The Ability of Hop Extracts to Reduce the Methane Production of Methanobrevibacter ruminantium.

BACKGROUND: Methane emissions from agriculture are responsible for over 40% of the world's greenhouse gas emissions. In the past, antibiotics were used to control methane production by animals, but concerns over the emergence and spread of antibiotic-resistant bacteria to humans have prompted a search for alternative approaches. Hops are the flowers of the hop plant Humulus lupulus. They have been used to feed cattle for many years and are known to contain antibacterial compounds, and their extracts have been shown to kill members of the Mycobacterium spp including Mycobacterium bovis, the causative agent of bovine tuberculosis as well as a number of human pathogens. In this study, hop extracts were studied for their ability to inhibit methane production from Methanobrevibacter ruminantium, a major methane-producing archaeon found in the rumen of cattle. METHODS: Methanobrevibacter ruminantium M1T (DSM 1093) was grown at 37°C for 30 days, and the amount of methane produced at different time points during this period was measured using gas chromatography. The archaeon was exposed to commercial hop extracts (tetra-hydro-iso-alpha acid and beta acid) and to aqueous hop extracts of a range of hop variants, and their effect on methane production was determined. RESULTS: All of the extracts reduced the level of methane production of M. ruminantium over the 30-day period compared to the negative control (sterile distilled water). The commercial hop extracts were the most effective at inhibiting methane production over the course of the experiment in contrast to the aqueous extracts, which showed a gradual reduction of inhibition with time. CONCLUSIONS: Hops contain compounds which inhibit methane production. Given that hops can be safely fed to cattle, this raises the possibility of rationally designing a feed strategy which could reduce greenhouse gas emissions and protect against bovine tuberculosis. This study recommends that further research be undertaken to further identifying bioactive components from hops and their efficacy against a range of archaea.

KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype.

To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.

Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring.

The period around the time of conception is one characterised by considerable cytological and molecular restructuring as ovulation occurs, the oocyte is fertilised and the embryonic developmental programme begins. The intrinsic processes regulating peri-conceptional progression are supplemented by environmental factors, which contribute important metabolic information that influences several aspects of the developmental programme. Indeed, there is growing evidence from different mammalian animal models, reviewed here, that the peri-conceptional environment mediated through maternal nutrition can modify development throughout gestation and affect the physiological and metabolic health of adult offspring. The concept that adult disease risk may owe its origin to the quality of peri-conceptional maternal nutrition is one, which merits further research for mechanistic understanding and devising preventive strategies.

Tissue-specific selection of reference genes is required for expression studies in the mouse model of maternal protein undernutrition.

Suboptimal maternal nutrition during gestation results in the establishment of long-term phenotypic changes and an increased disease risk in the offspring. To elucidate how such environmental sensitivity results in physiological outcomes, the molecular characterisation of these offspring has become the focus of many studies. However, the likely modification of key cellular processes such as metabolism in response to maternal undernutrition raises the question of whether the genes typically used as reference constants in gene expression studies are suitable controls. Using a mouse model of maternal protein undernutrition, we have investigated the stability of seven commonly used reference genes (18s, Hprt1, Pgk1, Ppib, Sdha, Tbp and Tuba1) in a variety of offspring tissues including liver, kidney, heart, retro-peritoneal and inter-scapular fat, extra-embryonic placenta and yolk sac, as well as in the preimplantation blastocyst and blastocyst-derived embryonic stem cells. We find that although the selected reference genes are all highly stable within this system, they show tissue, treatment and sex-specific variation. Furthermore, software-based selection approaches rank reference genes differently and do not always identify genes which differ between conditions. Therefore, we recommend that reference gene selection for gene expression studies should be thoroughly validated for each tissue of interest.

Impact of the periconceptional environment on the programming of adult disease.

The periconceptional period of mammalian development has been identified as an early 'developmental window' during which environmental conditions may influence the pattern of future growth and physiology. Studies in humans and animal models have revealed that factors such as maternal nutritional status or in vitro culture and manipulation of developing gametes and preimplantation embryos can impact upon the long-term health and physiology of the offspring. However, the mechanisms involved in the programming of adult disease in response to altered periconceptional development require increased investigation. The role of epigenetic modifications to DNA and chromatin organisation has been identified as a likely mechanism through which environmental perturbations can affect gene expression patterns resulting in phenotypic change. This study will highlight the sensitivity of two critical stages in early mammalian development, gametogenesis and preimplantation development. We will detail how changes to the immediate environment can not only impact upon developmental processes taking place at that time, but can also affect long-term aspects of offspring health and physiology. We will also discuss the emerging role of epigenetics as a mechanistic link between the environment and the later phenotype of the developing organism.

