Hematologic and biochemical inflammatory markers increase with body mass and positively correlate in adolescents.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease that has its origins in childhood. The goal of this study was to explore the relationships of hematologic inflammatory markers to body mass, biochemical inflammatory markers and cardiometabolic risk factors. METHODS: Healthy, white, non-Hispanic identifying adolescents (n = 75, age 12 to 18 years) were enrolled. Measures studied included body mass index percentile (BMI%), neutrophil and platelet to lymphocyte ratio (NLR, PLR), pan immune inflammation value (PIV), lipids, augmentation index, reactive hyperemia, inflammatory markers (interleukin 6: IL6, c-reactive protein: CRP), complement (C3, C3a, C4, C4a, C5a) insulin secretion and insulin sensitivity (oral glucose tolerance test: Matusda index, and disposition index (DI)). RESULTS: NLR (rS = 0.31, p < 0.01), PLR (rS = 0.32, p < 0.01), PIV (rS = 0.32, p < 0.01) and CRP (rS = 0.51, p < 0.001) all positively correlated with BMI% but IL-6 did not. NLR, PLR and PIV all positively correlated with each other. NLR correlated with the reactive hyperemia response (rS = 0.29, p < 0.02) but this relationship was lost when BMI% was included. NLR positively correlated with C3a, C4, CRP and IL6 even when BMI% was included. CONCLUSION: In healthy adolescents hematologic markers of inflammation increase with increasing body mass and neutrocyte to lymphocyte ratio is associated with increased complement and inflammatory markers independent of obesity. IMPACT STATEMENT: Hematologic and biochemical markers of inflammation increase with increased body mass in healthy adolescents. Hematologic and biochemical markers of inflammation are positively related independent of body mass in healthy adolescents. Hematologic inflammatory markers are not related to markers of cardiometabolic risk in healthy adolescents.

Identifying depression, diabetes distress, and suicidality among adolescents with diabetes.

This study explored the frequency of adolescents with diabetes who endorse suicidality on the Patient Health Questionnaire (PHQ-9) with varying degrees of depression scores. Additionally, compared whether diabetes distress levels from the Problem Areas in Diabetes-Teen (PAID-T) assessment tool is associated with and without suicidal ideation. Χ2 analysis was used to assess differences in subjects with or without suicidal ideation based on depression severity. Since all the data were nonparametrically distributed (Shapiro-Wilk test, p < .05), Kruskal-Wallis test assessed differences in continuous variables. Overall, 27 of 355 adolescents screened endorsed suicidal ideation. Both PHQ-9 [13 (9-17.8) vs 1 (0-4.5)] and PAID-T [88 (61.8-104.5) vs 40 (30-58.8)] scores were significantly higher in patients with suicidal ideation. The frequency of suicidal ideation increased with the severity of depression. The frequency of severe depression was higher in adolescents with type 2 diabetes (n = 48) than in type 1, but there was no difference in suicidality. Adolescents with no demonstrable or minimal depression can still have potential suicidal ideation. Suicidality is a separate construct that should be screened routinely and apart from any measures screening for distress or adjustment disorders associated with adolescents experiencing life-long chronic conditions in a healthcare follow-up setting.

The complement system and human autoimmune diseases.

Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis.

Expect the unexpected: Adolescent and pre-teens' experience of diabetes technology self-management.

OBJECTIVE: Only 17% of adolescents with type 1 diabetes (T1D) are currently meeting their glycemic targets despite advances in diabetes technologies. Self-management behaviors and challenges specific to use of diabetes technologies are insufficiently studied in adolescents. We aimed to describe the experience of diabetes technology self-management, including facilitators and barriers, among preteens/adolescents with low and high A1C. RESEARCH DESIGN AND METHODS: Youth (10-18 years of age) with T1D who use insulin pump therapy were recruited from the larger quantitative cohort of a mixed methods study for participation in semi-structured qualitative interviews. Maximum variability sampling was used to recruit youth with A1C <7.5% (n = 5) and A1C >9% (n = 5). Participants' personal insulin pump and continuous glucose monitoring data were downloaded and served as a visual reference. Interviews were analyzed using a qualitative descriptive approach. RESULTS: Participants were 50% female with a median age of 14.9 years and 80% used CGM. The sample was predominantly white (90.0%). Analysis produced four major themes, Bad Day, Expect the Unexpected, Nighttime Dependence, and Unpredictability, It's Really a Team and interconnecting subthemes. Youth characterized ''Bad Days'' as those requiring increased diabetes focus and self-management effort. The unpredictability (''Expect the Unexpected'') of glucose outcomes despite attention to self-management behaviors was considerable frustration. CONCLUSIONS: Diabetes devices such as insulin pumps are complex machines that rely heavily on individual proficiency, surveillance, and self-management behaviors to achieve clinical benefit. Our findings highlight the dynamic nature of self-management and the multitude of factors that feed youths' self-management behaviors.

