The value of "diaphragmatic relaxing incision" for the durability of the crural repair in patients with paraesophageal hernia: a double blind randomized clinical trial.

Background: Surgical repair of paraesophageal hernias (PEHs) is burdened with high recurrence rates, and hitherto various techniques explored to enforce the traditional crural repair have not been successful. The hiatal reconstruction in PEH is exposed to significant tension, which may be minimized by adding a diaphragmatic relaxing incision to enhance the durability of the crural repair. Patients and methods: All individuals undergoing elective laparoscopic repair of a large PEH, irrespective of age, were considered eligible. PEHs were classified into types II-IV. The preoperative work-up program included multidetector computed tomography and symptom assessment questionnaires, which will be repeated during the postoperative follow-up. Patients were randomly divided into a control group with crural repair alone and an intervention group with the addition of a left-sided diaphragmatic relaxing incision at the edge of the upper pole of the spleen. The diaphragmatic defect was then covered by a synthetic mesh. Results: The primary endpoint of this trial was the rate of anatomical PEH recurrence at 1 year. Secondary endpoints included symptomatic gastroesophageal reflux disease, dysphagia, odynophagia, gas bloat, regurgitation, chest pain, abdominal pain, nausea, vomiting, postprandial pain, cardiovascular and pulmonary symptoms, and patient satisfaction in the immediate postoperative course (3 months) and at 1 year. Postoperative complications, morbidity, and disease burden were recorded for each patient. This was a double-blind study, meaning that the operation report was filed in a locked archive to keep the patient, staff, and clinical assessors blinded to the study group allocation. Blinding must not be broken during the follow-up unless required by any emergencies in the clinical management of the patient. Likewise, the patients must not be informed about the details of the operation. Trial Registration: ClinicalTrials.gov, identification number NCT04179578.

Genetic trends for fertility, udder health and protein yield in Swedish red cattle estimated with different models.

The aim of this study was to estimate and compare genetic trends in Swedish Red cattle using a full multiple-trait (MT) model and trait-group-wise models for female fertility, udder health and protein yield. Field data for maiden heifers from 1989 and cows with a first and second lactation between 1990 and 2007 were included. (Co)variance components were estimated prior to prediction of breeding values. The estimated genetic trends were clearly favourable for protein yield and udder conformation, and in most cases neutral to favourable for clinical mastitis and calving to first insemination. In maiden heifers, the trends were neutral for number of inseminations per service period. Unfavourable genetic trends were estimated for number of inseminations in the first two lactations, but the trends seemed less unfavourable from evaluations within trait groups compared with when using the full MT model. Excluding maiden heifer data affected genetic trends less than using trait-group-wise analyses instead of a full MT model. Unfavourable genetic trends in functional traits may be missed unless the traits are evaluated in a MT model including traits under strong selection.

Breakeven prices for recording of indicator traits to reduce the environmental impact of milk production.

A breeding scheme using genomic selection and an indicator trait for environmental impact (EI) was studied to find the most effective recording strategy in terms of annual monetary genetic gain and breakeven price for the recording of indicator traits. The breakeven price shows the investment space for developing a recording system for an indicator trait. The breeding goal consisted of three traits ­ milk production, functional trait and environmental impact ­ with economic values of €83, €82 and €-83, respectively. The first scenario included only breeding goal traits and no indicator traits (NoIT). The other scenarios included all three breeding goal traits and one indicator trait (IT) for EI. The indicator traits were recorded on a large scale (stayability after first lactation and stature), medium scale (live weight and greenhouse gases (GHG) measured in the breath of the cow during milking) or small scale (residual feed intake and total enteric methane measured in a respiration chamber). In the scenario with stayability, the genetic gain in EI was over 11% higher than it was in NoIT. The breakeven price of recording stayability was €8 per record. Stayability is easy to record in the national milk recording system, and its use as an indicator trait for EI would not generate any additional recording costs. Therefore, stayability would be a good indicator trait to use to mitigate EI. The highest genetic gain in EI (23% higher compared to NoIT) was achieved when the GHG measured in the breath of the cow was used as indicator trait. The breakeven price for this indicator trait was €29 per record in the reference population. Ideally the recording of a specific indicator trait for EI would take place when: (i) the genetic correlation between the IT and EI is high; and (ii) the number of phenotypic records for the indicator trait is high enough to achieve a moderately high reliability of direct genomic values.

