Type 2 diabetes is associated with a worse functional outcome of ischemic stroke

AIM: To assess whether ischemic stroke severity and outcome is more adverse in patients with type 2 diabetes mellitus(T2DM). METHODS: Consecutive patients hospitalized for acute ischemic stroke between September 2010 and June 2013 were studied prospectively(n = 482; 40.2% males, age 78.8 ± 6.7 years). T2 DM was defined as self-reported T2 DM or antidiabetic treatment. Stroke severity was evaluated with the National Institutes of Health Stroke Scale(NIHSS) score at admission. The outcome was assessed with the modified Rankin scale(m RS) score at discharge and with in-hospital mortality. Adverse outcome was defined as m RS score at discharge ≥ 2 or in-hospital death. The length of hospitalization was also recorded.RESULTS: T2 DM was present in 32.2% of the study population. Patients with T2 DM had a larger waist circumference, higher serum triglyceride and glucose levels and lower serum high-density lipoprotein cholesterol levels as well as higher prevalence of hypertension, coronary heart disease and congestive heart failure than patients without T2 DM. On the other hand, diabetic patients had lower low-density lipoprotein cholesterol levels and reported smaller consumption of alcohol than non-diabetic patients. At admission, the NIHSS score did not differ between patients with and without T2DM(8.7 ± 8.8 and 8.6 ± 9.2, respectively; P = NS). At discharge, the m RS score also did not differ between the two groups(2.7 ± 2.1 and 2.7 ± 2.2 in patients with and without T2 DM, respectively; P = NS). Rates of adverse outcome were also similar in patients with and without T2DM(62.3% and 58.5%, respectively; P = NS). However, when we adjusted for the differences between patients with T2 DM and those without T2 DM in cardiovascular risk factors, T2 DM was independently associated with adverse outcome [relative risk(RR) = 2.39; 95%CI: 1.21-4.72, P = 0.012]. Inhospital mortality rates did not differ between patients with T2 DM and those without T2DM(9.0% and 9.8%, respectively; P = NS). In multivariate analysis adjusting for the difference in cardiovascular risk factors between the two groups, T2 DM was again not associated with in-hospital death. CONCLUSION: T2 DM does not appear to affect ischemic stroke severity but is independently associated with a worse functional outcome at discharge.     

Untargeted serum metabolomics and tryptophan metabolism profiling in type 2 diabetic patients with diabetic glomerulopathy

Diabetic glomerulopathy (DG) remains the prevalent microvascular complication and leading cause of shortened lifespan in type-2 diabetes mellitus (T2DM) despite improvement in hyperglycemia control. Considering the pivotal role of kidney in metabolism, using untargeted metabolomic techniques to globally delineate the serum metabolite profiles will help advance understanding pathogenetic underpinnings of renal biopsy-confirmed DG from the perspective of metabolism specifically. Fourteen pathologically diagnosed DG patients secondary to T2DM and 14 age- and gender-matched healthy controls (HCs) were recruited for study. We employed mass spectrometry-based untargeted metabolomic methods to reveal the metabolite profiles of serum samples collected from all included subjects. We identified a total of 334 and 397 metabolites in positive and negative ion mode respectively. One hundred and eighty-two important differential metabolites whose variable importance in projection (VIP) > 1 and p value <0.05 were selected and annotated to metabolic pathways. KEGG pathway enrichment analysis revealed tryptophan metabolism enriched most significantly. Among the tryptophan derivatives, L-tryptophan (L-Trp) and serotonin were relatively accumulated in DGs compared with HCs, while 5-hydroxyindoleacetic acid (5-HIAA) and indole-3-acetamide were depleted. Correlation analysis showed serotonin and L-Trp are negatively correlated with 24 h urine protein and glycosylated hemoglobin (Ghb). To exclude the interference of preexisting T2DM on DG exacerbation, we selected 5-HIAA and 3-(3-hydroxyphenyl) propionic acid (3-OHPPA) which are not correlated with Ghb and analyzed their correlation relationship with crucial renal indices. We found 3-OHPPA is positively correlated with urine total protein and creatinine ratio (T/Cr) and 24 h urine protein, 5-HIAA is positively correlated with serum creatinine and urea.     