Relationships of complement components C3 and C4 and their genetics to cardiometabolic risk in healthy, non-Hispanic white adolescents.

BACKGROUND: Complement promotes inflammatory and immune responses and may affect cardiometabolic risk. This study was designed to investigate the effect of complement components C3 and C4 on cardiometabolic risk in healthy non-Hispanic white adolescents. METHODS: Body mass index (BMI), BMI percentile, waist circumference, and percent body fat were assessed in 75 adolescents. Arterial stiffness was assessed using arterial tomography and endothelial function using reactive hyperemia. Fasting lipids, inflammatory markers, and complement levels were measured and oral glucose tolerance test was performed. A single C3 polymorphism and C4 gene copy number variations were assessed. RESULTS: C3 plasma levels increased with measures of obesity. Endothelial function worsened with increased C3 and C4 levels. Triglycerides and low-density lipoprotein increased and high-density lipoprotein (HDL) and insulin sensitivity decreased with increasing C3 levels, but the relationships were lost when body habitus was included in the model. C4 negatively related to HDL and positively to inflammatory markers. Subjects with at least one C3F allele had increased BMI and fat mass index. HDL was significantly related to C4L, C4S, C4A, and C4B gene copy number variation. CONCLUSIONS: C3 levels increase with increasing body mass and increased C4 levels and copy number are associated with increased cardiometabolic risk in healthy adolescents.

Self-management among pre-teen and adolescent diabetes device users.

OBJECTIVE: Despite increased diabetes device use, few adolescents with type 1 diabetes (T1D) meet glycemic targets. We examine associations between utilization of insulin pumps and continuous glucose monitoring (CGM) and glycemic control. RESEARCH DESIGN AND METHODS: This prospective cohort study included 80 youths (10-18 years of age) with T1D. Multiple linear regression and linear mixed models (LMM) were used to estimate the effects of device self-management on HbA1c and daily time in range (70-180 mg/dL), respectively. RESULTS: Every blood glucose (BG) input/day was associated with a 0.2% decrease in HbA1c (95% CI: -0.297, -0.013), each bolus/day was associated with a 0.2% decrease (-0.327, -0.057), and use of CGM was associated with a 0.5% decrease (-1.00, -0.075). Among CGM users (n = 45) every 10% increase in CGM use was associated with a 0.3% decrease in HbA1c (-0.390, -0.180). In LMM accounting for within subject and between subject variability, there was a negative association between BG input/day frequency (coefficient = -1.880, [-2.640, -1.117]) and time in range. Residual random effects for CGM users were large showing time in range varied between youth with a SD of 15.0% (3 hours and 36 minutes) (SE 2.029, [11.484, 19.530]). Time in range varied significantly from day-to-day with SD of 18.6% (4 hours and 40 minutes) (SE0.455, [17.690, 19.473]). CONCLUSIONS: Device self-management behaviors among youth are significantly associated with both HbA1c and time in range. Our findings showing an association between reduced time in range and increased self-management behaviors is novel and deserves further investigation.

Increased body fat and reduced insulin sensitivity are associated with impaired endothelial function and subendocardial viability in healthy, non-Hispanic white adolescents.

