Review: State of the knowledge on the importance of folates and cobalamin for dairy cow metabolism.

Synthesis of B vitamins by the rumen microbiota is usually sufficient to avoid the appearance of clinical deficiency symptoms in dairy cows under normal feeding conditions. Nevertheless, it is now generally accepted that vitamin deficiency is much more than the appearance of major functional and morphological symptoms. Subclinical deficiency, which is present as soon as the supply is lower than the need, causes cellular metabolic changes leading to a loss of metabolic efficiency. Folates and cobalamin, two B vitamins, share close metabolic relationships. Folates act as co-substrates in one-carbon metabolism, providing one-carbon unit for DNA synthesis and de novo synthesis of methyl groups for the methylation cycle. Cobalamin acts as a coenzyme for reactions in the metabolism of amino acids, odd-numbered chain fatty acids including propionate and de novo synthesis of methyl groups. Both vitamins are involved in reactions to support lipid and protein metabolism, nucleotide synthesis, methylation reactions and possibly, maintenance of redox status. Over the last decades, several studies have reported the beneficial effects of folic acid and vitamin B12 supplements on lactation performance of dairy cows. These observations indicate that, even when cows are fed diets adequately balanced for energy and major nutrients, B-vitamin subclinical deficiency could be present. This condition reduces casein synthesis in the mammary gland and milk and milk component yields. Folic acid and vitamin B12 supplements, especially when given together, may alter energy partitioning in dairy cows during early and mid-lactation as indicated by increased milk, energy-corrected milk, or milk component yields without affecting DM intake and BW or even with reductions in BW or body condition loss. Folate and cobalamin subclinical deficiency interferes with efficiency of gluconeogenesis and fatty acid oxidation and possibly alters responses to oxidative conditions. The present review aims to describe the metabolic pathways affected by folate and cobalamin supply and the consequences of a suboptimal supply on metabolic efficiency. The state of knowledge on the estimation of folate and cobalamin supply is also briefly mentioned.

Impacts of production conditions on goat milk vitamin, carotenoid contents and colour indices.

The content, composition and variation of vitamin compounds in goat milk have been little studied. An experimental design was based on 28 commercial farms, selected considering the main feeding system (based on main forage and especially pasture access), goat breed (Alpine vs Saanen) and reproductive management (seasonal reproduction), in the main French goat milk production area. Each farm received two visits (spring and autumn) that included a survey on milk production conditions and bulk milk sampling. Milk vitamins (A, E, B2, B6, B9, B12) and carotenoid concentrations plus colour indices were evaluated. A stepwise approach determined the variables of milk production conditions that significantly altered milk indicators. The main forage in the diet was the major factor altering goat milk vitamin and carotenoid concentrations and colour indices. Bulk milk from goats eating fresh grass as forage was richer in α-tocopherol (+64%), pyridoxal (+35%) and total vitamin B6 (+31%), and b* index (characterising milk yellowness in the CIELAB colour space) was also higher (+12%) than in milk from goats eating conserved forages. In milk from goats eating fresh grass, concentrations of pyridoxamine, lutein and total carotenoids were higher than in milk of goats fed corn silage (+24, +118 and +101%, respectively), and retinol and α-tocopherol concentrations were higher than in milk of goats fed partially dehydrated grass (+45 and +55%). Vitamin B2 concentration was higher in milk of goats eating fresh grass than in milk of goats fed hay or corn silage as forage (+10%). However, bulk milk when goats had access to fresh grass was significantly poorer in vitamin B12 than when fed corn silage (-46%) and in γ-tocopherol (-31%) than when fed conserved forage. Alpine goats produced milk with higher vitamin B2 and folate concentrations than Saanen goats (+18 and +14%, respectively). Additionally, the milk colour index that discriminates milks based on their yellow pigment contents was 7% higher in milk from Alpine than Saanen herds, but milk from Saanen goats was richer in lutein (+46%). Goat milks were richer in vitamins B2 and B12 and folates, but poorer in vitamin B6 in autumn than in spring (+12, +133, +15 and -13%, respectively). This work highlights that goat milk vitamin and carotenoid concentrations and colour indices vary mainly according to the main forage of the diet and secondly according to the breed and season.

Combined biotin, folic acid, and vitamin B12 supplementation given during the transition period to dairy cows: Part II. Effects on energy balance and fatty acid composition of colostrum and milk.

