bluuebunny/crossref_metadata_2025 huggingface dataset:
Obesity Is a Major Determinant of the Association of C-Reactive Protein Levels and the Metabolic Syndrome in Type 2 Diabetes
Authors: Kahn Steven E. , Zinman Bernard , Haffner Steven M. , O’Neill M. Colleen , Kravitz Barbara G. , Yu Dahong , Freed Martin I. , Herman William H. , Holman Rury R. , Jones Nigel P. , Lachin John M. , Viberti Giancarlo C. ,   the ADOPT Study Group
Published: July 2006

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA1c [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (≤3 years), drug-naive, type 2 diabetic subjects (fasting plasma glucose ≤10 mmol/l), we examined a representative subgroup (n = 921) of the U.S. cohort in ADOPT (A Diabetes Outcome Progression Trial). The relationship between levels of CRP, fibrinogen, PAI-1 antigen and PAI-1 activity, and baseline variables including National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome phenotype were explored. All four factors increased significantly with increasing numbers of metabolic syndrome components (P = 0.0136 to P < 0.0001). BMI (P < 0.0001) and HOMA-IR (P < 0.0001) but not A1C (P = 0.65) increased with increasing numbers of metabolic syndrome components. Adjustment of CRP levels for BMI eliminated the association between CRP and the number of metabolic syndrome components, while adjusting for HOMA-IR did not (P = 0.0028). The relationships of PAI-1 antigen and PAI-1 activity with the number of metabolic syndrome components were maintained after adjusting for BMI (P = 0.0002 and P = <0.0001, respectively) or HOMA-IR (P = 0.0008 and P = <0.0001, respectively), whereas that with fibrinogen was eliminated after adjusting for BMI but not after adjusting for HOMA-IR (P = 0.013). Adjustment for A1C had no effect on any of the relationships between the inflammatory and fibrinolytic factors and the metabolic syndrome. We conclude that in recently diagnosed, drug-naive type 2 diabetic subjects, markers of inflammation and fibrinolysis are strongly related to the number of metabolic syndrome components. Further, for CRP and fibrinogen this relationship is determined by body adiposity and not by insulin sensitivity or glucose control.
Granzyme B–Mediated Death of Pancreatic β-Cells Requires the Proapoptotic BH3-Only Molecule Bid
Authors: Estella Eugene , McKenzie Mark D. , Catterall Tara , Sutton Vivien R. , Bird Phillip I. , Trapani Joseph A. , Kay Thomas W. , Thomas Helen E.
Published: July 2006

Perforin-deficient NOD mice are protected from diabetes, suggesting that cytotoxic granule contents of CD8+ T-cells have a significant role in killing β-cells. Despite this, cytotoxic granule effects on human or mouse pancreatic islets have not been reported. We tested the susceptibility of human and mouse islet cells to purified recombinant perforin and granzyme B and measured apoptotic death using a number of assays. Perforin and granzyme B impaired insulin secretion from islet cells, and this was accompanied by cytochrome c release, caspase activation, and DNA fragmentation. Granzyme B–mediated apoptotic changes only occurred in the presence of perforin. When compared with hemopoietic cells, traditionally used as targets to measure cytotoxic T-cell function in vitro, islet cells were relatively resistant to perforin and granzyme B. Inhibition of caspases prevented DNA fragmentation but not cytochrome c release, indicating that mitochondrial disruption due to granzyme B is independent of caspase activation. Consistent with this, islet cells from mice deficient in the BH3-only protein Bid were resistant to cytochrome c release and were protected from apoptosis after exposure to perforin/granzyme B. Our data suggest that Bid cleavage by granzyme B precedes mitochondrial disruption and apoptosis in pancreatic islets.
Assessment of the Role of Common Genetic Variation in the Transient Neonatal Diabetes Mellitus (TNDM) Region in Type 2 Diabetes
Authors: Gloyn Anna L. , Mackay Deborah J.G. , Weedon Michael N. , McCarthy Mark I. , Walker Mark , Hitman Graham , Knight Bridget A. , Owen Katharine R. , Hattersley Andrew T. , Frayling Timothy M.
Published: July 2006

Recent evidence supports the strong overlap between genes implicated in monogenic diabetes and susceptibility to type 2 diabetes. Transient neonatal diabetes mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlapping genes in this region: the transcription factor zinc finger protein associated with cell cycle control and apoptosis (ZAC also known as PLAGL1) and HYMA1, which encodes an untranslated mRNA. Several type 2 diabetes linkage studies have reported linkage to chromosome 6q22–25. We hypothesized that common genetic variation at this TNDM region influences type 2 diabetes susceptibility. In addition to the coding regions, we used comparative genomic analysis to identify conserved noncoding regions, which were resequenced for single nucleotide polymorphism (SNP) discovery in 47 individuals. Twenty-six SNPs were identified. Fifteen tag SNPs (tSNPs) were successfully genotyped in a large case-control (n = 3,594) and family-based (n = 1,654) study. We did not find any evidence of association or overtransmission of any tSNP to affected offspring or of a parent-of-origin effect. Using a study sufficiently powered to detect odds ratios of <1.2, we conclude that common variation in the TNDM region does not play an important role in the genetic susceptibility to type 2 diabetes.
Pioglitazone but Not Glibenclamide Improves Cardiac Expression of Heat Shock Protein 72 and Tolerance Against Ischemia/Reperfusion Injury in the Heredity Insulin-Resistant Rat
Authors: Taniguchi Yayoi , Ooie Tatsuhiko , Takahashi Naohiko , Shinohara Tetsuji , Nakagawa Mikiko , Yonemochi Hidetoshi , Hara Masahide , Yoshimatsu Hironobu , Saikawa Tetsunori
Published: July 2006