BACKGROUND: Cardiovascular disease has its origins in adolescents. Endothelial dysfunction, arterial stiffness, and decreased endocardial oxygen supply: demand ratios are early functional markers of cardiovascular risk. The goal of this study was to determine the relationships of these markers to physical, inflammatory, and metabolic markers in healthy non-Hispanic, white adolescents. METHODS: Thirty-four of the 75 subjects were female. Mean age was 15.0 ± 1.7 years and mean body mass index (BMI) was 22.0 ± 5.8 kg/m2 (mean ± SD). Reactive hyperemia was measured using venous occlusion plethysmography. Arterial tonometry was used to measure the augmentation index (AIx75 ) and the Buckberg subendocardial viability ratio. Blood samples were taken to measure inflammatory and lipid markers and oral glucose tolerance test was used to assess insulin sensitivity. RESULTS: Reactive hyperemia decreased as body mass and fat mass increased. It also decreased with increasing neutrophil count. The Buckberg index was higher in males and was positively related to insulin sensitivity even when accounting for age, sex, and resting heart rate. AIx75 was not related to any of the other variables. CONCLUSIONS: These results demonstrate that increased fat mass and decreased insulin sensitivity are related to poorer vascular function and cardiac risk in adolescents before the development of actual cardiovascular disease.

Does preoperative calcium and 1, 25 OH vitamin D supplementation impact postoperative hypocalcemia and length of stay following pediatric thyroidectomy?

OBJECTIVE: To investigate whether perioperative calcium and 1,25 OH vitamin D supplementation (PCDS) influences the rates of postoperative hypocalcemia and length of stay (LOS) following pediatric thyroidectomy. STUDY DESIGN: Retrospective Cohort Review. SETTING: Tertiary children's hospital. METHODS: 94 patients who underwent completion or total thyroidectomy with or without concomitant neck dissection from 2010 to 2020 at a single institution were included. Patients with pre-existing hypocalcemia or preoperative vitamin D insufficiency were excluded. Rates of postoperative hypocalcemia and LOS were compared for patients receiving PCDS to those receiving no supplementation. RESULTS: Thirty percent of patients with PCDS had documented postoperative hypocalcemia compared to 64% of patients without PCDS (p = 0.01). Patients with PCDS had a median LOS of 30 h compared to 36 h (p = 0.002). Multivariable analyses confirmed that patients with PCDS had lower odds of postoperative hypocalcemia (OR: 0.32, CI: 0.11, 0.89) and shorter LOS by 17 h (SE: 8, p = 0.04) after adjustment for confounders. CONCLUSION: PCDS is associated with significantly lower risk of hypocalcemia and shorter LOS. Standardizing preoperative care for pediatric patients undergoing thyroidectomy may decrease variability and improve outcomes following surgery.

Ascorbic acid blocks hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes.

OBJECTIVE: To determine whether acute ascorbic acid infusions alter the effect of hyperglycemia on endothelial function in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: The forearm blood flow (FBF) reactive hyperemic response to 5 min of upper arm occlusion was studied in eight adolescents with type 1 diabetes during euglycemic and hyperglycemic insulin clamp (40 mU/m2/min) with and without ascorbic acid infusion (3 mg/min). RESULTS: The ratio of post- to preocclusion FBF decreased during hyperglycemia without ascorbic acid (p = 0.013), but did not change during hyperglycemia with ascorbic acid. The changes during hyperglycemia were different between the two studies (p = 0.038). Similar results were found when the percent change in forearm vascular resistance following occlusion was assessed. CONCLUSIONS: These results indicate that antioxidant treatment with ascorbic acid blocks acute hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes.

Gene CNVs and protein levels of complement C4A and C4B as novel biomarkers for partial disease remissions in new-onset type 1 diabetes patients.