Biotin (B8), folate (B9), and vitamin B12 (B12) are involved in several metabolic reactions related to energy metabolism. We hypothesized that a low supply of one of these vitamins during the transition period would impair metabolic status. This study was undertaken to assess the interaction between B8 supplement and a supplementation of B9 and B12 regarding body weight (BW) change, dry matter intake, energy balance, and fatty acid (FA) compositions of colostrum and milk fat from d -21 to 21 relative to calving. Thirty-two multiparous Holstein cows housed in tie stalls were randomly assigned, according to their previous 305-d milk yield, to 8 incomplete blocks in 4 treatments: (1) a 2-mL weekly i.m. injection of saline (0.9% NaCl; B8-/B9B12-); (2) 20 mg/d of dietary B8 (unprotected from ruminal degradation) and 2-mL weekly i.m. injection of 0.9% NaCl (B8+/B9B12-); (3) 2.6 g/d of dietary B9 (unprotected) and 2-mL weekly i.m. injection of 10 mg of B12 (B8-/B9B12+); (4) 20 mg/d of dietary B8, 2.6 g/d of dietary B9, and 2-mL weekly i.m. injection of 10 mg of B12 (B8+/B9B12+) in a 2 × 2 factorial arrangement. Colostrum was sampled at first milking. and milk samples were collected weekly on 2 consecutive milkings and analyzed for FA composition. Body condition score and BW were recorded every week throughout the trial. Within the first 21 d of lactation, B8-/B9B12+ cows had an increased milk yield by 13.5% [45.5 (standard error, SE: 1.8) kg/d] compared with B8-/B9B12- cows [40.1 (SE: 1.9)], whereas B8 supplement had no effect. Even though body condition score was not affected by treatment, B8-/B9B12+ cows had greater BW loss by 24 kg, suggesting higher mobilization of body reserves. Accordingly, milk de novo FA decreased and preformed FA concentration increased in B8-/B9B12+ cows compared with B8-/B9B12- cows. In addition, cows in the B8+/B9B12- group had decreased milk de novo FA and increased preformed FA concentration compared with B8-/B9B12- cows. Treatment had no effect on colostrum preformed FA concentration. Supplemental B8 decreased concentrations of ruminal biohydrogenation intermediates and odd- and branched-chain FA in colostrum and milk fat. Moreover, postpartum dry matter intake for B8+ cows tended to be lower by 1.6 kg/d. These results could indicate ruminal perturbation caused by the B8 supplement, which was not protected from rumen degradation. Under the conditions of the current study, in contrast to B8+/B9B12- cows, B8-/B9B12+ cows produced more milk without increasing dry matter intake, although these cows had greater body fat mobilization in early lactation as suggested by the FA profile and BW loss.

Combined biotin, folic acid, and vitamin B12 supplementation given during the transition period to dairy cows: Part I. Effects on lactation performance, energy and protein metabolism, and hormones.

Biotin (B8), folates (B9), and vitamin B12 (B12) are involved and interrelated in several metabolic reactions related to energy and protein metabolism. We hypothesized that a low supply of one of the latter vitamins during the transition period would impair metabolic status. The purpose of this study was to evaluate the effect of B8 supplementation on the response of lactation performance and selected energy and protein metabolites and hormones to a combined supplementation of B9 and B12 given to periparturient dairy cows, from d -21 to 21 relative to calving. A total of 32 multiparous Holstein cows housed in tie stalls were randomly assigned, according to their previous 305-d milk yield, to 8 incomplete blocks of 4 treatments: (1) a 2-mL weekly i.m. injection of saline (0.9% NaCl; B8-/B9B12-); (2) 20 mg/d of dietary B8 (unprotected from ruminal degradation) and 2-mL weekly i.m. injection of 0.9% NaCl (B8+/B9B12-); (3) 2.6 g/d of dietary B9 (unprotected) and 2-mL weekly i.m. injection of 10 mg of B12 (B8-/B9B12+); and (4) 20 mg/d of dietary B8, 2.6 g/d of dietary B9, and weekly i.m. injection of 10 mg of B12 (B8+/B9B12+) in a 2 × 2 factorial arrangement. Milk yield and dry matter intake were obtained daily and milk components weekly. Blood samples were taken weekly from d -21 to calving and 3 times per week from calving to 21 d following parturition. Prepartum plasma concentrations of glucose, insulin, nonesterified fatty acids (NEFA), ß-hydroxybutyrate (BHB), and adiponectin were unaffected by treatments. Biotin, B9, and B12 supplements increased their respective concentrations in plasma and milk. Cows fed the B8 supplement tended to have lower dry matter intake, but only cows in B8+/B9B12- had greater plasma concentrations of NEFA compared with B8-/B9B12-. Milk and total solid yields were greater by 13.5 and 13.9%, respectively, for B8-/B9B12+ [45.5 (standard error, SE: 1.8) and 5.81 (0.22) kg/d, respectively] compared with B8-/B9B12- [40.1 (1.9) and 5.10 (0.23) kg/d, respectively], but these effects were suppressed when combined with the B8 supplement. Cows in the B8-/B9B12+ group had decreased plasma insulin and tended to have increased NEFA concentrations, but postpartum plasma concentrations of glucose, BHB, leptin, and adiponectin were not affected. These cows also mobilized more body fat reserves, as suggested by a tendency to increased plasma NEFA and more milk total solids compared with B8-/B9B12- cows. However, plasma concentrations of BHB and adiponectin were similar among treatments. This suggests that the B9 and B12 supplements enhanced efficiency of energy metabolism in early lactation cows. Folic acid and B12 supplementation increased postpartum plasma Cys and homocysteine concentrations but did not affect plasma Met concentration, suggesting an upregulation of the transsulfuration pathway. In summary, our results showed that, under the current experimental conditions, increasing B8 supply did not improve responses to the B9 and B12 supplementation.