We tested the hypothesis that pioglitazone could restore expression of heat shock protein (HSP)72 in insulin-resistant rat heart. At 12 weeks of age, male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control (LETO) rats were treated with pioglitazone (10 mg · kg−1 · day−1) or glibenclamide (5 mg · kg−1 · day−1) for 4 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. In response to hyperthermia, the activation of serine/threonine kinase Akt depending on phosphatidylinositol 3 (PI3) kinase was necessary for cardiac expression of HSP72. Hyperthermia-induced activation of Akt and HSP72 expression were depressed in OLETF rat hearts. Pioglitazone but not glibenclamide improved insulin sensitivity in OLETF rats, which was associated with the restoration of Akt activation and HSP72 expression. In experiments with isolated perfused heart, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by pioglitazone but not glibenclamide. Our results suggest that PI3 kinase–dependent Akt activation, an essential signal for HSP72 expression, is depressed in the heart in insulin-resistant OLETF rats, and the results suggest also that the restoration of HSP72 expression and tolerance against ischemia/reperfusion injury by treatment with pioglitazone might be due to an improvement of insulin resistance, leading to restoration of impaired PI3 kinase–dependent Akt activation in response to hyperthermia.
Mechanisms of Impaired Fasting Glucose and Glucose Intolerance Induced by a ∼50% Pancreatectomy
Authors: Matveyenko Aleksey V. , Veldhuis Johannes D. , Butler Peter C.
Published: July 2006

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) often coexist and as such represent a potent risk factor for subsequent development of type 2 diabetes. β-Cell mass is ∼50% deficient in IFG and ∼65% deficient in type 2 diabetes. To establish the effect of a ∼50% deficit in β-cell mass on carbohydrate metabolism, we performed a ∼50% partial pancreatectomy versus sham surgery in 14 dogs. Insulin secretion was quantified from insulin concentrations measured in the portal vein at 1-min sampling intervals under basal conditions, after a 30-g oral glucose, and during a hyperglycemic clamp. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp combined with isotope dilution. Partial pancreatectomy resulted in IFG and IGT. After partial pancreatectomy both basal and glucose-stimulated insulin secretion were decreased through the mechanism of a selective ∼50 and ∼80% deficit in insulin pulse mass, respectively (P < 0.05). These defects in insulin secretion were partially offset by decreased hepatic insulin clearance (P < 0.05). Partial pancreatectomy also caused a ∼40% decrease in insulin-stimulated glucose disposal (P < 0.05), insulin sensitivity after partial pancreatectomy being related to insulin pulse amplitude (r = 0.9, P < 0.01). We conclude that a ∼50% deficit in β-cell mass can recapitulate the alterations in glucose-mediated insulin secretion and insulin action in humans with IFG and IGT. These data support a mechanistic role of a deficit in β-cell mass in the evolution of IFG/IGT and subsequently type 2 diabetes.
Diabetes, Hyperglycemia, and Inflammation in Older Individuals
Authors: de Rekeneire Nathalie , Peila Rita , Ding Jingzhong , Colbert Lisa H. , Visser Marjolein , Shorr Ronald I. , Kritchevsky Stephen B. , Kuller Lewis H. , Strotmeyer Elsa S. , Schwartz Ann V. , Vellas Bruno , Harris Tamara B.
Published: July 2006

OBJECTIVE—The objective of this study was to assess the association of inflammation with hyperglycemia (impaired fasting glucose [IFG]/impaired glucose tolerance [IGT]) and diabetes in older individuals.

RESEARCH DESIGN AND METHODS—Baseline data from the Health, Aging and Body Composition study included 3,075 well-functioning black and white participants, aged 70–79 years.

RESULTS—Of the participants, 24% had diabetes and 29% had IFG/IGT at baseline. C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels (P < 0.001) were significantly higher among diabetic participants and those with IFG/IGT. Odds of elevated IL-6 and TNF-α (>75th percentile) were, respectively, 1.95 (95% CI 1.56–2.44) and 1.88 (1.51–2.35) for diabetic participants and 1.51 (1.21–1.87) and 1.14 (0.92–1.42) for those with IFG/IGT after adjustment for age, sex, race, smoking, alcohol intake, education, and study site. Odds ratios for elevated CRP were 2.90 (2.13–3.95) and 1.45 (1.03–2.04) for diabetic women and men and 1.33 (1.07–1.69) for those with IFG/IGT regardless of sex. After adjustment for obesity, fat distribution, and inflammation-related conditions, IL-6 remained significantly related to both diabetes and IFG/IGT. CRP in women and TNF-α in both sexes were significantly related to diabetes, respectively, whereas risk estimates for IFG/IGT were decreased by adjustment for adiposity. Among diabetic participants, higher levels of HbA1c were associated with higher levels of all three markers of inflammation, but only CRP remained significant after full adjustment.

CONCLUSIONS—Our findings show that dysglycemia is associated with inflammation, and this relationship, although consistent in diabetic individuals, also extends to those with IFG/IGT.
A Critical Appraisal of the Continuous Glucose–Error Grid Analysis
Authors: Wentholt Iris M. , Hoekstra Joost B. , DeVries J. Hans
Published: July 2006

OBJECTIVE—There is no consensus on how to optimally assess the accuracy of continuous glucose sensors. We examined the continuous glucose–error grid analysis (CG-EGA) and compared it with classical accuracy assessment methods, using data from a previously reported study comparing two different continuous glucose sensors in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS—Drift, delay, mean absolute difference (MAD), sensitivity, and specificity for detecting hypo- and hyperglycemia were calculated, and a Clarke error grid and a CG-EGA were constructed for both sensors, also including an examination of the influence of choosing different time intervals for paired sensor and reference glucose values.