Genomic selection using indicator traits to reduce the environmental impact of milk production.

The aim of this simulation study was to test the hypothesis that phenotype information of specific indicator traits of environmental importance recorded on a small-scale can be implemented in breeding schemes with genomic selection to reduce the environmental impact of milk production. A stochastic simulation was undertaken to test alternative breeding strategies. The breeding goal consisted of milk production, a functional trait, and environmental impact (EI). The indicator traits (IT) for EI were categorized as large-, medium-, or small-scale, depending on how the traits were recorded. The large-scale traits were stayability and stature; the medium-scale traits were live weight and methane in the breath of the cow measured during milking; and the small-scale traits were residual feed intake and methane recorded in a respiration chamber. Simulated scenarios considered information for just one IT in addition to information for milk production and functional traits. The annual monetary genetic gain was highest in the large-scale scenario that included stayability as IT. The annual monetary gain in the scenarios with medium- or small-scale IT varied from €50.5 to 47.5. The genetic gain improvement in EI was, however, best in the scenarios where the genetic correlation between IT and EI was ≥0.30 and the accuracy of direct genomic value was ≥0.40. The genetic gain in EI was 26 to 34% higher when indicator traits such as greenhouse gases in the breath of the cow and methane recorded in respiration chamber were used compared with a scenario where no indicator trait was included. It is possible to achieve increased genetic gain in EI by using a highly correlated indicator trait, but it requires that the established reference population for the indicator trait is large enough so that the accuracy of direct genomic values will be reasonably high.

Selection of bull dams for production and functional traits in an open nucleus herd.

The aim of this study was to compare different scenarios for bull dam selection in a nucleus herd. A deterministic simulation study using selection index methodology was undertaken. In the scenarios studied, differing amounts of information on functional traits were available when bull dams were selected, and the resulting genetic responses in these traits were compared. Field-recorded fertility traits used in the scenarios were available as progeny test results of artificial insemination bulls: these included pregnant at first insemination (PFI), interval between calving and first insemination (CFI), and cases of reproductive disorders (RD). Similarly, field-recorded cases of clinical mastitis (CM), lactation somatic cell score (LSCS), and protein yield (PY) were included for pedigree selection. In the scenarios, heat intensity score and progesterone levels were treated as new indicator traits of fertility recorded in the nucleus herd. Traits CFI and LSCS were assumed to be better recorded with higher heritability in the nucleus herd than in ordinary herds. Economic weights currently used in Nordic Cattle Genetic Evaluation (NAV) were adapted and used in the scenarios. The results showed that these weights, if used in multiple trait genetic evaluation, would lead to undesirable genetic changes in functional traits for the bull dam selection path in a nucleus environment. More frequent recording of additional traits failed to improve selection for functional traits, as did more frequent recording of ordinary traits. Restriction index methodology was used to derive the bull dam total weights that gave no unfavorable response (i.e., zero genetic change) in traits PFI, CFI, and CM. When summarized over lactations, the new bull dam total weights, when additional records from nucleus were used, had to be 12 to 23 times higher for fertility, and 3 times higher for mastitis, than the presently used NAV weights, if these traits were to remain unchanged through the bull dam selection path. Thus, nucleus herd selection of bull dams is questionable for low heritability traits that are already recorded in the field.

Transient receptor potential vanilloid 1, vanilloid 2 and melastatin 8 immunoreactive nerve fibers in human skin from individuals with and without Norrbottnian congenital insensitivity to pain.

