Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

The impact of the introduction of selective screening in the UK on the epidemiology, presentation, and treatment outcomes of developmental dysplasia of the hip.

Aims: Developmental dysplasia of the hip (DDH) can be managed effectively with non-surgical interventions when diagnosed early. However, the likelihood of surgical intervention increases with a late presentation. Therefore, an effective screening programme is essential to prevent late diagnosis and reduce surgical morbidity in the population. Methods: We conducted a systematic review and meta-analysis of the epidemiological literature from the last 25 years in the UK. Articles were selected from databases searches using MEDLINE, EMBASE, OVID, and Cochrane; 13 papers met the inclusion criteria. Results: The incidence of DDH within the UK over the last 25 years is 7.3/1,000 live births with females making up 86% of the DDH population (odds ratio 6.14 (95% confidence interval 3.3 to 11.5); p < 0.001). The incidence of DDH significantly increased following the change in the Newborn and Infant Physical Examination (NIPE) guidance from 6.5/1,000 to 9.4/1,000 live births (p < 0.001). The rate of late presentation also increased following the changes to the NIPE guidance, rising from 0.7/1,000 to 1.2/1,000 live births (p < 0.001). However, despite this increase in late-presenting cases, there was no change in the rates of surgical intervention (0.8/1,000 live births; p = 0.940). Conclusion: The literature demonstrates that the implementation of a selective screening programme increased the incidence of DDH diagnosis in the UK while subsequently increasing the rates of late presentation and failing in its goal of reducing the rates of surgical intervention for DDH.

The cost effectiveness of potential risk factors for developmental dysplasia of the hip within a national screening programme.

Early detection of developmental dysplasia of the hip (DDH) is associated with improved outcomes of conservative treatment. Therefore, we aimed to evaluate a novel screening programme that included both the primary risk factors of breech presentation and family history, and the secondary risk factors of oligohydramnios and foot deformities. A five-year prospective registry study investigating every live birth in the study's catchment area (n = 27,731), all of whom underwent screening for risk factors and examination at the newborn and six- to eight-week neonatal examination and review. DDH was diagnosed using ultrasonography and the Graf classification system, defined as grade IIb or above or rapidly regressing IIa disease (≥4o at four weeks follow-up). Multivariate odds ratios were calculated to establish significant association, and risk differences were calculated to provide quantifiable risk increase with DDH, positive predictive value was used as a measure of predictive efficacy. The cost-effectiveness of using these risk factors to predict DDH was evaluated using NHS tariffs (January 2021). The prevalence of DDH that required treatment within our population was 5/1,000 live births. The rate of missed presentation of DDH was 0.43/1000 live births. Breech position, family history, oligohydramnios, and foot deformities demonstrated significant association with DDH (p < 0.0001). The presence of breech presentation increased the risk of DDH by 1.69% (95% confidence interval (CI) 0.93% to 2.45%), family history by 3.57% (95% CI 2.06% to 5.09%), foot deformities by 8.95% (95% CI 4.81% to 13.1%), and oligohydramnios nby 11.6% (95 % CI 3.0% to 19.0%). Primary risk factors family history and breech presentation demonstrated an estimated cost-per-case detection of £6,276 and £11,409, respectively. Oligohydramnios and foot deformities demonstrated a cost-per-case detected less than the cost of primary risk factors of £2,260 and £2,670, respectively. The inclusion of secondary risk factors within a national screening programme was clinically successful as they were more cost and resource-efficient predictors of DDH than primary risk factors, suggesting they should be considered in the national guidance.

Delay to elective colorectal cancer surgery and implications for survival: a systematic review and meta-analysis.