RESULTS—For sensor II, there was a delay between blood glucose and sensed glucose (7.1 min, P < 0.001). Sensor II was more accurate than sensor I during hypo- and hyperglycemia (e.g., smaller MAD, P = 0.011 and P = 0.024, respectively; better sensitivity for detecting hypoglycemia, P = 0.018). Correction for the 7-min delay improved sensor II MAD with 2.2% in every range. In contrast, CG-EGA did not reveal a difference in accuracy between the sensors. Paradoxically, CG-EGA results for sensor II deteriorated when corrected for the delay. CG-EGA calculated with shorter time intervals resulted in worsening accuracy for both sensors.

CONCLUSIONS—CG-EGA did not detect differences in accuracy whereas conventional methods did. CG-EGA is time demanding; results are hard to interpret and seem to vary with chosen time intervals. At present, CG-EGA does not contribute to a combination of various established assessment methods.
A Clinico-microbiological Study of Diabetic Foot Ulcers in an Indian Tertiary Care Hospital
Authors: Gadepalli Ravisekhar , Dhawan Benu , Sreenivas Vishnubhatla , Kapil Arti , Ammini A.C. , Chaudhry Rama
Published: July 2006

OBJECTIVE—To determine the microbiological profile and antibiotic susceptibility patterns of organisms isolated from diabetic foot ulcers. Also, to assess potential risk factors for infection of ulcers with multidrug-resistant organisms (MDROs) and the outcome of these infections.

RESEARCH DESIGN AND METHODS—Pus samples for bacterial culture were collected from 80 patients admitted with diabetic foot infections. All patients had ulcers with Wagner’s grade 3–5. Fifty patients (62.5%) had coexisting osteomyelitis. Gram-negative bacilli were tested for extended spectrum β-lactamase (ESBL) production by double disc diffusion method. Staphylococcal isolates were tested for susceptibility to oxacillin by screen agar method, disc diffusion, and mec A–based PCR. Potential risk factors for MDRO-positive samples were explored.

RESULTS—Gram-negative aerobes were most frequently isolated (51.4%), followed by gram-positive aerobes and anaerobes (33.3 and 15.3%, respectively). Seventy-two percent of patients were positive for MDROs. ESBL production and methicillin resistance was noted in 44.7 and 56.0% of bacterial isolates, respectively. MDRO-positive status was associated with presence of neuropathy (P = 0.03), osteomyelitis (P = 0.01), and ulcer size >4 cm2 (P < 0.001) but not with patient characteristics, ulcer type and duration, or duration of hospital stay. MDRO-infected patients had poor glycemic control (P = 0.01) and had to be surgically treated more often (P < 0.01).

CONCLUSIONS—Infection with MDROs is common in diabetic foot ulcers and is associated with inadequate glycemic control and increased requirement for surgical treatment. There is a need for continuous surveillance of resistant bacteria to provide the basis for empirical therapy and reduce the risk of complications.
Evidence for Independent Heritability of the Glycation Gap (Glycosylation Gap) Fraction of HbA1c in Nondiabetic Twins
Authors: Cohen Robert M. , Snieder Harold , Lindsell Christopher J. , Beyan Huriya , Hawa Mohammed I. , Blinko Stuart , Edwards Raymond , Spector Timothy D. , Leslie R. David G.
Published: July 2006

OBJECTIVE—HbA1c (A1C) is substantially determined by genetic factors not shared in common with glucose. Fractions of the variance in A1C, the glycation gap (GG; previously called the glycosylation gap) and the hemoglobin glycosylation index, correlate with diabetes complications. We therefore tested whether GG (measured A1C − A1C predicted from glycated serum proteins [GSPs]) was genetically determined and whether it accounted for the heritability of A1C.

RESEARCH DESIGN AND METHODS—We conducted a classic twin study on A1C and GSP collected in 40 and 46 pairs of monozygotic and dizygotic healthy female twins, respectively. The predicted A1C was based on the regression line between A1C and GSP in a separate population spanning the pathophysiologic range.

RESULTS—GG was more strongly correlated between monozygotic (r = 0.65) than dizygotic (r = 0.48) twins, adjusted for age and BMI. The best-fitting quantitative genetic model adjusted for age and BMI showed that 69% of population variance in GG is heritable, while the remaining 31% is due to unique environmental influences. In contrast, GSP was similarly correlated between monozygotic (r = 0.55) and dizygotic (r = 0.49) twins, hence not genetically determined. GG was strongly correlated to A1C (r = 0.48), attributable mostly to genetic factors. About one-third of the heritability of A1C is shared with GG; the remainder is specific to A1C.

CONCLUSIONS—Heritability of the GG accounts for about one-third of the heritability of A1C. By implication, there are gene(s) that preferentially affect erythrocyte lifespan or glucose and/or nonenzymatic glycation or deglycation in the intracellular, rather than extracellular, compartment.
Assessing the Outcome of the Management of Diabetic Foot Ulcers Using Ulcer-Related and Person-Related Measures
Authors: Jeffcoate William J. , Chipchase Susan Y. , Ince Paul , Game Fran L.
Published: July 2006

OBJECTIVE—The purpose of this study was to compare different outcome measures in the audit of management of diabetic foot ulcers

RESEARCH DESIGN AND METHODS—Data collected prospectively in a consecutive cohort of patients referred to a specialist multidisciplinary foot care clinic between 1 January 2000 and 31 December 2003 were analyzed. A single index ulcer was selected for each patient and classified according to both the Size (Area and Depth), Sepsis, Arteriopathy, and Denervation [S(AD)SAD] and University of Texas (UT) systems. Ulcer-related outcomes (healing, resolution by ipsilateral amputation or by death, and persisting unhealed) were determined at 6 and 12 months and compared with patient-related outcomes (survival, any amputation, and being free from any ulcer) at 12 months.