Association of β-cell function and insulin resistance with pediatric type 2 diabetes among Chinese children

BACKGROUNDIn addition to insulin resistance, impaired insulin secretion has recently been identified as a crucial factor in the pathogenesis of type 2 diabetes mellitus (T2DM). Scarce clinical data exist for pediatric T2DM.AIMTo investigate the association of β-cell function and insulin resistance with pediatric T2DM in the first Chinese multicenter study.METHODSThis multicenter cross-sectional study included 161 newly diagnosed T2DM children and adolescents between January 2017 and October 2019. Children with normal glycemic levels (n = 1935) were included as healthy control subjects. The homeostasis models (HOMAs) were used to assess the β-cell function (HOMA2-%B) and insulin resistance (HOMA2-IR) levels. The HOMA index was standardized by sex and age. We performed logistic regression analysis to obtain odds ratios (ORs) for T2DM risk using the standardized HOMA index, adjusted for confounding factors including sex, Tanner stage, T2DM family history, body mass index z-score, and lipid profile.RESULTSThe male-female ratio of newly diagnosed T2DM patients was 1.37:1 (OR = 2.20, P = 0.011), and the mean ages of onset for boys and girls were 12.5 ± 1.9 years and 12.3 ± 1.7 years, respectively. The prevalence of related comorbidities including obesity, elevated blood pressure, and dyslipidemia was 58.2%, 53.2%, and 80.0%, respectively. The T2DM group had lower HOMA2-%B levels (P < 0.001) and higher HOMA2-IR levels (P < 0.001) than the control group. Both the decrease in HOMA2-%B z-score (OR = 8.40, 95%CI: 6.40–11.02, P < 0.001) and the increase in HOMA2-IR z-score (OR = 1.79, 95%CI: 1.60–2.02, P < 0.001) were associated with a higher risk of T2DM, and the decrease in HOMA2-%B z-score always had higher ORs than the increase in HOMA2-IR z-score after adjusting for confounding factors.CONCLUSIONBesides insulin resistance, β-cell function impairment is also strongly associated with Chinese pediatric T2DM. Gender difference in susceptibility and high comorbidities warrant specific T2DM screening and prevention strategies in Chinese children.     

Altered spontaneous brain activity patterns in patients with diabetic retinopathy using amplitude of low-frequency fluctuation

BACKGROUNDDiabetes mellitus is a metabolic disorder characterized by prolonged elevation of blood glucose due to various causes. Currently, the relationship between diabetic retinopathy (DR) and altered connectivity of brain function is unclear.AIMTo investigate the relationship between this brain activity and clinical manifestations and behaviors of DR patients by using the amplitude of low-frequency fluctuation (ALFF) technique.METHODSTwenty-four DR patients and 24 healthy controls (HCs) matched for age and gender were enrolled. We measured and recorded average ALFF values of DR patients and HCs and then classified them using receiver operating characteristic (ROC) curves.RESULTSALFF values of both left and right posterior cerebellar lobe and right anterior cingulate gyrus were remarkably higher in the DR patients than in the HCs; however, DR patients had lower values in the bilateral calcarine area. ROC curve analysis of different brain regions demonstrated high accuracy in the area under the curve analysis. There was no significant relationship between mean ALFF values for different regions and clinical presentations in DR patients. Neuronal synchronization abnormalities in some brain regions of DR patients were associated with cognitive and visual disorders.CONCLUSIONAbnormal spontaneous brain activity was observed in many areas of DR patients’ brains, which may suggest a possible link between clinical manifestations and behaviors in DR patients.     

Attention and sentence processing deficits in Parkinson's disease: the role of anterior cingulate cortex.