AIM: The Covid-19 pandemic has delayed elective colorectal cancer (CRC) surgery. The aim of this study was to see whether or not this may affect overall survival (OS) and disease-free survival (DFS). METHOD: A systematic review was carried out according to PRISMA guidelines (PROSPERO ID: CRD42020189158). Medline, EMBASE and Scopus were interrogated. Patients aged over 18 years with a diagnosis of colon or rectal cancer who received elective surgery as their primary treatment were included. Delay to elective surgery was defined as the period between CRC diagnosis and the day of surgery. Meta-analysis of the outcomes OS and DFS were conducted. Forest plots, funnel plots and tests of heterogeneity were produced. An estimated number needed to harm (NNH) was calculated for statistically significant pooled hazard ratios (HRs). RESULTS: Of 3753 articles identified, seven met the inclusion criteria. Encompassing 314 560 patients, three of the seven studies showed that a delay to elective resection is associated with poorer OS or DFS. OS was assessed at a 1 month delay, the HR for six datasets was 1.13 (95% CI 1.02-1.26, p = 0.020) and at 3 months the pooled HR for three datasets was 1.57 (95% CI 1.16-2.12, p = 0.004). The estimated NNH for a delay at 1 month and 3 months was 35 and 10 respectively. Delay was nonsignificantly negatively associated with DFS on meta-analysis. CONCLUSION: This review recommends that elective surgery for CRC patients is not postponed longer than 4 weeks, as available evidence suggests extended delays from diagnosis are associated with poorer outcomes. Focused research is essential so patient groups can be prioritized based on risk factors in future delays or pandemics.

Hepatobiliary clearance of labelled mebrofenin in normal and D-galactosamine HCl-induced hepatitis rats and the protective effect of turmeric extract.

This study was carried out to see the hepatobiliary clearance of 99m Tc-Mebrofenin radiopharmaceutical in D-galactosamine induced hepatic rats. Furthermore, protective effect of turmeric extract has been studied in these hepatitis rats. Hepatitis was induced with intraperitoneal injection of D-galactosamine (400 mg/kg b. wt) in these rats. 1% turmeric extract was given along with their normal diet for 15 days. Turmeric extract treatment significantly increased the hepatic uptake of radioactivity and accelerated the excretion of 99m Tc-Mebrofenin as compared to control rats. (P < 0.001). In D-galactosamine administered rats, a significant delay was observed in 99m Tc-Mebrofenin excretion as compared to controls. However, D-galactosamine administered rats, pretreated with turmeric extract or concurrently treated with turmeric extract showed a near normal pattern of 99m Tc-Mebrofenin excretion. Hence, it can be suggested that turmeric extract may improve the liver function by detoxification.

Body fat distribution and flow-mediated endothelium-dependent vasodilation in older men.

OBJECTIVE: Recent studies indicate that abdominal fat accumulation, in particular intra-abdominal fat, is related to impaired endothelial function in young healthy volunteers. The aim of this study was to examine whether the distribution of body fat depots is related to impaired endothelial function in older men. METHODS: Cross-sectional sample of 38 older (68+/-1 y) sedentary (VO(2max)=2.4+/-0.1 l/min) men. Flow-mediated endothelial dependent vasodilation (EDD) was assessed in the brachial artery in response to reactive hyperemia using high-resolution ultrasound. Abdominal subcutaneous and visceral fat depots were assessed by computed tomography scan (CT-scan) at the L(4)-L(5) region in the supine position. Percentage body fat was assessed via dual-energy X-ray absorptiometry (DEXA). RESULTS: Flow-mediated percentage change in brachial artery was 7.6+/-0.7%, suggesting an impaired flow-mediated EDD. Using simple linear regression analysis, there were no statistically significant relationship observed between flow-mediated EDD and the indices of total and abdominal adiposity (percentage body fat=29.3+/-0.9%, r=-0.11; total abdominal fat area=465+/-23 cm(2), r=-0.1; intra-abdominal fat area=200+/-14 cm(2), r=-0.14; subcutaneous fat area=265+/-13 cm(2), r=-0.05; BMI=29.3+/-0.9 kg/m(2), r=-0.07; and waist to hip ratio=0.98+/-0.01, r=-0.20). CONCLUSION: These findings suggest that in older sedentary men there is no clear correlation between adiposity and body fat distribution and impairment of flow-mediated endothelium dependent vasodilation.

Short-term moderate weight loss and resistance training do not affect insulin-stimulated glucose disposal in postmenopausal women.