RESULTS—In 449 patients (63.7% male, mean age 66.7 ± 13.2 years), 352 (78.4%) ulcers were superficial [S(AD)SAD/UT grade 1] and 134 of these (38.1% of 352) were neither ischemic nor infected. A total of 183 (40.8% of 449) ulcers were clinically infected, and peripheral arterial disease was present in 216 patients (48.1%). Seventeen patients (3.8%) were lost to follow-up and were excluded from analysis. Of the ulcers, 247 (55.0% of 449) and 295 (65.7%) healed without amputation by 6 and 12 months, respectively. Median (range) time to healing was 78 (7–364) days. Of all index ulcers, 5.8 and 8.0% were resolved by amputation, and 6.2 and 10.9% by death by the same time points; 27.8 and 11.6% persisted unhealed. In contrast, patient-related outcomes revealed that of 449 patients only 202 (45.0%) were alive, without amputation, and ulcer free at 12 months. This group had had 272 (1–358) days without any ulcer. A total of 48 (10.7%) patients had undergone some form of amputation, and 75 (16.7%) had died.

CONCLUSIONS—These data illustrate the extent to which ulcer-related outcomes may underestimate the true morbidity and mortality associated with diabetic foot disease. It is suggested that when attempts are made to compare the effectiveness of management in different centers, greater emphasis should be placed on patient-related outcome measures.
Prevalence of Cardiovascular Disease Risk Factors in U.S. Children and Adolescents With Diabetes
Authors: Rodriguez Beatriz L. , Fujimoto Wilfred Y. , Mayer-Davis Elizabeth J. , Imperatore Giuseppina , Williams Desmond E. , Bell Ronny A. , Wadwa R. Paul , Palla Shana L. , Liu Lenna L. , Kershnar Ann , Daniels Stephen R. , Linder Barbara ,   for the SEARCH for Diabetes in Youth Study Group
Published: July 2006

OBJECTIVE—The purpose of this study was to determine the prevalence and correlates of selected cardiovascular disease (CVD) risk factors among youth aged <20 years with diabetes.

RESEARCH DESIGN AND METHODS—The analysis included 1,083 girls and 1,013 boys examined as part of the SEARCH for Diabetes in Youth study, a multicenter, population-based study of youth 0–19 years of age with diabetes. Diabetes type was determined by a biochemical algorithm based on diabetes antibodies and fasting C-peptide level. CVD risk factors were defined as follows: HDL cholesterol <40 mg/dl; age- and sex-specific waist circumference >90th percentile; systolic or diastolic blood pressure >90th percentile for age, sex, and height or taking medication for high blood pressure; and triglycerides >110 mg/dl.

RESULTS—The prevalence of having at least two CVD risk factors was 21%. The prevalence was 7% among children aged 3–9 years and 25% in youth aged 10–19 years (P < 0.0001), 23% among girls and 19% in boys (P = 0.04), 68% in American Indians, 37% in Asian/Pacific Islanders, 32% in African Americans, 35% in Hispanics, and 16% in non-Hispanic whites (P < 0.0001). At least two CVD risk factors were present in 92% of youth with type 2 and 14% of those with type 1A diabetes (P < 0.0001). In multivariate analyses, age, race/ethnicity, and diabetes type were independently associated with the odds of having at least two CVD risk factors (P < 0.0001).

CONCLUSIONS—Many youth with diabetes have multiple CVD risk factors. Recommendations for weight, lipid, and blood pressure control in youth with diabetes need to be followed to prevent or delay the development of CVD as these youngsters mature.
Isn’t This Just Bedtime Snacking?
Authors: Morse Shereen A. , Ciechanowski Paul S. , Katon Wayne J. , Hirsch Irl B.
Published: July 2006

OBJECTIVE—Night-eating syndrome is characterized by excessive eating in the evening and nocturnal awakening with ingestion of food. Psychosocial variables and emotional triggers may be associated with these behaviors. In patients with diabetes, such behaviors may lead to glucose dysregulation and contribute to obesity and complications.

RESEARCH DESIGN AND METHODS—In 714 tertiary care patients with type 1 and 2 diabetes, we determined the proportion of patients reporting eating >25% of their daily food intake after regular suppertime. We also screened patients for major depression, childhood maltreatment histories, nonsecure attachment styles, and emotional eating triggers. We examined whether patients reporting night-eating behaviors had greater psychosocial distress, higher HbA1c (A1C) levels, more obesity, and more diabetes complications compared with patients without night-eating behaviors.

RESULTS—Night-eating behaviors were reported in 9.7% of patients. Compared with patients without night-eating behaviors, those with these behaviors were less adherent with diet, exercise, and glucose monitoring and more likely to be depressed, to report childhood maltreatment histories, to have nonsecure attachment styles, and to report eating in response to anger, sadness, loneliness, worry, and being upset. Controlling for age, sex, race, and major depression, patients with night-eating behaviors, compared with patients without night-eating behaviors, were more likely to be obese (odds ratio 2.6 [95% CI 1.5–4.5]), to have A1C values >7% (2.2 [1.1–4.1]) and to have two or more diabetes complications (2.6 [1.5–4.5]).

