Eight weeks of overfeeding alters substrate partitioning without affecting metabolic flexibility in men.

BACKGROUND/OBJECTIVE: Impairments in metabolic flexibility (MF) and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured MF and substrate handling before and after 8 weeks of overfeeding in initially healthy adults as a model of the early stages of insulin resistance. SUBJECTS/METHODS: Twenty-nine healthy men (27±5 years old; body mass index 25.5±2.3 kg m-2) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6±2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation and MF were measured in two ways: (a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter and (b) during a two-step hyperinsulinemic-euglycemic clamp. RESULTS: Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (P=0.001 and P=0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (from 0.877±0.020 to 0.864±0.026; P=0.05) and at low insulin levels during the clamp (from 0.927±0.047 to 0.907±0.032; P=0.01). Overfeeding did not affect MF as measured during a clamp (P⩾0.17), but it tended to increase 24-h MF (awake RQ-sleep RQ) as measured by chamber by 0.010±0.028 (P=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation by 13±23 g day-1 (P=0.003) and tended to increase fat oxidation by 6±16 g day-1 (P=0.07) but did not affect carbohydrate oxidation (P=0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r=0.66, P=8 × 10-5) but not fat oxidation rates (P=0.09). CONCLUSIONS: The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.

Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study.

OBJECTIVE: To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. DESIGN: Inter-rater agreement study. SETTING: Five urban surgical centres. POPULATION: Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. METHODS: Laparoscopies were diagnosed, digitally recorded, and reassessed. MAIN OUTCOME MEASURES: Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging. RESULTS: Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. CONCLUSION: Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. TWEETABLE ABSTRACT: Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.

Pain typology and incident endometriosis.

STUDY QUESTION: What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Müllerian anomalies) or a normal pelvis. WHAT IS KNOWN ALREADY: Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at one of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months. MAIN RESULTS AND THE ROLE OF CHANCE: There was a high prevalence (≥30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location. LIMITATIONS, REASONS FOR CAUTION: Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Comparative biodistribution of PAMAM dendrimers and HPMA copolymers in ovarian-tumor-bearing mice.

The biodistribution profile of a series of linear N-(2-hydroxylpropyl)methacrylamide (HPMA) copolymers was compared with that of branched poly(amido amine) dendrimers containing surface hydroxyl groups (PAMAM-OH) in orthotopic ovarian-tumor-bearing mice. Below an average molecular weight (MW) of 29 kDa, the HPMA copolymers were smaller than the PAMAM-OH dendrimers of comparable molecular weight. In addition to molecular weight, hydrodynamic size and polymer architecture affected the biodistribution of these constructs. Biodistribution studies were performed by dosing mice with (125)iodine-labeled polymers and collecting all major organ systems, carcass, and excreta at defined time points. Radiolabeled polymers were detected in organ systems by measuring gamma emission of the (125)iodine radiolabel. The hyperbranched PAMAM dendrimer, hydroxyl-terminated, generation 5 (G5.0-OH), was retained in the kidney over 1 week, whereas the linear HPMA copolymer of comparable molecular weight was excreted into the urine and did not show persistent renal accumulation. PAMAM dendrimer, hydroxyl-terminated, generation 6.0 (G6.0-OH), was taken up by the liver to a higher extent, whereas the HPMA copolymer of comparable molecular weight was observed to have a plasma exposure three times that of this dendrimer. Tumor accumulation and plasma exposure were correlated with the hydrodynamic sizes of the polymers. PAMAM dendrimer, hydroxyl-terminated, generation 7.0 (G7.0-OH), showed extended plasma circulation, enhanced tumor accumulation, and prolonged retention with the highest tumor/blood ratio for the polymers under study. Head-to-head comparative study of HPMA copolymers and PAMAM dendrimers can guide the rational design and development of carriers based on these systems for the delivery of bioactive and imaging agents.

Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth.

A low molecular weight, iron-binding factor was isolated from horse liver. This host-associated iron transfer factor (HAITF) is capable of binding iron and stimulating bacterial growth by promoting iron uptake into bacteria. Also, when injected into infected animals, HAITF increases the virulence of bacterial infections. HAITF bioactivity is ubiquitous in animal tissues and present in serum. It is proposed that HAITF is a factor that inadvertently plays a role in the host-parasite competition for iron.

