Basal-State Hyperinsulinemia in Healthy Normoglycemic Adults Is Predictive of Type 2 Diabetes Over a 24-Year Follow-Up: A preliminary report

OBJECTIVE

We examined the predictive value of hyperinsulinemia in the basal state on the 24-year progression from normoglycemia to dysglycemia.

RESEARCH DESIGN AND METHODS

A sample of 515 normoglycemic men and women were studied again after 24 years for glycemic status.

RESULTS

Half of the participants developed dysglycemia: 11.1% progressed to impaired fasting glucose (IFG), 9.9% to impaired glucose tolerance (IGT), 4.5% to both IFG and IGT, and another 24.3% to type 2 diabetes. Elevated levels of overnight fasting (basal) insulin, triglycerides, BMI ≥27 kg/m², fasting blood glucose, blood pressure, North African or Yemenite background, and male sex each favored conversion to dysglycemia after 24 years. In multiple ordered logistic regression analysis, the most significant predictor of progression to dysglycemia was hyperinsulinemia (upper quintile), after adjusting for BMI, ethnic origin, sex, age, smoking, physical activity, blood pressure, and triglycerides.

CONCLUSIONS

Basal hyperinsulinemia in normoglycemic adults constitutes an independent risk factor for developing dysglycemia over 24 years.This study examined hyperinsulinemia in the basal state as an independent factor associated with the 24-year progression to dysglycemia (impaired fasting glucose [IFG]/impaired glucose tolerance [IGT] or type 2 diabetes) in normoglycemic ethnically diverse adult men and women.In the 1980s, Modan et al. (1,2), following the analysis of baseline information of the present cohort, proposed that hyperinsulinemia, reflecting peripheral insulin resistance, is linked to hypertension, obesity, dyslipidemia, and glucose intolerance, a cluster termed “metabolic syndrome” by Reaven (3). Insulin resistance has since been assigned a central place in the metabolic disturbances associated with obesity and type 2 diabetes. We previously reviewed the evidence for the possible role of hyperinsulinemia, especially in the basal state, in sustaining, expanding, or initiating insulin resistance (4).     

Efficient retroviral transduction of human bone marrow progenitor and long-term culture-initiating cells: partial reconstitution of cells from patients with X-linked chronic granulomatous disease by gp91-phox expression

The primary immunodeficiencies are attractive candidates for the development of gene therapy approaches based on the transduction of hematopoietic cells. We have constructed a high-titer recombinant retrovirus for expression of gp91-phox, deficiencies of which cause the X-linked form of chronic granulomatous disease (X-CGD). We have used this vector to transduce human bone marrow, using either unfractionated mononuclear cells or purified CD34+ cells as targets and evaluated several infection protocols. Efficient gene transfer to progenitors and long-term culture-initiating cells (LTC-IC) was obtained for each target population. Importantly for potential clinical application, this could be achieved without the use of exogenous cytokines or polybrene. Progenitors representing each of the lineages detectable in vitro were transduced at equal efficiencies. The vector was shown partially to restore gp91-phox deficiency and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in transduced cells derived from X- CGD patients. These data demonstrate that it is possible to transduce primitive human hematopoietic cells efficiently and reconstitute NADPH oxidase.     

Patterns of hematopoietic lineage involvement in children with neurofibromatosis type 1 and malignant myeloid disorders

Children with neurofibromatosis type 1 (NF1) are at increased risk of developing malignant myeloid disorders, particularly juvenile chronic myelogenous leukemia/juvenile myelomonocytic leukemia (JCML/JMML). We investigated bone marrows from 11 such patients (8 boys and 3 girls) and detected allelic losses at the NF1 locus in 4 of them and probable losses in 2 others. To determine which hematopoietic cell lineages were derived from the abnormal clones, Epstein-Barr virus (EBV)-transformed cell lines and CD34+ cells were analyzed from 3 children with JCML with allelic losses in unfractionated marrow. CD34 cells from these 3 patients lacked the normal NF1 allele, whereas EBV cell lines retained it. Erythroblasts plucked from the burst-forming unit-erythroid colonies of one of these children lacked the normal NF1 allele. We also studied a 10-month-old boy with NF1 who developed an unusual myeloproliferative syndrome. His bone marrow and EBV cell line both showed loss of the normal NF1 allele. In our series and in the literature, male sex and maternal transmission of NF1 were associated with the highest risk of myeloid leukemia. These data (1) provide strong genetic evidence that NF1 functions as a tumor-suppressor in early myelopoiesis, (2) confirm the clonal nature of JCML/JMML, (3) suggest that the elevation in fetal hemoglobin seen in JCML/JMML is a result of primary involvement of erythroid progenitors in the malignant clone, (4) show consistent loss of NF1 in the CD34 cells of affected children and show that the malignant clone may also give rise to pre-B cells in some cases, and (5) implicate epigenetic factors in the development of leukemia in children with NF1.     