Meta-analysis of apparent ruminal synthesis and postruminal flow of B vitamins in dairy cows.

As milk production has significantly increased over the past decade(s), existing estimates of the B-vitamin needs of the modern dairy cow are currently being reconsidered, as suboptimal B-vitamin supply may affect metabolic efficiency. At the same time, however, "true" (i.e., biologically active forms, excluding nonfunctional analogs) B-vitamin supply also cannot be adequately estimated by dietary intake, as the rumen microbiota has been shown to play a significant role in synthesis and utilization of B vitamins. Given their complex impact on the metabolism of dairy cows, incorporating these key nutrients into the next generation of mathematical models could help to better predict animal production and performance. Therefore, the purpose of this study was to generate hypotheses of regulation in the absence of supplemental B vitamins by creating empirical models, through a meta-analysis, to describe true B-vitamin supply to the cow (postruminal flow, PRF) and apparent ruminal synthesis (ARS). The database used for this meta-analysis consisted of 340 individual cow observations from 15 studies with 16 experiments, where diet and postruminal digesta samples were (post hoc) analyzed for content of B vitamins (B1, B2, B3, B6, B9, B12). Equations of univariate and multivariate linear form were considered. Models describing ARS considered dry matter intake (DMI, kg/d), B-vitamin dietary concentration [mg/kg of dry matter (DM)] and rumen-level variables such as rumen digestible neutral detergent fiber (NDF) and starch (g/kg of DM), total volatile fatty acids (VFA, mM), acetate, propionate, butyrate, and valerate molar proportions (% of VFA), mean pH, and fractional rates of degradation of NDF and starch (%/h). Models describing PRF considered dietary-level driving variables such as DMI, B-vitamin dietary concentration (mg/kg of DM), starch and crude protein (g/kg of DM) and forage NDF (g/kg of DM). Equations developed were required to contain all significant slope parameters and contained no significant collinearity between driving variables. Concordance correlation coefficient was used to evaluate the models on the developmental data set due to data scarcity. Overall, modeling ARS yielded better-performing models compared with modeling PRF, and DMI was included in all prediction equations as a scalar variable. The B-vitamin dietary concentration had a negative effect on the ARS of B1, B2, B3, and B6 but increased the PRF of B2 and B9. The rumen digestible NDF concentration had a negative effect on the ARS of B2, B3, and B6, whereas rumen digestible starch concentration had a negative effect on the ARS of B1 and a positive effect on the ARS of B9. In the best prediction models, the dietary starch increased PRF of B1, B2, and B9 but decreased PRF of B12. The equations developed may be used to better understand the effect of diet and ruminal environment on the true supply of B vitamins to the dairy cow and stimulate the development of better-defined requirements in the future.

Palmoplantar pustulosis and acrodermatitis continua of Hallopeau: demographic and clinical comparative study in a large multicentre cohort.