Monozygotic twinning associated with assisted reproductive technologies: a review.

Twin birth rates have increased markedly in developed countries since the 1970s for two primary reasons: increasing maternal age and the advent and increasing use of fertility treatments. In addition, monozygotic (MZ) twin pregnancies have been reported to occur at a significantly higher rate following assisted reproductive technologies (ART) procedures compared with the natural incidence. Twin pregnancies are of concern due to a dramatically increased risk of associated complications. Monozygotic twin pregnancies carry a 10-20% risk of twin-twin transfusion syndrome, and monoamniotic monochorionic twins are additionally at risk for cord entanglement. While the mechanisms and contributory factors for dizygotic twinning are well established, very little is known about the mechanisms involved in MZ twinning or the factors that contribute to its occurrence. In this review, we will discuss a number of potential mechanisms involved in MZ twinning and explore factors that may be contributing to the increased incidence of ART-associated MZ twins. An improved understanding of the factors that contribute to increased MZ twinning associated with ART will help to elucidate the poorly understood mechanisms involved in the process and will further aid in reducing the overall incidence of multiple pregnancies with their associated risks following ART procedures.

Human energy expenditure: advances in organ-tissue prediction models.

Humans expend energy at rest (REE), and this major energy exchange component is now usually estimated using statistical equations that include weight and other predictor variables. While these formulas are useful in evaluating an individual's or group's REE, an important gap remains: available statistical models are inadequate for explaining underlying organ-specific and tissue-specific mechanisms accounting for resting heat production. The lack of such systems level REE prediction models leaves many research questions unanswered. A potential approach that can fill this gap began with investigators who first showed in animals and later in humans that REE reflects the summated heat production rates of individual organs and tissues. Today, using advanced imaging technologies, REE can be accurately estimated from the measured in vivo mass of 10 organ-tissue mass components combined with their respective mass-specific metabolic rates. This review examines the next frontier of energy expenditure models and discusses how organ-tissue models have the potential not only to better predict REE but also to provide insights into how perturbations in organ mass lead to structure-function changes across other interacting organ systems. The introductory ideas advanced in this review provide a framework for future human energy expenditure modelling research.

Reduced fibrinogen survival in diabetes mellitus. A reversible phenomenon.

Fibrinogen survival and turnover were examined in 15 adult-onset diabetic patients. (125)I-labeled fibrinogen was prepared from each patient during the period of poor carbohydrate control, or hyperglycemic period, and fibrinogen survival determined. Improved control was established in each patient and during this euglycemic period, fibrinogen survival was determined simultaneously with (125)I-fibrinogen saved from the hyperglycemic period and (131)I-labeled fibrinogen prepared from the patient during the euglycemic period. The results confirm reduced fibrinogen survival in hyperglycemic diabetic patients and demonstrate reversal of the fibrinogen abnormality when euglycemia is achieved. The results of the double-label experiments in the euglycemic period suggest that the fibrinogen molecule is not altered functionally and that an abnormal plasma or vascular environment is a more likely basis for reduced fibrinogen survival during hyperglycemia. Electrophoretic and chromatographic experiments demonstrated no gross chemical differences between the fibrinogens prepared from the hyperglycemic and euglycemic periods and normal fibrinogen. Fibrinogen survival gave a better correlation with serial glucose measurements than with correction of hemoglobin A(Ic) levels indicating that the reduced fibrinogen survival noted in diabetics is a rapidly reversible phenomenon. During the hyperglycemic period, pharmacological intervention with aspirin and dipyrimadole was attempted to examine the role of platelets in reduced fibrinogen survival. No significant change in fibrinogen survival was observed. Heparin infusion during hyperglycemia normalized the fibrinogen kinetics of hyperglycemic diabetic patients, suggesting that reduced fibrinogen survival during hyperglycemia is secondary to an effect on thrombin or one of its antagonists.

Acetaldehyde adducts with hemoglobin.

