Muscle-specific, liver-detargeted adeno-associated virus gene therapy rescues Pompe phenotype in adult and neonate Gaa-/- mice.

Pompe disease (PD) is a neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency. Reduced GAA activity leads to pathological glycogen accumulation in cardiac and skeletal muscles responsible for severe heart impairment, respiratory defects, and muscle weakness. Enzyme replacement therapy with recombinant human GAA (rhGAA) is the standard-of-care treatment for PD, however, its efficacy is limited due to poor uptake in muscle and the development of an immune response. Multiple clinical trials are ongoing in PD with adeno-associated virus (AAV) vectors based on liver- and muscle-targeting. Current gene therapy approaches are limited by liver proliferation, poor muscle targeting, and the potential immune response to the hGAA transgene. To generate a treatment tailored to infantile-onset PD, we took advantage of a novel AAV capsid able to increase skeletal muscle targeting compared to AAV9 while reducing liver overload. When combined with a liver-muscle tandem promoter (LiMP), and despite the extensive liver-detargeting, this vector had a limited immune response to the hGAA transgene. This combination of capsid and promoter with improved muscle expression and specificity allowed for glycogen clearance in cardiac and skeletal muscles of Gaa-/- adult mice. In neonate Gaa-/- , complete rescue of glycogen content and muscle strength was observed 6 months after AAV vector injection. Our work highlights the importance of residual liver expression to control the immune response toward a potentially immunogenic transgene expressed in muscle. In conclusion, the demonstration of the efficacy of a muscle-specific AAV capsid-promoter combination for the full rescue of PD manifestation in both neonate and adult Gaa-/- provides a potential therapeutic avenue for the infantile-onset form of this devastating disease.

Prospective study comparing the conventional and same-day strategies to diagnose pulmonary tuberculosis.

OBJECTIVE: The WHO recommends same-day sputum smear microscopy for the diagnosis of smear-positive tuberculosis (TB) in countries with high TB burden for earlier diagnosis and treatment, a cornerstone to prevent air-borne transmission. We aimed to compare the conventional strategy (sputum collection on three consecutive days) and the same-day strategy (hour h, h+1, h+2) in France, a country with low TB burden. PATIENTS AND METHODS: Over a six-month period, all adult individuals presenting with presumptive smear-positive TB were eligible for the study, registered in https://clinicaltrials.gov/ ID (NCT02961569). Sputum specimens were collected three times the first day, then once on the second day and once on the third day. The concordance between the two strategies regarding smears and cultures were assessed. RESULTS: Of the 131 eligible individuals, 34 were given a TB treatment. Smears from hour h, h+1, h+2, day two and three were negative in 19 of these 34 patients. Positive smears were obtained in 15, 14, 15, 14, and 14 patients at hour h, h+1, h+2, on day two and three, respectively. Concordance regarding smear or culture was good, with Kappa 0.69 and 0.64, respectively. CONCLUSION: The same-day strategy seems to be a good alternative to the conventional strategy.

Does region of origin influence the timing and outcome of first-line antiretroviral therapy in France?

OBJECTIVES: The aim of the study was to assess whether the timing of combination antiretroviral therapy (cART) initiation, the choice of cART and virological response differ in migrants versus European natives in the north and east of Paris area, after dissemination of French recommendations for universal treatment. METHODS: Antiretroviral therapy-naïve HIV-1-infected adults with at least two follow-up visits at one of 15 participating centres between 1 January 2014 and 31 March 2015 were included in the study. Factors associated with cART initiation before 31 March 2015, with protease inhibitor (PI)-containing cART among individuals initiating cART, and with 1-year virological success after cART initiation were assessed using multivariable logistic regression models. Sex, age, region of origin [Western Europe, sub-Saharan Africa (SSA) or other], HIV transmission group, baseline AIDS status, CD4 cell count and plasma viral load (VL), and hepatitis B and/or C virus infection were considered in the analyses. RESULTS: Among 912 individuals, only 584 (64%) started cART during the study period. After adjustment, migrants from SSA were half as likely to initiate cART and to have a subsequent virological response compared with individuals from Western Europe [adjusted odds ratio (aOR) 0.54; 95% confidence interval (CI) 0.36-0.82; and aOR 0.52; 95% CI 0.28-0.98, respectively]. PI-containing cART was more frequently prescribed in migrants from SSA, in people with lower CD4 cell counts and in people with higher VL. CONCLUSIONS: Even in the context of universal cART recommendations and of free access to care, migrants from SSA still have delayed access to cART and a lower virological response. Efforts are still necessary to provide immediate cART to all people living with HIV.