BACKGROUND: Acral pustular disease within the pustular psoriasis/psoriasis-like spectrum mainly includes palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH). Scarce data argue for a distinction between these two entities, but no study has compared the clinical and epidemiologic characteristics of ACH and PPP. OBJECTIVES: We aimed to perform a comparative description of the epidemiological and clinical characteristics of PPP and ACH in a multicentre retrospective cohort. METHODS: In this multicentre national retrospective cohort study, we compared the epidemiological characteristics, comorbidities and psoriasis characteristics of patients with PPP and ACH. RESULTS: A total of 234 patients were included: 203 (87%) with PPP, 18 (8%) with ACH and 13 (6%) with both, according to 2017 ERASPEN criteria. As compared with ACH, PPP was associated with female sex, smoking activity and higher median BMI (P = 0.01, P = 0.02 and P = 0.05 respectively). A family background of psoriasis was more frequent in PPP than ACH. Age of onset of palmoplantar disease was similar between PPP and ACH patients, median age 44 and 48 years respectively. Peripheral joint inflammatory involvement was the only rheumatic disease associated with ACH. The association with another psoriasis type was similar in PPP and ACH (57.6% and 61.1% respectively). CONCLUSION: Our study confirms in a large PPP cohort the predominance of females and a high prevalence of smoking and elevated body mass index but also shows an association of these features in PPP as compared with ACH. In addition, it highlights peripheral arthritis as the only arthritis endotype associated with ACH. Increased knowledge of the immunogenetic backgrounds underlying these two entities is warranted to better stratify pustular psoriasis or psoriasis-like entities for precision medicine.

French guidelines for the management of oral lichen planus (excluding pharmacological therapy).

INTRODUCTION: Oral lichen is a chronic inflammatory disease for which diagnostic management and follow-up are heterogeneous given the absence of specific guidelines in France. Our objective was to develop French multidisciplinary guidelines for the management of oral lichen. MATERIALS AND METHODS: Working groups from the Groupe d'Etude de la Muqueuse Buccale (GEMUB) formulated a list of research questions and the corresponding recommendations according to the "formal consensus" method for developing practice guidelines. These recommendations were submitted to a group of experts and the degree of agreement for each recommendation was assessed by a scoring group. RESULTS: Twenty-two research questions, divided into 3 themes (nosological classification and initial assessment, induced oral lichenoid lesions, and follow-up) resulted in 22 recommendations. Initial biopsy for histology is recommended in the absence of reticulated lesions. Biopsy for direct immunofluorescence is recommended for ulcerated, erosive, bullous types and for diffuse erythematous gingivitis. Management should include a periodontal and dental check-up, and investigation for extra-oral lesions. Hepatitis C testing is recommended only if risk factors are present. Definitions, triggering factors and the management of "induced oral lichenoid lesions" were clarified. Oral lichen must be monitored by a practitioner familiar with the disease at least once a year, using objective tools. CONCLUSION: This formalised consensus of multidisciplinary experts provides clinical practice guidelines on the management and monitoring of oral lichen.

[Granulomatous lung disease induced by kayexalate inhalation during immunotherapy for metastatic melanoma]. / Pneumopathie granulomateuse induite par l'inhalation de Kayexalate® sous immunothérapie: Un diagnostic différentiel de progression tumorale et de toxicité pulmonaire spécifique des inhibiteurs de checkpoints immunitaires.

INTRODUCTION: When a patient treated by immune checkpoint inhibitors for metastatic melanoma presents with pulmonary symptoms, several diagnoses are possible. We report a case of acute granulomatous lung disease secondary to repeated kayexalate inhalations, and probably stimulated by immunotherapy. CASE REPORT: A patient treated with pembrolizumab and then ipilimumab presented with fever and acute shortness of breath. His pulmonary symptoms got progressively worse, leading to an acute respiratory distress syndrome. Chest CT displayed a pattern of non-specific organized pneumonia. Pulmonary infection, tumor progression, specific immune-related lung toxicity and immunotherapy-induced sarcoidosis were discussed. Histopathological examination of a lung biopsy showed a foreign body granulomatous macrophage reaction associated with crystalline, basophilic, purple and laminated elements, evoking kayexalate particles. These elements helped rewrite the diagnosis and confirmed a kayexalate-induced granulomatous lung disease secondary to repeated aspiration. The patient's respiratory condition got better following discontinuation of kayexalate together with systemic corticosteroids. Symptoms relapsed with resumption of the immunotherapy but were controlled with the addition of a new course of prolonged systemic corticosteroid therapy. We can hypothesize that immunotherapy played a role in the recurrence of the granulomatous lung reaction, or that there was an association between an aspiration pneumonia and an immunotherapy-induced lung toxicity. CONCLUSION: Facing respiratory symptoms during immunotherapy, the treatment may be the cause, but lung biopsy should be performed rapidly to arrive to a certain diagnosis.

Methods and approaches to estimate B vitamin status in dairy cows: Knowledge, gaps and advances.