Clinical studies on the minor hemoglobins (hemoglobin A1a-c) have suggested that a novel adduct may form in people abusing alcohol. Such patients were found to have an elevated concentration of minor hemoglobins, but normal or subnormal amounts of glycosylated hemoglobin (hemoglobin A1c) as determined by radioimmunoassay, Acetaldehyde, a reactive metabolite of ethanol, was postulated to form adducts with hemoglobin A that change its chromatographic properties. At physiological concentrations, acetaldehyde was found to form adducts with hemoglobin that were stable to extensive dialysis for several days. The amount of hemoglobin adducts formed were a function of the concentration and number of exposures to acetaldehyde. The reaction of acetaldehyde with hemoglobin A produced chromatographic variants, some of which migrated in the hemoglobin A1a-c region. Analysis of stable acetaldehyde-hemoglobin adducts demonstrated that valine, lysine, and tyrosine residues of globin were sites of reaction. The acetaldehyde-modified amino acid residues appear to exist in interconvertible conformations, only one of which is reducible by sodium borohydride. The amount of these adducts was found to be significantly elevated in hemoglobin from alcoholics as compared with normal volunteers.

Combination chemotherapy and photodynamic therapy with N-(2-hydroxypropyl) methacrylamide copolymer-bound anticancer drugs inhibit human ovarian carcinoma heterotransplanted in nude mice.

This study characterizes the efficacy and toxicity of: (a) free Adriamycin and N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Adriamycin conjugate (P-A); (b) free and HPMA copolymer-meso-chlorin e6 monoethylene diamine disodium salt (Mce6) conjugate (P-C) and light-induced photodynamic therapy; and (c) combinations of the HPMA copolymer conjugates (P-A and P-C) in the destruction of human epithelial ovarian carcinoma heterotransplanted in the nude mouse (OVCAR-3). Eight-week-old female nu/nu mice were injected in both flanks with 0.04-0.05 cm3 OVCAR-3 solid tumor dispersed in media. When bilateral tumors reached a minimum volume of 0.18 cm3 (one axis, 2.0-mm minimum) and demonstrated consistent growth, the experiments were initiated. Drugs were given i.v. unless otherwise noted. Tumor-bearing mice were allocated to the following protocols: (a) Adriamycin at 1 mg/kg, P-A at 30 mg/kg (2.2 mg/kg Adriamycin equivalent), and controls (n = 6 each); (b) Mce6 and light (2 h after administration: 650 nm light for 15 min to deliver 220 J/cm2) at 1.25, 2.5, 5, and 10 mg/kg (n = 6 each), 2.5 mg/kg i.p. (n = 4), and controls (n = 6); (c) P-C at 12.5, 25, and 75 mg/kg (1.5, 2.9, and 8.7 mg/kg Mce6 equivalent, respectively with light (18 h after administration; 650 nm light for 15 min to deliver 220 J/cm2), P-C at 25 mg/kg (2.9 mg/kg Mce6 equivalent) with no light administration, and controls (n = 7 each); and (d) a combination of P-A (30 mg/kg, 2.2 mg/kg adriamycin equivalent) and P-C (12.5 and 75 mg/kg, 1.5 mg/kg and 8.7 mg/kg Mce6 equivalent, respectively) with and without light (n = 7 each; 18 h after administration; 650 nm light for 15 min to deliver 220 J/cm2) and controls (n = 12). Tumor volumes and animals weights were assessed for significant differences from the treated and controls groups by Student's t test. Adriamycin (1 mg/kg) and P-A (30 mg/kg. 2.2 mg/kg Adriamycin equivalent) caused less than a 10% weight loss, and treated tumor volumes (day 10-32) were significantly less than those of controls (all P < 0.045). Mce6 (2.5-10 mg/kg i.v.), caused tumor regression in 80% of tumors and a shock syndrome in 17-83%. i.p. dosing (2.5 mg/kg) was uniformly fatal. Mce6 at 1.25 mg/kg did not show reproducible efficacy. P-C with light (25 and 75 mg/kg, 2.9 and 8.7 mg/kg Mce6 equivalent, respectively) demonstrated significant tumor destruction (P < 0.003) but not complete ablation. The combinations of P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) plus P-C (12.5 and 75 mg/kg; 1.5 mg/kg and 8.7 mg/kg of Mce6 equivalent, respectively) with light resulted in tumor volumes that were significantly less than control tumor volumes and the tumor volumes of mice receiving either P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) or P-C with light (12.5 or 75 mg/kg. 1.5 or 8.7 mg/kg Mce6 equivalent, respectively) alone (all P < 0.02). P-C (75 mg/kg, 8.7 mg/kg Mce6 equivalent) added to P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) resulted in complete tumor ablation. Free Mce6 demonstrates a narrow margin of safety, which is extended by incorporation into HPMA copolymers. P-A demonstrates safety and efficacy in vivo. The combined chemotherapy and photodynamic therapy of P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) with P-C and light (12.5 and 75 mg/kg 1.5 and 8.7 mg/kg Mce6 equivalent, respectively) was nontoxic and allowed us to attain a significant improvement in tumor cures than those obtained by P-A or P-C with light alone.