Parkinson's disease (PD) is a complex neurodegenerative condition involving a motor disorder that is related to reduced dopaminergic input to the striatum. Intellectual deficits are also seen in PD, but the pathophysiology of these difficulties is poorly understood. Regional cerebral blood flow (rCBF) was studied in neurologically intact subjects during the performance of attention-demanding, sentence processing tasks using positron emission tomography (PET). The results demonstrated significantly increased rCBF in a distributed set of cerebral regions during the detection of an adjective or a particular agent in a sentence, including anterior cingulate cortex, left inferior and middle frontal cortex, left inferior temporo-occipital cortex, posterolateral temporal cortex, left caudate, and left thalamus. We identified defects in this cerebral network by studying PD patients with two PET techniques. Resting PET studies revealed a significant correlation between regional cerebral glucose metabolism in anterior cingulate cortex and deficits in attending to subtle grammatical aspects of sentences. Studies of PD patients with the PET activation technique revealed little change in anterior cingulate and left frontal CBF during performance of the adjective detection or agent detection tasks. These data suggest that a defect in anterior cingulate cortex contributes to the cognitive impairments observed in PD.     

Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.     

Role of Established Type 2 Diabetes–Susceptibility Genetic Variants in a High Prevalence American Indian Population

Several single nucleotide polymorphisms (SNPs) associated with type 2 diabetes mellitus (T2DM) have been identified, but there is little information on their role in populations at high risk for T2DM. We genotyped SNPs at 63 T2DM loci in 3,421 individuals from a high-risk American Indian population. Nominally significant (P < 0.05) associations were observed at nine SNPs in a direction consistent with the established association. A genetic risk score derived from all loci was strongly associated with T2DM (odds ratio 1.05 per risk allele, P = 6.2 × 10⁻⁶) and, in 292 nondiabetic individuals, with lower insulin secretion (by 4% per copy, P = 4.1 × 10⁻⁶). Genetic distances between American Indians and HapMap populations at T2DM markers did not differ significantly from genomic expectations. Analysis of U.S. national survey data suggested that 66% of the difference in T2DM prevalence between African Americans and European Americans, but none of the difference between American Indians and European Americans, was attributable to allele frequency differences at these loci. These analyses suggest that, in general, established T2DM loci influence T2DM in American Indians and that risk is mediated in part through an effect on insulin secretion. However, differences in allele frequencies do not account for the high population prevalence of T2DM.     

Simultaneous progression patterns of scoliosis,pelvic obliquity,and hip subluxation/dislocation in non-ambulatory neuromuscular patients: an approach to deformity documentation

Background

A triad of deformities—thoracolumbar scoliosis, pelvic obliquity, and femoral head (hip) subluxation/dislocation—occurs frequently in non-ambulatory neuromuscular patients, but their close inter-relationship is infrequently appreciated or quantified. We propose a deformity documentation approach to assess each component simultaneously.

Methods

The documentation assesses each component for maximal functional level, deformity, and flexibility/rigidity: deformity from antero-posterior radiographs (scoliosis—maximal functional position, pelvic obliquity—sitting, hip position—supine) and flexibility/rigidity from extent of repositioning on supine (spine, pelvis) and frog lateral (hip) radiographs. The approach was applied in 211 patients: Duchenne muscular dystrophy (110), spinal muscular atrophy (49), cerebral palsy (26), and other neuromuscular disorders (26).

Results

Measurement of 2124 radiological data points allowed for deformity (mild to moderate to severe) and flexibility/rigidity (fully reducible to partially to non-reducible) gradations for scoliosis, pelvic obliquity, and hip subluxation/dislocation. The charting documented: (1) numerical deformity and flexibility/rigidity changes [x-axis: age; y-axis: angulation (scoliosis and pelvic obliquity) and percent coverage (hip subluxation or dislocation) from 0–120]; and (2) grade deformity and flexibility/rigidity changes [x-axis: age; y-axis: deformity and flexibility/rigidity, following conversion of numerical measurements to a 1–5 grade scale]. In subgroups with the most extensive documentation, thoracolumbar and lumbar scoliosis extended into the sacrum with 98 % (114/116) accompanied by pelvic obliquity; and scoliosis developed more rapidly than hip deformity in 44 % (28/63), scoliosis and hip deformity developed at the same time in 40 % (25/63), and hip deformity developed more rapidly than scoliosis in 16 % (10/63) (Pearson’s chi-squared test p = 0.0501, almost significant).

Conclusion and significance

Documentation of the triad of neuromuscular deformities is applicable to all diagnoses; it outlines maximal functional level, deformity, and flexibility/rigidity at each site; and it shows the relationship between spine, pelvic, and hip deformation. Prospective charting will enhance both clinical management and clinical research into neuromuscular deformity.     

