Citations

Abstract In the current study, we examined a panel of serially passaged glioblastoma xenografts, in the context of an intracranial tumor therapy response model, to identify associations between glioblastoma molecular characteristics and tumor sensitivity to the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. From an initial evaluation of 11 distinct glioblastoma xenografts, two erlotinib-sensitive tumors were identified, each having amplified EGFR and expressing wild-type PTEN. One of these tumors expressed truncated EGFRvIII, whereas the other expressed full-length EGFR. Subsequent cDNA sequence analysis revealed the latter tumor as expressing an EGFR sequence variant with arginine, rather than leucine, at amino acid position 62; this was the only EGFR sequence variant identified among the 11 xenografts, other than the aforementioned vIII sequence variant. EGFR cDNAs were then examined from 12 more xenografts to determine whether additional missense sequence alterations were evident, and this analysis revealed one such case, expressing threonine, rather than alanine, at amino acid position 289 of the extracellular domain. This glioblastoma was also amplified for EGFR, but did not display significant erlotinib sensitivity, presumably due to its lacking PTEN expression. In total, our study identified two erlotinib-sensitive glioblastoma xenografts, with the common molecular characteristics shared by each being the expression of wild-type PTEN in combination with the expression of amplified and aberrant EGFR. [Mol Cancer Ther 2007;6(3):1167–74]

Using the Minnesota Multiphasic Personality Inventory (MMPI), this study investigated preoperative and postoperative emotional and personality adjustment of temporal lobectomy patients from two major epilepsy surgery centers. Temporal lobectomy patients were included only if they were without evidence of lesional pathology on magnetic resonance imaging (MRI; other than evidence of mesial temporal sclerosis), were left-hemisphere language-dominant, and had Wide Range Achievement Test-Revised (WRAT-R) reading achievement standard scores of 70 or higher. The MMPI was completed by 175 patients before and after a temporal lobectomy. There were no significant preoperative differences on any MMPI scale between right temporal (n = 79) and left temporal (n = 96) lobectomy patients. Analysis of MMPI data from one of the surgical centers revealed significant effects for postoperative seizure control. Minimal effects of laterality of seizure onset on preoperative or postoperative psychological adjustment were found. Adequacy of preoperative psychological adjustment and postoperative seizure control have a greater impact on preoperative to postoperative psychological adjustment than side of seizure onset.

Lipolysis of adipose tissue triglycerides releases glycerol. Twenty-four volunteers, of whom 6 were obese and 13 were women, received a primed-constant infusion of 2H5-glycerol for 120 min during postabsorptive steady-state conditions. Arterial, abdominal venous, and interstitial (microdialysis) samples were taken, and a four-compartment model was applied to assess subcutaneous abdominal adipose tissue glycerol kinetics. Adipose tissue blood flow was measured using 133Xe washout. Venous glycerol concentrations (median 230 μmol/l [interquartile range 210–268]) were consistently greater than those of arterial blood (69.1 μmol/l [56.5–85.5]), while glycerol isotopic enrichments (tracer-to-tracee ratio) were greater in arterial blood (8.34% [7.44–10.1]) than venous blood (2.34% [1.71–2.69], P < 0.01). Microdialysate glycerol enrichment was 1.44% (1.11–1.79), indicating incomplete permeability of glycerol between capillary blood and interstitium. Calculated interstitial glycerol concentrations were between 270 μmol/l (256–350) and 332 μmol/l (281–371) (examining different boundary conditions). The calculated capillary diffusion capacity (ps) was between 2.21 ml · 100 g tissue−1 · min−1 (1.31–3.13) and 3.09 ml · 100 g tissue−1 · min−1 (1.52–4.90) and correlated inversely with adiposity (Rs ≤ −0.45, P < 0.05). Our results support previous estimates of interstitial glycerol concentration within adipose tissue and reveal capillary diffusion capacity is reduced in obesity.