Lifestyle modification intervention improves glycemic control in Mongolian adults who are overweight or obese with newly diagnosed type 2 diabetes.

OBJECTIVE: To evaluate the effectiveness of a weight loss intervention in Mongolian adults with newly diagnosed type 2 diabetes mellitus and with BMIs ≥ 25.0 kg/m2. METHODS: Eighty participants (33 men/47 women) aged 32-56 years old received education sessions to improve nutritional habits and increase physical activity. Participants were counselled in-person on two occasions with regular follow-up by phone to eat less (reduce calorie intake by 30-40% and consume fewer fatty foods), shift food intake to earlier in a day and increase physical activity such as walking, jogging, running and biking. Measurements were performed before and after the 6-month intervention. RESULTS: After 6 months, the average weight loss was 4.3 ± 4.7 kg, representing a 4.9 ± 5.4% reduction in body weight (p < 0.0001). Mean HbA1c decreased from 8.5 ± 2.7% to 6.0 ± 1.8% (p < 0.0001), and the percent of individuals with HbA1c in the diabetic range dropped from 76.3% to 27.5%. These changes were accompanied by marked improvements in cardiovascular risk factors, including total cholesterol (3.92 ± 1.02 to 3.13 ± 0.80 mmol/l; p < 0.0001) and triglycerides (2.11 ± 0.82 to 1.54 ± 0.51 mmol/l; p < 0.0001), and modest reductions in systolic and diastolic blood pressure (p < 0.05). CONCLUSION: The remarkable improvement in glycemic control and lipid profile in participants suggests that a lifestyle modification intervention targeting weight loss may be highly effective for early diabetes treatment and prevention in Mongolians.

Why are there race/ethnic differences in adult body mass index-adiposity relationships? A quantitative critical review.

Body mass index (BMI) is now the most widely used measure of adiposity on a global scale. Nevertheless, intense discussion centers on the appropriateness of BMI as a phenotypic marker of adiposity across populations differing in race and ethnicity. BMI-adiposity relations appear to vary significantly across race/ethnic groups, but a collective critical analysis of these effects establishing their magnitude and underlying body shape/composition basis is lacking. Accordingly, we systematically review the magnitude of these race-ethnic differences across non-Hispanic (NH) white, NH black and Mexican American adults, their anatomic body composition basis and potential biologically linked mechanisms, using both earlier publications and new analyses from the US National Health and Nutrition Examination Survey. Our collective observations provide a new framework for critically evaluating the quantitative relations between BMI and adiposity across groups differing in race and ethnicity; reveal new insights into BMI as a measure of adiposity across the adult age-span; identify knowledge gaps that can form the basis of future research and create a quantitative foundation for developing BMI-related public health recommendations.

The fluid phase of coagulation and the accelerated atherosclerosis of diabetes mellitus.

The early and accelerated atherosclerosis associated with diabetes mellitus is probably multifactorial in origin. Hyperglycemia, in addition to its numerous pathologic effects on lipids, hormonal profiles, the vascular tree, and platelets, is also associated with effects on the fluid phase of coagulation. The most striking abnormality of coagulation described in diabetes mellitus is a decrement in fibrinogen survival that is rapidly reversible with correction of hyperglycemia or the administration of heparin but not with aspirin and dipyridamole administration, suggesting a hypercoagulable state. Abnormalities of clotting factor assays and circulating levels have been reported in patients with diabetes mellitus, but most of these studies are complicated by the controversy over the results being due to diabetes mellitus or due to the presence of vascular lesions concomitant with diabetes. Nevertheless, an increasing amount of evidence implicates the participation of the fluid phase of coagulation in both the initiation and propagation of diabetic vascular complications.