Transient receptor potential vanilloid 1 (TRPV1), vanilloid 2 (TRPV2) and melastatin 8 (TRPM8) are thermosensitive cation channels expressed on primary sensory neurons. In contrast to TRPV1, which is present on nociceptive primary afferents and keratinocytes in human skin, less is known about the distribution of TRPV2 and TRPM8 in this tissue. Immunohistochemistry of human forearm skin identified TRPV2 and TRPM8 immunoreactive nerve fibers in epidermis-papillary dermis and around blood vessels and hair follicles in dermis, although these nerve fibers were less abundant than TRPV1 immunoreactive nerve fibers throughout the skin. The TRPV2 and TRPM8 immunoreactive nerve fibers also showed immunoreactivity for calcitonin gene-related peptide (CGRP) and to a lesser extent substance P (SP). Neither of the TRP ion channels co-localized with neurofilament 200 kDa (NF200), vasoactive intestinal peptide (VIP) or tyrosine hydroxylase (TH). Nerve fibers immunoreactive for TRPV1, TRPV2, TRPM8, CGRP and SP were absent or substantially reduced in number in individuals with Norrbottnian congenital insensitivity to pain, an autosomal disease selectively affecting the development of C-fiber and Adelta-fiber primary afferents. Quantitative real time PCR detected mRNA transcripts encoding TRPV1 and TRPV2, but not TRPM8, in skin from healthy volunteers, suggesting that these ion channels are also expressed extraneuronally. In conclusion, nerve fibers in human skin express TRPV1, TRPV2 and TRPM8 that co-localize with the sensory neuropeptides CGRP and SP, but not with NF200, VIP or TH. A dramatic loss of such nerve fibers was seen in skin from individuals with Norrbottnian congenital insensitivity to pain, further suggesting that these ion channels are expressed primarily on nociceptive primary sensory neurons in human skin.

Rates of metabolism of chlorzoxazone, dextromethorphan, 7-ethoxycoumarin, imipramine, quinidine, testosterone and verapamil by fresh and cryopreserved rat liver slices, and some comparisons with microsomes.

In the present study we have investigated the disappearance of chlorzoxazone, dextromethorphan, 7-ethoxycoumarin, imipramine, quinidine, testosterone and verapamil from the medium in which fresh and cryopreserved rat liver slices were incubated. These compounds are all substrates of major isoforms of cytochrome P450 expressed in the liver. The metabolism of five of these compounds in microsomes from rat liver was also examined. Determinations of the concentrations of the compounds were performed employing LC/MS. Intrinsic clearance values (CL(ints)) were calculated on the basis of the concentration-vs.-time curves. No significant differences in the CL(int) values obtained with fresh and cryopreserved rat liver slices were observed for any of the compounds. The highest CL(int) value estimated with liver slices was observed for testosterone and the lowest values were with chlorzoxazone and 7-ethoxycoumarin. The total CL(int) values for 7-ethoxycoumarin and imipramine, calculated using scaling factors, were similar for liver slices and microsomes. In the case of testosterone, this total CL(int) was approximately 3.7-fold lower, whereas for dextromethorphan and quinidine it was 2.5- and 8.5-fold higher, respectively, with liver slices than with microromes. In conclusion, the rate of metabolism of the seven compounds tested with rat liver slices was not affected by cryopreservation. This finding adds further support to the general conclusion that the major activities involved in drug metabolism are not affected by cryopreservation of rat liver slices.

Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia.

MCG 101 tumors were implanted sc. on wild-type C57 Bl and gene knockout mice to evaluate the role of host-produced cytokines [interleukin (IL)-6, IL-12, IFNgamma, tumor necrosis factor (TNF) receptor 1, and TNF receptor 2] to explain local tumor growth, anorexia, and carcass weight loss in a well-defined model with experimental cachexia. Indomethacin was provided in the drinking water to explore interactions between host and tumor-derived prostaglandins and proinflammatory cytokines for tumor growth. Wild-type tumor-bearing mice developed cachexia because of rapid tumor growth, which were both attenuated in IL-6 gene knockouts. Similar findings were observed after provision of anti-IL-6 to wild-type tumor-bearing mice. Alterations in food intake were not directly related to systemic IL-6 but rather secondarily to IL-6-dependent tumor growth. The absence of host-derived IL-12, IFN-gamma, or the TNF receptor 1 or receptor 2 gene did not attenuate tumor growth or improve subsequent cachexia. Thus, carcass weight loss was not improved by the omission of host cytokine (TNF-alpha, IL-12, or IFN-gamma) except for IL-6. Systemic indomethacin provision decreased plasma prostaglandin E2 in five of six groups of gene knockout tumor-bearing mice, which was associated with improved carcass weight in these groups. Indomethacin seemed to improve food intake to a similar extent in both wild-type and gene knockouts, which agree with the speculation that eicosanoids are more important to explain anorexia than host cytokines. Our results demonstrate that host- and tumor-derived cytokines and prostaglandins interact with tumor growth and promote cachexia in a more complex fashion than usually presented based on previous information in studies on either anti-cytokine experiments in vivo or on gene knockouts with respect to a "single cytokine model." Overall, host cytokines were quantitatively less important than tumor-derived cytokines to explain net tumor growth, which indirectly explains subsequent cachexia and anorexia.