Clinical symptoms of B vitamin deficiency are rarely observed in ruminants because these vitamins are synthesized by the rumen microbiota. However, over the last decades, numerous reports of beneficial effects on production and metabolic efficiency of dairy cows have been published supporting that, under some conditions, B vitamin subclinical deficiency is present in these animals. Due to their roles as coenzymes or cofactors in major metabolic pathways, an adequate supply in B vitamins is critical to optimize metabolic efficiency. Nowadays, taking into account the growing interest for the Smart Farming concept, fulfilling ruminant requirements for B vitamins according to their physiological stage under different feeding management cannot be neglected. In dairy cows, B vitamin supply is greatly dependent of the activity of the ruminal microbiota. Indeed, the amount of vitamins reaching the small intestine is dependent of the utilization of the vitamins provided by the diet and their synthesis by the microorganisms present in the rumen. The two major challenges faced to determine B vitamin status of ruminants are the difficulty to estimate B vitamin supply due to the lack of knowledge on factors driving the fate of B vitamins in the digestive tract, especially in the rumen, and the choice and thresholds of biomarkers reflecting adequately the animal status. The present paper aims to present the actual state of knowledge on the methodological approaches used to estimate B vitamin supply and status of ruminant and to point out future research orientations.

Response to a glucose tolerance test in early-lactation Holstein cows receiving a supplementation of biotin, folic acid, and vitamin B12.

The aim of the study was to evaluate glucose and insulin metabolism of cows receiving a supplementation of biotin (B8), folic acid (B9), and vitamin B12 (B12) during the transition period. According to a 2 × 2 factorial arrangement, 32 cows were randomly assigned to 9 incomplete blocks according to their previous 305-d milk yield. Within each block, cows were randomly assigned to 1 of the following levels of biotin from -27 to 28 d relative to the parturition: (1) no biotin supplement (B8-) or (2) 20 mg/d of dietary biotin (B8+). Within each level of biotin, the cows received either (1) 2-mL weekly intramuscular injections of saline 0.9% NaCl (B9B12-) or (2) 2.6 g/d of dietary folic acid and 2-mL weekly intramuscular injections of 10 mg of vitamin B12 (B9B12+). An intravenous glucose tolerance test was performed at 25 d in milk. Baseline plasma glucagon, glucose, and nonesterified fatty acid concentrations did not differ among treatments. For B9B12+ cows, baseline plasma insulin concentration and maximal glucose concentration after glucose administration were greater when also combined with biotin compared with no biotin combination, whereas there was no effect in B9B12- cows. There was no treatment effect on time to reach half-maximal glucose and insulin concentrations, glucose positive incremental area under the curve, and glucose and insulin clearance rates. Regarding insulin results, maximal plasma concentration and positive incremental area under the curve were respectively 51 and 74% greater for cows receiving the B8 supplement than for cows who did not. Moreover, plasma nonesterified fatty acid concentration nadir tended to be reached later for B8 cows. Insulin peak was reached earlier for cows in the group B9B12+ than cows in B9B12-, regardless of B8 supplementation. Under the current conditions, our results suggested that cows receiving a B8 supplement had a reduced insulin sensitivity in early lactation. Insulin response was faster for B9B12+ cows, but this was not translated into further improvements following the glucose administration challenge.

Short communication: Potential prediction of vitamin B12 concentration based on mid-infrared spectral data using Holstein Dairy Herd Improvement milk samples.

The purpose of this study was (1) to predict the quantitative concentration of vitamin B12 in milk using mid-infrared (MIR) spectrometry, and (2) to evaluate the potential of MIR spectra to discriminate different clusters of records based on their B12 concentration. Milk samples were collected from 4,340 Holstein cows between 3 and 592 d in milk and located in 100 herds. Samples were taken using in-line milk meters and divided into 2 aliquots: one for MIR spectrometry and the other for B12 concentration reference analyses by radioassay. Analyses were performed on 311 selected spectral wavelengths. A partial least squares regression model was built to quantify B12 concentration. Discriminant analysis was used to isolate B12 concentration clusters. A B12 concentration threshold was set at 442 ng/dL, because this represents the cutoff value for a 250-mL glass of milk to fulfill 46% of the daily vitamin B12 recommended dietary allowance for individuals 14 yr or older. For each analysis, records coming from two-thirds of herds were used to calibrate prediction equations, and the remaining records (one-third of herds for validation) were used to assess the prediction performance. In the case of discriminant analysis, validation sets were divided into evaluation sets (one-third of herds) to obtain alternate probability cutoffs and in test sets (two-thirds of herds) to validate equations. Spectral and B12 concentration outliers were identified by calculating standardized Mahalanobis distance and with a residual analysis, respectively (n = 3,154). Regarding quantitative B12 concentration, cross-validation and validation coefficients of determination averaged 0.51 and 0.46, respectively, which are relatively low, which would limit the potential use of the developed quantitative equations. In addition, root mean square errors of prediction of cross validation and validation sets averaged 88.9 and 94.7 ng/dL, respectively. Area under the receiver operating characteristic curve of test sets averaged 0.81 based on the 442 ng/dL threshold, which could be considered to represent good accuracy of classification. However, the false discovery rate averaged 36%. In summary, models predicting quantitative B12 concentration had low cross-validation and validation coefficients of determination, limiting their use, but the proposed discriminant models could be used to identify milk samples with naturally high B12.

