a 4-day interval. Comparisons between groups were performed with Wilcoxon signed rank and paired t tests. RESULTS: Anesthesia induction was poor in 2 gazelles receiving S-ketamine, but other phases of anesthesia were uneventful. A dominant male required an additional dose of S-ketamine (0.75 mg/kg, i.m.). After administration of atipamezole, gazelles were uncoordinated for a significantly shorter period with S-ketamine than with racemic ketamine. Recovery quality was poor in 3 gazelles with racemic ketamine. No significant differences between treatments were found for any other variables. Time from drug administration to antagonism was similar between racemic ketamine (44.5 to 53.0 minutes) and S-ketamine (44.0 to 50.0 minutes). CONCLUSIONS AND CLINICAL RELEVANCE: Administration of S-ketamine at a dose 60% that of racemic ketamine resulted in poorer induction of anesthesia, an analogous degree of sedation, and better recovery from anesthesia in gazelles with unremarkable alterations in physiologic variables, compared with racemic ketamine.

Anticipatory cognitive stress appraisal and the acute procoagulant stress response in men

OBJECTIVE: Acute mental stress elicits blood hypercoagulability. Following a transactional stress model, we investigated whether individuals who anticipate stress as more threatening, challenging, and as exceeding their coping skills show greater stress reactivity of the coagulation activation marker D-dimer, indicating fibrin generation in plasma. METHODS: Forty-seven men (mean age 44 +/- 14 years; mean blood pressure [MBP] 101 +/- 12 mm Hg; mean body mass index [BMI] 26 +/- 3 kg/m(2)) completed the Primary Appraisal Secondary Appraisal (PASA) scale before undergoing the Trier Social Stress Test (combination of mock job interview and mental arithmetic task). Heart rate, blood pressure, plasma catecholamines, and D-dimer levels were measured before and after stress, and during recovery up to 60 minutes poststress. RESULTS: Hemodynamic measures, catecholamines, and D-dimer changed across all time points (p values <.001). The PASA "Stress Index" (integrated measure of transactional stress perception) correlated with total D-dimer area under the curve (AUC) between rest and 60 minutes poststress (r = 0.30, p = .050) and with D-dimer change from rest to immediately poststress (r = 0.29, p = .046). Primary appraisal (combined "threat" and "challenge") correlated with total D-dimer AUC (r = 0.37, p = .017), D-dimer stress change (r = 0.41, p = .004), and D-dimer recovery (r = 0.32, p = .042). "Challenge" correlated more strongly with D-dimer stress change than "threat" (p = .020). Primary appraisal (DeltaR(2) = 0.098, beta = 0.37, p = .019), and particularly its subscale "challenge" (DeltaR(2) = 0.138, beta = 0.40, p = .005), predicted D-dimer stress change independently of age, BP, BMI, and catecholamine change. CONCLUSIONS: Anticipatory cognitive appraisal determined the extent of coagulation activation to and recovery from stress in men. Particularly individuals who anticipated the stressor as more challenging and also more threatening had a greater fibrin stress response.

Rapid restoration of microcirculatory blood flow with hyperviscous and hyperoncotic solutions lowers the transfusion trigger in resuscitation from hemorrhagic shock

Resuscitation from hemorrhagic shock relies on fluid retransfusion. However, the optimal properties of the fluid have not been established. The aim of the present study was to test the influence of the concentration of hydroxyethyl starch (HES) solution on plasma viscosity and colloid osmotic pressure (COP), systemic and microcirculatory recovery, and oxygen delivery and consumption after resuscitation, which were assessed in the hamster chamber window preparation by intravital microscopy. Awake hamsters were subjected to 50% hemorrhage and were resuscitated with 25% of the estimated blood volume with 5%, 10%, or 20% HES solution. The increase in concentration led to an increase in COP (from 20 to 70 and 194 mmHg) and viscosity (from 1.7 to 3.8 and 14.4 cP). Cardiac index and microcirculatory and metabolic recovery were improved with HES 10% and 20% when compared with 5% HES. Oxygen delivery and consumption in the dorsal skinfold chamber was more than doubled with HES 10% and 20% when compared with HES 5%. This was attributed to the beneficial effect of restored or increased plasma COP and plasma viscosity as obtained with HES 10% and 20%, leading to improved microcirculatory blood flow values early in the resuscitation period. The increase in COP led to an increase in blood volume as shown by a reduction in hematocrit. Mean arterial pressure was significantly improved in animals receiving 10% and 20% solutions. In conclusion, the present results show that the increase in the concentration of HES, leading to hyperoncotic and hyperviscous solutions, is beneficial for resuscitation from hemorrhagic shock because normalization of COP and viscosity led to a rapid recovery of microcirculatory parameters.

Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation

A key energy-saving adaptation to chronic hypoxia that enables cardiomyocytes to withstand severe ischemic insults is hibernation, i.e., a reversible arrest of contractile function. Whereas hibernating cardiomyocytes represent the critical reserve of dysfunctional cells that can be potentially rescued, a lack of a suitable animal model has hampered insights on this medically important condition. We developed a transgenic mouse system for conditional induction of long-term hibernation and a system to rescue hibernating cardiomyocytes at will. Via myocardium-specific induction (and, in turn, deinduction) of a VEGF-sequestering soluble receptor, we show that VEGF is indispensable for adjusting the coronary vasculature to match increased oxygen consumption and exploit this finding to generate a hypoperfused heart. Importantly, ensuing ischemia is tunable to a level at which large cohorts of cardiomyocytes are driven to enter a hibernation mode, without cardiac cell death. Relieving the VEGF blockade even months later resulted in rapid revascularization and full recovery of contractile function. Furthermore, we show that left ventricular remodeling associated with hibernation is also fully reversible. The unique opportunity to uncouple hibernation from other ischemic heart phenotypes (e.g., infarction) was used to determine the genetic program of hibernation; uncovering hypoxia-inducible factor target genes associated with metabolic adjustments and induced expression of several cardioprotective genes. Autophagy, specifically self-digestion of mitochondria, was identified as a key prosurvival mechanism in hibernating cardiomyocytes. This system may lend itself for examining the potential utility of treatments to rescue dysfunctional cardiomyocytes and reverse maladaptive remodeling.