Effect of vitamin D on inflammatory and clinical outcomes in patients with rheumatoid arthritis: a systematic review and dose-response meta-analysis of randomized controlled trials.

CONTEXT: Rheumatoid arthritis is a chronic inflammatory disease that causes synovitis. Vitamin D deficiency is common in rheumatoid arthritis. OBJECTIVE: This systematic review and meta-analysis investigated whether vitamin D supplementation affects the inflammatory and clinical outcomes in patients with rheumatoid arthritis on the basis of randomized clinical trials. DATA SOURCES: A literature search was performed in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE, Embase, and Google Scholar for articles published until May 2022. DATA EXTRACTION: The studies were selected according to PRISMA guidelines, and the risk of bias was assessed for randomized controlled trials. DATA ANALYSIS: A random effects model was used to conduct a meta-analysis, and heterogeneity was assessed using the I2 statistic. Of 464 records, 11 studies were included from 3049 patients. Conclusion: Vitamin D supplementation did not significantly reduce C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), disease activity score in 28 joints (DAS28), or the health assessment questionnaire score; however, the response to supplementation was highly heterogeneous. The pooled analysis showed that vitamin D significantly reduced the pain-visual analogue scale (VAS) weighted mean difference (WMD = -1.30, 95% confidence interval [CI] [-2.34, -27], P = .01), DAS28-CRP (WMD = -.58, 95% CI [-.86, -.31], P < .0001), and DAS28-ESR (WMD = -.58, 95% CI [-.86, -.31], P = .0001). Subgroup analysis for vitamin D doses (>100 µg per day versus <100 µg per day) showed that the higher doses had a more significant effect on CRP than the lower doses (P < .05). CONCLUSIONS: There was no significant difference between the effect of 2 vitamin D doses on ESR and DAS28. To minimize the high heterogeneity among studies in this meta-analysis, other confounding factors such as baseline vitamin D, age, dietary vitamin D, time of year, sun exposure, drug interaction, effect dosage, and power of study should be examined.

The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.

Cilia are important cellular organelles for signaling and motility and are constructed via intraflagellar transport (IFT). RabL2 is a small GTPase that localizes to the basal body of cilia via an interaction with the centriolar protein CEP19 before downstream association with the IFT machinery, which is followed by initiation of IFT. We reconstituted and purified RabL2 with CEP19 or IFT proteins to show that a reconstituted pentameric IFT complex containing IFT81/74 enhances the GTP hydrolysis rate of RabL2. The binding site on IFT81/74 that promotes GTP hydrolysis in RabL2 was mapped to a 70-amino-acid-long coiled-coil region of IFT81/74. We present structural models for RabL2-containing IFT complexes that we validate in vitro and in cellulo and demonstrate that Chlamydomonas IFT81/74 enhances GTP hydrolysis of human RabL2, suggesting an ancient evolutionarily conserved activity. Our results provide an architectural understanding of how RabL2 is incorporated into the IFT complex and a molecular rationale for why RabL2 dissociates from anterograde IFT trains soon after departure from the ciliary base.

ß-Hydroxybutyrate and Medium-Chain Fatty Acids are Metabolized by Different Cell Types in Mouse Cerebral Cortex Slices.

Ketogenic diets and medium-chain triglycerides are gaining attention as treatment of neurological disorders. Their major metabolites, ß-hydroxybutyrate (ßHB) and the medium-chain fatty acids (MCFAs) octanoic acid (C8) and decanoic acid (C10), are auxiliary brain fuels. To which extent these fuels compete for metabolism in different brain cell types is unknown. Here, we used acutely isolated mouse cerebral cortical slices to (1) compare metabolism of 200 µM [U-13C]C8, [U-13C]C10 and [U-13C]ßHB and (2) assess potential competition between metabolism of ßHB and MCFAs by quantifying metabolite 13C enrichment using gas chromatography-mass spectrometry (GC-MS) analysis. The 13C enrichment in most metabolites was similar with [U-13C]C8 and [U-13C]C10 as substrates, but several fold lower with [U-13C]ßHB. The 13C enrichment in glutamate was in a similar range for all three substrates, whereas the 13C enrichments in citrate and glutamine were markedly higher with both [U-13C]C8 and [U-13C]C10 compared with [U-13C]ßHB. As citrate and glutamine are indicators of astrocytic metabolism, the results indicate active MCFA metabolism in astrocytes, while ßHB is metabolized in a different cellular compartment. In competition experiments, 12C-ßHB altered 13C incorporation from [U-13C]C8 and [U-13C]C10 in only a few instances, while 12C-C8 and 12C-C10 only further decreased the low [U-13C]ßHB-derived 13C incorporation into citrate and glutamine, signifying little competition for oxidative metabolism between ßHB and the MCFAs. Overall, the data demonstrate that ßHB and MCFAs are supplementary fuels in different cellular compartments in the brain without notable competition. Thus, the use of medium-chain triglycerides in ketogenic diets is likely to be beneficial in conditions with carbon and energy shortages in both astrocytes and neurons, such as GLUT1 deficiency.