Symposium review: One-carbon metabolism and methyl donor nutrition in the dairy cow.

The present review focuses on methyl donor metabolism and nutrition in the periparturient and lactating dairy cow. Methyl donors are involved in one-carbon metabolism, which includes the folate and Met cycles. These cycles work in unison to support lipid, nucleotide, and protein synthesis, as well as methylation reactions and the maintenance of redox status. A key feature of one-carbon metabolism is the multi-step conversion of tetrahydrofolate to 5-methyltetrahyrofolate. Homocysteine and 5-methyltetrahyrofolate are utilized by vitamin B12-dependent Met synthase to couple the folate and Met cycles and generate Met. Methionine may also be remethylated from choline-derived betaine under the action of betaine hydroxymethyltransferase. Regardless, Met is converted within the Met cycle to S-adenosylmethionine, which is universally utilized in methyl-group transfer reactions including the synthesis of phosphatidylcholine. Homocysteine may also enter the transsulfuration pathway to generate glutathione or taurine for scavenging of reactive oxygen metabolites. In the transition cow, a high demand exists for compounds with a labile methyl group. Limited methyl group supply may contribute to inadequate hepatic phosphatidylcholine synthesis and hepatic triglyceride export, systemic oxidative stress, and compromised milk production. To minimize the perils associated with methyl donor deficiency, the peripartum cow relies on de novo methylneogenesis from tetrahydrofolate. In addition, dietary supplementation of rumen-protected folic acid, vitamin B12, Met, choline, and betaine are potential nutritional approaches to target one-carbon pools and improve methyl donor balance in transition cows. Such strategies have merit considering research demonstrating their ability to improve milk production efficiency, milk protein synthesis, hepatic health, and immune response. This review aims to summarize the current understanding of folic acid, vitamin B12, Met, choline, and betaine utilization in the dairy cow. Methyl donor co-supplementation, fatty acid feeding strategies that may optimize methyl donor supplementation efficacy, and potential epigenetic mechanisms are also considered.

Effects of increasing amounts of extruded linseed in the diet on apparent ruminal synthesis of some B vitamins in dairy cows.

Many studies have shown that metabolic efficiency of ruminants can be significantly decreased when B-vitamin supply is insufficient. Under the present state of knowledge, the amounts of B vitamins available for intestinal absorption cannot be predicted based on diet composition. Therefore, in an attempt to increase our understanding of the effects of dietary factors, on B-vitamin supply for dairy cows, the effects of increasing amounts of extruded linseed in diets based on hay (permanent grassland hay, H; Experiment 1) or corn silage (CS; Experiment 2) on apparent ruminal synthesis (ARS) of thiamin, riboflavin, niacin, vitamin B6, folates and vitamin B12 were evaluated. In each experiment, four lactating Holstein cows fitted with cannulas in the rumen and the proximal duodenum were used in a 4 × 4 Latin square design. In both experiments, the dietary treatments consisted of an increasing supply of extruded linseed representing 0%, 5%, 10% or 15% of diet DM. The forage : concentrate ratios were 50 : 50 and 60 : 40 for Experiments 1 and 2, respectively. Duodenal flow was determined using YbCl3 as a marker. The ARS of each B vitamin was calculated as duodenal flow - daily intake. In both experiments, treatments did not affect thiamin, riboflavin, niacin and vitamin B12 duodenal flow or ARS. Increasing the dietary concentration of extruded linseed decreased folate intake in Experiment 1 and vitamin B6 intake in Experiment 2 but resulted in a greater duodenal flow of vitamin B6 and folates regardless of the forage used in basal diet. Greater dietary linseed concentrations decreased vitamin B6 apparent degradation in the rumen in CS-based diet only and increased folate ARS in both H- and CS-based diets. Increasing linseed concentration of isonitrogenous and isoenergetic diets increased vitamin B6 and folate supply to dairy cows, both with H- and CS-based diets.