OBJECTIVE: To determine the roles of complement C4A and C4B gene copy-number variations and their plasma protein concentrations in residual insulin secretion and loss of pancreatic ß-cell function in new-onset type 1 diabetes (T1D) patients. METHODS: We studied 34 patients of European ancestry with new-onset T1D, aged between 3 and 17 yr (10.7 ± 3.45), at Nationwide Children's Hospital in Columbus, Ohio. Gene copy-number and size variations of complement C4A and C4B were determined by genomic Southern blot analyses. C4A and C4B protein phenotypes were elucidated by immunofixation and radial immunodiffusion. Two-digit human leukocyte antigen (HLA)-DRB1 genotypes were determined by sequence-specific polymerase chain reaction. At 1- and 9-month post diagnosis, stimulated C-peptide levels were measured after a standardized mixed-meal tolerance test. RESULTS: The diploid gene copy-numbers of C4A varied from 0 to 4, and those of C4B from 0 to 3. Patients with higher copy-number of C4A or higher C4A plasma protein concentrations at diagnosis had higher C-peptide levels at 1-month post diagnosis (p = 0.008; p = 0.008). When controlled by the Z-score of body mass index, C4A copy-numbers, C4A protein concentrations, the age of disease onset, and the number of HLA-DR3 but not DR4 alleles were significant parameters in determining C-peptide levels. At 9-month post diagnosis, 42.3% of patients remained in partial remission, and these patients were characterized by lower total C4B copy-numbers or lower C4B protein concentrations (p = 0.02; p = 0.0004). CONCLUSIONS: C4A appears to associate with the protection of residual ß-cell function in new-onset T1D; C4B is correlated with the end of disease remission at 9-month post diagnosis.

Non-glycemic Adverse Effects of Insulin.

Insulin is primarily considered for its glycemic effects in patients with diabetes. There are, however, non-glycemic adverse effects of insulin that may significantly impact patient health and interfere with glycemic control. Insulinogenic edema primarily occurs with rapid improvement in glycemic control either in patients with newly discovered diabetes or in patients with poorly-controlled diabetes. Insulin-induced sympathetic activation, vasodilation, changes in vascular permeability, and most importantly, sodium retention play significant etiologic roles in the development of edema. Clinically, it is usually self-limited, but significant complications can develop. Allergic reactions to all insulin preparations and various compounds used in insulin formulations with a wide range of severity have been reported. Frequently, changing the type of insulin or delivery method is sufficient, but more advanced treatments such as insulin desensitization and anti-IgE antibody treatment may be needed. Lipohypertrophy and lipoatrophy frequently develop with the overuse of injection sites. Lipohypertrophy can affect tissue insulin absorption and glycemic control.

Glycemic control, depression, diabetes distress among adolescents with type 2 diabetes: effects of sex, race, insurance, and obesity.

AIMS: To determine (1) differences in depression and distress scores between adolescents with type 1 (T1D) and type 2 diabetes (T2D), (2) how socioeconomic factors, obesity, race, and treatment regimen affect depression and diabetes distress in adolescent T2D, (3) the relationships between depression and diabetes distress scores in adolescents with T2D, and (4) how depression and diabetes distress scores relate to current and future glycemic control in adolescents with T2D. BACKGROUND: Diabetes distress is a negative emotional reaction to diabetes complications, self-management demands, unresponsive providers, poor interpersonal relationships, and to diabetes itself. It is frequently mistaken for depression and the two are interrelated. Increases in both predict poor glycemic control in adolescents with T1D. METHOD: Depression (PHQ-9) and diabetes distress (PAID-T) scores from self-administered tests were studied in 364 patients with diabetes between the ages of 13-17. Kruskal-Wallis test was used to assess differences between types of diabetes, sexes, races, and insurance status. Spearman correlations, and robust rank order multivariable regression analysis were used to assess relationships. Medical records were reviewed for follow-up hemoglobin A1c (HbA1c) levels over 3 years. RESULTS: HbA1c was significantly lower in females with T2D than with T1D (p = 0.019) but not in males. It, also, did not differ between females and males with T2D. Median PHQ-9 score in females with T2D was significantly greater than in females with T1D (p = 0.007) but did not differ between females and males with T2D. PHQ-9 scores did not differ between males with T2D and T1D. PAID-T scores, however, were higher in males with T2D than in males with T1D but did not differ between females. PHQ-9 scores and PAID-T scores were significantly related in T2D (rs = 0.65, p < 0.001). Neither was related to HbA1c in T2D. CONCLUSIONS: As in adolescents with T1D, depression and diabetes distress screening scores are closely related in adolescent T2D. However, unlike T1D, they are not related to glycemic control in T2D. Depression and diabetes distress may be more closely related to weight and lifestyle concerns.