Percentage of carbohydrate and glycemic response to breakfast, lunch, and dinner in women with gestational diabetes.

We studied the relationship between 1-h glucose response and the percentage of carbohydrates in a given meal in 14 gestational diabetic women who did not require insulin therapy and were between 32 and 36 wk gestation. Each subject was greater than 130% ideal body weight and was placed on a diet of 24 kcal.kg-1.24 h-1, with 12.5% of calories at breakfast and 28% of the calories at lunch and again at dinner, with other calorie intake divided among three snacks. Glycemic response was monitored by self-monitoring of blood glucose 1 h after the start of each meal. Ten postprandial values for each meal were averaged for each of the 14 women. The correlation between percentage of carbohydrates and postprandial glucose level at 1 h was strongest for dinner (r = 0.95, P less than 0.001), with more variability seen at breakfast (r = 0.75, P = 0.002) and lunch (r = 0.86, P = 0.001). To maintain a 1-h postprandial whole-blood glucose level less than 7.78 mM required the following percentages of carbohydrates in each meal: 45% at breakfast, 55% at lunch, and 50% at dinner. If 1-h postprandial whole-blood glucose level was to remain less than 6.67 mM, then the respective values were 33, 45, and 40%. We conclude that the glycemic response to a mixed meal in subjects with gestational diabetes is highly correlated with the percentage of carbohydrates of the ingested meal and varies among individuals and among breakfast, lunch, and dinner.(ABSTRACT TRUNCATED AT 250 WORDS)

Is exercise safe or useful for gestational diabetic women?

The mainstay of management of the gestational diabetic woman is dietary manipulation to achieve and maintain normoglycemia. If normoglycemia cannot be sustained by diet alone, then insulin therapy is initiated. We instituted a series of studies to observe the value and safety of a cardiovascular fitness program to improve glucose tolerance in gestational diabetic women. We first evaluated the safety for pregnant women of five aerobic exercise machines by observing the effect of these different forms of exercise on uterine activity during the third trimester. We found that upper-extremity exercise produced no uterine contractions, but lower-extremity exercise tended to produce contractions. Upper-extremity exercise, in addition to dietary therapy, was then assigned to 10 gestational diabetic women who were matched for amount of glucose intolerance to 10 gestational diabetic women managed by diet alone. The mean fasting plasma glucose +/- SD after 6 wk was 4.87 +/- 0.34 mM in the diet group versus 3.89 +/- 0.37 mM in the diet-plus-exercise group. The mean postglucose challenge in the diet group was 10.40 +/- 0.16 mM versus 5.9 +/- 1.1 mM in the diet-plus-exercise group. Thus, upper-arm exercise may provide a useful treatment option for gestational diabetes and may obviate the need for insulin.

Screening for gestational diabetes. Optimum timing and criteria for retesting.

Because of the morbidity associated with undiagnosed gestational diabetes (GDM), screening programs are advocated in all pregnancy clinics. The purpose of this study was to elucidate the optimum time to test for diabetes during gestation, the indication for retesting, and the predictive value of a positive screening test for a large (greater than 4000 g) infant. Women (N = 300) were screened at three time points: 9-20 wk, 27-31 wk, and 33-36 wk. An additional group of 300 women were screened at two time points: 27-31 wk and 33-36 wk. The prevalence of GDM in this group was 3.2%. The optimum timing for screening for highest yield was 27-31 wk. Retesting at 33-36 wk appeared cost effective if (1) maternal age was greater than or equal to 33 yr, (2) a positive screen was present at 27-31 wk, and (3) the mother was obese (greater than 120% ideal body wt).

Platelet survival in patients with diabetes mellitus.