Botulinum toxin B is not an effective treatment of refractory overactive bladder.

OBJECTIVES: To determine the efficacy and safety of botulinum toxin-B (BTX-B) in two groups of patients with urodynamically proven idiopathic detrusor overactivity (IDO) or neurogenic DO (NDO) refractory to conservative treatment. METHODS: This was a nonrandomized, prospective study. We diluted 5000 U of BTX-B in 20 mL of normal saline and injected it at 20 sites around the bladder, avoiding the trigone. The data collected at recruitment and 10 and 26 weeks postoperatively included number of incontinent episodes, frequency, and nocturia, King's Health Questionnaire score, and the urodynamic parameters of volume at the first overactive contraction and maximal cystometric capacity. RESULTS: A total of 25 patients were recruited, 20 with IDO and 5 with NDO. Only 7 patients, all with IDO, reported symptomatic improvement at the 10-week assessment. The symptoms had returned in these 7 patients at a median of 136 days (range 106 to 151) after injection. Of the remaining 20 patients, 16 (13 with IDO and 3 with NDO) thought an initial improvement had occurred but it had worn off or was wearing off by the first assessment. Two patients (both with NDO) reported no improvement. CONCLUSIONS: BTX-B had a limited duration of action, with most of its symptomatically beneficial effects wearing off by 10 weeks in most of our patients. The short duration of action for BTX-B suggests it is unlikely to gain widespread use in the treatment of DO.

Inhibiting vascular endothelial growth factor receptor-2 signaling reduces tumor burden in the ApcMin/+ mouse model of early intestinal cancer.

The Apc(Min/+) mouse model is a clinically relevant model of early intestinal cancer. We used AZD2171, an oral, highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor, to investigate the role of VEGF receptor-2 (VEGFR-2) signaling in adenoma development and growth in Apc(Min/+) mice. AZD2171 (5 mg/kg body wt/day) was administered once daily for 28 days to 6-week-old (early-intervention) or 10-week-old (late intervention) mice. In the early-intervention study, AZD2171 reduced the number of macroscopic polyps in the small bowel and colon. Macropolyp diameter was lower in the small bowel, but remained unchanged in the colon. In animals receiving AZD2171, microscopic evaluation of the small intestine showed a significant reduction in the number of larger lesions. In the late-intervention study, AZD2171 treatment reduced macropolyp diameter (but not number) in the small intestine. Microscopic analysis revealed that AZD2171 significantly reduced the number of larger micropolyps in the small bowel, with no large micropolyps present in the colon. AZD2171 treatment had no effect on microvessel density or localization of beta-catenin staining in adenomas or non-tumor intestinal tissue, but significantly reduced the number of cells expressing VEGFR-2 mRNA. In conclusion, the effects of AZD2171 in the small intestine of Apc(Min/+) mice are consistent with an antiangiogenic mechanism of action, limiting growth of adenomas to < or =1 mm. These data also suggest that an early step in adenoma development may depend on VEGFR-2 signaling. Together, these results indicate that VEGFR-2 signaling may play key roles in the development and progression of intestinal adenomas.

Antegrade continence enema in the treatment of obstructed defaecation with or without faecal incontinence.

BACKGROUND: Obstructed defaecation and faecal incontinence are complex functional disorders that pose management challenges. In recent times, the antegrade continence enema (ACE) has been tried both as a primary procedure and as a final resort to avoid a colostomy in patients with a variety of functional problems. The purpose of this study was to evaluate the role of the ACE procedure as a treatment option for adult patients suffering from obstructed defaecation with or without faecal incontinence, some of whom also had slow transit constipation. METHODS: Twenty female patients underwent ACE as an appendicostomy (65%) or caecostomy (35%). The median age was 44 years (range, 20-65 years). The indications were obstructed defaecation with faecal incontinence (65%) and obstructed defaecation alone (35%). Fifteen of these patients were followed for 3-51 months (median, 6 months). Cleveland continence score, bowel score and quality of life score were recorded pre- and postoperatively along with post-procedure complications. RESULTS: Thirteen (65%) patients were satisfied with the outcome and recorded improvement in their scores while two (10%) remained the same and one (5%) was worse. This latter woman and another patient stopped using their ACE, whilst follow-up data was unavailable for three patients. Minor wound infections were noted in nine patients (45%), of whom one needed drainage of an abscess; the rest settled with antibiotics and dressings. Bowel and Cleveland continence scores improved postoperatively (p<0.001 and p=0.001, respectively) but SF36 scores did not. To date, no patient has had a colostomy following an ACE procedure. CONCLUSIONS: Colostomies can be avoided in patients with obstructed defaecation. There is, however, a need to minimise wound infections which seem to be the most troublesome complication.