What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.

BACKGROUND: We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background. METHODS: HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined. FINDINGS: Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles. INTERPRETATION: This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection.

Disrupted trabecular bone micro-architecture in middle-aged male HIV-infected treated patients.

OBJECTIVES: HIV-infected individuals are at increased risk of incident fractures. Evaluation of trabecular bone micro-architecture is an important tool to assess bone strength, but its use has not yet been reported in middle-aged HIV-infected male individuals. The aim of the study was to compare bone micro-architecture between HIV-infected and HIV-uninfected men. METHODS: In this cross-sectional study, 53 HIV-infected male individuals with a mean (± standard deviation) age of 49 ± 9 years who had been receiving antiretroviral therapy including tenofovir disoproxil fumarate (DF) for at least 60 months were compared with 50 HIV-uninfected male controls, matched for age and ethnic origin. We studied the volumetric bone density and micro-architecture of the radius and tibia using high-resolution peripheral quantitative computed tomography (HR-p QCT). RESULTS: Volumetric trabecular bone density was 17% lower in the tibia (P < 10(-4) ) and 16% lower in the radius (P < 10(-3) ) in HIV-infected patients compared with controls. By contrast, the cortical bone density was normal at both sites. The tibial trabecular micro-architecture differed markedly between patients and controls: bone volume/total volume (BV/TV) and trabecular number were each 13% lower (P < 10(-4) for both). Trabecular separation and inhomogeneity of the network were 18% and 24% higher in HIV-infected patients than in controls, respectively. The radial BV/TV and trabecular thickness were each 13% lower (P < 10(-3) and 10(-2) , respectively). Cortical thickness was not different between the two groups. CONCLUSIONS: The findings of lower volumetric trabecular bone density and disrupted trabecular micro-architectural parameters in middle-aged male HIV-infected treated patients help to explain bone frailty in these patients.

[Prevalence of granulomatous lesions in minor salivary gland biopsy in a case series of 65 patients with tuberculosis]. / Étude de la prévalence des granulomes à la biopsie des glandes salivaires accessoires chez 65 patients atteints de tuberculose.

PURPOSE: The distinction between tuberculosis (TB), a worldwide infectious granulomatosis requiring specific antibiotic therapy, and sarcoidosis, a rare granulomatous disease that may require corticosteroids is not straightforward and may result in diagnostic and therapeutic delay. METHODS: We prospectively and consecutively evaluated the presence of epithelioid granulomas in minor salivary gland biopsy of 65 consecutive patients with TB. RESULTS: In our study, 10.8 % of our TB patients had epithelioid granulomas without caseous necrosis identified in their minor salivary gland biopsy, regardless of the location of TB, HIV status and whether or not the sputum examination was positive for tuberculous bacilli. CONCLUSION: The presence of epithelioid granulomas in minor salivary gland biopsy may not be helpful to the clinician to rule out TB in a patient with suspected sarcoidosis.

C1 inhibitor function using contact-phase proteases as target: evaluation of an innovative assay.

BACKGROUND: Controlling prekallikrein activation by C1 inhibitor (C1Inh) represents the most essential mechanism for angioedema patient protection. C1Inh function in the plasma is usually measured based on the residual activity of the C1s protease not involved in the pathological process. We have hereby proposed an alternative enzymatic measurement of C1Inh function based on contact-phase activation and correlation with angioedema diagnostic requirements. METHODS: The contact phase was reconstituted using the purified components, with C1Inh standard or plasma sample. The kinetics of the amidase activity were monitored using Pro-Phe-Arg-pNA, independently of alpha2-macroglobulin. We prevented any interference from a possible high plasma kininogenase activity by preincubating the samples with protease inhibitor. Receiver operating characteristics (ROC) were used to calculate the assay's diagnostic performance. RESULTS: The calibration curve was built using C1Inh standard (threshold limit 0.10 × 10(-3) U, i.e., 0.2 pmol), and C1Inh function was quantified in the sample, with a reference interval established based on healthy individuals (n = 281; men: 0.61-1.10 U/ml, median: 0.85 U/ml; women: 0.42-1.08 U/ml, median: 0.74 U/ml). The median values of female donors were lower than those of the others due to estrogen, yet C1Inh function remained within the reference interval. The ROC curve calculation provided the following optimum diagnostic cutoff values: women 0.36 U/ml (area under curve [AUC]: 0.99; sensitivity: 93.48%; specificity: 99.37%); and men 0.61 U/ml (AUC: 1; sensitivity: 100.0%; specificity: 100.0%). CONCLUSION: The performance outcome provided features suitable for angioedema diagnostic or follow-up. Established by means of the kinin formation process, this assay should be preferred over the method based on a C1s protease target.

