Linseed oil and DGAT1 K232A polymorphism: Effects on methane emission, energy and nitrogen metabolism, lactation performance, ruminal fermentation, and rumen microbial composition of Holstein-Friesian cows.

Complex interactions between rumen microbiota, cow genetics, and diet composition may exist. Therefore, the effect of linseed oil, DGAT1 K232A polymorphism (DGAT1), and the interaction between linseed oil and DGAT1 on CH4 and H2 emission, energy and N metabolism, lactation performance, ruminal fermentation, and rumen bacterial and archaeal composition was investigated. Twenty-four lactating Holstein-Friesian cows (i.e., 12 with DGAT1 KK genotype and 12 with DGAT1 AA genotype) were fed 2 diets in a crossover design: a control diet and a linseed oil diet (LSO) with a difference of 22 g/kg of dry matter (DM) in fat content between the 2 diets. Both diets consisted of 40% corn silage, 30% grass silage, and 30% concentrates (DM basis). Apparent digestibility, lactation performance, N and energy balance, and CH4 emission were measured in climate respiration chambers, and rumen fluid samples were collected using the oral stomach tube technique. No linseed oil by DGAT1 interactions were observed for digestibility, milk production and composition, energy and N balance, CH4 and H2 emissions, and rumen volatile fatty acid concentrations. The DGAT1 KK genotype was associated with a lower proportion of polyunsaturated fatty acids in milk fat, and with a higher milk fat and protein content, and proportion of saturated fatty acids in milk fat compared with the DGAT1 AA genotype, whereas the fat- and protein-corrected milk yield was unaffected by DGAT1. Also, DGAT1 did not affect nutrient digestibility, CH4 or H2 emission, ruminal fermentation or ruminal archaeal and bacterial concentrations. Rumen bacterial and archaeal composition was also unaffected in terms of the whole community, whereas at the genus level the relative abundances of some bacterial genera were found to be affected by DGAT1. The DGAT1 KK genotype was associated with a lower metabolizability (i.e., ratio of metabolizable to gross energy intake), and with a tendency for a lower milk N efficiency compared with the DGAT1 AA genotype. The LSO diet tended to decrease CH4 production (g/d) by 8%, and significantly decreased CH4 yield (g/kg of DM intake) by 6% and CH4 intensity (g/kg of fat- and protein-corrected milk) by 11%, but did not affect H2 emission. The LSO diet also decreased ruminal acetate molar proportion, the acetate to propionate ratio, and the archaea to bacteria ratio, whereas ruminal propionate molar proportion and milk N efficiency increased. Ruminal bacterial and archaeal composition tended to be affected by diet in terms of the whole community, with several bacterial genera found to be significantly affected by diet. These results indicate that DGAT1 does not affect enteric CH4 emission and production pathways, but that it does affect traits other than lactation characteristics, including metabolizability, N efficiency, and the relative abundance of Bifidobacterium. Additionally, linseed oil reduces CH4 emission independent of DGAT1 and affects the rumen microbiota and its fermentative activity.

Chronic elevation of plasma cortisol causes differential expression of predominating glucocorticoid in plasma, saliva, fecal, and wool matrices in sheep.

There is increasing interest in using nonblood measures of glucocorticoids to assess the physiological response to chronic stress conditions. In sheep, cortisol has been measured in various matrices including saliva, feces, and wool, but comprehensive studies of the relationship between plasma concentrations of cortisol and concentrations in these nonblood matrices are lacking. Therefore, we tested the hypothesis that administration of cortisol to sheep would result in elevated concentrations of cortisol in blood, saliva, feces, and wool. Merino ewes were administered with saline or 2 mg/kg BW/d hydrocortisone acetate (HCA) by intramuscular (i.m.) injection for 28 d. This treatment was imposed to mimic circulating cortisol concentrations experienced during periods of chronic stress. Cortisol and cortisone were directly measured in plasma, saliva, and wool before, during, and after treatment with saline or HCA. A 14-d pre-treatment and a 14-d post-treatment period were used to measure time taken for glucocorticoid concentrations in each of the matrices to return to baseline levels. Cortisol was also measured in feces before, during, and after treatment. Wool growth was also measured. Before treatment, there was no difference in the concentration of cortisol or cortisone in plasma, saliva, feces, or wool in animals treated with saline or HCA. In contrast, treatment with HCA increased (P < 0.05) concentrations of both cortisol and cortisone in plasma, saliva, and wool and of cortisol in feces. In plasma, cortisol concentrations were higher than cortisone (P < 0.05), whereas saliva cortisol and cortisone concentrations did not differ significantly. In wool, the concentration of cortisone was about 19-fold higher than that of cortisol during treatment and post-treatment periods. Treatment with HCA inhibited wool growth. These results demonstrate that an increase in glucocorticoids in the blood of sheep is reflected in increases in saliva (after 7 d of treatment), feces (21 d), and wool (14 d). Therefore, measures of glucocorticoids in these matrices may provide a measure of activation of the adrenal glands over time in sheep, thereby providing a retrospective indicator of chronic stress. With respect to wool, it appears that cortisol is predominantly metabolized to cortisone in the skin or wool follicle and is stored as cortisone. Therefore wool cortisone may also provide an important measure in quantifiying chronic stress in sheep.