Stereological study of the effects of vitamin E on testis structure in rats treated with para-nonylphenol

This study was organized to see whether vitamin E, as a strong antioxidant, could affect the abnormalities of testis structure caused by para-nonylphenol （p-NP） during its development. A total of 32 female Wistar rats after mating were divided into four groups （n = 8）： control, vitamin E （100 mg kg^-1 per day）, p-NP （250 mg kg^-1 per day） and p-NP ＋ vitamin E. The rats were treated from the seventh day of pregnancy till the twenty-first day. After weaning, the male pups were divided into the same groups and were treated orally for 90 days. Finally, the right testis was fixed, processed, stained and studied using stereological methods. The weight and volume of testis, volume of seminiferous tubules and its diameter, thickness of the basement membrane, height of the germinal epithelium, total number of types A and B spermatogonia, spermatocyte, spermatid and Sertoli cells were significantly reduced in p-NP group when compared with other groups. Co-administration of vitamin E and p-NP compensated for the adverse effects of p-NP on the above parameters. In addition, treatment with only vitamin E caused a significant increase in diameter, basement membrane thickness and height of germinal epithelium, number of spermatogonia and spermatocytes. Co-administration of vitamin E with p-NP could prevent the adverse effects ofp-NP on the testis structure during its development.     

Polymorphonuclear neutrophils from human immunodeficiency virus- infected patients show enhanced activation, diminished fMLP-induced L- selectin shedding, and an impaired oxidative burst after cytokine priming

Impaired polymorphonuclear neutrophil (PMN) function may contribute to the onset of certain life-threatening bacterial and fungal infections in human immunodeficiency virus (HIV)-infected patients. Published data on PMN functional activity in HIV infection are controversial, possibly because most studies have involved PMNs isolated from their blood environment by means of various procedures that may differently affect surface receptor expression and thereby alter cellular responses. We therefore used flow cytometry to study the expression of adhesion molecules at the PMN surface, actin polymerization, and the oxidative burst of whole-blood polymorphonuclear neutrophils in 42 HIV-infected patients at different stages of the disease. These PMNs were activated in vivo, as demonstrated by increased expression of the adhesion molecule CD11b/CD18, reduced L-selectin antigen expression, increased actin polymerization, and increased H2O2 production. The alterations were present in asymptomatic patients with CD4+ cell counts greater than 500/microL and did not increase with the progression of the disease. Stimulation by bacterial N-formyl peptides showed dysregulation of L-selectin shedding and decreased H2O2 production after ex vivo priming with tumor necrosis factor alpha or interleukin-8 (IL-8). These latter impairments, which correlated with the decrease in CD4+ lymphocyte numbers and with IL-8 and IL-6 plasma levels, could contribute to the increased susceptibility of HIV-infected patients to bacterial infections.     