Phenotypic and genetic relationships between growth and feed intake curves and feed efficiency and amino acid requirements in the growing pig.

Improvement of feed efficiency in pigs has been achieved essentially by increasing lean growth rate, which resulted in lower feed intake (FI). The objective was to evaluate the impact of strategies for improving feed efficiency on the dynamics of FI and growth in growing pigs to revisit nutrient recommendations and strategies for feed efficiency improvement. In 2010, three BWs, at 35±2, 63±9 and 107±7 kg, and daily FI during this period were recorded in three French test stations on 379 Large White and 327 French Landrace from maternal pig populations and 215 Large White from a sire population. Individual growth and FI model parameters were obtained with the InraPorc® software and individual nutrient requirements were computed. The model parameters were explored according to feed efficiency as measured by residual feed intake (RFI) or feed conversion ratio (FCR). Animals were separated in groups of better feed efficiency (RFI- or FCR-), medium feed efficiency and poor feed efficiency. Second, genetic relationships between feed efficiency and model parameters were estimated. Despite similar average daily gains (ADG) during the test for all RFI groups, RFI- pigs had a lower initial growth rate and a higher final growth rate compared with other pigs. The same initial growth rate was found for all FCR groups, but FCR- pigs had significantly higher final growth rates than other pigs, resulting in significantly different ADG. Dynamic of FI also differed between RFI or FCR groups. The calculated digestible lysine requirements, expressed in g/MJ net energy (NE), showed the same trends for RFI or FCR groups: the average requirements for the 25% most efficient animals were 13% higher than that of the 25% least efficient animals during the whole test, reaching 0.90 to 0.95 g/MJ NE at the beginning of the test, which is slightly greater than usual feed recommendations for growing pigs. Model parameters were moderately heritable (0.30±0.13 to 0.56±0.13), except for the precocity of growth (0.06±0.08). The parameter representing the quantity of feed at 50 kg BW showed a relatively high genetic correlation with RFI (0.49±0.14), and average protein deposition between 35 and 110 kg had the highest correlation with FCR (-0.76±0.08). Thus, growth and FI dynamics may be envisaged as breeding tools to improve feed efficiency. Furthermore, improvement of feed efficiency should be envisaged jointly with new feeding strategies.

Divergent selection for residual feed intake in group-housed growing pigs: characteristics of physical and behavioural activity according to line and sex.

The aim of the study was to assess the impact of selection for residual feed intake (RFI) on the behavioural activity of lines divergently selected for RFI during seven generations. In all, six successive batches from the seventh generation of selection were raised in collective pens equipped with a single-place electronic feeder (SEF) from 10 weeks of age to 100 kg BW. Each batch included four groups of 12 pigs: high RFI (RFI+) castrated males, RFI+ females, low RFI (RFI-) castrated males, RFI- females. At 17 weeks of age, health criteria were evaluated using a gradient scale for increased severity of lameness, body lesions, bursae and tail biting. Individual behavioural activities were recorded by 24-h video tape on the day after health evaluation. The investigative motivation towards unfamiliar objects was quantified at 18 weeks of age. The daily individual feeding patterns were computed from SEF records during the 4 weeks surrounding 12, 17 and 22 weeks of age. All pigs spent significantly most of their time lying in diurnal (80% of total scan) and nocturnal (>89%) periods. The RFI- pigs showed a lower proportion of health problems (P<0.01) than RFI+ pigs. The RFI- pigs used the SEF less than the RFI+ pigs, in diurnal (5.3% v. 6.4% of video scans, P<0.05) and nocturnal periods (3.6% v. 4.5% of video scans, P<0.05). This was confirmed by a significantly lower daily number and duration of visits to the SEF computed from the SEF data. The feeding activity measured from the video recording was significantly correlated (R>0.34; P<0.05) with feeding patterns computed from the SEF. The RFI- pigs spent less time standing over the 24-h period (9.7% v. 12.2% of scans, i.e. 35 min/day, P<0.05). In terms of energy costs, this amounted to 14% of the line difference in terms of daily metabolizable energy intake. The castrated males used the SEF more than females, especially at night (4.7% v. 3.4% of total scans, P<0.05), whereas females displayed greater investigation of their environment (7.7±0.3% v. 6.6±0.2% of total scans, P<0.05) and the novel objects (10.7% v. 4.9% of total scans, P<0.05). In conclusion, the lower physical activity associated with reduced energy expenditure in RFI- pigs compared with RFI+ pigs contributed significantly to their improved efficiency and was not related to worsened health scores.