Domesticated equine species and their derived hybrids differ in their fecal microbiota.

BACKGROUND: Compared to horses and ponies, donkeys have increased degradation of dietary fiber. The longer total mean retention time of feed in the donkey gut has been proposed to be the basis of this, because of the increased time available for feed to be acted upon by enzymes and the gut microbiota. However, differences in terms of microbial concentrations and/or community composition in the hindgut may also underpin the increased degradation of fiber in donkeys. Therefore, a study was conducted to assess if differences existed between the fecal microbiota of pony, donkey and hybrids derived from them (i.e. pony × donkey) when fed the same forage diet. RESULTS: Fecal community composition of prokaryotes and anaerobic fungi significantly differed between equine types. The relative abundance of two bacterial genera was significantly higher in donkey compared to both pony and pony x donkey: Lachnoclostridium 10 and 'probable genus 10' from the Lachnospiraceae family. The relative abundance of Piromyces was significantly lower in donkey compared to pony × donkey, with pony not significantly differing from either of the other equine types. In contrast, the uncultivated genus SK3 was only found in donkey (4 of the 8 animals). The number of anaerobic fungal OTUs was also significantly higher in donkey than in the other two equine types, with no significant differences found between pony and pony × donkey. Equine types did not significantly differ with respect to prokaryotic alpha diversity, fecal dry matter content or fecal concentrations of bacteria, archaea and anaerobic fungi. CONCLUSIONS: Donkey fecal microbiota differed from that of both pony and pony × donkey. These differences related to a higher relative abundance and diversity of taxa with known, or speculated, roles in plant material degradation. These findings are consistent with the previously reported increased fiber degradation in donkeys compared to ponies, and suggest that the hindgut microbiota plays a role. This offers novel opportunities for pony and pony × donkey to extract more energy from dietary fiber via microbial mediated strategies. This could potentially decrease the need for energy dense feeds which are a risk factor for gut-mediated disease.

Multi-kingdom characterization of the core equine fecal microbiota based on multiple equine (sub)species.

BACKGROUND: Equine gut microbiology studies to date have primarily focused on horses and ponies, which represent only one of the eight extant equine species. This is despite asses and mules comprising almost half of the world's domesticated equines, and donkeys being superior to horses/ponies in their ability to degrade dietary fiber. Limited attention has also been given to commensal anaerobic fungi and archaea even though anaerobic fungi are potent fiber degrading organisms, the activity of which is enhanced by methanogenic archaea. Therefore, the objective of this study was to broaden the current knowledge of bacterial, anaerobic fungal and archaeal diversity of the equine fecal microbiota to multiple species of equines. Core taxa shared by all the equine fecal samples (n = 70) were determined and an overview given of the microbiota across different equine types (horse, donkey, horse × donkey and zebra). RESULTS: Equine type was associated with differences in both fecal microbial concentrations and community composition. Donkey was generally most distinct from the other equine types, with horse and zebra not differing. Despite this, a common bacterial core of eight OTUs (out of 2070) and 16 genus level groupings (out of 231) was found in all the fecal samples. This bacterial core represented a much larger proportion of the equine fecal microbiota than previously reported, primarily due to the detection of predominant core taxa belonging to the phyla Kiritimatiellaeota (formerly Verrucomicrobia subdivision 5) and Spirochaetes. The majority of the core bacterial taxa lack cultured representation. Archaea and anaerobic fungi were present in all animals, however, no core taxon was detected for either despite several taxa being prevalent and predominant. CONCLUSIONS: Whilst differences were observed between equine types, a core fecal microbiota existed across all the equines. This core was composed primarily of a few predominant bacterial taxa, the majority of which are novel and lack cultured representation. The lack of microbial cultures representing the predominant taxa needs to be addressed, as their availability is essential to gain fundamental knowledge of the microbial functions that underpin the equine hindgut ecosystem.