Retrospective chart review of children with type 2 diabetes mellitus evaluating the efficacy of metformin vs. insulin vs. combination insulin/metformin.

OBJECTIVES: Type 2 diabetes mellitus is a growing problem in pediatrics and there is no consensus on the best treatment. We conducted this chart review on newly diagnosed pediatric patients with type 2 diabetes mellitus to compare the effect of treatment regimen on body mass index (BMI) and hemoglobin A1c over a 6-month period. METHODS: We conducted a retrospective chart review on patients with type 2 DM who presented to Nationwide Children's Hospital. Data were collected on therapy type, BMI, and hemoglobin A1c over a 6-month follow-up. Therapy type was divided into metformin, insulin, or combination insulin and metformin. 1,997 charts were reviewed for inclusion based on ICD-9 codes consistent with a diagnosis of diabetes, abnormal oral glucose tolerance test, or insulin resistance. RESULTS: Of the 47 charts eligible for the review, 26 subjects were treated with metformin 1000-1500 mg daily, 14 patients were treated with insulin therapy, and 7 patients were treated with a combination of insulin and metformin therapy. At baseline, the only significant difference among groups was A1c (P = 0.012). In regression analysis with baseline A1c as a covariate, the only predictor of change in A1c over time was the A1c at onset (P < 0.001). Therapy type was not predictive of change (P = 0.905). Regression analysis showed a greater BMI at onset predicted a greater decrease in BMI (P = 0.006), but therapy type did not predict a change (P = 0.517). CONCLUSION: Metformin may be as effective as insulin or combination therapy for treatment of diabetes from onset to 6-month follow-up.

Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents.

OBJECTIVES: In obese adults the shape of the glucose response curve during an oral glucose tolerance test (OGTT) predicts future type 2 diabetes. Patients with an incessant increase or monophasic curves have increased risk compared to those with biphasic curves. Since type 2 diabetes is associated with increased cardiometabolic risk, we studied whether differences in OGTT response curve are associated with differences in cardiometabolic risk factors in healthy adolescents across a wide body mass index (BMI) range. METHODS: Sixty-nine (33F/36M), white adolescents (age: 15.2 ± 1.7 years; BMI: 21.5 ± 4.7 kg/m2; mean ± SD) were studied. Risk factors measured included percent body fat, blood pressure, lipids, augmentation index, reactive hyperemia, endothelin 1, plasminogen activator 1, inflammatory markers (interleukin 6, c-reactive protein), insulin secretion, insulin sensitivity (Matusda index), and disposition index (DI). RESULTS: Thirty-two subjects had biphasic responses; 35 subjects had monophasic responses and two females had incessant increases. Sex did not affect the frequency of responses. Glucose area under the curve during OGTT was greater in those with a mono vs. biphasic curves (p=0.01). Disposition index was markedly lower in subjects with a monophasic curve than in those with a biphasic curve (3.6 [2.3-5.0] vs. 5.8 [3.8-7.6], median [25th, 75th%] p=0.003). Triglyceride to high-density lipoprotein cholesterol (HDL) ratio was higher in subjects with a monophasic curve (p=0.046). CONCLUSIONS: The decreased disposition index indicates that in healthy adolescents a monophasic response to OGTT is due to decreased insulin secretion relative to the degree of insulin resistance present. This was not associated with differences in most other cardiometabolic risk markers. TRIAL REGISTRATION: Clinical Trials.gov, NCT02821104.

Glycemic control, depression, diabetes distress among adolescents with type 1 diabetes: effects of sex, race, insurance, and obesity.