Genetics of residual feed intake in growing pigs: Relationships with production traits, and nitrogen and phosphorus excretion traits.

Residual feed intake (RFI) is defined as the difference between the observed ADFI and the ADFI predicted from production and maintenance requirements. The objectives of this study were to evaluate RFI as a selection criterion to improve feed efficiency and its potential to reduce N and P excretion in 4 pig breeds. Data were collected between 2000 and 2009 in French central test stations for 2 dam breeds [French Landrace (LR) and Large White (LWD)], and 2 sire breeds [Large White (LWS) and Piétrain (PP)]. Numbers of recorded pigs were 6407, 10,694, 2342, and 2448 for the LR, LWD, LWS, and PP breeds, respectively. All PP animals were genotyped for the halothane mutation. This data set was used to calculate RFI equations for each of the 4 breeds, and to estimate genetic parameters for RFI together with growth, carcass, and meat quality traits, and N and P excretion during the test period (35 to 110 kg BW). The RFI explained 20.1% in PP, 26.5% in LWS, 27.6% in LWD, and 29.5% in LR of the phenotypic variability of ADFI. The PP breed differed from the others in this respect, probably due to a lower impact of the variation of body composition on ADFI. Heritability estimates of RFI ranged from 0.21 ± 0.03 (LWD) to 0.33 ± 0.06 (PP) depending on the breed. Heritabilities of N and P excretion traits ranged from 0.29 ± 0.06 to 0.40 ± 0.06. The RFI showed positive genetic correlations with feed conversion ratio (FCR) and excretion traits, these correlations being greater in the sire breeds (from 0.57 to 0.86) than in the dam breeds (from 0.38 to 0.53). Compared with FCR, RFI had weaker genetic correlations with carcass composition, growth rate, and excretion traits. Estimates of genetic correlations between FCR and excretion traits were very close to 1 for all breeds. Finally, excretion traits were, at the genetic level, correlated positively with ADFI, negatively with growth rate and carcass leanness, whereas the halothane n mutation in PP was shown to reduce N and P excretion levels. To conclude, new selection indexes including RFI can be envisaged to efficiently disentangle the responses to selection on growth rate and body composition from those on feed efficiency, with favorable impacts on N and P excretions, particularly in sire pig breeds. However, the switch from FCR to RFI in selection indexes should not resolve the genetic antagonism between feed efficiency and meat quality.

Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score.

OBJECTIVES: Previous studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals. METHODS: We analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores. Patients were evaluated with a short neuropsychological battery. Using linear regression, we examined the relationship between results of cognitive tests and CPE scores in all patients. RESULTS: Patients were divided into three similarly sized groups (CPE ≤ 1, CPE between 1.5 and 2.5, and CPE ≥ 2.5). We found that ART with high CPE scores was associated with poorer executive performances in HIV-1-infected patients. CONCLUSION: These results suggest that cognitive performance in treated HIV-infected patients could be influenced by ART.

BK-virus infections: a literature review.