Diet-induced ketosis in adult patients with subacute acquired brain injury: a feasibility study.

Background: Research in animal models on cerebral metabolism after brain injury highlights the potential benefits of ketosis in reducing secondary brain injury, but studies in humans are lacking. Aim: This study aimed to examine if a 6-week ketogenic diet intervention with added medium-chain triglycerides (MCT) was feasible in adult patients with acquired brain injury in the subacute phase, whether ketosis could be achieved and maintained, and to what extent serious adverse reactions, adverse reactions, serious adverse events, and adverse events occured. Methods: Patients ≥18 years of age diagnosed with subacute acquired brain injury and an expectation of hospitalisation ≥6 weeks were included in the intervention group. Patients not included in the intervention group were included in a standard care reference group. The intervention consisted of a ketogenic diet supplemented with MCT to obtain a plasma concentration of ß-hydroxybutyrate (BHB) ≥0.5 mmol/L. Patients who were enterally fed were given KetoCal® 2.5:1 LQ MCT Multi Fiber (Nutricia A/S, Allerød, Denmark), supplemented with Liquigen® (Nutricia A/S, Allerød, Denmark). Patients consuming oral nutrition were given KetoCal® 2.5:1 LQ MCT Multi Fiber supplemented with Liquigen®, in addition to ketogenic meals. Results: During a 13-week inclusion period, 12 of 13 eligible patients (92% [95% CI: 67% to 99%]) were included in the intervention group, and 17 of 18 excluded patients (94% [95% CI: 74% to 99%]) were included in the reference group. Eight patients (67%) completed the 6-week intervention. It took a median of 1 day to achieve ketosis from starting a 100% MCT ketogenic diet, and it was maintained for 97% of the intervention period after ketosis was obtained. There were no serious adverse reactions to the MCT ketogenic diet, and patients experienced adverse reactions not considered serious in 9.5% of days with the intervention. The MCT ketogenic diet was accepted by patients on all intervention days, and in the two patients transitioning from enteral feeding to oral intake, there were no complications related to transitioning. Conclusion: Intervention with MCT ketogenic diet is feasible and tolerated for 6 weeks in hospitalised adult patients with subacute acquired brain injury. Randomised controlled trials are needed to assess the benefits and harms of the MCT ketogenic diet and the effect on patients' recovery.Clinical trial registration: ClinicalTrials.gov, identifier [NCT04308577].

Treatment of Vitamin K Deficiency in Hemodialysis Patients - A Pilot Study Comparing Menaquinone-7 Tablets and a Vitamin K Rich Diet.

Purpose: Vitamin K deficiency and hence a high level of plasma dephosphorylated undercarboxylated matrix Gla protein (dp-ucMGP) is frequent in patients on hemodialysis. This group is recommended to restrict their potassium intake which often leads to restriction of vitamin K rich foods. A menaquinone-7 (MK-7) supplement has been shown to decrease dp-ucMGP, but it has yet to be examined if a vitamin K rich diet could be equally effective. Patients and Methods: A prospective randomized crossover intervention trial with two arms; 6 weeks of 360 µg MK-7 tablet/day and 6 weeks of a vitamin K rich diet with a 3-week washout period in between. Participants were 10 patients in hemodialysis and the primary outcome measures were changes in dp-ucMGP, total MGP (tMGP), and undercarboxylated osteocalcin (ucOC). Furthermore, the level of potassium and phylloquinone in broccoli was determined after different durations of boiling. Results: During the MK-7 intervention the dp-ucMGP and ucOC decreased significantly compared to baseline (-0.42 [-0.93; -0.22] nmol/L (p=<0.01) and -1.85 [-2.91; -1.30] nmol/L (p<0.01)), while these were unchanged during the dietary intervention (0.03 [-0.64; 0.37] nmol/L (p=1.00) and 0.30 [-1.71; 1.41] nmol/L (p=0.77)). Between the two interventions there was a greater decrease in ucOC (p=0.02) during the MK-7 compared to the dietary period. No significant changes in the total MGP levels were found in any of the periods. The retention of potassium following boiling for 2 minutes and 8 minutes was 76% and 49%, respectively, while for phylloquinone the retention was 92%, and independent of duration of boiling. Conclusion: A daily MK-7 supplement for 6 weeks lowered dp-ucMGP and ucOC significantly, while a vitamin K rich diet was not able to induce any significant effect. Boiled broccoli maintains a reasonable content of phylloquinone while potassium is extracted and is a reasonable source of phylloquinone for patients on hemodialysis.