Insulin resistance increases and muscle oxidative capacity decreases during aging, but lifestyle changes—especially physical activity—may reverse these trends. Here we report the effect of a 16-week aerobic exercise program (n = 65) or control activity (n = 37) performed by men and women aged 21–87 years on insulin sensitivity and muscle mitochondria. Insulin sensitivity, measured by intravenous glucose tolerance test, decreased with age (r = −0.32) and was related to abdominal fat content (r = −0.65). Exercise increased peak oxygen uptake (Vo2peak; 10%), activity of muscle mitochondrial enzymes (citrate synthase and cytochrome c oxidase, 45–76%) and mRNA levels of mitochondrial genes (COX4, ND4, both 66%) and genes involved in mitochondrial biogenesis (PGC-1α, 55%; NRF-1, 15%; TFAM, 85%). Exercise also increased muscle GLUT4 mRNA and protein (30–52%) and reduced abdominal fat (5%) and plasma triglycerides (25%). None of these changes were affected by age. In contrast, insulin sensitivity improved in younger people but not in middle-aged or older groups. Thus, the muscle mitochondrial response to 4 months of aerobic exercise training was similar in all age-groups, although the older people did not have an improvement in insulin sensitivity.

The major predisposing genetic component in type 1 diabetes maps to the major histocompatibility complex locus in both mice and humans. To verify the HLA class II association with disease pathogenesis, we adopted the transgenic approach. Expression of HLA-DQ8, the molecule showing the strongest association with human type 1 diabetes, in the diabetes-predisposing milieu of NOD mice in the absence of the endogenous class II molecule I-Ag7 did not render susceptibility to type 1 diabetes. To study if providing a local proinflammatory environment would lead to diabetes in these mice, Aβo.NOD.DQ8 were bred with C57BL/6 mice expressing tumor necrosis factor (TNF)-α in the β-cells of the islets of Langerhans. Surprisingly, although diabetes was evident in the F1 intercross expressing rat insulin promoter (RIP)-TNF, offspring lacking either endogenous or transgenic class II molecules developed accelerated diabetes with high frequency in both sexes. Moreover, expression of any functional class II molecule seemed to confer significant protection from diabetes in this model. Thus, neonatal expression of TNF-α in an islet-specific manner bypassed the requirement of CD4+ T-cells and resulted in diabetes that could be mediated by CD8+ T-cells. We also show for the first time that diabetes in NOD.RIP-TNF mice can occur independent of inheritance of NOD-derived idd1.

Specific HLA DQ and DR alleles have been associated with susceptibility to type 1 diabetes. HLA DQ8 and DQ2 have been shown to strongly predispose to disease and to be in linkage disequilibrium with at-risk DR4 and DR3 alleles, respectively. Inheritance of a mixed DR3/DR4 haplotype confers the greatest risk. A double transgenic mouse expressing both DR3 and DQ8 was generated to investigate potential major histocompatibility complex class II interactions. The DR3/DQ8 transgenic mice developed a spontaneous loss of tolerance to GAD65, in which the T-cell response to GAD65 was restricted by HLA DR. Although the mice also showed spontaneous insulitis, they did not progress to overt diabetes. Mice expressing either transgene (DQ8 or DR3) alone showed mild infiltration of their islets, which disappeared when DQ8 or DR3 was co-expressed with a resistant DR2 allele or the neutral DQ6 allele. Therefore, in a fashion analogous to human diabetes, the murine model demonstrated a requirement for a combination of at-risk DR and DQ allotypes for the initiation of spontaneous autoimmunity.

Retinopathy is an important sequela of diabetes mellitus, but clinical risk factors for this condition have rarely been assessed in a geographically defined population. In this population-based study, the 1135 Rochester, Minnesota, residents with diabetes mellitus initially diagnosed between 1945 and 1969 (incidence cohort) were followed through their complete medical records in the community to January 1, 1982. Because most of the cases of diabetic retinopathy in Rochester residents developed in patients with non-insulin-dependent diabetes mellitus (NIDDM), risk factors for diabetic retinopathy were examined in this group (N = 1031). A proportional hazards model identified the following risk factors for diabetic retinopathy in NIDDM: elevated initial fasting blood glucose level, marked obesity, and earlier age at onset of diabetes. Stratified analyses indicated that duration of diabetes was also significantly associated with an increased risk of retinopathy. Two secular trends, increasing detection of “mild” NIDDM and decreasing risk of diabetic retinopathy, had a major effect on retinopathy risk assessment. These data also suggest that insulin therapy is not an independent risk factor for diabetic retinopathy.