Nutrient induced thermogenesis during major colorectal excision--a pilot study.

OBJECTIVE: Hypothermia may occur during general anaesthesia and is associated with postoperative coagulopathy, ischaemic cardiac events, wound infections and increased metabolic expenditure due to shivering. The purpose of the present pilot study was to determine whether the administration of certain amino acids (Vamin 18) during general anaesthesia could prevent postoperative hypothermia. PATIENTS AND METHODS: Two groups of patients were studied. The study group comprised 10 patients who underwent complex major colorectal operations. In this group an infusion of 500 mls of Vamin 18 (Fresenius Kabi Ltd) was commenced immediately after induction of anaesthesia but prior to the skin incision. In a control group (n=10) who underwent similar surgical procedures Vamin 18 was not administered. In both groups core body temperature, using an oesophageal probe was recorded during the procedure and recovery period. Ambient theatre and recovery room temperature and other body warming techniques were standardized for all patients. Statistical analysis was performed using t-test for comparison of linear temperature changes at different times during the procedure for both groups of patients. RESULTS: The body temperature was statistically significantly reduced in both groups at skin incision when compared with temperature prior to induction of anaesthesia. ( STUDY GROUP: mean 0.74 degrees C, SD=0.38, P =<0.001; CONTROL GROUP: mean 0.54 degrees C, SD=0.43, P=0.003]. The increase in body temperature between the time of skin incision and recovery period was statistically significant (P=0.012) in the study group but not so in the control group (P=0.730). CONCLUSION: The results of the present pilot study demonstrate that complex colorectal operations are associated with a decrease in body temperature which is most marked immediately after the induction of anaesthesia. The perioperative administration of Vamin 18 appears to increase the rate of recovery of body temperature. The impact of this thermogenic effect on perioperative morbidity and mortality should be studied in a prospective randomised clinical trial.

A prospective audit of stomas--analysis of risk factors and complications and their management.

AIM: To prospectively audit stomas and to determine the nature and rate of complications and their relationship with various risk factors and their management. MATERIALS AND METHODS: The study was performed prospectively on 97 consecutive patients who had stomas formed between January 2000 to August 2000. Patients were followed up for one year. Risk factors including age, body mass index (BMI), preoperative siting, contour of the abdominal wall, smoking, grade of operating surgeon, emergency or elective procedure, diabetes, type of stoma and suture material used were noted. The type of surgery, and indications for surgery were also recorded. The complications were documented by two qualified stoma nurses and a photographic record taken. Statistical analysis comprising both univariate and multivariate methods, was performed by SPSS 10. RESULTS: The mean age was 65 years (standard deviation 16.01, range 16-99) and mean body mass index was 24.5 (standard deviation 4.66, range 15-37). Forty-nine of 97 (50.5%) stomas developed one or more complications. Twenty-three patients experienced retraction, 18 had stomas sited in a skin crease, 16 had early and 12 had late skin excoriation, 12 had detachments and a further 12 had parastomal hernia. Eleven further stoma complications were noted including prolapse, necrosis, ischaemia and sloughing. None of the risk factors achieved statistical significance when analysed against the overall complication rate. However, when the risk factors were analysed against individual complications using univariate logistic regression, a high body mass index was associated with more retractions (P = 0.003), early skin excoriation (P = 0.036) and poor siting (stoma in crease) occurred more commonly in emergencies (P = 0.022). Diabetes was associated with late skin excoriation (P = 0.02). Multivariate logistic regressions confirmed an independent association of body mass index, diabetes and emergency surgery with complications. Forty-five of 49 patients who had complications needed some conservative management such as a convexity appliance. Four patients needed refashioning. CONCLUSION: Body mass index, diabetes and emergency surgery were the significant risk factors identified in our study. Overall complications compare favourably with other series. We found that preoperative siting by stoma nurses and the grade of operating surgeon did not affect the outcome.

The influence of early reflections on the identification and lateralization of vowels.