Rotator cuff tears after total shoulder arthroplasty in primary osteoarthritis: A systematic review

Rotator cuff tears have been reported to be uncommon following total shoulder arthroplasty (TSA). Postoperative rotator cuff tears can lead to pain, proximal humeral migration, and glenoid component loosening. The purpose of this paper was to evaluate the incidence of post-TSA rotator cuff tears or dysfunction in osteoarthritic patients. A systematic review of multiple databases was performed using preferred reporting items for systematic reviews and meta-analyses guidelines. Levels I-IV evidence clinical studies of patients with primary osteoarthritis with a minimum 2-year follow-up were included. Fifteen studies with 1259 patients (1338 shoulders) were selected. Student''s t-tests were used with a significant alpha value of 0.05. All patients demonstrated significant improvements in motion and validated clinical outcome scores (P < 0.001). Radiographic humeral head migration was the most commonly reported data point for extrapolation of rotator cuff integrity. After 6.6 ± 3.1 years, 29.9 ± 20.7% of shoulders demonstrated superior humeral head migration and 17.9 ± 14.3% migrated a distance more than 25% of the head. This was associated with an 11.3 ± 7.9% incidence of postoperative superior cuff tears. The incidence of radiographic anterior humeral head migration was 11.9 ± 15.9%, corresponding to a 3.0 ± 13.6% rate of subscapularis tears. We found an overall 1.2 ± 4.5% rate of reoperation for cuff injury. Nearly all studies reported indirect markers of rotator cuff dysfunction, such as radiographic humeral head migration and clinical exam findings. This systematic review suggests that rotator cuff dysfunction following TSA may be more common than previously reported. IV, systematic review of Levels I-IV studies.     

Anterior Cranial Fossa Traumas: Clinical Value,Surgical Indications,and Results—A Retrospective Study on a Series of 223 Patients

Objective Frontobasal fractures are relatively common traumas but surgical indications are still discussed. The authors report their results on patients showing anterior cranial fossa fractures; clinical data, surgical indications, and results are reported and critically analyzed.Methods From 1991 to 2010, 223 patients were admitted in our institution with diagnosis of anterior cranial fossa fracture. Fractures were classified as type A—fracture of the anterior wall of the frontal sinus; type B—fracture of the posterior wall of the frontal sinus; and type C—frontobasal traumas without involvement of the frontal sinus. All patients entered a follow-up program consisting in periodic controls.Results A total of 105 patients were conservatively treated, while 118 patients underwent surgical intervention. The presence of pneumocephalus (p < 0.0001) and rhinoliquorrhea (p = 0.001) were the factors influencing the surgical indication. In the fractures of group B with signs of pneumocephalus and or rhinoliquorrhea, full sinus cranialization represents the variable mainly influencing the outcome (p < 0.001).Conclusion Patients with frontobasal traumas should be carefully evaluated to choose the best treatment option. Clinical and radiological data suggest that patients with frontobasal fractures with massive pneumocephalus and/or rhinoliquorrhea should be always surgically treated.     

Equivalent Weight Loss with Marked Metabolic Benefit Observed in a Matched Cohort with and Without Type 2 Diabetes 12?Months Following Gastric Bypass Surgery

Background

Bariatric surgery results in dramatic weight loss and improves metabolic syndrome and type 2 diabetes (T2DM). However, previous studies have noted that morbidly obese patients with T2DM experience less weight loss benefits than non-diabetic patients following bariatric surgery. We sought to determine longitudinal effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) on percent excess body mass index (BMI) loss (%EBMIL) and clinical metabolic syndrome parameters in patients with T2DM compared with appropriately matched cohort without T2DM.

Methods

Retrospective cohort analysis of T2DM patients (n?=?126) to non-T2DM patients (n?=?126) matched on age (M?=?48.1?±?9.5), sex (81?% female), race (81?% Caucasian), and pre-surgical BMI (M?=?49.3?±?9.5). Lipids, glucose, hemoglobin A1c, blood pressure, co-morbidities of obesity, medications for co-morbidities, and T2DM medications were collected at baseline, 6?months and 12?months post-surgery. %EBMIL was collected at 1, 3, 6, 9, and 12?months post-surgery. One-way analyses of variance with effect sizes estimates were conducted to compare the two groups.