BK-virus is a very common polyomavirus in the global population, similar to the JC-virus responsible for Progressive Multifocal Leukoencephalopathy. BK-virus infections are an important diagnostic and therapeutic challenge in immuno-compromised patients, including: bone marrow transplant pediatric recipients in whom it may cause hemorrhagic cystitis, renal transplant recipients in whom it may cause interstitial nephropathy leading to graft loss, and in HIV infected patients in whom it may cause some types of encephalitis. Indeed, this poorly documented virus is responsible for infections with various clinical profiles, probably under-diagnosed, but could also be involved in the genesis of some cancers, especially cervix and prostate cancer. We reviewed the latest published data on this virus focusing on its possible pro-oncogenic properties. We also listed the diseases in which it is involved, with an emphasis on rare and insufficiently investigated entities. Finally, we studied the new tools available for diagnosis and treatment, and their importance in current practice.

Genetic correlations between males, females and castrates for residual feed intake, feed conversion ratio, growth rate and carcass composition traits in Large White growing pigs.

Data were collected in the course of a divergent selection experiment for residual feed intake (RFI) of Large White growing pigs. This data set was used to estimate (i) heritability for RFI and genetic correlations of RFI with growth and carcass traits within the three sexes (male, castrate and female) and (ii) genetic correlations between sexes for these traits. Individual feed intake of animals raised in collective pens was measured by single-place electronic feeders on 1121 males (candidates for selection), 508 females and 535 castrates (sibs of candidates). Variance components were estimated using the REML methodology applied to a multitrait animal model. Estimates of heritability for RFI were 0.16 ± 0.04, 0.16 ± 0.08 and 0.23 ± 0.10 for males, females and castrates, respectively. Estimates of genetic correlations between sexes for homologous traits were not significantly different from 1 (0.88 to 0.99 for RFI, 0.79 to 0.99 for growth traits and 0.65 to 0.99 for carcass composition traits). The relatively low genetic correlations between castrates and males or females for backfat thickness (0.65 and 0.69, respectively) suggest the presence of genotype by sex interactions for this trait.

Correlated responses in sow appetite, residual feed intake, body composition, and reproduction after divergent selection for residual feed intake in the growing pig.

Residual feed intake (RFI) has been explored as an alternative selection criterion to feed conversion ratio to capture the fraction of feed intake not explained by expected production and maintenance requirements. Selection experiments have found that low RFI in the growing pig is genetically correlated with reduced fatness and feed intake. Selection for feed conversion ratio also reduces sow appetite and fatness, which, together with increased prolificacy, has been seen as a hindrance for sow lifetime performance. The aims of our study were to derive equations for sow RFI during lactation (SRFI) and to evaluate the effect of selection for RFI during growth on sow traits during lactation. Data were obtained on 2 divergent lines selected for 7 generations for low and high RFI during growth in purebred Large Whites. The RFI was measured on candidates for selection (1,065 pigs), and sow performance data were available for 480 sows having from 1 to 3 parities (1,071 parities). Traits measured were sow daily feed intake (SDFI); sow BW and body composition before farrowing and at weaning (28.4 ± 1.7d); number of piglets born total, born alive, and surviving at weaning; and litter weight, average piglet BW, and within-litter SD of piglet BW at birth, 21 d of age (when creep feeding was available), and weaning. Sow RFI was defined as the difference between observed SDFI and SDFI predicted for sow maintenance and production. Daily production requirements were quantified by litter size and daily litter BW gain as well as daily changes in sow body reserves. The SRFI represented 24% of the phenotypic variability of SDFI. Heritability estimates for RFI and SRFI were both 0.14. The genetic correlation between RFI and SRFI was 0.29 ± 0.23. Genetic correlations of RFI with sow traits were low to moderate, consistent with responses to selection; selection for low RFI during growth reduced SDFI and increased number of piglets and litter growth, but also increased mobilization of body reserves. No effect on rebreeding performance was found. Metabolic changes previously observed during growth in response to selection might explain part of the better efficiency of the low-RFI sows, decreasing basal metabolism and favoring rapid allocation of resources to lactation. We propose to consider SRFI as an alternative to SDFI to select for efficient sows with reduced input demands during lactation.

Muscle characteristics and meat quality traits are affected by divergent selection on residual feed intake in pigs.