Prospective randomized controlled trial: conventional versus powered phlebectomy

OBJECTIVES: Transilluminated powered phlebectomy (TriVex) is a new surgical technique that uses tumescent dissection, transillumination, and powered phlebectomy. The purpose of this study was to compare TriVex with conventional varicose vein surgery in terms of pain, cosmesis, recurrence, complications, and operating time. METHODS: One hundred eighty-eight limbs in 141 patients (33 men, 108 women; mean age, 42.5 years) with varicose veins were randomised to conventional (n = 100) or TriVex (n = 88). Exclusion criteria were venous ulceration or deep venous disease. Varicosities were graded with CEAP and clinical assessment (grades 1-3), and were similar in both groups. Randomization was single blinded. Long or short saphenous vein ligation or stripping was performed as indicated with duplex scanning. Operative time was from skin incision to leg bandaging. Phlebectomy was performed with conventional stab avulsions or TriVex. Patients completed assessment forms preoperatively and postoperatively (2, 6, 26, 52 weeks), and this was supplemented with physician clinical evaluation. Pain was assessed with visual analog score. RESULTS: There was a significant difference in the number of incisions for phlebectomy in the two groups (conventional, n = 29; TriVex, n = 5; P <.0001). TriVex was faster in the grade 3 (extensive) group, but this did not reach statistical significance. There was no difference in mean postoperative pain score over 8 days in the two groups (P =.4624). At 2 weeks there was no significant difference between the groups with regard to bruising (P =.77), cellulitis (P =.33), and numbness (P =.33). At 6 weeks there was no significant difference between the groups with regard to nerve injury (P =.97), residual veins (P =.79), cosmetic score (P =.837), and overall satisfaction (P =.878). At 6 and 12 months, there was no significant difference in cosmesis (P =.955, P =.088, respectively) or recurrence (P =.27, P =.11, respectively). CONCLUSIONS: TriVex is a safe and effective method for excision of varicosities and compares well, after a learning curve, with conventional surgery in regard to complications and recurrence. It has the advantage of a trend toward reduced operating time in extensive varicosities, and significantly fewer incisions, although there was no perceived difference in cosmesis during follow-up.     

Erect chest radiography in the setting of the acute abdomen: essential tool or an unnecessary waste of resources?

INTRODUCTION

It has been suggested that changes to the training schemes of junior doctors and the increased pressure on emergency departments to manage their patients within a limited time might increase the number of unnecessary investigations performed on emergency admission patients. This, in turn, may lead to an increased number of investigations with normal results. In this study we try to analyse the role of the chest X-ray (CXR) as a diagnostic tool in patients presenting with acute abdominal pain.

PATIENTS AND METHODS

A retrospective study was performed of the request forms and results of all chest radiography performed on patients admitted on the emergency surgical intake with acute abdominal pain through utilisation of the prospec-tively maintained electronic radiology database. The indications were compared to the guidelines published by the Royal College of Radiologists (RCR) which have been adopted as the standard of care.

RESULTS

A total of 334 chest X-rays were identified of which only 23 (7%) had new findings. Four (1%) patients had free gas under the diaphragm. Of the CXRs, 258 (77%) were reported normal whilst 53 (16%) had old changes which were described in their hospital records and previous radiographs. Of the CXRs with new findings, only 20 were clinically significant and, of these, four (1%) were surgically significant.

CONCLUSIONS

The majority of CXRs performed on emergency surgical admissions with abdominal pain are unnecessary. By obtaining a clear history, performing a thorough clinical examination and following the RCR guidelines most of the CXRs could be avoided. This would lead to less radiation exposure, reduce delays to diagnosis, and provide significant financial savings.     

Loss of attachment to fibronectin with terminal human erythroid differentiation

Human erythroblastic progenitors (colony-forming unit-erythroid [CFU-E] and burst-forming unit-erythroid [BFU-E]) have been shown to attach to fibronectin (Fn), a property that might be involved in the local regulation of erythropoiesis. In this study, we have investigated changes in cell attachment to Fn upon terminal erythroid differentiation. We first purified CFU-E from human marrow by avidin- biotin immune rosetting. This negative selection procedure yielded a cell population containing approximately 80% blasts that, after characterization by colony-assays and electron microscopy, appeared to consist of CFU-E (10% to 15%) and their immediate progeny (85% to 90%), here defined as "preproerythroblasts." In the presence of erythropoietin, purified cells differentiated into reticulocytes in 7 to 10 days. Cell attachment to Fn was inversely correlated to the stage of differentiation of the erythroid cell: more than 50% of the CFU-E population reproducibly adhered to Fn, whereas at most 30% of the preproerythroblasts had the same capacity. Adhesion was further lost at late maturation stages, and a constant finding was the inability of reticulocytes to adhere to Fn. Finally, CFU-E adhesion to Fn was blocked by polyclonal lgG raised against the Fn receptor and by a monoclonal antibody against VLA-5. These results demonstrate that adhesion to Fn is developmentally regulated during normal human erythropoiesis. Restriction of its expression to CFU-E and its first divisions strikingly correlates with the migratory capacity of these cells.