OBJECTIVES: Moderate weight loss and exercise have been proposed as important tools in the treatment and prevention of type 2 diabetes. Therefore, we tested the hypothesis that short-term (4 weeks) moderate energy restriction (-750 kcal/day) would result in a significant increase in insulin-stimulated glucose disposal (40 mU x m(-2) x min(-1) hyperinsulinemic-euglycemic clamp) in moderately overweight postmenopausal women and that when combined with resistance training (RT) an even greater effect would be seen. RESEARCH DESIGN AND METHODS: Older women were randomly assigned to energy restriction (WLoss group; n = 9) or energy restriction plus RT (RT + WLoss group; n = 10). RESULTS: For the WLoss versus the RT + WLoss groups, changes in body weight (-3.0 +/- 0.2 kg vs. -3.2 +/- 0.3 kg), fat mass (FM) (-3.0 +/- 0.3 kg vs. -3.2 +/- 0.3 kg), and percent body fat (BF) (-2.1 +/- 0.4 vs. -2.4 +/- 0.3%) were not different between groups. Muscle mass (group-by-time interaction, P = 0.04) was preserved in RT + WLoss (0.40 +/- 0.40 kg) and reduced in WLoss (-0.64 +/- 0.18 kg). There were no changes in fat-free mass (FFM) and waist-to-hip ratio in either group. Whole body glucose disposal (WLoss 6.14 +/- 0.57 vs. 6.03 +/- 0.53, RT + WLoss 5.85 +/- 0.60 vs. 6.09 +/- 0.56 mg/kg of FFM/min) did not change in either group. CONCLUSIONS: The results of this study demonstrate that short-term energy restriction resulting in moderate decreases in body weight (4.0 +/- 0.3%) and FM (8.2 +/- 0.7%) did not improve insulin-stimulated glucose disposal. The addition of RT to the hypoenergetic diet preserved muscle mass but provided no synergistic effect on insulin action. These results suggest that a greater change in body weight or FM may be necessary to observe a significant improvement in insulin action.

Resistance training affects iron status in older men and women.

OBJECTIVE: To examine the effects of resistance training on hematological and selected indices of iron status in 17 women aged 54-71 years and 18 men aged 56-69 years. DESIGN: Tests and evaluations were done before and after all subjects participated in a resistance-training program twice weekly for 12 weeks. RESULTS: The resistance training was effective as evidenced by increases in skeletal muscle strength of 20 +/- 9% and 23 +/- 13% for the men and women, respectively. Hematological parameters and serum iron concentrations were within normal clinical ranges and were unchanged by resistance training for both the men and the women. Total iron binding capacity (TIBC) and transferrin saturation were also unaffected by resistance training in the women but were significantly affected in the men. The men showed a decreased TIBC (p < .0001) and an increased transferrin saturation (p = .050). Serum ferritin concentrations decreased significantly in the women (p = .041) but were unchanged in the men. Transferrin receptor concentrations were unaffected by resistance training in the women but increased significantly in the men (p = .030). CONCLUSIONS: With resistance training, iron status of older men and women changes in a sex specific way.

Relationships of plasma C-peptide and gender to the urinary excretion of inositols in older people.