Sound coming directly from a source is often accompanied by reflections arriving from different directions. However, the "precedence effect" occurs when listeners judge such a source's direction: information in the direct, first-arriving sound tends to govern the direction heard for the overall sound. This paper asks whether the spectral envelope of the direct sound has a similar, dominant influence on the spectral envelope perceived for the whole sound. A continuum between two vowels was produced and then a "two-part" filter distorted each step. The beginning of this filter's unit-sample response simulated a direct sound with no distortion of the spectral envelope. The second part simulated a reflection pattern that distorted the spectral envelope. The reflections' frequency response was designed to give the spectral envelope of one of the continuum's end-points to the other end-point. Listeners' identifications showed that the reflections in two-part filters had a substantial influence because sounds tended to be identified as the positive vowel of the reflection pattern. This effect was not reduced when the interaural delays of the reflections and the direct sound were substantially different. Also, when the reflections were caused to precede the direct sound, the effects were much the same. By contrast, in measurements of lateralization the precedence effect was obtained. Here, the lateral position of the whole sound was largely governed by the interaural delay of the direct sound, and was hardly affected by the interaural delay of the reflections.

A systematic analysis of how medical school characteristics relate to graduates' choices of primary care specialties.

PURPOSE: To examine medical school characteristics, in particular federal funding for biomedical research, as they relate to the graduates' choices of family medicine, general internal medicine, general pediatrics, or all three specialties. METHOD: Data were collected for 121 U.S. medical schools, including information on funding, faculty, curricula, and other school characteristics. In addition, a questionnaire was mailed to the schools requesting information about non-federal funding for primary care, primary care department characteristics, and primary care representation on the admission, curriculum, and promotion and tenure committees. Analyses were carried out separately for each specialty and for all three combined. The first multiple regression analysis was done to predict specialty choice (proximate predictors), the second to predict the predictors of specialty choice (intermediate predictors), and the third to predict those predictors (distal predictors). RESULTS: Prediction was best for family medicine practice. Interest at matriculation and required third-year and fourth-year time in primary care were the two best proximate predictors. The best predictors of initial interest were the percentage of rural students and special programs for primary care, while the best predictors of required time in primary care were funding for family medicine and the percentage of faculty in family medicine (intermediate predictors). The best predictor of the percentage of faculty in family medicine was funding for family medicine (distal predictor). CONCLUSION: The results suggest that the most effective way to increase the number of physicians with generalist practices is to increase the number of students interested in a family medicine career at matriculation.

Motor-vehicle crash fatalities among American Indians and non-Indians in Arizona, 1979 through 1988.

OBJECTIVES: This study evaluated the contributions of rural residence, alcohol use, and pedestrian fatalities to the high American Indian motor-vehicle crash mortality rate in Arizona. METHODS: Records from the Fatal Accident Reporting System were used to examine mortality rates between 1979 and 1988. RESULTS: American Indians had increased relative risks in all motor-vehicle crash categories in all residence-gender groups. The percentage of excess mortality associated with alcohol varied from 36.8% to 66.7%, and the percentage associated with pedestrian deaths ranged from 27.2% to 55.4%. CONCLUSIONS: Efforts to reduce excess motor-vehicle crash mortality among American Indians should concentrate on preventing pedestrian and alcohol-related fatalities.

Effects of spectral contrast on perceptual compensation for spectral-envelope distortion.

Features in a sound's spectral envelope are important for perceptual identification but they are likely to be accompanied by spurious features due to distortion by the transmission channel between source and listener. Previous experiments have demonstrated that there is perceptual compensation for this distortion, and the present experiments ask whether the compensation involves a separation of spurious and salient features. Listeners identified words containing a vowel test sound in an /aept/ to /ppt/ continuum, with a carrier phrase before each word. Effects of transmission channels were simulated by filtering the carrier and the /pt/ following the test sound. Filters were pairs with frequency responses that were the difference of the spectral envelopes from the end-point vowels. Contrasts were altered by multiplying decibel values of the carrier filter's frequency response or the test sound's spectral envelope by a positive number. This keeps features such as peaks at the same frequencies but changes the difference in level between peaks and valleys. When the contrasts of the carrier filters and test sound were the same, the continuum's phoneme boundary was shifted in a manner consistent with a perceptual compensation for the filters that affects the neighboring test sound. However, this shift decreased when the carrier-filter's contrast was less than that of the test sound, and increased slightly when the test-sound's contrast was less than the carrier-filter's contrast. Therefore, the amount of compensation increases with the amount of distortion, even when spectral features such as peaks are kept at the same frequencies. So compensation seems to occur before any perceptual extraction of these features.

Some effects of filtered contexts on the perception of vowels and fricatives.