Results

As expected, T2DM subjects had significantly greater pre-surgical HbA1c, blood glucose, blood pressure, and lipid parameters at baseline vs. non-T2DM (all p values of<0.05). At 1, 3, 6, 9, and 12?months after LRYRB, both groups had similar reduction in %EBMIL (p?>?0.10). At 6?months, there was a significant reduction in HbA1c, blood glucose, and lipid in the T2DM cohort compared with pre-surgical levels (p?<?0.0001). At 12?months, these values were not different to that of the non-T2DM subjects (p?>?0.10).

Conclusions

When matched on appropriate factors associated with weight loss outcomes, severely obese patients with T2DM have similar post-LRYGB weight loss outcomes in the first 12?months following surgery compared with non-T2DM patients. Furthermore, T2DM surgical patients achieved significant improvement in metabolic syndrome components.     

Serum insulin-like growth factor-binding protein 2 levels as an indicator for disease severity in enterohemorrhagic Escherichia coli induced hemolytic uremic syndrome

BackgroundInsulin-like growth factor-binding protein (IGFBP) 2 plays an important role in the regulation of cell adhesion, migration, growth, and apoptosis. This study aimed to investigate the clinical significance of serum IGFBP2 as a biomarker for disease activity and severity in hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC).MethodsIGFBP2 production by human renal glomerular endothelial cells (RGECs) after exposure to Shiga toxin 2 (Stx-2) was investigated in vitro. Serum IGFBP2 levels in blood samples obtained from 22 patients with HUS and 10 healthy controls (HCs) were quantified using an enzyme-linked immunosorbent assay. The results were compared to the clinical features of HUS and serum tau and cytokine levels.ResultsStx-2 induced the production of IGFBP2 in RGECs in a dose-dependent manner. Serum IGFBP2 levels were significantly higher in patients with HUS than in HCs and correlated with disease severity. Additionally, serum IGFBP2 levels were significantly higher in patients with encephalopathy than in those without encephalopathy. A serum IGFBP2 level above 3585 pg/mL was associated with a high risk of encephalopathy. Furthermore, serum IGFBP2 levels significantly correlated with serum levels of tau and inflammatory cytokines associated with the development of HUS.ConclusionsCorrelation of serum IGFBP2 level with disease activity in patients with HUS suggests that IGFBP2 may be considered as a possible indicator for disease activity and severity in HUS. Larger studies and additional experiments using various cells in central nervous system should elucidate the true value of IGFBP2 as a clinical diagnostic marker.AbbreviationsIGFBP: insulin-like growth factor-binding protein; HUS: hemolytic uremic syndrome; EHEC: enterohemorrhagic Escherichia coli; RGECs: renal glomerular endothelial cells; STx-2: Shiga toxin 2; HCs: healthy controls; LPS: lipopolysaccharide; ROC: receiver operating characteristic; sTNFR: soluble tumor necrosis factor receptor.     

Large-scale functional connectivity predicts cognitive impairment related to type 2 diabetes mellitus

BACKGROUNDLarge-scale functional connectivity (LSFC) patterns in the brain have unique intrinsic characteristics. Abnormal LSFC patterns have been found in patients with dementia, as well as in those with mild cognitive impairment (MCI), and these patterns predicted their cognitive performance. It has been reported that patients with type 2 diabetes mellitus (T2DM) may develop MCI that could progress to dementia. We investigated whether we could adopt LSFC patterns as discriminative features to predict the cognitive function of patients with T2DM, using connectome-based predictive modeling (CPM) and a support vector machine.AIMTo investigate the utility of LSFC for predicting cognitive impairment related to T2DM more accurately and reliably.METHODSResting-state functional magnetic resonance images were derived from 42 patients with T2DM and 24 healthy controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Patients with T2DM were divided into two groups, according to the presence (T2DM-C; n = 16) or absence (T2DM-NC; n = 26) of MCI. Brain regions were marked using Harvard Oxford (HOA-112), automated anatomical labeling (AAL-116), and 264-region functional (Power-264) atlases. LSFC biomarkers for predicting MoCA scores were identified using a new CPM technique. Subsequently, we used a support vector machine based on LSFC patterns for among-group differentiation. The area under the receiver operating characteristic curve determined the appearance of the classification.RESULTSCPM could predict the MoCA scores in patients with T2DM (Pearson’s correlation coefficient between predicted and actual MoCA scores, r = 0.32, P=0.0066 [HOA-112 atlas]; r = 0.32, P=0.0078 [AAL-116 atlas]; r = 0.42, P=0.0038 [Power-264 atlas]), indicating that LSFC patterns represent cognition-level measures in these patients. Positive (anti-correlated) LSFC networks based on the Power-264 atlas showed the best predictive performance; moreover, we observed new brain regions of interest associated with T2DM-related cognition. The area under the receiver operating characteristic curve values (T2DM-NC group vs. T2DM-C group) were 0.65-0.70, with LSFC matrices based on HOA-112 and Power-264 atlases having the highest value (0.70). Most discriminative and attractive LSFCs were related to the default mode network, limbic system, and basal ganglia.CONCLUSIONLSFC provides neuroimaging-based information that may be useful in detecting MCI early and accurately in patients with T2DM.     