Residual feed intake (RFI) is defined as the difference between the observed feed intake and that expected based on requirements for maintenance and production. A divergent selection was conducted during 4 generations in Large White male pigs to produce low and high RFI lines. The present study aims at determining the influence of this selection on biochemical and histological traits of skeletal muscle, and relating these changes to correlated effects on growth, carcass composition, and meat quality traits. At 8 d preslaughter, biopsies from the LM were taken in the fed state on 14 females from each RFI line fed ad libitum. Animals were slaughtered at 107.8 ± 8.0 kg of BW without any previous fasting. Samples of LM, semimembranosus (SM), biceps femoris (BFM), and rhomboideus muscles were taken at both 30 min and 24 h postmortem. Myofiber typing was only assessed in LM. Low RFI pigs ("efficient") had leaner carcasses with greater muscle content (P < 0.001), less backfat thickness (P < 0.001), and less intramuscular fat content in all 4 muscles (P < 0.01 to P = 0.04). Their greater muscle content was associated with hypertrophy of all fast-twitch fibers. Glycogen content in all glycolytic muscles (i.e., LM, SM and BFM), was greater in low than high RFI pigs. The greater accumulation of glycogen in LM of low RFI pigs was specifically located in the fast-twitch glycolytic IIBW fibers, which correspond to fibers containing IIb, IIb + IIx, or IIx myosin heavy chains. The difference in muscle glycogen content between RFI line pigs was more significant in the living animals (P = 0.0003) than at 30 min postmortem (P = 0.08). This was associated with a decreased ultimate pH (P = 0.001), and greater lightness of color (P = 0.002) and drip loss (P = 0.04) in LM of low than high RFI line pigs, suggesting that selection for reduced RFI may impair some meat quality traits, such as water-holding capacity. Pigs from the low RFI line exhibited a greater (P = 0.02) percentage of IIBW fibers in LM and tended (P < 0.10) to have less lipid ß-oxidative capacity in LM, SM, and BFM. In contrast, no difference (P > 0.10) between lines was found for citrate synthase and lactate dehydrogenase activities, mitochondrial activity, and expression of genes coding for uncoupling proteins 2 and 3. Differences between RFI pigs in plasma leptin, cortisol, and thyroid hormone concentrations are presented and discussed. In conclusion, selection for low RFI influenced muscle properties in a way favoring muscle mass, but likely impairing meat quality.

Energy utilization in pigs selected for high and low residual feed intake.

Genetic selection on residual feed intake (RFI) can be used as an alternative method to G:F to improve feed efficiency in pigs. The objective of this study was to determine the effects of selection for RFI on digestive and metabolic utilization of energy in 2 lines of purebred French Large White castrated male pigs obtained from a divergent selection experiment over 6 generations. The RFI(+) (high RFI) line consumed more feed than predicted from performance compared with the RFI(-) (low RFI) line. Digestibility of energy and nutrients, total heat production (HP), HP related to physical activity, and energy and N balance were measured in respiration chambers for a 6-d period in pigs offered feed ad libitum. Pigs remained in the chamber for an additional day and did not receive any feed to estimate the fasting HP and calculate the thermic effect of feeding. Five pairs of 2 littermates from the same farrowing batch were used in each line. Because 2 respiration chambers were available for the trial, pigs were measured regularly during the 25- to 95-kg growing period. Two pigs per chamber were used until pigs reached 45 kg of BW, and 1 pig per chamber was used thereafter. Individual feed intake and BW gain were measured continuously from weaning to the end of the trial. Pigs were fed 3 diets with decreasing CP contents during the 25 to 45 (period 1), 45 to 65 (period 2), and 65 to 95 (period 3) kg of BW periods. Average daily feed intake was greater in RFI(+) pigs than in RFI(-) pigs between 25 and 65 kg of BW (2,128 vs. 1,891 g/d; P < 0.01) and G:F was 8% greater in RFI(-) pigs compared with RFI(+) pigs (P < 0.01). There was no line effect on digestibility coefficients or N retention, irrespective of the experimental period studied. Nitrogen retention was 31.2, 28.7, and 20.8 g/d at periods 1, 2, and 3, respectively (P < 0.001). The HP was greater in RFI(+) pigs than in RFI(-) pigs (1,497 vs. 1,383 kJ.kg of BW(-0.60).d(-1); P < 0.01), with no subsequent line effect on energy retention. The activity-related HP tended to be greater in RFI(+) pigs than in RFI(-) pigs (250 vs. 218 kJ.kg of BW(-0.60).d(-1); P = 0.09), and the fasting HP was 10% greater (P = 0.04) in RFI(+) pigs than in RFI(-) pigs (846 vs. 771 kJ.kg of BW(-0.60).d(-1)). The thermic effect of feeding, expressed as a percentage of ME intake, was the same for both lines of pigs (average, 14.7%). In conclusion, the RFI(+) pigs are energetically less efficient because of their greater HP related to physical activity and basal metabolic rate.