Among the 1135 Rochester residents discovered to have diabetes in the period 1945–69, the prevalence of retinopathy was 2.6% at the time of initial diagnosis. Among those free of retinopathy at diagnosis of diabetes, the subsequent incidence of any retinopathy was 17.4 per 1000 person-years and for proliferative retinopathy alone was 1.6 per 1000 person-years, based on 12,000 person-years of follow-up. The incidence rate of retinopathy was almost three times greater among residents with insulin-dependent (IDDM) than with non-insulin-dependent diabetes (NIDDM); however, the actual number of retinopathy cases was over four times greater among the more numerous residents with NIDDM. By 20 yr after diagnosis of diabetes, the cumulative incidence of retinopathy approached 70% among IDDM subjects and was 30% and 36%, respectively, among the obese and nonobese NIDDM residents. The epidemiologic patterns for proliferative retinopathy were qualitatively similar to those for nonproliferative retinopathy. The risk of blindness was greater among those with proliferative than with nonproliferative retinopathy but was substantial even for those without retinopathy. Most blindness was caused by factors other than isolated diabetic retinopathy.

OBJECTIVE—Management of diabetes is frequently suboptimal in primary care settings, where providers often fail to intensify therapy when glucose levels are high, a problem known as clinical inertia. We asked whether interventions targeting clinical inertia can improve outcomes. RESEARCH DESIGN AND METHODS—A controlled trial over a 3-year period was conducted in a municipal hospital primary care clinic in a large academic medical center. We studied all patients (4,138) with type 2 diabetes who were seen in continuity clinics by 345 internal medicine residents and were randomized to be control subjects or to receive one of three interventions. Instead of consultative advice, the interventions were hard copy computerized reminders that provided patient-specific recommendations for management at the time of each patient’s visit, individual face-to-face feedback on performance for 5 min every 2 weeks, or both. RESULTS—Over an average patient follow-up of 15 months within the intervention site, improvements in and final HbA1c (A1C) with feedback + reminders (ΔA1C 0.6%, final A1C 7.46%) were significantly better than control (ΔA1C 0.2%, final A1C 7.84%, P < 0.02); changes were smaller with feedback only and reminders only (P = NS vs. control). Trends were similar but not significant with systolic blood pressure (sBP) and LDL cholesterol. Multivariable analysis showed that the feedback intervention independently facilitated attainment of American Diabetes Association goals for both A1C and sBP. Over a 2-year period, overall glycemic control improved in the intervention site but did not change in other primary care sites (final A1C 7.5 vs. 8.2%, P < 0.001). CONCLUSIONS—Feedback on performance aimed at overcoming clinical inertia and given to internal medicine resident primary care providers improves glycemic control. Partnering generalists with diabetes specialists may be important to enhance diabetes management in other primary care settings.

OBJECTIVE—The prevalence of autonomic symptoms and deficits in certain systems is known, but a comprehensive autonomic symptom profile in diabetes is not available. We aimed to estimate this using a laboratory evaluation of autonomic function and a validated self-report measure of autonomic symptoms in patients and matched control subjects from the population-based Rochester Diabetic Neuropathy Study. RESEARCH DESIGN AND METHODS—Participants included 231 patients with diabetes (type 1, n = 83; type 2, n = 148) and 245 healthy age-matched control subjects. We assessed symptoms using a validated self-report instrument (Autonomic Symptom Profile) and evaluated the severity and distribution of autonomic deficits (cardiovagal, sudomotor, adrenergic) with the objective, laboratory-based Composite Autonomic Severity Score (CASS). RESULTS—Autonomic symptoms were present more commonly in type 1 than in type 2 diabetes, with symptoms of orthostatic intolerance, secretomotor, urinary control, diarrhea, and sleep disturbance and pupillomotor, vasomotor, and erectile dysfunction significantly increased over healthy control subjects in type 2 diabetic patients. The prevalence of autonomic impairment was 54% in type 1 and 73% in type 2 diabetic patients. Severity of autonomic failure was mild overall (mean CASS 2.3; maximum 10), with orthostatic hypotension occurring in 8.4 and 7.4% of type 1 and 2 diabetic patients, respectively. Fourteen percent of patients had a CASS ≥5, indicating moderate to severe generalized autonomic failure. The correlation of symptoms with autonomic deficits (CASS) was better in type 1 than type 2 diabetic subjects and was weak overall. CONCLUSIONS—These findings indicate that autonomic symptoms and deficits are common in diabetes, but mild in severity, and that the correlation between symptom scores and deficits is overall weak in mild diabetic neuropathy, emphasizing the need to separately evaluate autonomic symptoms.