Neuroendocrine peptide levels in the gastrointestinal tract of mice after unilateral cervical vagotomy.

The effects of left and right unilateral cervical vagotomy on the content of several neuroendocrine peptides were studied in different parts of the murine gastrointestinal tract, known to receive vagal innervation. The neuroendocrine peptides investigated were secretin, gastric inhibitory peptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, substance P, VIP, neurotensin, neuropeptide Y (NPY), and galanin. The neuroendocrine peptide concentration was affected after both left and right vagotomy, and that the changes in the concentrations of the neuroendocrine peptide levels occurred in all the gastrointestinal segments investigated, namely antrum, small and large intestine. However, these changes varied, depending on which side was vagotomized and the interval after vagotomy. It is concluded that the vagus nerve had an important impact on the neuroendocrine system in the murine gut. It is suggested, furthermore that the contradictory results obtained earlier on the effect of vagotomy on the gastrointestinal peptides may depend on differences in the vagotomy methods used and on differences in observation time after vagotomy.

Physiological changes in pigs exposed to a blast wave from a detonating high-explosive charge.

The aim of this project was to study respiration, circulation, and brain activity in pigs during and after a blast wave exposure. Ten anesthetized pigs were used. Seven were exposed to blast and three were controls. Physiological parameters of respiration and circulation as well as cortical activity were followed from 30 minutes before until 120 minutes after the real or simulated blast. There were no significant changes in heart rhythm, cardiac output, arterial oxygen or carbon dioxide tension, blood pH, or mixed venous saturation during the experiment. The blast exposure caused intestinal injuries but no lung damage. A transient flattening of the electroencephalogram was seen immediately after the blast in four experimental animals, in contrast to the unchanged baseline electroencephalogram of the control animals. This momentary depression of cortical activity accompanied by short-lasting apnea indicates a blast wave-induced effect on the brainstem or higher controlling center.

Effects of gallstone-promoting diet and vagotomy on the mouse gallbladder epithelium.

BACKGROUND/AIMS: An increased incidence in gallstone disease has been suggested in patients subjected to vagotomy, therefore we studied whether vagotomy influences the gallbladder epithelium and the secretion of glucoprotein granules in mice fed a gallstone-inducing diet. METHODOLOGY: Ten mice were given a lithogenic diet for 7 weeks. Five of them were subjected to left truncal vagotomy. As controls, 5 mice were sham-operated and 5 were subjected to vagotomy. Seven weeks after the operation, the morphological changes in the gallbladder epithelium were quantified with an electron microscopic morphometric method. RESULTS: In mice on a lithogenic diet, an increase in the volume density of the secretory granules and the profile area of the principal cells of the epithelium were found. The morphological changes were identical in animals subjected to truncal vagotomy and given a lithogenic diet. CONCLUSIONS: The effect of a gallstone-promoting diet in mice, seen as an increase in the volume density of the secretory granules and in the profile area of the principal cells of the gallbladder epithelium, was not influenced by deprivation of vagal innervation.