Effects of Postdischarge High-Protein Oral Nutritional Supplements and Resistance Training in Malnourished Surgical Patients: A Pilot Randomized Controlled Trial.

The presence of malnutrition is increasingly becoming a postdischarge problem in surgical patients. We aimed to investigate whether oral nutritional supplements combined with resistance training could minimize skeletal muscle atrophy in surgical patients after discharge. This randomized controlled study was conducted at the Department of Surgery, National Hospital of Faroe Islands from 2018 to 2020. A total of 45 patients aged 37−74 years participated and were allocated to one of three groups: diet (DI; n = 13), exercise and diet (EX + DI; n = 16), or control (CON; n = 16). The intervention period lasted 8 weeks. The intervention groups received individual dietary counselling and a protein-rich oral nutritional supplement twice a day containing 22 g of protein/day. Patients in the EX + DI group were assigned to resistance training sessions. Patients in the CON group received standard care. The primary outcome was change in lean body mass (LBM). Secondary outcomes were change in body weight, handgrip strength, quality of life, surgery-related side effects, energy and protein intake, length of stay and one-year mortality. To estimate within-group changes, linear mixed models including group−time interactions as fixed effects and patients as random effects were fitted. Within-group change in LBM was 233, 813 and 78 g in the DI, EX + DI and CON groups, respectively, with no significant between-group difference (p > 0.05). Pain score declined more (p = 0.04) in the EX + DI group compared with the CON group. Body weight, handgrip strength, quality of life and surgery-related side effects did not differ between groups. At the end of study, mean cumulative weight change in the DI and EX + DI groups was 0.4% and 1.6%, respectively, whereas the CON group experienced a weight loss of −0.6%. No significant difference in primary outcome between groups was noted. However, our results indicate some benefits from exercise and nutrition for malnourished surgical patients.

Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply.

The medium-chain fatty acids octanoic acid (C8) and decanoic acid (C10) are gaining attention as beneficial brain fuels in several neurological disorders. The protective effects of C8 and C10 have been proposed to be driven by hepatic production of ketone bodies. However, plasma ketone levels correlates poorly with the cerebral effects of C8 and C10, suggesting that additional mechanism are in place. Here we investigated cellular C8 and C10 metabolism in the brain and explored how the protective effects of C8 and C10 may be linked to cellular metabolism. Using dynamic isotope labeling, with [U-13C]C8 and [U-13C]C10 as metabolic substrates, we show that both C8 and C10 are oxidatively metabolized in mouse brain slices. The 13C enrichment from metabolism of [U-13C]C8 and [U-13C]C10 was particularly prominent in glutamine, suggesting that C8 and C10 metabolism primarily occurs in astrocytes. This finding was corroborated in cultured astrocytes in which C8 increased the respiration linked to ATP production, whereas C10 elevated the mitochondrial proton leak. When C8 and C10 were provided together as metabolic substrates in brain slices, metabolism of C10 was predominant over that of C8. Furthermore, metabolism of both [U-13C]C8 and [U-13C]C10 was unaffected by etomoxir indicating that it is independent of carnitine palmitoyltransferase I (CPT-1). Finally, we show that inhibition of glutamine synthesis selectively reduced 13C accumulation in GABA from [U-13C]C8 and [U-13C]C10 metabolism in brain slices, demonstrating that the glutamine generated from astrocyte C8 and C10 metabolism is utilized for neuronal GABA synthesis. Collectively, the results show that cerebral C8 and C10 metabolism is linked to the metabolic coupling of neurons and astrocytes, which may serve as a protective metabolic mechanism of C8 and C10 supplementation in neurological disorders.