CONCLUSIONS—Night-eating behaviors are associated with adverse outcomes in patients with diabetes. Use of clinical screening tools may help identify patients with night-eating behaviors.
Advantage of Premeal-Injected Insulin Glulisine Compared With Regular Human Insulin in Subjects With Type 1 Diabetes
Authors: Rave Klaus , Klein Oliver , Frick Annke D. , Becker Reinhard H.A.
Published: July 2006

OBJECTIVE—Insulin glulisine, a rapid-acting insulin analog, provides prandial insulin replacement. In this study, we compared postprandial blood glucose control after pre- and postmeal insulin glulisine with regular human insulin (RHI).

RESEARCH DESIGN AND METHODS—In a single-dose, randomized, four-way complete cross-over study, subjects received standardized, 15-min meals, covered by subcutaneous injections of either insulin glulisine (immediately premeal or 15 min postmeal; 0.15 unit/kg per injection) or RHI (30 min or immediately premeal; 0.15 unit/kg per injection). Twenty-one patients with type 1 diabetes (mean age 36.4 years; mean BMI 26.0 kg/m2) were enrolled; 20 patients completed the study. Postprandial baseline-subtracted blood glucose exposure, maximum excursion, maximum and minimum blood glucose concentrations, and time to the maximum excursion and minimum concentration were assessed, along with serum insulin concentrations.

RESULTS—Lower maximum blood glucose excursion (65 vs. 89 mg/dl), total blood glucose exposure within 2 h (279 vs. 334 mg · h/dl, maximum blood glucose concentration (180 vs. 209 mg/dl), and less time to maximum blood glucose excursion (48 vs. 70 min) were seen with immediately premeal insulin glulisine versus immediately premeal RHI. The maximum serum concentration of insulin glulisine was almost double that of RHI (82 vs. 45 μU/ml), achieved in approximately half the time (55 vs. 97 min). Conversely, insulin glulisine (15 min postmeal) versus RHI (immediately premeal) and RHI (30 min premeal) versus insulin glulisine (immediately premeal) resulted in comparable blood glucose control.

CONCLUSIONS—Insulin glulisine renders postprandial glucose disposal closer to physiologic requirements compared with RHI and enables appropriate timing of prandial insulin administration.
Different Mechanisms for Impaired Fasting Glucose and Impaired Postprandial Glucose Tolerance in Humans
Authors: Meyer Christian , Pimenta Walkyria , Woerle Hans J. , Van Haeften Timon , Szoke Ervin , Mitrakou Asimina , Gerich John
Published: July 2006

OBJECTIVE—To compare the pathophysiology of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a more comprehensive and standardized fashion than has hitherto been done.

RESEARCH DESIGN AND METHODS—We studied 21 individuals with isolated IFG (IFG/normal glucose tolerance [NGT]), 61 individuals with isolated IGT (normal fasting glucose [NFG]/IGT), and 240 healthy control subjects (NFG/NGT) by hyperglycemic clamps to determine first- and second-phase insulin release and insulin sensitivity. Homeostasis model assessment (HOMA) indexes of β-cell function (HOMA-%B) and insulin resistance (HOMA-IR) were calculated from fasting plasma insulin and glucose concentrations.

RESULTS—Compared with NFG/NGT, IFG/NGT had similar fasting insulin concentrations despite hyperglycemia; therefore, HOMA-IR was increased ∼30% (P < 0.05), but clamp-determined insulin sensitivity was normal (P > 0.8). HOMA-%B and first-phase insulin responses were reduced ∼35% (P < 0.002) and ∼30% (P < 0.02), respectively, but second-phase insulin responses were normal (P > 0.5). NFG/IGT had normal HOMA-IR but ∼15% decreased clamp-determined insulin sensitivity (P < 0.03). Furthermore, HOMA-%B was normal but both first-phase (P < 0.0003) and second-phase (P < 0.0001) insulin responses were reduced ∼30%. IFG/NGT differed from NFG/IGT by having ∼40% lower HOMA-%B (P < 0.012) and ∼50% greater second-phase insulin responses (P < 0.005).

CONCLUSIONS—Since first-phase insulin responses were similarly reduced in IFG/NGT and NFG/IGT, we conclude that IFG is due to impaired basal insulin secretion and preferential resistance of glucose production to suppression by insulin, as reflected by fasting hyperglycemia despite normal plasma insulin concentrations and increased HOMA-IR, whereas IGT mainly results from reduced second-phase insulin release and peripheral insulin resistance, as reflected by reduced clamp-determined insulin sensitivity.
Harmful or Not: Trichostatin A treatment of embryos generated by ICSI or ROSI
Authors: Kishigami Satoshi , Ohta Hiroshi , Mizutani Eiji , Wakayama Sayaka , Bui Hong-Thuy , Thuan Nguyen , Hikichi Takafusa , Suetsugu Rinako , Wakayama Teruhiko
Published: July 2006

Trichostatin A (TSA), a histone deacetylase inhibitor, is a known teratogen causing malformations such as vertebral fusions when applied during the postimplantation period; TSA also causes developmental arrest when applied during the preimplantation period. Regardless of these hindrances, we have succeeded in the establishment of an efficient somatic cloning method for the mouse where reconstructed embryos are treated with TSA. To elucidate this apparent discrepancy, we treated fertilized mouse embryos generated either by intracytoplasmic sperm injection (ICSI) or round spermatid injection (ROSI) with 50 nM TSA for 20 h after fertilization as well as parthenogenetic embryos and found that TSA treatment inhibited the preimplantation development of ICSI embryos but not ROSI or parthenogenetic embryos. And, although we often observed hypomorphism following TSA treatment in embryos grown to full term produced by both ICSI (av. of body weight: 1.7 g vs. 1.5 g) and ROSI (1.6 g vs. 1.2 g), TSA treatment reduced the offspring production rate for ICSI from 57% to 34% but not for ROSI from 30% to 36%. Thus, these data indicate that the effects, harmful or not, of TSA treatment on embryonic development depend on their nuclear derivations. Also, the resulting hypomorphism after TSA treatment is a caveat for this procedure in current Assisted Reproductive Technologies.
Enhanced expression of selenocysteine lyase in acute glomerulonephritis and its regulation by AP-1
Authors: Jafari Claudia , Panzer Ulf , Steinmetz Oliver , Zahner Gunther , Stahl Rolf , Harendza Sigrid
Published: July 2006