Adaptation to flavomycin in the ruminal bacterium, Prevotella bryantii.

AIMS: The recent EU ban of growth-promoting antibiotics in animal production was based on fears concerning antibiotic resistance being transmitted to human pathogens. This paper explores the adaptation mechanism of a common ruminal bacterium, Prevotella bryantii, to one of the banned compounds, flavomycin (flavophospholipol). METHODS AND RESULTS: Growth in the presence of flavomycin (2 and 20 microg ml(-1)) was characterized by a concentration-dependent increase in the length of the lag phase, which decreased after previous flavomycin exposure. From growth patterns on solid medium, decreased sensitivity appeared to be due to a whole-population adaptation. Proteomic analysis indicated upregulation of three native proteins occurred following flavomycin adaptation. Further analysis of two of these proteins resulted in no database matches, suggesting that they may be species-specific. Flavomycin adaptation also resulted in co-adaptation to bacitracin and vancomycin. CONCLUSIONS: Adaptation of P. bryantii to flavomycin, which also resulted in co-adaptation to bacitracin and vancomycin, may involve an increased availability of undecaprenyl pyrophosphate. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of flavomycin, and similar growth-promoting antibiotics, in animal production may prompt adaptive responses in ruminal bacteria which can significantly change their antibiotic sensitivity.

Specificity and sensitivity of eubacterial primers utilized for molecular profiling of bacteria within complex microbial ecosystems.

Efficient profiling of eubacterial diversity within complex communities requires that primers are specific for eubacterial 16S rRNA. Specificity of published primers against eubacterial and archaeal 16S rRNA as well as protozoal and fungal 18S rRNA was assessed in silico. The specificity and sensitivity of the V3 and V6-V8 (F968gc and R1401) Denaturing Gradient Gel Electrophoresis (DGGE) primers was subsequently verified using rumen-derived samples. An assessment of the effects of employing touchdown PCR cycling conditions was also made. For DGGE profiling of eubacteria within rumen samples, primers F968gc and R1401 proved the most specific and sensitive providing that touchdown PCR is not used.

Genetic parameters for wool traits, live weight, and ultrasound carcass traits in Merino sheep.

Genetic correlations between 29 wool production and quality traits and live weight and ultrasound fat depth (FAT) and eye muscle depth (EMD) traits were estimated from the Information Nucleus (IN). The IN comprised 8 genetically linked flocks managed across a range of Australian sheep production environments. The data were from a maximum of 9,135 progeny born over 5 yr from 184 Merino sires and 4,614 Merino dams. The wool traits included records for yearling and adult fleece weight, fiber diameter (FD), staple length (SL), fiber diameter CV (FDCV), scoured color, and visual scores for breech and body wrinkle. We found high heritability for the major yearling wool production traits and some wool quality traits, whereas other wool quality traits, wool color, and visual traits were moderately heritable. The estimates of heritability for live weight generally increased with age as maternal effects declined. Estimates of heritability for the ultrasound traits were also higher when measured at yearling age rather than at postweaning age. The genetic correlations for fleece weight with live weights were positive (favorable) and moderate (approximately 0.5 ± 0.1), whereas those with FD were approximately 0.3 (unfavorable). The other wool traits had lower genetic correlations with the live weights. The genetic correlations for FAT and EMD with FD and SL were positive and low, with FDCV low to moderate negative, but variable with wool weight and negligible for the other wool traits. The genetic correlations for FAT and EMD with postweaning weight were positive and high (0.61 ± 0.18 to 0.75 ± 0.14) but were generally moderate with weights at other ages. Selection for increased live weight will result in a moderate correlated increase in wool weight as well as favorable reductions in breech cover and wrinkle, along with some unfavorable increases in FD and wool yellowness but little impact on other wool traits. The ultrasound meat traits, FAT and EMD, were highly positively genetically correlated (0.8), and selection to increase them would result in a small unfavorable correlated increase in FD, moderately favorable reductions in breech cover and wrinkle, but equivocal or negligible changes in other wool traits. The estimated parameters provide the basis for calculation of more accurate Australian Sheep Breeding Values and selection indexes that combine wool and meat objectives in Merino breeding programs.