N-3 fatty acid EPA supplementation in cancer patients receiving abdominal radiotherapy - A randomised controlled trial.

BACKGROUND & AIMS: Malnutrition occurs frequently in patients with cancer during and after radiotherapy to the gastrointestinal (GI) and pelvic area and can lead to negative outcomes. N-3 fatty acids from fish, especially eicosapentaenoic acid (EPA) may possess anticachectic properties. The aim of this study was to investigate the effect of two nutritional interventions; dietary counselling and a daily oral nutritional supplement (ONS) containing 33.8 g of protein and 2.2 g EPA and 1.1 g docosahexaenoic acid (DHA) or standard care, including dietary counselling and protein supplementation when needed. METHODS: Outpatients commencing radiotherapy to the GI area were randomized to receive dietary counselling and daily supplementation over a 5-7-week period or standard care. Outcome parameters were measured at baseline (onset of radiotherapy), week 5, and 12 weeks after commencing radiotherapy, with one additional measurement of body weight at week 2. Quality of life (QoL) was measured using the EORTC QLQ-C30 questionnaire. Radiotherapy-related side effects were assessed using a questionnaire developed specifically for this study. Data from a historical control group collected in a previous observational study were included in this study to compare incidence of weight loss. RESULTS: In total, 30 patients were recruited to this study and 26 patients were enrolled and randomised. The rate of withdrawals was 7.7% at week 2, 15.4% at week 5, and 19.2% at week 12. In total, 22 patients completed the intervention. All the patients in the ONS-group and 85% in the control group experienced weight-loss. Using the intention to treat principle, there were no significant differences between groups in any of the outcomes. All patients experienced side effects. Five out of 11 patients consumed more than 75% of prescribed dose of the fish oil enriched oral nutritional supplement. Post hoc analysis showed that at week 2 the weight changed in high-compliant patients was +1.7% (1.0-2.6) compared with -0.7% (-2.8 to -0.1) in low compliant patients (p < 0,01). The results indicated a dose-response relationship, as correlation analysis recovered a significant positive correlation between weight change and compliance to the fish oil enriched nutritional supplement at both week 2 and 5 (p < 0.05 and p < 0.01, respectively), but not at week 12, indicating a dose-response relationship during radiotherapy but not after. The proportion of patients experiencing weight loss throughout the study period was higher in this study (84.2%) than in the historical control group (73%) (p<0.05%). CONCLUSION: This study showed no effect from dietary counselling and intended protein/fish-oil supplementation on weight loss, quality of life, and nutritional intake, micronutrient status in plasma or radiotherapy-related side effects compared to the control group. However, the compliance to the fish oil enriched oral nutritional supplement was low. Post hoc analysis of dose-response relations indicate a positive correlation between the compliance and the ability to reduce weight loss in cancer patients during radiotherapy treatment. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT04687124.

Causes of Vitamin K Deficiency in Patients on Haemodialysis.

Background: A low vitamin K status is common in patients on haemodialysis, and this is considered one of the reasons for the accelerated atherosclerosis in these patients. The vitamin is essential in activation of the protein Matrix Gla Protein (MGP), and the inactive form, dp-ucMGP, is used to measure vitamin K status. The purpose of this study was to investigate possible underlying causes of low vitamin K status, which could potentially be low intake, washout during dialysis or inhibited absorption capacity. Moreover, the aim was to investigate whether the biomarker dp-ucMGP is affected in these patients. Method: Vitamin K intake was assessed by a Food Frequency Questionnaire (FFQ) and absorption capacity by means of D-xylose testing. dp-ucMGP was measured in plasma before and after dialysis, and phylloquinine (vitamin K1) and dp-ucMGP were measured in the dialysate. Changes in dp-ucMGP were measured after 14 days of protein supplementation. Results: All patients had plasma dp-ucMGP above 750 pmol/L, and a low intake of vitamin K. The absorption capacity was normal. The difference in dp-ucMGP before and after dialysis was -1022 pmol/L (p < 0.001). Vitamin K1 was not present in the dialysate but dp-ucMGP was at a high concentration. The change in dp-ucMGP before and after protein supplementation was -165 pmol/L (p = 0.06). Conclusion: All patients had vitamin K deficiency. The reason for the low vitamin K status is not due to removal of vitamin K during dialysis or decreased absorption but is plausibly due to a low intake of vitamin K in food. dp-ucMGP is washed out during dialysis, but not affected by protein intake to a clinically relevant degree.