PURPOSE: The urinary excretions of myo-inositol and D-chiro-inositol are elevated in diabetes, and have been suggested as possible markers or effectors of insulin action. The aim of the present study was to measure the urinary excretion of these compounds, and to assess possible relationships with the metabolic control of glucose, in older, non-diabetic men and women. SUBJECTS: 32 older (age range 54-71 yrs), moderately overweight (body mass index 29.1 +/- 0.4 kg/m2, mean +/- SEM), non-diabetic men (n = 17) and women (n = 15). METHODS: 75 g oral glucose tolerance testing was done the day after all subjects had consumed nutrient-defined menus for five days. Plasma samples were analyzed for the concentrations of glucose, insulin, and C-peptide, and the 180-minute area under the curve (AUC) for each of these compounds was calculated. Samples from 24-hour urine collections were analyzed for the concentrations of myo-inositol, D-chiro-inositol, L-chiro-inositol, and pinitol. RESULTS: The fasting glucose, insulin, and C-peptide, and the AUC for glucose and insulin, were not different between men and women. C-peptide AUC was greater in the men versus the women (p < 0.001). The median urinary excretions (micromol/g creatinine) of myo-inositol (p < 0.001), D-chiro-inositol (p < 0.001), L-chiro-inositol (p < 0.05), and pinitol (p < 0.001) were higher, and the myo-inositol:D-chiro-inositol ratio was lower (p < 0.001), in the men versus women. For all subjects combined, C-peptide AUC was positively correlated with the urinary excretion of each of the measured inositols, as well as the myo-inositol:D-chiro-inositol ratio. The correlations between C-peptide AUC and these inositols were strongly influenced by the co-linear relationship between C-peptide AUC and gender. CONCLUSIONS: Collectively, these data show that older, moderately overweight, non-diabetic men and women with gender-related differences in glucose-stimulated C-peptide AUC, an indirect indicator of insulin secretion, also display differences in the urinary excretion of myo-inositol, D-chiro-inositol, L-chiro-inositol, and pinitol. The gender-related difference in the myo-inositol:D-chiro-inositol ratio suggests that, while the urinary excretion of all of the inositols measured were higher in the men than the women, the difference was more pronounced for D-chiro-inositol.

Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease.

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality. Endothelial function, which is a measure of vascular health, is impaired in patients with PAD. We examined the effects of 6 months of aerobic exercise rehabilitation on brachial artery endothelial function, assessed using high-frequency ultrasonography, and calf blood flow in 19 older PAD patients (age 69 +/- 1 years, mean +/- SEM) with intermittent claudication (ankle to brachial artery index of 0.73 +/- 0.04). After exercise, the time to onset of claudication pain increased by 94%, from 271 +/- 49 to 525 +/- 80 seconds (p <0.01), and the time to maximal claudication pain increased by 43%, from 623 +/- 77 to 889 +/- 75 seconds (p <0.05). Exercise rehabilitation increased the flow-mediated brachial arterial diameter by 61%, from 0.18 +/- 0.03 to 0.29 +/- 0.04 mm (p <0.005), as well as the relative change in brachial arterial diameter from the resting state by 60%, from 4.81 +/- 0.82% to 7.97 +/- 1.03% (p <0.005). Maximal calf blood flow (14.2 +/- 1.0 vs 19.2 +/- 2.0 ml/100 ml/min; p = 0.04), and postocclusive reactive hyperemic blood flow (9.8 +/- 0.8 vs 11.3 +/- 0.7 ml/100 ml/min; p = 0.1) increased 35% and 15%, respectively. In conclusion, exercise rehabilitation improved ambulatory function, endothelial-dependent dilation, and calf blood flow in older PAD patients with intermittent claudication.

Differential effect of resistance training on the body composition and lipoprotein-lipid profile in older men and women.

The effects of a 12-week resistance exercise training (RT) program on body composition and serum lipid concentrations were assessed in weight-stable, moderately overweight older men (n = 18) and women (n = 17) aged 54 to 71 years with a body mass index (BMI) of 26 to 36 kg/m2. Following RT, the men had a significant increase in fat-free mass (FFM) and a decrease in percent body fat (%BF) and fat mass (FM), whereas the women demonstrated no change, resulting in significant time-by-sex interactions for FFM (P = .002), %BF (P = .006), and FM (P = .005). There were no changes in total cholesterol (Chol), low-density lipoprotein cholesterol (LDL-C), or triacylglycerol (Tg) due to RT. However, following RT, high-density lipoprotein cholesterol (HDL-C) increased (0.06+/-0.02 mmol/L) in the men and decreased (0.09+/-0.03 mmol/L) in the women (time-by-sex interaction, P = .0004). The Chol/HDL-C ratio decreased (0.36+/-0.11) in the men and increased (0.29+/-0.10) in the women (time-by-sex interaction, P = .0001). For all subjects combined, the changes in HDL-C and the Chol/HDL-C ratio were not related to any changes in body fat stores (ie, %BF or FM), suggesting that RT may potentially alter the lipoprotein-lipid profile in older weight-stable men and women. In conclusion, although the changes in the lipoprotein-lipid profile were small, the men had a significantly increased HDL-C level and decreased Chol/HDL-C ratio, while the women demonstrated opposite changes.