Description of liver disease in a cohort of HIV/HBV coinfected patients.

BACKGROUND: Factors associated with advanced liver disease have been incompletely explored in HIV/HBV coinfected patients. OBJECTIVES: To describe liver-related morbidity, mortality, and related risk factors, in HIV/HBV coinfected patients. STUDY DESIGN: We followed-up 107 consecutive HIV/HBV coinfected patients. Clinical, biological and virological data were collected every 3 months. Liver-related mortality and a composite score were used to define advanced liver disease. RESULTS: The patients were mainly sub-Saharan Africans (61%) or Europeans (33%). Forty-four percent of patients had liver biopsy, 78% of patients received lamivudine. Advanced liver disease (ALD) was diagnosed in 19/107 patients during follow-up (mean 4.8 years): 10 extensive fibrosis, 5 cirrhosis, 3 hepatocellular carcinoma resulting from cirrhosis, and 1 fulminant hepatitis following lamivudine withdrawal. Eleven patients died, 4 from HBV-related liver disease. In univariate analysis, male gender, mean HIV and HBV viral loads, and raised AST/ALT transaminases were associated with increased risk of ALD. The strongest associations, in a multivariate model, were mean AST transaminase and cumulated time receiving lamivudine, with a favourable effect. 39% of patients with increased mean AST presented with ALD, versus 7% when normal mean AST (Relative Risk 5.5). CONCLUSIONS: During HIV/HBV coinfection, transaminase levels are strongly associated with ALD. Normal mean AST has a high negative predictive value, contrary to previously reported data in HIV/HCV patients.

Genetic parameters for tissue and fatty acid composition of backfat, perirenal fat and longissimus muscle in Large White and Landrace pigs.

Genetic parameters pertaining to the same chemical characteristics of three porcine tissues, that is backfat (BF), perirenal fat (PF) and longissimus muscle (LM), were estimated in centrally tested Large White and Landrace pigs. Animals were fed ad libitum. They were slaughtered at an average BW of 99.6 kg, and samples of BF (both inner and outer layers) and LM were removed at the 13th to 14th rib level of the carcass on the day after slaughter. The data set included 2483 animals recorded for average daily gain (ADG; 35 to 100 kg), estimated carcass lean percentage (LEAN) and lean tissue growth rate (LTGR). Among these animals, around 950 pigs were recorded for lipid content (L%) and water content (W%) of BF and LM and for fatty acid composition (FAC) of BF, whereas FAC of LM was measured on 297 pigs and L%, W%, and FAC of PF on around 210 pigs. Heritabilities (h2) and genetic correlations (ra) were estimated using REML-animal model methodology. Estimates of h2 for L%, W% and FAC of BF, PF and LM were of moderate-to-high magnitude: for example 0.47 ± 0.09 for L% of LM, 0.59 ± 0.11 for W% of BF, 0.45 ± 0.08 for the ratio of polyunsaturated to saturated fatty acids (P/S) of BF, 0.61 ± 0.15 and 0.29 ± 0.10 for the coefficient of unsaturation of lipids (UNSAT, average number of double bonds of unsaturated fatty acids) of PF and LM, respectively. Genetic correlations of L% with P/S or UNSAT were strongly negative (from -0.4 to -0.9) in BF and LM, but not in PF. The 'between-tissue' genetic correlations for homologous compositional traits were far from being unity (e.g. ra = 0.57 ± 0.05 'between' BF and PF for UNSAT). Genetic relationships between ADG and tissue compositional traits were globally weak. By contrast, genetic correlations were moderate-to-high between carcass leanness and tissue compositional traits, especially those of fat depots: for example -0.66 ± 0.14 between LEAN and L% of BF, 0.50 ± 0.07 between LEAN and UNSAT of PF, -0.44 ± 0.08 between LEAN and L% of LM, and 0.27 ± 0.03 between LEAN and UNSAT of LM. On the basis of the parameter estimates found here, breeding for higher LTGR is expected to increase the ratio of water to lipids and the unsaturation degree of lipids in subcutaneous BF and, to a lesser extent, in PF. Tissue composition and FAC of LM would be less affected.