Multinutrient Supplementation Increases Collagen Synthesis during Early Wound Repair in a Randomized Controlled Trial in Patients with Inguinal Hernia.

BACKGROUND: Inguinal hernia disease is associated with an imbalanced collagen metabolism. Surgical stress has a negative impact on nutrients important for collagen synthesis. OBJECTIVE: We hypothesized that supplementation with a combination of nutrients would enhance collagen biosynthesis in inguinal hernia disease patients when undergoing hernia repair. METHODS: In this exploratory randomized controlled trial, 21 men (age: 55.2 ± 2.8 y; BMI: 25.0 ± 0.7 kg/m2) scheduled for Lichtenstein inguinal hernia repair were assigned to multinutrient supplementation (n = 10; multinutrient group) or no multinutrient supplementation (n = 11; control group). The multinutrient group received 14 g l-arginine, 14 g l-glutamine, 1250 mg vitamin C, and 55 mg zinc daily starting 14 d before surgery and ending 14 d after surgery. The multinutrient and control groups received high-quality protein to ensure a daily intake of 1.5 g protein/kg. Collagen biosynthesis was measured by the biomarkers type I procollagen propeptide (CICP), type III procollagen propeptide (PRO-C3), and type V procollagen propeptide (PRO-C5) in the sera on days -14, 0, and 1, and in the wound fluids on postoperative days 1 and 2. Compliance was recorded after the 28-d intervention period. RESULTS: Serum PRO-C5 concentrations decreased (P < 0.05) postoperatively in the control but not the multinutrient group. Neither CICP nor PRO-C3 serum concentrations differed significantly between the 2 groups. In wound fluid, the CICP concentrations increased (P < 0.05) from days 1 to 2 in the multinutrient group and were 49% higher (P = 0.10) than those in the control group on day 2. Wound fluid concentrations PRO-C3 and PRO-C5 showed no significant time or group differences. The 28-d compliance was similar (P = 0.27) in the 2 groups. CONCLUSION: Oral supplementation with arginine, glutamine, vitamin C, and zinc augment collagen synthesis during the first 2 d after inguinal hernia repair. This trial was registered at clinicaltrials.gov as NCT03221686.

Fish oil supplementation in cancer patients. Capsules or nutritional drink supplements? A controlled study of compliance.

BACKGROUND & AIMS: Fish-oil, rich in Omega-3 long chain polyunsaturated fatty acids (n-3 LC PUFAs), may in high doses inhibit the development or progression of cancer cachexia. However, poor compliance to oral nutritional supplements is a well-known problem. We aimed to investigate acceptability and compliance to a nutritional drink with fish-oil compared to an equivalent dose of fish-oil administered as capsules in patients receiving chemotherapy for GI tract cancers. Moreover, we aimed to investigate, if there was a difference between a nutritional drink or capsules with respect to nutritional status and side effects. Finally, we aimed to examine, if n-3 LC PUFAs affect leukocyte and platelet counts, and markers of dose-limiting toxicities of chemotherapy. METHODS: We consecutively included 41 patients with advanced cancer in the controlled study. Patients were allocated (not randomized) to ingest either 10 capsules/day for four weeks or 400 mL/day of a nutritional drink with same dose of n-3 LC PUFA dose. Compliance was assessed by daily self-registration and n-3 LC PUFAs in whole blood. Side effects were assessed by 10 cm visual analog scales. RESULTS: Compliance and daily consumption of n-3 LC PUFAs were 96.4% (94.1-99.3) and 4.8 (4.7-4.9) g/day in the capsule group and 80.8 (55.4-93.6) % and 4.0 (2.8-4.7) g/day in the group, respectively (p ≤ 0.02). We found no differences between the groups with respect to changes in whole blood n-3 LC PUFAs, weight, nutritional status, acceptability or side effects. However, in the capsule group the whole blood n-3 LC PUFAs correlated negatively with the increase in nausea (rs = -0.39, p = 0.05), but not in the nutritional drink group. Nausea, reduced appetite and loose stools were of greatest importance for the deviations from recommended doses. The number of capsules had a negative impact on acceptability and compliance, whereas this was mainly related to taste and texture in the nutritional drink group. No changes in median thrombocyte or leukocyte blood counts were observed. CONCLUSIONS: Fish oil in capsules appeared to result in better compliance compared to a nutritional drink with an equivalent dose of n-3 LC PUFAs. However, capsules and the drink did not differ with respect to the effect on nutritional status or side effects. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT03751384.