A Genome-Wide Association Study in American Indians Implicates DNER as a Susceptibility Locus for Type 2 Diabetes

Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥45 years of age, and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls, and a family-based association test was conducted. Tag SNPs (n = 311) were selected for 499 SNPs associated with diabetes (P < 0.0005 in case-control analyses or P < 0.0003 in family-based analyses), and these SNPs were genotyped in up to 6,834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio = 1.29 per copy of the T allele; P = 6.6 × 10⁻⁸, which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic β-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.     

Chronic Reduction of Plasma Free Fatty Acid Improves Mitochondrial Function and Whole-Body Insulin Sensitivity in Obese and Type 2 Diabetic Individuals

Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) ¹H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.     

Evidence for eosinophil activation in bronchiectasis unrelated to cystic fibrosis and bronchopulmonary aspergillosis: discrepancy between blood eosinophil counts and serum eosinophil cationic protein levels

BACKGROUND—Increased serum levelsof eosinophil cationic protein (ECP) have been detected in adolescentpatients with cystic fibrosis. However, ECP concentrations in adultpatients with bronchiectasis unrelated to cystic fibrosis have not been studied.
METHODS—Eosinophil numbers and serumconcentrations of ECP were determined in 14 patients with known ornewly diagnosed bronchiectasis and compared with age and sex matchedpatients with allergic bronchial asthma, chronic obstructive pulmonarydisease (COPD), and controls in whom bronchiectasis or obstructivepulmonary disease could be excluded.
RESULTS—Serum ECP levels were significantlyraised both in patients with bronchiectasis (median (range) 22.5 µg/l(7-85)) and allergic asthma (35.0 µg/l (7-128)) compared with thesex and age matched subjects suffering from COPD (6.7 µg/l (1.5-28);p<0.006) and non-obstructive normal controls (7.5 µg/l (3.5-19);p<0.003). In contrast, significantly increased peripheral eosinophilnumbers were observed in patients with bronchial asthma (305 × 10⁶/l; p<0.01) but not in those with bronchiectasis(10² × 10⁶/l), COPD (117 × 10⁶/l), and healthy controls (101 × 10⁶/l).
CONCLUSIONS—The discrepancy betweeneosinophil counts and eosinophil numbers in patients withbronchiectasis suggests that serum ECP levels may be more relevant inassessing local eosinophil involvement than blood eosinophil numbers.

     

Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCR_I). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m² ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCR_I was calculated during the insulin-clamp performed with [3-³H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCR_I during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m², P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCR_I during the insulin clamp was strongly and inversely correlated with IR (r = −0.52, P < 0.0001). During the OGTT, the MCR_I was suppressed within 15–30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCR_I that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.     

Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions.