AIMS: To determine whether diabetes distress or depression screening better predict increased hemoglobin A1c (HbA1c) and to assess interactions with age, sex, race, obesity, and insurance status. BACKGROUND: Diabetes distress is a negative emotional reaction to diabetes, diabetes complications, self-management demands, unresponsive providers, and/or poor interpersonal relationships. Guidelines recommend annual depression screening, however diabetes distress may be mistaken for depression. METHOD: Depression (PHQ-9) and diabetes distress (PAID-T) scores from self-administered tests were studied in 313 patients with type 1 diabetes (T1D) between the ages of 13-17. Spearman correlations and robust rank order multivariable regression analysis were used to assess relationships to age, duration, HbA1c. Kruskal-Wallis test was used to assess differences between sexes, races, and insurance status. Receiver operator curves (ROC) were constructed to see whether PAID-T or PHQ-9 scores more closely predicted HbA1c greater than 9%. RESULTS: HbA1c was more strongly correlated with PAID-T (rs = 0.37, p < 0.01), than PHQ-9 (rs = 0.27, p < 0.01) scores. Area under ROC curve for poor HbA1c was 0.75 for PAID and 0.64 for PHQ-9. PAID-T and PHQ-9 scores were increased in females and subjects with public insurance and both were significantly related to HbA1c even when accounting for age, sex, race obesity, and insurance status. PHQ-9 and PAID-T scores correlated with BMI-Z scores in Blacks, but not Whites. CONCLUSIONS: Both depression and diabetes distress are associated with increased HbA1c in adolescents with T1D, though distress is more so. Diabetes distress and depression should be routinely assessed in T1D adolescents, particularly those with public insurance.

Pediatric adaptions are needed to improve the diagnostic accuracy of thyroid ultrasound using TI-RADS.

BACKGROUND/PURPOSE: Thyroid Imaging Reporting and Data System (TI-RADS) is validated in adults but not yet in children. The purpose of this study was to determine the sensitivity, specificity, and accuracy of TI-RADS in predicting thyroid malignancy for pediatric nodules, and to compare the diagnostic accuracy to the current American Thyroid Association (ATA) guidelines. METHODS: A single institution retrospective review was performed of patients younger than 21 years who underwent thyroid nodule fine needle aspiration biopsy (FNAB). Two radiologists were blinded to the pathology and independently classified all biopsied thyroid nodules based on TI-RADS. ATA and TI-RADS guidelines were analyzed to determine the diagnostic sensitivity and specificity of both scoring systems. RESULTS: 115 patients (median age 15.5 years, 90 females) with 138 nodules were scored using TI-RADS. There was moderate inter-rater agreement between radiologists (Kappa = 0.51; p < 0.0001). Evaluating several potential TI-RADS criteria, 23.2%-68.1% of nodules were recommended for FNAB, compared to 82.6% of nodules using ATA guidelines. Using TI-RADS ≥ 3 (without size cutoff) as an indication for FNAB had 100% sensitivity with no missed suspicious or malignant nodules on cytology or pathology. CONCLUSIONS: Using TI-RADS for diagnostic management of pediatric thyroid nodules improves accuracy in predicting malignancy.

Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases.

Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his single C4B gene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype with HLA-A30, B18 and DR7 that segregated with two defective C4B genes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, the C4B gene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype with HLA-DRB1*04:06 and B*15:27. The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation of C4 sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules.

Low prevalence of primary HIV resistance in western Massachusetts.

Most studies of primary antiretroviral (ARV) resistance have been conducted in large metropolitan areas with reported rates of 8% to 25%. We collected data on 99 HIV-1-infected antiretroviral-naive patients from several sites in Springfield, MA, who underwent genotypic resistance assay between 2004 and 2008. Only major resistance mutations per International AIDS Society-USA (IAS-USA) drug resistance mutations list were considered. The prevalence of resistance was 5% (5 of 99). Three patients had one nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation: 103N, 103N, and 190A, 1 patient had a protease inhibitor (PI) mutation: 90M; and 1 patient had 3-class resistance with NNRTI: 181C, 190A, PI: 90M, and nucleoside analogue reverse transcriptase inhibitor (NRTI): 41L, 210W. Mean time from HIV diagnosis to resistance testing was shorter in patients with resistance versus those without: 9 (range 0.3-42 months) versus 27 (range 0.1-418 months), P = .11. There was a trend to lower mean CD4 count in those with resistance, 170 versus 318 cells/mm(3), P = .06. No differences were noted in gender, age, HIV risk category, or HIV RNA level. The low prevalence of primary resistance may be explained by differences in demographic and risk factors or may reflect the time from infection to resistance testing. Our findings emphasize the importance of continued resistance surveillance.

Complement Components, C3 and C4, and the Metabolic Syndrome.

INTRODUCTION: Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity. CONCLUSION: Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.