Detecting QTL for feed intake traits and other performance traits in growing pigs in a Piétrain-Large White backcross.

Knowing the large difference in daily feed intake (DFI) between Large White (LW) and Piétrain (PI) growing pigs, a backcross (BC) population has been set up to map QTL that could be used in marker assisted selection strategies. LW × PI boars were mated with sows from two LW lines to produce 16 sire families. A total of 717 BC progeny were fed ad libitum from 30 to 108 kg BW using single-place electronic feeders. A genome scan was conducted using genotypes for the halothane gene and 118 microsatellite markers spread on the 18 porcine autosomes. Interval mapping analyses were carried out, assuming different QTL alleles between sire families to account for within breed variability using the QTLMap software. The effects of the halothane genotype and of the dam line on the QTL effect estimates were tested. One QTL for DFI (P < 0.05 at the chromosome-wide (CW) level) and one QTL for feed conversion ratio (P < 0.01 at the CW level) were mapped to chromosomes SSC6 - probably due to the halothane alleles - and SSC7, respectively. Three putative QTL for feed intake traits were detected (P < 0.06 at the CW level) on SSC2, SSC7 and SSC9. QTL on feeding traits had effects in the range of 0.20 phenotypic s.d. The relatively low number of QTL detected for these traits suggests a large QTL allele variability within breeds and/or low effects of individual loci. Significant QTL were detected for traits related to carcass composition on chromosomes SSC6, SSC15 and SSC17, and to meat quality on chromosome SSC6 (P < 0.01 at the genome-wide level). QTL effects for body composition on SSC13 and SSC17 differed according to the LW dam line, which confirmed that QTL alleles were segregating in the LW breed. An epistatic effect involving the halothane locus and a QTL for loin weight on SSC7 was identified, the estimated substitution effects for the QTL differing by 200 g between Nn and NN individuals. The interactions between QTL alleles and genetic background or particular genes suggest further work to validate QTL segregations in the populations where marker assisted selection for the QTL would be applied.

Genetic parameters for residual feed intake in growing pigs, with emphasis on genetic relationships with carcass and meat quality traits.

Data were collected over the first 4 generations of a divergent selection experiment for residual feed intake of Large White pigs having ad libitum access to feed. This data set was used to obtain estimates of heritability for residual feed intake and genetic correlations (r(a)) between this trait and growth, carcass, and meat quality traits. Individual feed intake of group-housed animals was measured by single-space electronic feeders. Upward and downward selection lines were maintained contemporarily, with 6 boars and 35 to 40 sows per line and generation. Numbers of records were 793 for residual feed intake (RFI1) of boar candidates for selection issued from first-parity (P1) litters and tested over a fixed BW range (35 to 95 kg) and 657 for residual feed intake (RFI2) and growth, carcass, and meat quality traits of castrated males and females issued from second-parity (P2) litters and tested from 28 to 107 kg of BW. Variance and covariance components were estimated using REML methodology applied to a series of multitrait animal models, which always included the criterion for selection as 1 of the traits. Estimates of heritability for RFI1 and RFI2 were 0.14 +/- 0.03 and 0.24 +/- 0.03, respectively, whereas the estimate of r(a) between the 2 traits was 0.91 +/- 0.08. Estimates of r(a) indicated that selection for low residual feed intake has the potential to improve feed conversion ratio and reduce daily feed intake, with minimal correlated effect for ADG of P2 animals. Estimates of r(a) between RFI2 and body composition traits of P2 animals were positive for traits related to the amount of fat depots (r(a) = 0.44 +/- 0.16 for carcass backfat thickness) and negative for carcass lean meat content (r(a) = -0.55 +/- 0.14). There was a tendency for a negative genetic correlation between RFI2 and carcass dressing percent (r(a) = -0.36 +/- 0.21). Moreover, selection for low residual feed intake is expected, through lower ultimate pH and lighter color, to decrease pork quality (r(a) = 0.77 +/- 0.14 between RFI2 and a meat quality index intended to predict the ratio of the weight of ham after curing and cooking to the weight of defatted and boneless fresh ham).