Acute glomerulonephritis can lead to chronic glomerulonephritis or resolve without permanent damage to the kidneys. Differential gene expression was studied in a model of acute and chronic glomerulonephritis to identify factors influencing the course of glomerulonephritis towards healing or chronification. One of the differentially expressed genes was identified as SCL, encoding selenocysteine lyase. Its expression was higher in acute glomerulonephritis and lower in chronic glomerulonephritis. The transcriptional regulation of SCL was studied in vitro in rat mesangial cells (MC). SCL RNA expression increased eight-fold compared to the baseline after stimulation with interleukin-1β (IL-1β) for three hours. Luciferase expression and gel shift experiments revealed an enhancer element between bp −152 and −298 of the SCL 5’-regulatory region, with protein binding to an AP-1 binding site that may be involved in the regulation of SCL-RNA in vivo in an endogenous feedback mechanism to the inflammatory reaction in acute glomerulonephritis, leading to resolution of this disease.
Quantum Dots in Biological and Biomedical Research: Recent Progress and Present Challenges
Authors: Klostranec J. M. , Chan W. C. W.
Published: July 2006

The marriage of nanomaterials with biology has produced a new generation of technologies that can profoundly impact biological and biomedical research. Quantum dots (Qdots) are an archetype for this hybrid research area and have gained popularity and interest from diverse research communities because of their unique and tunable optical properties. In this Review, we will describe their history and development, optical and electronic properties, and applications in biology and medicine. A critical evaluation of barriers impacting current Qdot technologies will be discussed and insights into the future outlook of the field will be explored.
Inside Front Cover: Direct Printing of 3D and Curvilinear Micrometer‐Sized Architectures into Solid Substrates with Sub‐micrometer Resolution (Adv. Mater. 15/2006)
Authors: Campbell C. J. , Smoukov S. K. , Bishop K. J. M. , Baker E. , Grzybowski B. A.
Published: July 2006

The inside cover shows a hexagonal array of convex microlenses etched directly into glass using a reaction‐diffusion process initiated from a hydrogel stamp. The technique, reported by Grzybowski and co‐workers on p. 2004, allows for direct printing of complex microarchitectures into a variety of materials with sub‐micrometer resolution. The images were generated by longtime exposure of slowly rotating patterns. Cover design by Christopher J. Campbell.
Durometry for the assessment of skin disease in systemic sclerosis
Authors: Kissin Eugene Y. , Schiller Aileen M. , Gelbard Rondi B. , Anderson Jennifer J. , Falanga Vincent , Simms Robert W. , Korn Joseph H. , Merkel Peter A.
Published: July 2006

Objective

To examine the validity of a durometer to objectively measure skin hardness in systemic sclerosis (SSc), and to compare digital durometry with the modified Rodnan skin score (MRSS) and ultrasonography.

Methods

Patients with SSc and healthy controls underwent durometry measurements in 3 assessments: a Latin square experiment to establish durometry's intra‐ and interobserver reliability compared with skin scoring (5 SSc, 1 control); a longitudinal cohort to assess sensitivity to change in skin hardness (13 SSc, 5 controls); and an ultrasound cohort to evaluate correlation between durometry, ultrasound‐measured skin thickness, and clinical skin scoring (30 SSc, 12 controls).

Results

Intraobserver reproducibility was higher for durometry than for clinical skin scoring (intraclass correlation coefficient [ICC] 0.97 versus 0.85), whereas interobserver reproducibility was similar (0.75 versus 0.73). Interobserver reproducibility of durometry was good for all body areas (ICC 0.61–0.85), but for skin scoring it was moderate in the legs (0.51) and poor in the abdomen (0.08), feet (0.09), and fingers (0.27). Durometry scores correlated with clinical skin scores (Latin square: r = 0.44, P = 0.03; longitudinal cohort: r = 0.81, P < 0.001) and ultrasound‐measured skin thickness (hands: r = 0.58, forearms: r = 0.63, upper arms: r = 0.40; P ≤ 0.001 for all). Uninvolved skin in patients with SSc was harder than skin from controls (mean ± SD 23 ± 7 durometer units [DU] versus 19 ± 6 DU; P < 0.0001). Finally, there was a strong correlation between change in MRSS and change in durometry score (r = 0.77, P = 0.002).

Conclusion

Durometer‐measured skin hardness correlates well with MRSS and ultrasound‐measured skin thickness, provides greater reliability than MRSS, and is sensitive to changes in skin hardness over time. Durometry should be considered for use in clinical therapeutic SSc trials.
Channeling and prevalence of cardiovascular contraindications in users of cyclooxygenase 2 selective nonsteroidal antiinflammatory drugs
Authors: Mosis Georgio , Stijnen Theo , Castellsague Jordi , Dieleman Jeanne P. , van der Lei Johan , Stricker Bruno H. C. , Sturkenboom Miriam C. J. M.
Published: July 2006

Objective

To assess use and channeling of cyclooxygenase 2 selective inhibitors (coxibs) over time and to estimate the percentage of coxib users with cardiovascular contraindications.