Genetic correlations between wool traits and carcass traits in Merino sheep.

Genetic correlations between 29 wool production and quality traits and 14 whole carcass measures and carcass component traits were estimated from the Information Nucleus of 8 flocks managed across a range of Australian sheep production environments and genetically linked. Wool data were from over 5,000 Merino progeny born over 5 yr, whereas carcass data were from over 1,200 wether progeny of over 176 sires, slaughtered at about 21 kg carcass weight, on average. Wool traits included yearling and adult records for wool weight, fiber diameter, fiber diameter variation, staple strength, scoured color, and visual scores for breech and body wrinkle. Whole carcass measures included HCW, dressing percentage (DP), and various measures of fat depth and eye muscle dimensions. Carcass components were obtained by dissection, and lean meat yield (LMY) was predicted. Heritability estimates for whole carcass measures ranged from 0.12 ± 0.08 to 0.35 ± 0.10 and ranged from 0.17 ± 0.10 to 0.46 ± 0.10 for carcass dissection traits, with no evidence of important genotype × environment interactions. Genetic correlations indicated that selection for increased clean wool weight will result in reduced carcass fat (-0.17 to -0.34) and DP (-0.48 ± 0.15), with little effect on carcass muscle. Selection for lower fiber diameter will reduce HCW (-0.48 ± 0.15) as well as carcass fat (0.14 to 0.27) and muscle (0.21 to 0.50). There were high genetic correlations between live animal measures of fat and muscle depth and the carcass traits (generally greater than 0.5 in size). Selection to increase HCW (and DP) will result in sheep with fewer wrinkles on the body (-0.57 ± 0.10) and barer breeches (-0.74 ± 0.12, favorable), with minor deterioration in scoured wool color (reduced brightness and increased yellowness). Selection for reduced fat will also result in sheep with fewer body wrinkles (-0.42 to -0.79). Increasing LMY in Merinos through selection would result in a large reduction in carcass fat and DP (-0.66 to -0.84), with a smaller increase in carcass muscle and some increase in wool weight and wrinkles. Although no major antagonisms are apparent between the wool and carcass traits, developing selection indexes for dual-purpose wool and meat breeding objectives will require accurate estimates of genetic parameters to ensure that unfavorable relationships are suitably considered. The findings will aid development of dual-purpose wool and meat breeding objectives.

Genetic correlations between wool traits and meat quality traits in Merino sheep.

Genetic correlations between 29 wool production and quality traits and 25 meat quality and nutritional value traits were estimated for Merino sheep from an Information Nucleus (IN). Genetic correlations among the meat quality and nutritional value traits are also reported. The IN comprised 8 flocks linked genetically and managed across a range of sheep production environments in Australia. The wool traits included over 5,000 yearling and 3,700 adult records for fleece weight, fiber diameter, staple length, staple strength, fiber diameter variation, scoured wool color, and visual scores for breech and body wrinkle. The meat quality traits were measured on samples from the and included over 1,200 records from progeny of over 170 sires for intramuscular fat (IMF), shear force of meat aged for 5 d (SF5), 24 h postmortem pH (pHLL; also measured in the , pHST), fresh and retail meat color and meat nutritional value traits such as iron and zinc levels, and long-chain omega-3 and omega-6 polyunsaturated fatty acid levels. Estimated heritabilities for IMF, SF5, pHLL, pHST, retail meat color lightness (), myoglobin, iron, zinc and across the range of long-chain fatty acids were 0.58 ± 0.11, 0.10 ± 0.09, 0.15 ± 0.07, 0.20 ± 0.10, 0.59 ± 0.15, 0.31 ± 0.09, 0.20 ± 0.09, 0.11 ± 0.09, and range of 0.00 (eicosapentaenoic, docosapentaenoic, and arachidonic acids) to 0.14 ± 0.07 (linoleic acid), respectively. The genetic correlations between the wool production and meat quality traits were low to negligible and indicate that wool breeding programs will have little or no effect on meat quality. There were moderately favorable genetic correlations between important yearling wool production traits and the omega-3 fatty acids that were reduced for corresponding adult wool production traits, but these correlations are unlikely to be important in wool/meat breeding programs because they have high SE, and the omega-3 traits have little or no genetic variance. Significant genetic correlations among the meat quality traits included IMF with SF5 (-0.76 ± 0.24), fresh meat color * (0.50 ± 0.18), and zinc (0.41 ± 0.19). Selection to increase IMF will improve meat tenderness and color which may address some of the issues with Merino meat quality. These estimated parameters allow Merino breeders to combine wool and meat objectives without compromising meat quality.