Tolerability of the SQ Tree SLIT Tablet in Adults.

PURPOSE: The tree pollen sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) is being developed for the treatment of tree pollen induced allergic rhinitis with or without conjunctivitis. The objective of this Phase I trial was to investigate the tolerability and acceptable dose range of the SQ tree SLIT-tablet in adults with allergic rhinoconjunctivitis. METHODS: The trial was a randomized, double-blind, placebo-controlled, dose escalation Phase I trial that included 70 adults (aged 19-61 years) with birch pollen-induced rhinoconjunctivitis with or without mild to moderate asthma. The trial included 6 different dosage groups that were randomized 3:1 to active treatment or placebo once daily for 28 days. Adverse events (AEs) were coded in the Medical Dictionary for Regulatory Activities by medically qualified personnel. Immunologic assessments included IgE and IgE-blocking factor. FINDINGS: Most (96%) reported AEs were mild, and only 5 severe events (0.2%) were reported. The most frequently reported investigational medicinal product-related AEs were oral pruritus, ear pruritus, mouth edema, sensation of foreign body, throat irritation, pharyngolaryngeal pain, dry throat, tongue blistering, eye pruritus, and headache. The trial included doses ranging from 1 to 24 development units (DU), and the mean number of investigational medicinal product-related AEs per participant was highest in the 24 DU group. The 12 and 24 DU doses induced statistically significant changes from baseline compared with placebo in birch specific IgE and IgE-blocking factor. IMPLICATIONS: The trial found that doses up to 12 DU of the SQ tree SLIT tablet have a tolerability profile suitable for at-home administration. An immunomodulatory effect was found for all doses included in the trial, and doses up to 12 DU were thus chosen for further clinical development of the SQ tree SLIT tablet. EudraCT identifier: 2007-003234-42.

Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of Randomized Trials.

Arthritis patients often take fish oil supplements to alleviate symptoms, but limited evidence exists regarding their efficacy. The objective was to evaluate whether marine oil supplements reduce pain and/or improve other clinical outcomes in patients with arthritis. Six databases were searched systematically (24 February 2015). We included randomized trials of oral supplements of all marine oils compared with a control in arthritis patients. The internal validity was assessed using the Cochrane Risk of Bias tool and heterogeneity was explored using restricted maximum of likelihood (REML)-based meta-regression analysis. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to rate the overall quality of the evidence. Forty-two trials were included; 30 trials reported complete data on pain. The standardized mean difference (SMD) suggested a favorable effect (-0.24; 95% confidence interval, CI, -0.42 to -0.07; heterogeneity, I² = 63%. A significant effect was found in patients with rheumatoid arthritis (22 trials; -0.21; 95% CI, -0.42 to -0.004) and other or mixed diagnoses (3 trials; -0.63; 95% CI, -1.20 to -0.06), but not in osteoarthritis patients (5 trials; -0.17; 95% CI, -0.57-0.24). The evidence for using marine oil to alleviate pain in arthritis patients was overall of low quality, but of moderate quality in rheumatoid arthritis patients.

A mixed diet supplemented with L-arabinose does not alter glycaemic or insulinaemic responses in healthy human subjects.