Methods

The study population comprised all coxib and nonselective nonsteroidal antiinflammatory drug (NSAID) users in the Integrated Primary Care Information project between January 2000 and December 2004. The prevalence of risk factors for NSAID‐related upper gastrointestinal ulcer complications, cardiovascular disease, and cerebrovascular disease at the start of treatment was compared between users of coxibs and users of nonselective NSAIDs.

Results

The study population included 72,841 nonselective NSAID users and 10,739 coxib users. The prevalence of risk factors for NSAID‐related gastrointestinal complications was higher in coxib users than nonselective NSAID users (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.10–1.26). Similarly, the prevalence of prior cardiovascular disease was higher in coxib users than in nonselective NSAID users (OR 1.35, 95% CI 1.28–1.43). Channeling of coxibs to patients with NSAID‐related gastrointestinal risk factors declined after 2001 but increased again in 2004, whereas the channeling of coxibs to patients with cardiovascular disease remained constant. Less than 15% of all coxib users had history of ischemic coronary or cerebrovascular disease. Among coxib users with increased risk for NSAID‐related gastrointestinal disorders, 27% had history of ischemic coronary or cerebrovascular disease.

Conclusion

This study demonstrates that coxibs were preferentially prescribed to patients with risk factors for NSAID‐related gastrointestinal disorders and/or cardiovascular diseases. Only one‐quarter of coxib users with increased risk for NSAID‐related gastrointestinal complications had cardiovascular conditions compatible with recent European safety contraindications for coxibs.
Infliximab improves productivity and reduces workday loss in patients with ankylosing spondylitis: Results from a randomized, placebo‐controlled trial
Authors: van der Heijde Désirée , Han Chenglong , DeVlam Kirt , Burmester Gerd , van den Bosch Filip , Williamson Paul , Bala Mohan , Han John , Braun Jürgen
Published: July 2006

Objective

To examine whether clinical benefits observed after treatment with infliximab were accompanied by improvement in productivity and reduction in time lost from work in a randomized, double‐blind, placebo‐controlled, multicenter trial of patients with ankylosing spondylitis (AS).

Methods

Adults with active AS receiving standard antiinflammatory treatment were randomly assigned in a 3:8 ratio to receive infusions of placebo or 5 mg/kg infliximab at weeks 0, 2, 6, and every 6 weeks thereafter through week 24. Physical function was measured using the Bath Ankylosing Spondylitis Functional Index. The impact of disease on productivity was measured using a visual analog scale (range 0–10). Self‐reported employment status and time lost at work before and during the trial were collected. Spearman's correlation coefficient was used to examine factors associated with productivity.

Results

Patients treated with infliximab had a more significant reduction in limitations of work and daily activity due to physical or emotional problems than patients treated with placebo. Of the subset of patients employed full time, patients in the infliximab group had a significantly greater improvement in productivity as early as week 6 compared with the placebo group. The median change from baseline in the productivity score at week 24 was 0.7 (median percent change 11%) in the placebo group compared with 2.1 (62%) in the infliximab group (P< 0.05). Daily productivity was significantly correlated with physical function and disease activity at baseline and week 24.

Conclusion

The daily productivity of patients with active AS was significantly associated with functional impairment and disease activity. Infliximab treatment significantly improved productivity and reduced workday loss among employed patients with AS.
Perceived exercise barriers, enablers, and benefits among exercising and nonexercising adults with arthritis: Results from a qualitative study
Authors: Wilcox Sara , Der Ananian Cheryl , Abbott Jill , Vrazel JoEllen , Ramsey Cornelia , Sharpe Patricia A. , Brady Teresa
Published: July 2006

Objective

Rates of participation in regular exercise are lower among individuals with arthritis than those without arthritis. This study examined perceived exercise barriers, benefits, and enablers in exercising and nonexercising adults with arthritis.

Methods

Twelve focus groups were conducted with 68 adults with arthritis. Groups were segmented by exercise status, socioeconomic status, and race. Focus group discussions were transcribed verbatim and coded. NVivo software was used to extract themes for exercisers and nonexercisers.

Results

A wide range of physical, psychological, social, and environmental factors were perceived to influence exercise. Some of these factors were similar to those in general adult samples, whereas others were unique to individuals with chronic disease. Symptoms of arthritis were barriers to exercise, yet improvements in these outcomes were also seen as potential benefits of and motivations for exercise. Exercisers had experienced these benefits and were more likely to have adapted their exercise to accommodate the disease, whereas nonexercisers desired these benefits and were more likely to have stopped exercising since developing arthritis. Health care providers' advice to exercise and the availability of arthritis‐specific programs were identified as needs.

Conclusion

This study has implications for how to market exercise to individuals with arthritis and how communities and health care professionals can facilitate the uptake of exercise. These implications are discussed.
Scleroderma lung: Initial forced vital capacity as predictor of pulmonary function decline
Authors: Plastiras Sotiris C. , Karadimitrakis Stylianos P. , Ziakas Panayiotis D. , Vlachoyiannopoulos Panayiotis G. , Moutsopoulos Haralampos M. , Tzelepis George E.
Published: July 2006

Objective

To determine the ability of initial forced vital capacity (FVC) of patients with scleroderma to predict subsequent pulmonary function deterioration.

Methods

Data on 78 patients with scleroderma were retrospectively collected and analyzed. FVC (percent predicted), diffusing capacity for carbon monoxide (percent predicted), and various clinical and laboratory parameters were recorded. Pulmonary function decline (outcome) was defined as at least a 15‐point sustained decrease in FVC (percent predicted). Kaplan‐Meier analyses were performed separately for 60 patients initially assessed within the first 3 years from disease onset (group A) and 16 patients whose FVC values in the fourth or fifth year from disease onset were ascribed as baseline measurements (group B).