Pre-slaughter stress arising from on-farm handling and its interactions with electrical stimulation on tenderness of lambs.

The effect of electrical stimulation of lamb carcasses (n=269) or its absence (n=257) on shear force of m. longissimus thoracis et lumborum (LT) was monitored during ageing in pasture-fed merino lambs (n=526). The lambs were slaughtered on four different days allowing durations of between one to 10 days of recovery from pre-slaughter handling (yarding, weighing and crutching) that affected ultimate pH (pH(u)). The right LT was removed 20-40min post-slaughter, tightly-wrapped in cling film (prevents the muscle cross-section increasing and thus minimising shortening) and rapidly cooled to 15°C to enter rigor mortis and age. At 0, 4, 24 and 72h post-slaughter, pH measurements and samples for shear force measurement were taken. Pre-slaughter handling had a significant negative effect on pH(u) and several days recovery were required for pH(u) to reach values associated with optimal meat quality as reflected by pH(u). Lambs with one and three days recovery (no significant difference between them) had a pH(u)>5.7 in 50% of the muscles and 19.4%>pH(u) 5.8. Whereas, in lambs with 8-10 days recovery (no significant difference between them), only 8% had a pH(u)>5.7 and 3.1%>pH(u) 5.8. Within each slaughter day electrically stimulated lambs were always more tender than non-stimulated lambs. For non-stimulated muscles at 72h, shear force values >40N occurred for 11.2% of the muscles: for electrically stimulated muscles at 72h, shear force values >40N occurred for 1.9% of the muscles. The rates of tenderisation were slower for intermediate pH(u) values resulting in higher shear force values at all ageing durations. With ageing at 72h for intermediate pH(u), non-stimulated muscles (n=38) 17.64% were >40N and for stimulated muscles (n=34), 7.9% were >40N.

Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage.

Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4-, 8-, and 13-fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1-, 1.5-, and 1.7-fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2-fold).

Congenital anomalies involving the coronary sinus.

A classification is presented of anomalies involving the coronary sinus. These anomalies are classified into four anatomic groups on the basis of (1) enlargement of the coronary sinus, (2) absence of the coronary sinus, (3) atresia of the right atrial coronary sinus ostium, and (4) hypoplasia of the coronary sinus. Anomalies involving the coronary sinus often are associated with other venous anomalies, either of the systemic or the pulmonary circulation. In some there is no basic disturbance of the circulation. Those conditions involving the coronary sinus which are of major functional significance participate in shunts, either left-to-right or right-to-left in nature. Enlargement of the coronary sinus in the absence of a shunt usually indicates that a systemic venous channel joins the coronary sinus anomalously.

Floppy mitral valve and ventricular septal defect: an anatomic study.

Eighteen percent of heart specimens with isolated ventricular septal defect also had a floppy mitral valve. There was no statistical difference in the incidence of floppy mitral valve in the three age groups considered (less than 1 year, 1 to 16 years and 17 to 91 years). In no patient was a floppy mitral valve considered to be the cause of death. Complications of floppy mitral valve (ruptured chordae tendineae, bacterial endocarditis, mitral regurgitation and fibrin deposits at the mitral valve-left atrial angle) occurred at approximately the same frequency as that reported in autopsy studies of isolated floppy mitral valve. In the specimens with floppy mitral valve and ventricular septal defect, 63% also had floppiness of the tricuspid valve, 16% of the pulmonary valve and 5% of the aortic valve. The anatomic basis for floppy mitral valve was considered to be spongiosal invasion and disruption of the fibrosa of the valve leaflet. In this study, spongiosal invasion of the fibrosa was fully developed by 3 months of age and there was no evidence that the incidence or severity of spongiosal invasion increased between the ages of 3 months and 88 years. These data suggest that the floppy mitral valve is a congenital lesion that reaches full anatomic expression in infancy. No evidence was found that ventricular septal defect and floppy mitral valve share a common etiology.