Platelet survival by 51chromium labeling was determined in six normal control subjects and in twelve patients with diabetes mellitus, before and after improved glucose control (mean HbA1c 10.5 +/- 2.2% and 7.1 +/- 1.8%, respectively). Mean platelet survival was 9.47 +/- 0.85 days for the normal subjects and 9.04 +/- 1.40 and 9.90 +/- 1.05 for the diabetic subjects in hyperglycemic and improved glycemic states, respectively. The differences between these values were not statistically significant. However, platelet survivals performed in three diabetic patients who had severe retinal disease requiring photocoagulation were significantly shortened compared with nonsmoking control subjects (P less than 0.05) or to patients without severe retinopathy (P less than 0.01). These observations imply that measurable changes in in vivo platelet survival occur after the development of small vessel disease. It remains to be determined whether abnormalities described for diabetic platelets in vitro or changes in in vivo platelet physiology contribute to the initiation or propagation of vascular disease in the hyperglycemic individual.

Adoptive immunotherapy of diabetes in autologous nonobese diabetic mice with lymphoid cells ex vivo exposed to cyclosporin plus interleukin 2.

Between 12 and 26 wk of age, approximately 80% of female nonobese diabetic (NOD) mice from the inbred Sansum colony develop lymphocytic insulitis and become overtly diabetic. The disease in this animal model is similar to human insulin-dependent diabetes mellitus (IDDM) in both genetics and autoimmune pathogenesis. Cyclosporin A (CsA) has been used for immunosuppression in IDDM of recent onset in humans but has several limiting side effects. Therefore, a different regimen for CsA immunosuppression was investigated. Autologous splenic lymphoid cells from 12-wk-old not-yet-diabetic female NOD mice were cultured for 72 h with CsA plus interleukin 2 (IL-2) before reinfusion into the animal from which they were isolated. After this treatment, only 2 (18%) of 11 mice became overtly diabetic during an observation period of 19 wk, while 18 (86%) of 21 age-matched control mice developed diabetes during the same observation period (P less than .001). These data suggest an ex vivo preferential IL-2 activation of specific suppressor cells for the autoimmune process with CsA blockade of cytolytic/helper activities. Because the in vivo concentrations of CsA with this procedure would be negligible, these findings have implications for the potential nontoxic use of CsA in human protocols as well.

Levels of Tap-1 and Tap-2 mRNA and expression of Kd and Db on splenic lymphocytes are normal in NOD mice.

It has been reported that the level of Tap-1 (transporter associated with antigen processing) mRNA and the expression of class I on splenocytes are low in NOD mice. Class I expression at 37 degrees C depends on an adequate supply of peptides, so a decrease in Tap could lead to lower class I levels. Since hypoexpression of class I correlated uniformly with the development of diabetes, it has also been suggested that Tap-1nod is diabetogenic. However, others report normal Tap-1 and class I levels in NOD mice. We examined Tap-1 and Tap-2 mRNA levels in NOD/Smrf mice using a reverse transcriptase-polymerase chain reaction method that detects > or = 25% changes in mRNA. We also assessed class I expression with three monoclonal antibodies. No difference in Tap-1 or Tap-2 mRNA levels for females of different ages or between diabetic and nondiabetic animals was observed. Tap-1 mRNA levels were identical between NOD/Smrf and BALB/cJ mice. Kd expression was significantly lower on NOD lymphocytes than in BALB/cJ cells, but the difference was due to the smaller size of the NOD splenic lymphocyte. When cells of the same size were analyzed, no difference in class I levels was observed. Class I levels were also identical in diabetic and age-matched nondiabetic NOD and BALB/c females. Both NOD Tap-1 mRNA and class I were increased by interferon-gamma. We find no evidence for impaired NOD Tap gene activity or class I expression, as previously reported for this strain.

Correlation of serum triglyceride levels and hemoglobin AIc concentrations in diabetes mellitus.

Studies in 10 nonketotic diabetic subjects (five juvenile- and five adult-onset) before and after control of carbohydrate metabolism showed a high degree of correlation between hemoglobin AIc (HbAIc) concentrations and serum triglyceride levels. Serum triglyceride levels were found to correlate more closely with Hb AIc (r = 0.91, p less than 0.001) than did serum cholesterol (r = 0.47, p greater than 0.05), thus indicating a more direct relationship to carbohydrate metabolism.