Results

Based on baseline FVC, patients in each group were categorized into those with normal FVC (≥80% predicted) and those with decreased FVC (<80% predicted). In group A, the percent‐predicted FVC of 89% of patients with normal initial FVC and of 75% of patients with reduced baseline FVC did not decrease by ≥15 points at 5 years (log rank P = 0.04). Four patients with decreased baseline FVC developed respiratory failure (FVC <50% predicted) versus none with normal initial FVC. Analysis of group B showed no difference between patients with normal baseline FVC and those with decreased FVC in the ability to further predict pulmonary function decline (log rank P = 0.13). Clinical and laboratory parameters (age, male sex, baseline diffusion capacity, anti–topoisomerase I, or duration of Raynaud's phenomenon preceding skin manifestations) were not associated with pulmonary function decline.

Conclusion

Measured within the first 3 years from disease onset, baseline FVC (percent predicted) may predict deterioration of pulmonary function in patients with scleroderma. Patients with normal pulmonary function at initial assessment are at low risk to develop considerable impairment of pulmonary function.
Depression, fatigue, and pain in systemic lupus erythematosus (SLE): Relationship to the American College of Rheumatology SLE neuropsychological battery
Authors: Kozora Elizabeth , Ellison Misoo C. , West Sterling
Published: July 2006

Objective

To examine the frequency and reliability of depression, fatigue, and pain self‐report measures in patients with systemic lupus erythematosus (SLE) and healthy controls, and to examine the relationship between a cognitive impairment index (CII) derived from the American College of Rheumatology neuropsychology research battery of tests for SLE (ACR‐SLE battery) and measures of depression, pain, fatigue, and perceived cognitive dysfunction.

Methods

Thirty‐one patients with SLE with a history of overt neuropsychiatric symptoms (neuropsychiatric SLE [NPSLE]), 22 patients with SLE without overt neuropsychiatric symptoms (non‐NPSLE), and 25 healthy controls completed the following measures at baseline and 1‐month followup: ACR‐SLE battery, perceived cognitive difficulties, depression, fatigue, and pain.

Results

Patients with SLE (both NPSLE and non‐NPSLE) showed higher symptoms of depression, higher levels of fatigue, greater pain, and more perceived cognitive problems. All measures except the Center for Epidemiologic Studies Depression scale (CES‐D) demonstrated adequate reliability across the SLE groups at retest. Only patients with NPSLE had significant correlations between CII and depression, fatigue, and pain. Neither the non‐NPSLE patients nor the controls had significant relationships with the CII and these behavioral measures.

Conclusion

Patients with SLE report higher levels of cognitive difficulties, depression, pain, and fatigue compared with controls. Reliability for all measures, except the CES‐D, was established in the SLE group. Overall, results suggest that cognitive dysfunction, pain, fatigue, and depression in patients with NPSLE may represent global changes in the central nervous system that require ongoing evaluation and treatment.
Comparison between children with juvenile idiopathic arthritis and their parents concerning perceived treatment adherence
Authors: April Karine Toupin , Feldman Debbie Ehrmann , Platt Robert W. , Duffy Ciarán M.
Published: July 2006

Objective

Adherence to treatment in juvenile idiopathic arthritis (JIA) may be associated with better outcomes. Clinicians must be aware of possible divergence between parents and children regarding adherence, in order to gain a better understanding of adherence and factors associated with it. The objective was to determine the level of agreement between children with JIA and their parents concerning perception of the child's adherence to the treatment regimen (for both medications and exercises).

Methods

Fifty patients and their parents, who attended the JIA clinic at the Montreal Children's Hospital, completed the Child Adherence Report Questionnaire and the Parent Adherence Report Questionnaire. Paired t‐tests were used to compare parents' and children's scores for adherence questions and agreements were analyzed by intraclass correlation coefficients (ICCs).

Results

Parents reported that their children showed more negative reactions to taking medication and doing exercises, more helpfulness from the medication, and more difficulty to carry out the exercise program than their children reported. ICCs (95% confidence interval) for medications and exercises were, respectively, 0.32 (0.04, 0.56) and 0.77 (0.61, 0.87) for overall adherence, 0.33 (0.05, 0.57) and 0.39 (0.09, 0.62) for perceived difficulty to following treatment, and 0.37 (0.09, 0.60) and 0.45 (0.17, 0.67) for how often children had negative reactions following treatment. Levels of agreement for perceived helpfulness of treatments were quite low.

Conclusion

Agreement between parents and children concerning adherence was at best moderate, and generally better for the exercise program than for prescribed medications.
Protein analysis with terbium (III) and sodium dodecyl sulphonate by a second‐order scattering technique
Authors: Li Aiyun , Zhao Huichun , Jin Linpei
Published: July 2006

This is the first report of terbium(III) as a probe of second‐order scattering (SOS) for the determination of proteins in human serum at nanogram levels. A sensitive method has been developed using light scattering, based on the fact that the weak SOS of proteins can be enhanced in the presence of terbium(III) and sodium dodecyl sulphonate (SDS). With this method, 7.0 × 10−9–1.0 × 10−5 g/mL human serum albumin (HSA) and 5.0 × 10−9–5.0 × 10−6 g/mL γ‐globulin can be determined; the detection limits were 4.4 ng/mL for HSA and 3.1 ng/mL for γ‐globulin. The method has been applied to the detection of total proteins in human serum samples, and the results are consistent with those obtained by the Coomassie brilliant blue (CBB) G‐250 assay. Copyright © 2006 John Wiley & Sons, Ltd.