Acute insulin response is an independent predictor of type 2 diabetes mellitus in individuals with both normal fasting and 2-h plasma glucose concentrations

BACKGROUND: Earlier prospective studies have identified insulin action and secretion as predictors of T2DM in populations with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) (2-h OGTT < 7.8 and 7.8-11 mmol/L, respectively). Fasting plasma glucose (FPG), an additional and recently modified (normal <5.6 mmol/L) diagnostic criterion is associated with insulin secretion. We wanted to establish whether insulin secretion persists as an independent predictor of T2DM in individuals with no clinical evidence of impaired glucose regulation based on FPG and 2-h plasma glucose concentrations. METHODS: Insulin action (M, euglycemic-hyperinsulinemic clamp), insulin secretion (acute insulin response (AIR), IVGTT), and adiposity (%Fat, DXA or densitometry) were compared at baseline in 358 Pima Indians (232M/126F, 18-44 years old) with normal glucose regulation of whom 61 (35M/26F) developed diabetes (DIAB) during a median follow-up time of 7.6 years. RESULTS: In proportional-hazard analysis, % Fat (HR = 1.52, p = 0.03), M (HR = 0.51, p = 0.04) and AIR (HR = 0.64, p = 0.003) predicted the development of diabetes after adjustment for age and sex. In regression analysis adjusting for age, sex, %Fat and M at baseline, the non-diabetic group (NON-DM) had a higher AIR (p = 0.0002) than the DIAB group; the positive association of AIR with adiposity observed in the NON-DM group was absent in the DIAB group. Cumulative incidence rates (12y) for diabetes were highest (48%) in subjects with both M and AIR below the population median and lowest (11%) in subjects with both M and AIR above the population median. CONCLUSION: AIR can predict diabetes prior to the current clinical indicators of impaired glucose regulation.     

Repeatability and reproducibility of the hyperinsulinemic-euglycemic clamp and the tracer dilution technique in a controlled inpatient setting

The objective of the study was to evaluate the reproducibility and repeatability of the combined use of the hyperinsulinemic-euglycemic (H-E) clamp and tracer dilution techniques. Ten nondiabetic men underwent a low-dose (40 mU/[m² min]) H-E clamp that was repeated within 3 to 4 days using porcine or human insulin in a double-blinded, randomized, crossover design. Coefficients of variation (CVs) for intraindividual differences and repeatability coefficient were calculated to evaluate reproducibility and repeatability. The Bland and Altman method was used to quantify repeatability. The CVs for intraindividual differences were 5.7% ± 3.5% for steady-state (SS) insulin; 6.7% ± 6.2% and 54.2 ± 38.3% for basal and SS endogenous glucose product (EGP), respectively; and 10.3% ± 8.5% for total insulin-stimulated glucose disposal (M) values. Basal EGP, SS EGP, and SS glucose and insulin concentrations were similar for the 2 clamps; but glucose infusion rate (P = .02) and M (borderline significant, P = .06) were higher in the first clamp than the second clamp. No significant correlations between mean of differences and average of basal and SS EGP, SS insulin concentration, and M between the 2 clamps were observed. We also found that the different values were less than the repeatability coefficients of these parameters and that the 95% limits of agreement and the interval of repeatability coefficient of these parameters were similar. There were no differences in metabolic responses between clamps when compared by the type of insulin (porcine vs human) infused. Our findings indicate that, although SS EGP has a high CV, the clamp, which measures insulin action (ie, SS insulin, M), and the tracer dilution technique for assessing basal EGP are repeatable and reproducible. Decreased glucose infusion rate and M over a short period in the second clamp may reflect an accumulative effect of continued physical inactivity.     

Stability of Bovine Lactoferrin in Luminal Extracts and Mucosal Homogenates from Rat Intestine: A Prelude to Oral Absorption

Oral delivery is the most common method for bovine lactoferrin (bLf) administration. However, the presence of proteolytic enzymes in the stomach and intestine limits the effective absorption of bLf within the gastrointestinal (GI) tract. To determine the extent of bLf proteolysis, several digestion models were developed using luminal extracts and mucosal homogenates isolated from four regions of rat intestine: duodenum, jejunum, ileum, and proximal colon. The kinetics of bLf degradation followed a pseudo‐first‐order rate, and almost complete hydrolysis of bLf was observed in the luminal extracts, indicating that bLf is more susceptive to luminal peptidases rather than mucosal enzymes. Moreover, a significant reduction in bLf proteolysis was observed in the presence of soybean trypsin inhibitor (SBTI), bestatin, and bacitracin, suggesting that there exist trypsin‐like and aminopeptidase‐like proteases, which play a key role in the degradation of bLf in the intestine. Lactoferrin was then encapsulated in several lipid‐based delivery systems including liposomes and solid lipid particles (SLPs) with polymer modification, showing at least 50% of intact bLf remaining after 6 h of digestion compared with native bLf. These findings suggest that particle encapsulation may modulate protein digestion and possibly achieve sufficient oral bioavailability of bLf.     

An Exploratory Study of Spiritual Orientation and Adaptation to Therapeutic Community Treatment

ABSTRACT

The purpose of this study was to determine the extent to which spiritual orientation was associated with adaptation to therapeutic community treatment. Spiritual orientation was assessed by the Spirituality Self-Rating Scale, a measure consistent with the conceptualization of spirituality typically reflected in Alcoholics Anonymous members’ views. Spiritual orientation was positively correlated with acceptance of therapeutic community principles and clinical progress. Further assessment of spirituality related characteristics and their relation to treatment outcomes is important in informing the design of interventions aimed at improving progress in the therapeutic community, particularly those aspects involving the relative value of integrating the 12-Step group approach in therapeutic community programs.     