Calcified aortic sinotubular ridge: a source of coronary ostial stenosis or embolism.

This report reviews the findings in a calcified lesion involving the ridge at the junction of the sinus and tubular portions of the ascending aorta. The histologic features resemble the alterations in calcified aortic valve and do not exhibit those of atherosclerosis. The 37 cataloged cases are among the more severe and dramatic instances of a lesion more common than the cataloged number would suggest. The involved ridge may be related to any of the sinuses, although that related to the right aortic sinus is most commonly affected. Major complications include coronary ostial stenosis or embolism in an epicardial coronary artery. Ostial stenosis results either from overhanging of an ostium by the aortic lesion or from invasion of the wall of the aorta at the site of the arterial takeoff.

The disease-free wall in coronary atherosclerosis: its relation to degree of obstruction.

Coronary atherosclerotic lesions are more often located eccentrically (70%) than concentrically (30%). In this study, the configuration of eccentric coronary artery atherosclerotic lesions was assessed by means of computerized planimetry in 100 specimens of eccentric arterial lesions. Special attention was given to the relation between the disease-free wall and the severity of obstruction. The mean disease-free wall are length measured between 17 and 23% of the total vessel circumference in eccentric coronary artery lesions that obstructed 50 to 90% of the cross-sectional area. This ratio persisted irrespective of the location of the lesion within the vessel and was not significantly different with vessels of different sizes. The presence of disease-free arcs of coronary artery wall as observed in this pathologic study may relate to three factors in clinical coronary artery disease: The published observations of spasm in segments of arteries harboring structural obstructive lesions may be explained by the frequent presence of uninvolved arcs of coronary artery walls. Multiple views during coronary arteriography are necessary to accurately reflect the degree of obstruction. The results of percutaneous transluminal coronary angioplasty may be influenced by both the disease-free arc and the atheromatous obstruction.

Coexistent pulmonary and portal hypertension: morphologic and clinical features.

Patients with portal hypertension of varying etiology may develop pulmonary artery hypertension. In the present autopsy study, pulmonary and hepatic tissue was studied in 12 patients in whom pulmonary and portal hypertension coexisted. Plexogenic pulmonary arteriopathy was present in 10 patients, 7 of whom had coexistent thromboembolic lesions. One patient had isolated medial hypertrophy, which may be an early stage in the plexogenic category, whereas isolated thromboembolic pulmonary vascular disease was observed in one subject. Hepatic disease was consistent with alcoholic cirrhosis in seven patients, cryptogenic cirrhosis in four and extrahepatic portal hypertension without cirrhosis in one. Thrombocytopenia was present in all 10 patients whose platelet count was determined. This study suggests that pulmonary hypertension associated with portal hypertension commonly has a plexogenic appearance on histologic examination. However, thrombosis (whether embolic or in situ) may also contribute to vascular obstruction.

Predictive value of lung biopsy in ventricular septal defect: long-term follow-up.

Although the Heath-Edwards classification has been used for more than 25 years to evaluate pulmonary vascular changes, its potential to predict the long-term course after successful ventricular septal defect closure has not been proved. Operative lung biopsy slides obtained at the time of closure from 57 infants and children who had been among the first survivors (between 1954 and 1960) of such surgery were graded in blinded fashion according to the Heath-Edwards classification system, and the resultant biopsy grade of each was compared with the eventual long-term outcome of each child. In 53 (93%) of the 57 cases, the Heath-Edwards system correlated well with long-term clinical or hemodynamic status of the patient. Grade IV changes were predictive of a usually fatal outcome, while grade I and II changes were generally benign. Death from pulmonary vascular disease occurred, however, in four children whose operative lung biopsy had been classified as either grade I or II, indicating that the focal nature of the higher Heath-Edwards grades, or human error, must be considered when this classification system is employed.

Pulmonary circulation in pulmonary atresia associated with the asplenia cardiac syndrome.