Diaphragmatic activity after laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy is presumed to induce a reduction in diaphragmatic activity. Indirect indices of diaphragmatic function based on tidal changes in pressures and cross-section area measurements can be unreliable in the postoperative phase. The present study evaluates diaphragmatic activity by directly recording diaphragmatic EMG (EMGdia) data, along with indirect indices. METHODS: Thirteen adult patients (American Society of Anesthesiologists physical status I or II) undergoing laparoscopic cholecystectomy were examined preoperatively for inspiratory tidal changes in gastric (Pgas-insp) and esophageal (Peso-insp) pressures, and tidal changes in ribcage (Vthor) and abdominal (Vabd) cross-section areas and then again at 1, 6, and 24 h postoperatively combined with EMGdia recordings. Variations in inspiratory gastric (deltaPgas-insp) and inspiratory transdiaphragmatic (deltaPdi-insp) pressures were derived from the above. RESULTS: Laparoscopic cholecystectomy induced a significant reduction in mean deltaPgas-insp, mean deltaPdi-insp, and mean Vabd indicating a reduction of diaphragmatic activity postoperatively. DeltaPdi-insp decreased from 11.8+/-4.0 cm H2O preoperatively to 5.7+/-5.7 cm H2O at 1 h and 6.6+/-5.1 cm H2O at 6 h postoperatively (mean +/- SD; P < 0.05). Vabd decreased from 327.0+/-113.0 ml preoperatively to 174.0+/-65.0 ml at 1 h and 175.0+/-98.0 ml at 6 h postoperatively (mean +/- SD; P < 0.05). These values had partially recovered at 24 h. CONCLUSION: The direct and indirect indices of diaphragmatic activity taken together confirm the presence of reduction in diaphragmatic activity after laparoscopic cholecystectomy followed by its partial recovery at 24 h.

Effects of unilateral cervical vagotomy on antral endocrine cells in mouse.

The present study was carried out to investigate the effect of unilateral cervical vagotomy on the antral endocrine cells in mouse. Fifty-four mice were randomly divided into three groups, 18 in each, for left or right cervical vagotomy, or sham operation as controls. The animals were sacrificed 2, 4, and 8 weeks after the operation, respectively. Chromogranin-, gastrin/CCK-, serotonin-, and somatostatin-cells were detected by immunohistochemistry and quantitated by computerised image analysis. The results showed that the number of chromogranin-cells was decreased in both left and right vagotomized mice after 4 weeks and remained at the same level after 8 weeks. The numbers of gastrin-, serotonin- and somatostatin-cells did not change after right vagotomy. However, the numbers of gastrin- and somatostatin-cells were decreased after left vagotomy, whereas no change was found in serotonin-cells. Endocrine cells with vacuolated cytoplasm and pyknotic nuclei were also observed during the course of time. The alteration in the antral endocrine cells observed in this study seemed to be dynamic and depended on the observation time after the operation as well as the denervated branches of the vagus nerve. This may explain, at least partially the contradictory results obtained earlier by different investigators.

Changes in intestinal endocrine cells in the mouse after unilateral cervical vagotomy.

The effect of right or left unilateral cervical vagotomy on the intestinal endocrine cells was studied in 23 mice at 2 and 8 weeks after operation, respectively. The results were compared with that from 10 sham operated mice. Various types of endocrine cells in duodenum and proximal colon were detected by immunohistochemistry and quantified by computerized image analysis. In mouse duodenum, chromogranin-, CCK/gastrin-, GIP- and somatostatin-cells were significantly decreased at 2 weeks after right vagotomy, but returned to the control levels at 8 weeks. Serotonin-cells were reduced at both 2 and 8 weeks after right vagotomy. The amount of the duodenal endocrine cells did not change after left vagotomy with the exception of secretin-cells, which were diminished at 8 weeks after both right and left vagotomy. In the proximal colon, chromogranin-cells were also decreased at 2 weeks after right vagotomy. Serotonin-cells were reduced at 8 weeks after left vagotomy but not right vagotomy. There was no significant difference between the unilaterally vagotomized and the sham operated mice with regard to PYY- and glucagon-cells. It was concluded that vagotomy affected the intestinal endocrine cells in mouse. The influence was more pronounced in the small intestine than the proximal colon. The right vagus nerves seemed to exert more effect on the intestinal endocrine cells than the left ones.