Technical note: Extrapolation of hepatic glycogen concentration of the whole organ by performing a liver biopsy.

Glycogen, a complex polysaccharide, is the form of storage of glucose in mammals that can be released rapidly when needed. Recent studies have mainly reported hepatic glycogen concentration for early-lactating cows, when the energy demand is higher than the energy supply from dry matter intake, driving the cow to use the energy stored as hepatic glycogen. Generally, liver samples are obtained through percutaneous needle biopsies in the right lobe of the liver. Our objective was to analyze the variation of glycogen concentration in the livers of Holstein and Jersey cows among different liver locations representing all lobes, to evaluate whether samples obtained by liver biopsies are representative of the whole organ. Liver from 10 culled lactating cows (5 Holstein and 5 Jersey cows) from 30 to 113 mo of age at slaughter were obtained. Each liver was sampled no more than 3 h after death on the following sites: 3 sites in the right lobe (1 to 3), 2 in the diaphragmatic surface of the left lobe (4 and 5), 3 in the visceral surface of the left lobe (6 to 8), 1 in the quadrate lobe (9), and 1 in the caudate lobe (10). Samples were snap frozen in liquid N2 and were then analyzed for glucose concentration after conversion of glycogen to glucose using amyloglucosidase (EC 3.2.1.3). Glycogen results are reported as grams of glucose per 100 g of wet weight of liver (i.e., percent of wet weight of liver). Liver weights averaged 5.1 [standard deviation (SD) 1.2, minimum 3.3, maximum 6.2] kg for Holstein and 6.0 (SD 1.8, minimum 4.7, maximum 8.9) kg for Jersey cows. Holstein cows [1.31, standard error of the mean (SEM) 0.05% of wet weight] had greater liver glycogen concentration than did Jersey cows (0.75, SEM 0.05% of wet weight). No significant difference was noted among the 10 liver locations regarding glycogen concentration and averaged, for both breeds, 1.03% of wet weight (SEM 0.10). These results suggest that, in dairy cows, percutaneous needle liver biopsy in the right lobe is an accurate technique to fairly extrapolate glycogen concentration of the whole organ.

Efficacy and safety of TNF blockers and of ustekinumab in palmoplantar pustulosis and in acrodermatitis continua of Hallopeau.

BACKGROUND: Palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH) are rare variants of psoriasis. Knowledge of the efficacy of biologics is scarce. OBJECTIVES: To evaluate the real-life efficacy of tumour necrosis factor blockers and ustekinumab in PPP and in ACH. METHODS: A multicentre retrospective descriptive study was conducted in 19 dermatology departments, including all patients with PPP or ACH seen from 2014 to 2016 who received one of the studied biologics. The data were collected by a standardized document. Factors associated with complete clearance (CC) were analysed by multivariate analysis, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 92 patients included, 50 received adalimumab, 44 ustekinumab, 36 etanercept and 31 infliximab. Improvement and CC were observed in 83.9% and 20.0% patients receiving infliximab, 75.0% and 38.6% ustekinumab, 57.1% and 20.0% etanercept and 60.4% and 29.2% adalimumab. We found no significant difference in CC rates or duration of treatment among the biological treatments (P = 0.18 and P = 0.10, respectively). On multivariate analysis, CC with etanercept was associated with the ACH form and not smoking [OR = 9.5 (95% CI 1.1-82.7), P = 0.04 and 0.1 (0.01-0.9), P = 0.04]; with ustekinumab, male sex and absence of obesity [6.0 (1.3-28.6), P = 0.02 and 4.7 (1.0-22.7), P = 0.05]; with adalimumab, the ACH form [11.9 (2.7-52.3), P = 0.001]; and with infliximab, obesity [5.6 (1.1-29.4), P = 0.04]. CONCLUSIONS: We found no difference in efficacy between TNF blockers and ustekinumab and among the three different TNF blockers in real life for PPP or ACH, which reveals the heterogeneity of clinical response to biologics in pustular psoriasis as compared with plaque psoriasis.

[Use of rituximab in maintenance treatment of pemphigus: A retrospective series]. / Utilisation en pratique du rituximab en 2nde ligne et au-delà dans le traitement du pemphigus: série rétrospective.