The cingulate gyrus is a major part of the "anatomical limbic system" and, according to classic accounts, is involved in emotion. This view is oversimplified in light of recent clinical and experimental findings that cingulate cortex participates not only in emotion but also in sensory, motor, and cognitive processes. Anterior cingulate cortex, consisting of areas 25 and 24, has been implicated in visceromotor, skeletomotor, and endocrine outflow. These processes include responses to painful stimuli, maternal behavior, vocalization, and attention to action. Since all of these activities have an affective component, it is likely that connections with the amygdala are critical for them. In contrast, posterior cingulate cortex, consisting of areas 29, 30, 23, and 31, contains neurons that monitor eye movements and respond to sensory stimuli. Ablation studies suggest that this region is involved in spatial orientation and memory. It is likely that connections between posterior cingulate and parahippocampal cortices contribute to these processes. We conclude that there is a fundamental dichotomy between the functions of anterior and posterior cingulate cortices. The anterior cortex subserves primarily executive functions related to the emotional control of visceral, skeletal, and endocrine outflow. The posterior cortex subserves evaluative functions such as monitoring sensory events and the organism's own behavior in the service of spatial orientation and memory.     

The Vascular Basis of the Pronator Quadratus Muscle Flap and Its Use in Clinical Cases

Background  Pronator quadratus (PQ) is a deeply situated muscle in the forearm which may occasionally be utilized for soft-tissue reconstruction. The purpose of this anatomical and clinical study was to confirm vascular supply of PQ muscle (PQM) in order to optimize its transfer and confirm its utility in clinical situations. Methods  In Part A of the anatomical study, fresh human cadavers ( n = 7) were prepared with an intra-arterial injection of lead oxide and gelatin solution, and PQM and neurovascular pedicle were dissected ( n = 14). In the anatomical study Part B, isolated limbs of embalmed human cadavers ( n = 12) were injected with India ink-gelatin mixture and PQ were dissected. Results  PQ is a type II muscle flap, with one major pedicle, the anterior interosseous (AI) vessels and two minor pedicles from the radial and ulnar vessels. The mean dimensions of the muscle were 5.5 × 5.0 × 1.0 cm ³ , mean pedicle length was 9.6 cm, and the mean diameter of the artery and the vein was 2.3 mm and 2.8 mm, respectively. The dorsal cutaneous perforating branch (DPB) of the artery supplied the skin over the dorsal forearm and wrist. This branch also anastomosed with the 1, 2 intercompartmental supraretinacular artery (ICSRA). Conclusion  This study confirms the potential utility and vascular basis of the PQM flap and its associated cutaneous paddle. In the clinical part, two patients with nonhealing wounds exposing the median nerve and flexor tendons in the distal forearm were treated using the PQM flap with good results.     

The Permissive Safe Angle of the Tibial Tunnel in Transtibial Posterior Cruciate Ligament Reconstruction: A Three‐Dimensional Simulation Study

ObjectiveTo determine the permissive safe angle (PSA) of the tibial tunnel in transtibial posterior cruciate ligament (PCL) reconstruction based on a three‐dimensional (3D) simulation study.MethodsThis was a computer simulation study of transtibial PCL reconstruction using 3D knee models. CT images of 90 normal knee joints from 2017 to 2020 were collected in this study, and 3D knee models were established based on CT data. The tunnel approaches were subdivided into the anterior 1/3 of the anteromedial tibia (T1), middle 1/2 of the anteromedial tibia (T2), the tibial crest (T3), anterior 1/3 of the anterolateral tibia (T4), middle 1/2 of the anterolateral tibia (T5). Five tibial tunnels (T1–T5) were simulated on the 3D knee models. The PSAs, in different tibial tunnel approaches were measured, and subgroup analyses of sex, age and height were also carried out.ResultsThe mean PSAs of the tibial tunnels with 5 different approaches (T1–T5) were 58.49° ± 6.82°, 61.14° ± 6.69°, 56.12° ± 7.53°, 52.01° ± 8.89° and 49.90° ± 10.53°, respectively. The differences of the mean PSAs between the anteromedial and anterolateral approaches were significant (P < 0.05). However, there was no significant difference of the mean PSA value between the two anteromedial tibial tunnel approaches (T1–T2) (P > 0.05), as well as between the two anterolateral tibial tunnel approaches (T4–T5). The patient''s anthropomorphic characteristics of sex, age, and height were not associated with the PSAs.ConclusionsThe PSA varied with the anteromedial, tibial crest and anterolateral approaches for transtibial PCL reconstruction, and surgeons should limit the PCL drill guide by referring to the specific PSA for different surgical approaches.