Life expectancy and cost utility after total hip replacement.

In a prospective study of 410 cemented hip replacements in 372 patients with a mean age of 71 years, mortality after 8 years was 33%. Mortality for patients with osteoarthrosis was lower than in an age matched control population, probably because of a preoperative selection of patients. An estimate of costs and adjusted quality of life has shown that total hip replacement has a good cost utility even in the elderly patient. The conclusion of this study is that the indications for hip replacement in the elderly patient can be expanded. Such patients should undergo surgery earlier in the course of their disease.

A one-piece plexiglass access chamber for subcutaneous implantation in the dorsal skin fold of the mouse.

This technical report describes the production and installation of a newly developed, one-piece, light-weight (0.6 g) access plexiglass chamber for the dorsal skin fold of the mouse.

Chest wall velocity as a predictor of nonauditory blast injury in a complex wave environment.

Previous blast injury prediction criteria have been based on exposure to classic Friedlander or ideal blast waves. An ideal waveform is characterized by an instantaneous rise to a peak overpressure that decays exponentially to ambient pressure followed by a negative phase. The prediction criteria did not address injuries resulting from exposure to complex blast waves. It was difficult to establish a simple relationship between the two because complex blast waves typically consist of multiple shocks with variable frequency content and intensity that may be superimposed on a slow rising quasistatic pressure pulse. This paper deals with the application of a single degree of freedom mathematical model, originally developed to measure the response of the thorax to Friedlander waves, to calculate chest wall velocities resulting from various complex blast loads. Experimental results with sheep, exposed to complex blast waves in enclosures, demonstrated that there was a good relationship between the Adjusted Severity of Injury Index (which includes injury to the lungs, upper respiratory tract, gastrointestinal tract and solid intraabdominal organs) and the calculated peak inward chest wall velocity. In addition, there was a good correlation between these results and previously established Friedlander injury prediction curves. The velocity of complex blast waves was nearly the same as that of Friedlander waves for a given degree of injury: 3-4.5 meters/second for threshold injury, 8-12 meters/second for an LD1, and 12-17 meters/second for an LD50.

CCK- and VIP-induced glycoprotein secretion from mouse gallbladder epithelium following vagotomy: a quantitative electron microscopic study.

The glycoprotein secretion from the mouse gallbladder epithelium induced by vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) was investigated by electron microscopic morphometry. Both VIP and CCK caused a decrease in the volume density of the glycoprotein-containing granules of the principal cells. The effect on the gallbladder epithelium of a left-sided vagotomy was examined. Three and six weeks postvagotomy, slight decreases in cell and nuclear profile area and secretory granule volume density were noted. CCK induced a secretion of glycoprotein granules, whereas no such secretory effect due to VIP could be detected in animals 3 and 6 weeks after vagotomy. The results demonstrate that VIP, like CCK, is involved in glycoprotein secretion from the mouse gallbladder epithelium, but the secretory effect of VIP would appear to be dependent on an intact vagal innervation. The results are of interest in relation to the hypothesis that glycoprotein release may be a precipitating factor in the production of gallstones.

Isoprenoid biosynthesis in multiple sclerosis, II. A possible role of NADPH.

Genetic predisposition in MS, influence of fat consumption on the disease, and excretion of lipid metabolites in urine led us to investigate isoprenoid metabolism in this disease. Ubiquinone concentration and biosynthesis was normal in lymphocytes. Cytochrome oxidase, which contains an isoprenoid side chain, was normal in activity. Cholesterol biosynthesis from acetate was found to be elevated in MS, and so was triglyceride biosynthesis. Increased biosynthesis may offer a very simple explanation to all the metabolites excreted (3-methylglutaconic acid, 2-hydroxy-2-methyl-3-butenoic acid and adipic acid). Increased biosynthesis may be caused by an elevated NADPH/NADP ratio, since such an elevation may also account for many other biochemical anomalies in MS. Elevated NADPH/NADP ratio may be of direct importance in the pathogenesis.