When a phrase is filtered to simulate the effects of a transmission channel, a vowel played shortly afterward is heard as if there is perceptual compensation for the filter. However, a transmission channel would also have an effect on sounds that arrive after the vowel. The present experiments ask whether vowel test sounds are affected by the filtering of a subsequent affricate when there are no other sounds present. Effects on other types of test sounds from different subsequent sounds are measured as well. The experiments also ask whether these effects occur when there is information about the channel in a precursor phrase. Listeners identified words from continua between /It integral of/ and /epsilon t integral of/, /aept/ and /[symbol: see text]/, or /[symbol: see text]/ and /[symbol: see text]/. Filters' frequency responses were the difference of spectral envelopes from the end-point test sounds. The perceptual midpoints of all the continua were shifted in a manner consistent with compensation when the precursors were filtered, as well as when sounds subsequent to the test sound were filtered and there were no precursors. Also, when filtered precursors were present, the shifts increased when filtering was added to sounds subsequent to the test sound. These results indicate that mechanisms of perceptual compensation for filtering by transmission channels use information in preceding sounds in combination with information in following sounds and that these mechanisms operate between different types of speech sounds.

The effects of medical school curricula, faculty role models, and biomedical research support on choice of generalist physician careers: a review and quality assessment of the literature.

The authors evaluated and reviewed the literature on the effects of medical school curricula, faculty role models, and federal biomedical research support on the specialty choices of U.S. medical students. All 275 articles on these subjects published from 1984 through 1993 were considered. An instrument was developed to assess the quality of the articles. A total of 85 articles met study criteria and were reviewed. The mean score achieved was 42.7% of the total possible points. Major educational reforms emphasizing primary care have resulted in significant increases in the percentages of graduates choosing generalist careers. Except for required clinical training in family practice, individual curriculum components have generally not been successful. Students and physicians often stated that faculty role models influenced specialty choices, and there is some evidence that faculty composition is related to students' career choices. There was a consistent inverse correlation between the amount of federal biomedical research support received and the percentage of a school's graduates choosing generalist careers. It is unknown whether this relationship is causative and, if so, how research funds affect specialty choices. The best strategies to enlarge the proportion of medical students choosing generalist careers include institutional reform to emphasize generalist training, increasing the size of generalist faculty, and requiring clinical training in family practice. The relationship of federal biomedical research support to the specialty choices of medical students needs to be studied further. Research on specialty choice could be improved by including a larger number of schools and students, studying trends over several years, and using validated measures and outcomes, control groups, and multivariate analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Perceptual compensation for speaker differences and for spectral-envelope distortion.

This study asks whether perceptual mechanisms that compensate for the spectral-envelope distortion of transmission channels also contribute to compensation for speaker differences. Subjects identified test words that were played after a carrier sentence. In some conditions the carriers were synthesized with F1 in low- and high-frequency ranges and in others they were distorted by filters whose frequency response is the spectral envelope of one vowel minus the spectral envelope of another. The filter /I/ minus /epsilon/ and its inverse were used. Test words were drawn from an /Itch/ to /epsilon tch/ continuum. Carriers filtered by /I/ minus /epsilon/ and its inverse give a phoneme boundary difference, indicating compensation for spectral envelope distortion. A phoneme boundary difference also occurs between carriers with F1 in low and high ranges, indicating compensation for speaker differences. Neither of these effects is reduced by playing the carrier backwards, even though a measurement of the perceived naturalness of carriers is sharply reduced by this manipulation. Analysis of carriers synthesized with low and high F1 showed that they have different long-term spectra, and subsequent experiments used time-stationary filters to alter this characteristic. The results showed that the long-term spectra of the carriers govern their influence on the identity of subsequent test sounds. However, measurements of perceptual confusions among the carriers and of perceived talker-differences between carriers revealed that other, time-varying factors are more important for voice identification.

Attendance patterns of older adults in a health promotion program.

A group of 224 participants in a health promotion program for older adults had complete baseline data, including demographic information, self-perceived mental and physical health ratings, and measures of socialization and health limitations. Participants were offered exercise sessions 3 times a week, weekly health education classes, and a weekly stress management group. Their attendance at these classes varied from no classes to approximately 750 classes. Initially, participants were divided into the following 5 subgroups: 90 with virtually no attendance, and approximately 30 in each of 4 quartiles of class attendance. The group with the lowest attendance (first quartile) was found to be statistically like the group whose participants never attended any classes; these groups were combined. The Kruskal-Wallis One-Way Analysis of Variance was used to test for significant differences among the four groups on the variables of interest. In a comparison of the four groups from lowest to highest attendance, those participants with lowest attendance had lower incomes (P < .05), tended to live alone (P < .01), and were less likely to be able to climb two flights of stairs or walk a half-mile (P < .01) than those in greater attendance groups. Their socialization behaviors were poorer (P < .01), and their health often limited their activities (P < .05).