Effect of resistance training with or without chromium picolinate supplementation on glucose metabolism in older men and women.

The effect of 12 weeks of resistance training (RT) with or without chromium picolinate (Cr-pic) supplementation on glucose tolerance was assessed in moderately overweight older men and women (age, 62 +/- 4 years; body mass index [BMI], 29.1 +/- 2.5 kg/m2). Seventeen men and 15 women were randomized to groups that consumed either 17.8 micromol chromium per day (924 microg Cr/d) as Cr-pic or a placebo (<0.1 microg Cr/d) while performing RT twice weekly. For all 32 subjects combined, fasting glucose increased but there were no changes in insulin or C-peptide concentrations after 12 weeks of RT. In response to an oral glucose challenge, the glucose and C-peptide areas under the curve (AUCs) were unchanged, whereas there was a 19% decrease in the insulin AUC (from 68 +/- 53 to 55 +/- 29 x 10(3) pmol/L/180 min, P = .045). The RT responses for the fasting concentration or AUC for glucose, insulin, or C-peptide were not influenced by Cr-pic. The decrease in the insulin AUC without any change in insulin secretion, as evidenced by a lack of change in the C-peptide AUC, suggests enhanced insulin clearance from the circulation with RT. Collectively, these data suggest that RT decreases the insulin response following an oral glucose challenge in older moderately overweight men and women without affecting glucose tolerance. The data also suggest that the decrease in circulating insulin may result from an increase in insulin clearance, not a decrease in insulin secretion. High-dose Cr-pic supplementation had no effect on any measure of glucose metabolism during RT.

Effects of resistance training and chromium picolinate on body composition and skeletal muscle in older men.

The effects of chromium picolinate (CrPic) supplementation and resistance training (RT) on skeletal muscle size, strength, and power and whole body composition were examined in 18 men (age range 56-69 yr). The men were randomly assigned (double-blind) to groups (n = 9) that consumed either 17.8 micromol Cr/day (924 microg Cr/day) as CrPic or a low-Cr placebo for 12 wk while participating twice weekly in a high-intensity RT program. CrPic increased urinary Cr excretion approximately 50-fold (P < 0.001). RT-induced increases in muscle strength (P < 0.001) were not enhanced by CrPic. Arm-pull muscle power increased with RT at 20% (P = 0.016) but not at 40, 60, or 80% of the one repetition maximum, independent of CrPic. Knee-extension muscle power increased with RT at 20, 40, and 60% (P < 0.001) but not at 80% of one repetition maximum, and the placebo group gained more muscle power than did the CrPic group (RT by supplemental interaction, P < 0.05). Fat-free mass (P < 0.001), whole body muscle mass (P < 0.001), and vastus lateralis type II fiber area (P < 0.05) increased with RT in these body-weight-stable men, independent of CrPic. In conclusion, high-dose CrPic supplementation did not enhance muscle size, strength, or power development or lean body mass accretion in older men during a RT program, which had significant, independent effects on these measurements.

Chromium picolinate supplementation and resistive training by older men: effects on iron-status and hematologic indexes.

Chromium competes with iron for binding to transferrin, and high-dose chromium supplementation has been hypothesized to adversely affect iron status. This study examined the effects of chromium picolinate supplementation on hematologic indexes and selected indexes of iron status in 18 men aged 56-69 y who participated in an introductory resistive training program. The men were randomly assigned (double-blind design) to groups (n = 9) that consumed either 17.8 mumol Cr/d (924 micrograms Cr/d) as chromium picolinate or a low-chromium placebo for 12 wk while engaging in resistive training twice weekly (3 sets of 8-12 repetitions at 80% of one repetition maximum for 5 exercises). Hematocrit, hemoglobin, red blood cell (erythrocyte) count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution width, platelet count, and mean platelet volume were within normal clinical ranges and were unchanged by either chromium picolinate supplementation or resistive training. Resistive training decreased total-iron-binding capacity from 38.4 +/- 9.3 to 27.3 +/- 5.6 mumol/L (P < 0.0001) and increased transferrin saturation from 35.7 +/- 16.3% to 45.4 +/- 16.9% (P = 0.050). Chromium picolinate supplementation did not influence these responses. Serum iron concentrations and serum ferritin concentrations were unchanged by either resistive training or chromium picolinate supplementation. These data suggest that high-dose chromium picolinate supplementation for 12 wk did not influence hematologic indexes or indexes of iron metabolism or status in older men. The decrease in total-iron-binding capacity and increase in transferrin saturation (%) with resistive training are largely opposite to changes associated with iron depletion and suggest a novel effect of resistive training on iron transport.