In addition to a yet-to-be published study showing arabinose to have an inhibiting effect on maltase, in vitro studies have shown L-arabinose to exert an inhibiting effect on small-intestinal sucrase and maltase and the consumption of a sucrose-rich drink containing L-arabinose to exert positive effects on postprandial blood glucose, insulin and C-peptide responses in humans. However, the effects of adding L-arabinose to mixed meals on the indices of glucose control are unknown. The purpose of the present study was to investigate whether the positive effects of L-arabinose added to a sugar drink could be reproduced in subjects consuming a mixed meal containing sucrose and/or starch from wheat flour. A total of seventeen healthy men participated in study 1, a randomised, double-blind, cross-over trial. In this study, the subjects consumed two different breakfast meals containing sucrose and starch from wheat flour (meal A) or starch from wheat flour (meal B) supplemented with 0, 5 and 10 % L-arabinose by weight after a 12 h fast. A total of six healthy men participated in study 2, a randomised, double-blind, cross-over trial. In this study, the subjects also consumed meal B served in two different textures and a liquid meal with maltose supplemented with 0 and 20% L-arabinose. In addition, 1·5 g of paracetamol was chosen as an indirect marker to assess gastric emptying. Postprandial plasma glucose, insulin and C-peptide concentrations were measured regularly for 3 h. The results of the present study showed that the peak plasma concentration, time to reach peak plasma concentration or AUC values of glucose, insulin and C-peptide were not altered after consumption of the test meals. Overall, it was not possible to reproduce the beneficial effects of L-arabinose added to sucrose drinks when L-arabinose was mixed in a solid or semi-solid mixed meal.

Estimation of health-related utility (EQ-5D index) in subjects with seasonal allergic rhinoconjunctivitis to evaluate health gain associated with sublingual grass allergen immunotherapy.

BACKGROUND: Grass allergen immunotherapy (AIT) reduces symptom severity in seasonal allergic rhinoconjunctivitis (ARC) but its impact on general health-related utility has not been characterised for the purposes of economic evaluation. The aim of this study was to model the preferred measure of utility, EQ-5D index, from symptom severity and estimate incremental quality adjusted life years (QALYs) associated with SQ-standardised grass immunotherapy tablet (GRAZAX®, 75,000 SQ-T/2,800 BAU, ALK, Denmark). METHODS: Data were analysed from five consecutive pollen seasons in a randomised placebo controlled trial of GRAZAX®. Binomial and Gaussian mixed effects modelling related weekly EQ-5D index score to daily symptom and medication scores (DSS & DMS respectively). In turn, daily EQ-5D index was estimated from ARC symptoms and medication use. RESULTS: DSS and DMS were the principal predictors of 'perfect' health (EQ-5D = 1.000; binomial) and 'imperfect' health (EQ-5D < 1.000; Gaussian). Each unit increase in DSS and DMS reduced the odds of 'perfect' health (EQ-5D = 1.000) by 27% and 16% respectively, and reduced 'imperfect' health by 0.17 and 0.13, respectively. Gender remained the only other significant main fixed effect (Male odds ratio [OR] = 1.82). Incremental estimated EQ-5D index utility for GRAZAX® was observed from day -30 to day +70 of the pooled pollen season; mean daily utility for GRAZAX® = 0.938 units (95%CI 0.932-0.943) vs. 0.914 (0.907-0.921) for placebo, an incremental difference of 0.0238 (p < 0.001). This translates into an incremental 0.0324 Quality Adjusted Life Years over the five year study period. CONCLUSIONS: ARC symptoms and medication use are the main predictors of EQ-5D index. The incremental QALYs observed for GRAZAX® may not fully describe the health benefits of this treatment, suggesting that economic modelling may be conservative.

Randomized trial of the effects of individual nutritional counseling in cancer patients.

BACKGROUND & AIMS: Cancer-related malnutrition is multifactorial and related to a bad prognosis. The aim of this study was to investigate the effect of intensive, individual dietary counseling of patients in radiotherapy and/or chemotherapy for gynecologic-, gastric-, or esophageal cancer. METHODS: 61 outpatients were stratified by diagnoses and randomly assigned to one of two groups (G1; n = 32 and G2; n = 29). The basic regimen, applied to both groups, included measurement of body weight, 24-h dietary recall interview, micronutrient status and quality of life. In addition G1 received intensive, individual dietary counseling one hour per week and, if the patient accepted, a daily oral nutritional supplement containing 2531 kJ, 33.8 g protein and 2.2 g EPA. RESULTS: At the end of the treatment period, significantly fewer patients had lost weight in the intervention group (mean: 44% vs. 72%, p < 0.05), and the fulfillment of estimated energy requirements was better during treatment (mean: 107% vs. 95%, p < 0.05). A significant positive effect was observed on the fulfillment of protein requirement, both during the treatment period (mean: 92% vs. 71%, p < 0.001) and at follow-up (mean: 86% vs. 71%, p < 0.05). CONCLUSION: In these cancer patients, intensive, individual dietary counseling was associated with a better weight maintenance and a higher provision of adequate amounts of protein and energy. The intervention had no significant effects on patients' quality of life, incidence of treatment-related side effects or appearance of micronutrient deficiencies.