Alveolar Soft-Part Sarcoma of the Orbit

An 11-month-old white female with a three-month history of swelling of soft tissue around the right eye presented with a proptotic globe and marked limitation of motility. A CT scan showed a soft-tissue mass in the orbit, which was biopsied and examined by light and electron microscopy. The specimen consisted of large polygonal and cuboidal cells of uniform appearance arranged in seudo-alveoli around capillaries. The nuclei were pale and ovoid with prominent nucleoli and rare mitoses. The cytoplasm was packed with lipid droplets and the paranuclear region contained clusters of periodic acid-Schiff (PAS)-positive, diastase-resistant granules and needle-shaped crystals, which showed a linear periodicity of 100 nm by electron microscopy. These cytoplasmic crystals, which were diagnostic for alveolar soft-part sarcoma, were also found to be acid phosphatase-positive and, therefore, components of the lysosomal system. A lid-sparing exenteration of the right orbit was performed, and subsequent radiation therapy by cesium implant delivered 24,000 rads to the operative site. The patient is alive at 22 months following initial biopsy with no evidence of tumor recurrence.     

Local retention of soluble antigen by potential antigen-presenting cells in the anterior segment of the eye

PURPOSE: To determine the capacity of bone marrow-derived cells in the anterior segment of the eye to capture a fluorescence-labeled antigen (Ag) injected into the anterior chamber (AC). METHODS: Uveal tract and corneoscleral tissues from Lewis rats were cultured in vitro, with or without FITC-dextran (4 microg/mL final concentration), for 48 hours and examined by confocal microscopy. To investigate antigen uptake in vivo 2 microL (20 microg) of Cascade Blue-labeled dextran (CB-Dx) was injected into the right AC of Lewis rats. The density of Ag-positive cells in the iris at 1, 3, 5, or 12 days after injection was examined by in vivo video fluorescence microscopy. The distribution and phenotype of Ag-positive cells in frozen and paraffin-embedded sections of ocular tissues and in iris wholemounts from animals killed at 24 hours and day 7 were analyzed by fluorescence and confocal microscopy. RESULTS: In organ culture conditions numerous cells in the iris, ciliary body, choroid, and corneal limbus were capable of capturing fluorescence-labeled Ag. In vivo observations and microscopic examination of experimental eyes at days 1 and 7 after AC injection revealed Ag-positive cells within the iris, iridocorneal angle, the suprachoroidal space and around limbal-episcleral vessels. Ag-bearing cells in the iris express combinations of macrophage markers but rarely expressed major histocompatibility complex (MHC) class II molecules. A reduced number of Ag-bearing cells were still present in the iris at day 12. CONCLUSIONS: Potential antigen-presenting cells (APCs) in the iris and ciliary body are capable of internalizing intracameral Ag. The characteristics of these cells in the iris are consistent with a predominantly macrophage phenotype. These observations also suggest that the Ag leaving the eye through both the conventional and nonconventional aqueous outflow pathways may be captured by potential APCs in the episcleral tissues.     

Incidence of positive inguinal lymph node cultures during peripheral revascularization

Synthetic vascular graft infections occur more commonly at the inguinal incision, and there is contamination of the graft by transection of bacteria-laden lymphatics proximal to a distal extremity infection. In 45 consecutive peripheral revascularizations, significant positive inguinal lymph node cultures were not obtained in 30 normal extremities; two of 15 distally infected extremities demonstrated the same bacteria in the distal infection and the inguinal lymph node. Both patients subsequently developed graft infections. Inguinal lymph nodes proximal to a distal infection may harbor bacteria capable of causing a synthetic vascular graft infection. Consideration should be given to culture-directed rather than routine antibiotic prophylaxis under this circumstance.     

Deficient Response to Altered Auditory Feedback in Dyslexia

Although dyslexia is characterized by a deficit in phonological representations, the nature of this deficit is debated. Previously, it was shown that adults with dyslexia respond differently to online manipulations of auditory feedback. In the present study, we found that individual differences in reading and reading-related skills within a group of 30 children (10–13 years old) with dyslexia were associated with the response to altered feedback. The fractional anisotropy of the arcuate fasciculus/superior longitudinal fasciculus was not directly related to the response to altered feedback. This study corroborates that speech perception-production communication is important for phonological representations and reading.     

Retrograde axonal transport of horseradish peroxidase by ganglion cells of the albino rat retina

After introduction of small amounts of horseradish peroxidase (HRP) into known visual centers of the brain, retinal ganglion cells projecting to these regions were detected by the accumulation of HRP-positive granules in their somata. Control experiments indicated that the HRP-positive granules had reached the ganglion cell somata by retrograde axonal transport, and did not represent blood-borne or endogenous peroxidase. Using this technique, it has been determined that axons of both large and medium-sized neurons in the ganglion cell layer of adult and immature rat retinae terminate in the superior colliculus and lateral geniculate body, and that characteristic displaced ganglion cells with axonal connections to these visual centers occur regularly in these retinae. In addition, certain small cells in the retinal ganglion cell layer are described which may represent glia or interneurons, or ganglion cells which lack the ability to transport peroxidase or which lack central connections to these visual centers of the brain.