Effects of resistance training and dietary protein intake on protein metabolism in older adults.

Nitrogen (N) balance, fed-state leucine kinetics, and urinary 3-methylhistidine (3-MeH) excretion were examined in 12 men and women, aged 56-80 yr, before and during 12 wk of resistance training (RT). Subjects were randomized to groups that consumed diets providing either 0.80 +/- 0.02 g protein.kg-1.day-1 (lower protein, LP) or 1.62 +/- 0.02 g protein.kg-1.day-1 (higher protein, HP). At baseline, mean N balance was negative for LP (-4.6 +/- 3.4 mg N.kg-1.day-1) and positive for HP (13.6 +/- 1.0 mg N.kg-1.day-1). N retention increased similarly in LP and HP at the 11th wk of RT by 12.8 and 12.7 mg N.kg-1.day-1, respectively. Thus LP had an increased efficiency of N retention. LP had decreased leucine flux (P < 0.001), oxidation (P < 0.001), and uptake for protein synthesis (P < 0.02), relative to HP, both at baseline and after RT. Leucine flux increased with RT in both diet groups (P < 0.05) and was associated mainly with an increase in protein synthesis in LP (91% of change in flux) and an increase in oxidation in HP (72% of change in flux; RT-diet interaction, P < 0.05). RT increased actomyosin protein breakdown (increased 3-MeH-to-creatinine ratio, P < 0.01). Diet-related differences in protein metabolism did not influence body composition changes with RT. These data show that the efficiency of N retention and protein utilization during RT is higher in older subjects who consume 0.8 vs. 1.6 g protein.kg-1.day-1 dietary protein.

Fc gamma RII cross-linking inhibits anti-Ig-induced erg-1 and erg-2 expression in BCL1.

Activation of B cells through their Ag receptor is known to be negatively regulated by Fc gamma RII engagement. To explore the molecular and biochemical mechanisms of Fc gamma RII-mediated inhibition, we investigated the effect of Fc gamma RII engagement on the expression of two immediate-early genes, egr-1 and egr-2, and tyrosine phosphorylation events following the activation of the murine B cell line, BCL1. Egr-1 and egr-2 were expressed in BCL1 after slg cross-linking. The induction of egr-1 and egr-2 expression was prevented when the Fc gamma RII was co-cross-linked with slg in BCL1, but not in WEHI-231. The inhibitory effects of Fc gamma RII engagement on egr-1 and egr-2 expression occurred when the Fc gamma RII was cross-linked with either slgM or slgD. Treatment with cyclosporin A prevented the expression of egr-2 induced by slg cross-linking, but did not inhibit egr-1 expression. In addition, cyclosporin A did not prevent the negative-regulatory effects of Fc gamma RII engagement on egr-1 expression, suggesting that the Fc gamma RII works upstream from the site of action of cyclosporin A. To investigate activation signals more proximal to the plasma membrane, we compared tyrosine phosphorylation patterns of several effector molecules known to play a role in B cell activation. Cross-linking of slg induced tyrosine phosphorylation of the p62 GAP-associated protein. The p62 protein became hyperphosphorylated in response to co-cross-linking of slg with Fc gamma RII. Our results identify egr-1 and egr-2 as targets of Fc gamma RII-mediated inhibition of anti-Ig-induced B cell activation. In addition, they show that negative regulation by Fc gamma RII is effective in both cyclosporin A-sensitive and insensitive pathways. Further, we suggest a possible Fc gamma RII signaling pathway leading to the inhibition of egr-1 and egr-2 expression.