A phase 3 trial assessing the efficacy and safety of grass allergy immunotherapy tablet in subjects with grass pollen-induced allergic rhinitis with or without conjunctivitis, with or without asthma.

BACKGROUND: Design and execution of immunotherapy trials for seasonal allergies may be complicated by numerous factors including variable allergy testing methods, pollen levels, and timing and intensity of other seasonal allergens. We evaluated grass allergy immunotherapy tablet (AIT) treatment in North American adults with grass pollen-induced allergic rhinitis with or without conjunctivitis (AR/C), with/without asthma. METHODS: Subjects age 18-65 with clinical history of grass pollen-induced AR/C, with/without asthma were randomized 1:1 to once-daily 2800 BAU Timothy grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, containing approximately 15 µg of Phl p 5) or placebo. The AR/C symptom and medication scores were recorded daily. The primary end point was the average AR/C daily symptom score (DSS) during the entire grass pollen season (GPS). Ranked key secondary end points were Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, daily medication score (DMS), and percentage of well days, all over entire GPS. Safety was monitored through adverse event reporting. RESULTS: Efficacy analysis included 289 subjects. Over the entire GPS, mean DSS was 6% lower with AIT versus placebo (5.69 vs. 6.06), but this difference was not statistically significant (p = 0.3475) despite significantly higher immunological response in the grass AIT group. No significant between-group differences were seen for key secondary end points. In general, DSS was high before GPS began and no clear relationship between DSS and grass pollen counts was seen during GPS. In post hoc analysis of subjects with pre-seasonal DSS ≤3, mean DSS and DMS were both significantly lower with grass AIT versus placebo (27%; p = 0.0327 and 68%; p = 0.0060, respectively). In this subgroup a relationship between DSS and grass pollen counts was observed. Grass AIT was generally well tolerated, with no events of anaphylactic shock or respiratory compromise. CONCLUSIONS: In this trial, 2800 BAU grass AIT did not demonstrate significant symptom improvement versus placebo. Lack of relationship between pollen count and symptom score in the study population, and post hoc findings among subjects with low pre-seasonal symptoms, suggest that the symptoms reported in this study were not primarily reflective of the effects of grass pollen exposure. TRIAL REGISTRATION: NCT00421655.

SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial.

BACKGROUND: The main aim of specific immunotherapy is sustained effect due to changes in the immune system that can be demonstrated only in long-term trials. OBJECTIVE: To investigate sustained efficacy and disease modification in a 5-year double-blind, placebo-controlled trial, including 2 years of blinded follow-up after completion of a 3-year period of treatment, with the SQ-standardized grass allergy immunotherapy tablet, Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU,(∗) ALK, Denmark) or placebo. METHODS: A randomized, double-blind, placebo-controlled, multinational, phase III trial included adults with a history of moderate-to-severe grass pollen-induced allergic rhinoconjunctivitis, with or without asthma, inadequately controlled by symptomatic medications. Two hundred thirty-eight participants completed the trial. End points included rhinoconjunctivitis symptom and medication scores, combined scores, asthma symptom and medication scores, quality of life, days with severe symptoms, immunologic end points, and safety parameters. RESULTS: The mean rhinoconjunctivitis daily symptom score was reduced by 25% to 36% (P ≤ .004) in the grass allergy immunotherapy tablet group compared with the placebo group over the 5 grass pollen seasons covered by the trial. The rhinoconjunctivitis DMS was reduced by 20% to 45% (P ≤ .022 for seasons 1-4; P = .114 for season 5), and the weighted rhinoconjunctivitis combined score was reduced by 27% to 41% (P ≤ .003) in favor of active treatment. The percentage of days with severe symptoms during the peak grass pollen exposure was in all seasons lower in the active group than in the placebo group, with relative differences of 49% to 63% (P ≤ .0001). Efficacy was supported by long-lasting significant effects on the allergen-specific antibody response. No safety issues were identified. CONCLUSION: The results confirm disease modification by SQ-standardized grass allergy immunotherapy tablet in addition to effective symptomatic treatment of allergic rhinoconjunctivitis.