OBJECTIVE: The goal of this study was to determine the patterns of the pulmonary circulation in patients with pulmonary atresia and asplenia. BACKGROUND: The asplenic cardiac syndromes characteristically have complex cardiac anomalies including pulmonary stenosis or atresia. Definition of the pulmonary artery circulation and pulmonary venous connections is needed for consideration of surgical procedures. METHODS: In 35 patients, the sources of pulmonary blood flow, anatomic features of pulmonary arteries and pulmonary venous connections were determined from angiograms or autopsy specimens. RESULTS: The main pulmonary artery was absent or hypoplastic in 91% of patients; most had a ductus arteriosus. The right and left pulmonary arteries were confluent in 90% and usually of normal size (right 71%, left 63%). Total anomalous pulmonary venous connections were present in 38%. CONCLUSIONS: The anatomic features of the pulmonary arteries in pulmonary atresia associated with the asplenic cardiac syndrome are usually favorable for palliative surgical procedures. Total anomalous pulmonary venous connection may exist as a complicating factor.

Acute pain: individual patient meta-analysis shows the impact of different ways of analysing and presenting results.

Individual patient meta-analysis using information from clinically homogeneous acute pain trials with observations over 24h was used to investigate different ways trials can be analysed and reported. There were 13 third-molar extraction trials, with 1,330 patients using rofecoxib 50mg, 303 using ibuprofen 400mg, and 570 using placebo. Pain relief scores were available at individual time points, plus time to remedication. Many more patients remedicated with placebo than ibuprofen 400mg, and more with ibuprofen than rofecoxib 50mg. Median time to remedication, the proportion remedicated at various times, or survival curves would be useful outcomes. In dealing with missing data points when patients remedicated, baseline observation carried forward was more conservative than last observation carried forward, resulting in higher (worse) NNTs and lower average pain scores after 12 and 24h. Results based on both methods might be sensible for trials longer than eight hours. The distribution of pain relief was highly skewed, especially at later times, when almost no patient was average. Different cut points for pain relief (at least 25, 50 or 75% maxTOTPAR) and longer duration changed the NNT for ibuprofen compared with placebo, but less for rofecoxib, reflecting longer duration of action of rofecoxib. Reporting for each treatment group the percentage of patients with 25, 50 and 75% pain relief at various times after dose, and reporting the proportion of patients with good or complete pain relief, and inadequate pain relief, at each time point, would improve acute pain trial reporting.

Gabapentin for acute and chronic pain.

BACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for chronic neuropathic pain, especially when the pain is lancinating or burning. OBJECTIVES: To evaluate the analgesic effectiveness and adverse effects of gabapentin for pain management in clinical practice. SEARCH STRATEGY: Randomised trials of gabapentin in acute, chronic or cancer pain were identified by MEDLINE (1966-Nov 2004), EMBASE (1994-Nov 2004), SIGLE (1980-Jan 2004) and the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 4, 2004). Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. Date of most recent search: January 2004. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of gabapentin in patients, with subjective pain assessment as either the primary or a secondary outcome. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated, where possible, from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal. MAIN RESULTS: Fourteen reports describing 15 studies of gabapentin were considered eligible (1468 participants). One was a study of acute pain. The remainder included the following conditions: post-herpetic neuralgia (two studies), diabetic neuropathy (seven studies), a cancer related neuropathic pain (one study) phantom limb pain (one study), Guillain Barré syndrome (one study) , spinal chord injury pain (one study) and various neuropathic pains (one study). The study in acute post-operative pain (70 participants) showed no benefit for gabapentin compared to placebo for pain at rest. In chronic pain, the NNT for improvement in all trials with evaluable data is 4.3 (95%CI 3.5-5.7). Forty two percent of participants improved on gabapentin compared to 19% on placebo. The number needed to harm(NNH) for adverse events leading to withdrawal from a trial was not significant. Fourteen percent of participants withdrew from active arms compared to 10% in placebo arms. The NNH for minor harm was 3.7 (95% CI 2.4 to 5.4). The NNT for effective pain relief in diabetic neuropathy was 2.9 (95% CI 2.2 to 4.3) and for post herpetic neuralgia 3.9 (95% CI 3 to 5.7). AUTHORS' CONCLUSIONS: There is evidence to show that gabapentin is effective in neuropathic pain. There is limited evidence to show that gabapentin is ineffective in acute pain.