INTRODUCTION: Rituximab (RTX), currently recommended as first-line treatment in moderate to severe pemphigus vulgaris (PV) and superficial pemphigus (PS) along with initial systemic steroids, may also be used as second-line or subsequent treatment, and this therapeutic strategy was investigated in a real-life monocentre retrospective survey. MATERIAL AND METHODS: All patients treated between January 2010 and March 2018 with RTX as second-line or subsequent treatment for moderate to severe PV or PS and followed for at least one year were included. The main objective was to evaluate rates and times of complete clinical remission (CCR) after a first course of RTX. The secondary objectives consisted mainly of treatment safety, and frequency and time to relapse after the initial CCR. RESULTS: The 24 patients selected received on average 2 cycles of RTX (i.e. 24 initial cycles and 24 additional cycles in all) over a mean follow-up period of 45 months. 18/24 (75%) patients achieved initial CCR within a mean 7.7 months. Despite at least one relapse in 13/18 initially responding patients regardless of relapse time, 59% (14/24) and 33% (8/24) were either in CCR and off treatment, or in partial remission, whether treated or untreated, according to the latest patient news, with an overall response rate of 92%. Safety was fair in these fragile patients. DISCUSSION AND CONCLUSION: This survey of the practical use of RTX confirms its interest in moderate to severe pemphigus as a second-line or subsequent treatment, a situation that probably remains relevant even if this molecule is increasingly used as first-line therapy.

Cross-sectional study of the effect of diet composition on plasma folate and vitamin B12 concentrations in Holstein cows in the United States and Canada.

The objective of this cross-sectional study was to assess the variability of plasma folate and vitamin B12 concentrations in lactating Holstein cows across the United States and Canada. We also evaluated the effect of diet composition and cow characteristics on folate and vitamin B12 plasma vitamin concentrations. A total of 22 and 24 US and Canadian dairy herds were enrolled, totaling 427 and 476 cows at 10 to 197 days in milk across all US and Canadian herds, respectively. Blood samples were taken to analyze plasma folate and vitamin B12 concentrations, and ingredients of the diet were collected to determine nutrient composition. To reduce the number of interdependent variables in the analysis of the association of diet composition with plasma vitamin concentrations, we conducted a principal component analysis. Plasma folate concentrations were lower for US cows [13.4 ng/mL, 95% confidence interval (CI): 12.7-14.2] than for Canadian cows (14.5 ng/mL, 95% CI: 13.7-15.2), and the opposite was observed for plasma vitamin B12 concentrations (US 206 pg/mL, 95% CI: 192-221; Canada 170 pg/mL, 95% CI: 159-181). The highest plasma concentrations of both vitamins were observed in the Northwest region of the United States (Oregon and Washington). Cows in California had the lowest plasma folate concentrations, and cows in Québec and New York State had the lowest plasma vitamin B12 concentrations. Plasma folate concentrations were higher for multiparous than for primiparous cows and plasma vitamin B12 concentrations progressively increased from parity 1 to 3 and higher. For both studied vitamins, plasma concentrations were lower at 0 to 55 than at 56 to 200 days in milk. Of 3 principal components, the one associated with dietary carbohydrates was significantly correlated with plasma folate and vitamin B12 concentrations. Indeed, plasma folate concentrations decreased with dietary fiber concentrations (i.e., neutral and acid detergent fibers and lignin) and increased with dietary nonfiber carbohydrate concentrations. We obtained the opposite results for plasma vitamin B12 concentrations. Both multivariable models explained 41% (pseudo-R2) of the variation in plasma folate and vitamin B12 concentrations. Information gathered in this study is the first step toward determining sources of variation in plasma folate and vitamin B12 concentrations, as well as the vitamin status of cows.

Synthesis, evaluation and molecular modelling of piceatannol analogues as arginase inhibitors.

Arginase is involved in a wide range of pathologies including cardiovascular diseases and infectious diseases whilst it is also a promising target to improve cancer immunotherapy. To date, only a limited number of inhibitors of arginase have been reported. Natural polyphenols, among them piceatannol, are moderate inhibitors of arginase. Herein, we report our efforts to investigate catechol binding by quantum chemistry and generate analogues of piceatannol. In this work, we synthesized a novel series of amino-polyphenols which were then evaluated as arginase inhibitors. Their structure-activity relationships were elucidated by deep quantum chemistry modelling. 4-((3,4-Dihydroxybenzyl)amino)benzene-1,2-diol 3t displays a mixed inhibition activity on bovine and human arginase I with IC50 (K i) values of 76 (82) µM and 89 µM, respectively.