Measurement of serum thyrotropin levels using sensitive immunoradiometricassays in patients with chronic renal failure: alterations suggesting an intact pituitary thyroid axis.

Serum thyroid stimulating hormone (TSH) levels were measured in 127 patients with varying grade of chronic renal failure (CRF). Sensitive immunoradiometricassays (IRMA) were used so that small changes in TSH levels if any, could be appreciated, and to see if such alterations exhibit some relationship with those in thyroid hormone levels. Mean serum TSH levels in the patient group of 2.33 microU/ml (0.07-7.3) was significantly higher in comparison to 1.73 microU/ml (0.25-4.6) in normal subjects (p < 0.001). However, they were not significantly different when measured by radioimmunoassay (RIA) as compared to normals. Serum triiodothyronine (T3), thyroxine (T4) and free triiodothyronine (FT3) levels of 72 +/- 32 ng/dl, 7.4 +/- 2.6 micrograms/dl and 2.9 +/- 0.9 pg/ml were significantly lower than in normal subjects, whereas serum free thyroxine (FT4) showed a slight though not significant elevation. When patients were divided in three subgroups according to the degree of renal insufficiency, TSH levels showed a gradual rise with corresponding depression in their T3, FT3 and T4 levels. In 19 patients who were on hemodialysis (HD) and subsequently received successful renal transplantation, most of the thyroid function parameters returned towards the normals with TSH undergoing significant depression from their pretransplant levels as well as from normal levels. The results indicated that a slight but significant elevation in TSH levels could be revealed by sensitive IRMA in patients with CRF. Rising TSH levels with increasing renal insufficiency and its inverse relationship with T3 and T4 levels suggest maintenance of pituitary thyroid axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential induction of Egr-1 expression in WEHI-231 sublines does not correlate with apoptosis.

To determine whether the absence of inducible Egr-1 expression correlates with apoptosis and growth arrest, we compared the inducible expression of two Egr family members (Egr-1 and Egr-2) in three sublines of WEHI-231. Expression of Egr-2 is induced in all sublines of WEHI-231 following surface immunoglobulin (sIg) cross-linking, but Egr-1 expression is induced in only two. We find that the lack of inducible Egr-1 expression corresponded to an increase in the methylation pattern of the Egr-1 gene. In spite of these differences in Egr-1 expression, all the sublines demonstrate similar inhibition of [3H] thymidine incorporation following anti-Ig treatment. Growth arrest leads to apoptosis in only two of the sublines, but apoptosis does not correlate with the absence of inducible Egr-1 expression. Demethylation, by treatment with 5-azacytidine, in the Egr-1 non-expressing subline allows for induction of Egr-1 expression by anti-Ig, but fails to prevent growth arrest and apoptosis. Therefore, we conclude that the lack of Egr-1 expression is not responsible for either the apoptotic response or growth arrest induced by anti-Ig in WEHI-231.

Energy expenditure in lactating women: a comparison of doubly labeled water and heart-rate-monitoring methods.

Estimates of total daily energy expenditure (TDEE) by heart-rate (HR) monitoring were compared with those made by the doubly labeled water (DLW) method in nine exclusively breast-feeding women. Subjects recorded HR and dietary intake daily during the 8-d, isotope-measurement period. Milk energy output was determined by 3-d test weighing and analysis of 24-h milk samples. Total energy output (milk energy and TDEE) averaged 12.36 +/- 1.03 MJ/d with DLW compared with 11.74 +/- 1.3 MJ/d with HR monitoring, a 5.8% difference (NS). Individual differences ranged from -27.1% to +17.6%. The high water turnover and relatively low level of activity during lactation made the slopes of deuterium and 18O disappearance more similar, resulting in increased error in estimates of TDEE by DLW. Therefore, the DLW method may not be appropriate for use in lactating women. There are considerable individual deviations in estimating TDEE by HR monitoring, but it is satisfactory for estimating TDEE of groups.