Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor.

Gliptins are anti-type 2 diabetes (T2D) drugs that regulate glycaemia by preventing endogenous glucagon-like peptide-1 (GLP-1) degradation. Chronically administered gliptins before experimental stroke can also induce neuroprotection, and this effect is potentially relevant for reducing brain damage in patients with T2D and high risk of stroke. It is not known, however, whether acute gliptin treatment after stroke (mimicking a post-hospitalization treatment) is neuroprotective or whether gliptin-mediated neuroprotection occurs via GLP-1-receptor (GLP-1R) activation. To answer these two questions, wild-type and glp-1r(-/-) mice were subjected to transient middle cerebral artery occlusion (MCAO). Linagliptin was administered acutely (50 mg/kg intravenously), at MCAO time or chronically (10 mg/kg orally) for 4 weeks before and 3 weeks after MCAO. Neuroprotection was assessed by stroke volume measurement and quantification of NeuN-positive surviving neurons. Plasma/brain GLP-1 levels and dipeptidyl peptidase-4 activity were also measured. The results show that the linagliptin-mediated neuroprotection against stroke requires chronic pretreatment and does not occur via GLP-1R. The findings provide essential new knowledge with regard to the potential clinical use of gliptins against stroke, as well as a strong impetus to identify gliptin-mediated neuroprotective mechanisms.

Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety.

AIMS/HYPOTHESIS: The aim of this study was to determine whether exenatide improves haemodynamic function in patients with type 2 diabetes with congestive heart failure (CHF). METHODS: The main eligibility criteria for inclusion were: male/female (18-80 years) with type 2 diabetes and CHF (ejection fraction ≤ 35%, and New York Heart Association functional class III or IV). Out of 237 patients screened, 20 male type 2 diabetic patients participated in this crossover trial design and were allocated (sequentially numbered) to i.v. infusions during two consecutive days with (1) exenatide (0.12 pmol/kg/min); and (2) placebo for 6 h followed by a washout period for 18 h, at Stockholm South Hospital, Sweden. Patients and researchers were blinded to the assignment. Cardiac haemodynamic variables were determined by right heart catheterisation. The primary endpoint was defined as an increase in cardiac index (CI) or a decrease in pulmonary capillary wedge pressure (PCWP) of ≥ 20%. Secondary endpoints were tolerability and safety of exenatide infusion. RESULTS: CI increased at 3 and 6 h by 0.4 ± 0.1 (23%) and 0.33 ± 0.1 (17%) l min(-1) m(-2), during exenatide infusion vs -0.02 ± 0.1 (-1%) and -0.08 ± 0.1 (-5%) l min(-1) m(-2) during placebo (p = 0.003); and heart rate (HR) increased at 1, 3 and 6 h by 8 ± 3 (11%), 15 ± 4 (21%) and 21 ± 5 (29%) beats per min (bpm), during exenatide infusion vs -1 ± 2 (-2%), 1 ± 1 (2%) and 6 ± 2 (8%) bpm, during placebo (p = 0.006); and PCWP decreased at 1, 3 and 6 h by -1.3 ± 0.8 (-8%), -1.2 ± 1 (-8%) and -2.2 ± 0.9 (-15%) mmHg, during exenatide infusion vs 0.3 ± 0.5 (2%), 1 ± 0.6 (6%) and 1.4 ± 0.7 (8%) mmHg, during placebo (p = 0.001). No serious adverse event was observed. Adverse events were reported in nine patients (six, nausea; two, increased HR; one, increased systolic blood pressure). CONCLUSIONS/INTERPRETATION: Infusion of exenatide in male type 2 diabetic patients with CHF increased the CI as a result of chronotropy, with concomitant favourable effects on PCWP and reasonable tolerability of the drug. The clinical implications of using exenatide in patients with CHF are still not clear and further studies are warranted. TRIAL REGISTRATION: www.isrctn.org/ISRCTN47533126

Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men.

AIMS: Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest. METHODS: We aimed to investigate longitudinal relationships between plasma levels of fasting GLP-1 (fGLP-1), 60-min oral glucose tolerance test-stimulated GLP-1 levels (60GLP-1), and the dynamic GLP-1 response after oral glucose tolerance test (ΔGLP-1 = 60GLP-1 - fGLP-1) and incidence of hospitalized congestive heart failure, during a follow-up time of a maximum of 9.8 years in 71-year-old men. We also investigated, cross-sectionally, the association between GLP-1 and left ventricular function as estimated by echocardiography. R: During the follow-up period, 16 of 290 participants with normal glucose tolerance experienced a congestive heart failure event (rate 0.7/100 person-years at risk), as did eight of 136 participants (rate 0.8/100 person-years at risk) with impaired glucose tolerance and nine of 72 participants (rate 1.7/100 person-years at risk) with Type 2 diabetes mellitus. Although GLP-1 concentrations did not predict congestive heart failure (fGLP-1: HR 0.98, 95% CI 0.4-2.4; 60GLP-1: HR 1.1, 95% CI 0.4-2.6; ΔGLP-1: HR 0.9, 95% CI 0.3-2.3), there was an association between left ventricular diastolic function (E/A ratio) and fGLP-1 (r = 0.19, P = 0.001), 60GLP-1 (r = 0.20, P < 0.001) and ΔGLP-1 (r = 0.18, P = 0.004). There was a lack of differences in plasma levels of GLP-1 between the groups with Type 2 diabetes and normal glucose tolerance. CONCLUSIONS: There were no longitudinal associations between GLP-1 levels and incidence of hospitalization for congestive heart failure. However, without any causality proven, GLP-1 levels did correlate, cross-sectionally, with left ventricular diastolic function in this cohort, suggesting that pathways including GLP-1 might be involved in the regulation of cardiac diastolic function.

Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease.

AIMS/HYPOTHESIS: Besides the insulinotropic effects of glucagon-like peptide-1 (GLP-1) mimetics, their effects on endothelial dysfunction and myocardial ischaemia are of interest. No previous study has investigated associations between plasma levels of GLP-1 and CHD. METHODS: We investigated longitudinal relationships of fasting GLP-1 with the dynamic GLP-1 response after OGTT (difference between 60 min OGTT-stimulated and fasting GLP-1 levels [DeltaGLP-1]) and CHD in a population-based cohort of 71-year-old men. In the same cohort, we also cross-sectionally investigated the association between stimulated GLP-1 levels and: (1) cardiovascular risk factors (blood pressure, lipids, urinary albumin, waist circumference and insulin sensitivity index [M/I] assessed by euglycaemic-hyperinsulinaemic clamp); and (2) impaired glucose tolerance (IGT) and type 2 diabetes mellitus. RESULTS: During the follow-up period (maximum 13.8 years), of 294 participants with normal glucose tolerance (NGT), 69 experienced a CHD event (13.8 years), as did 42 of 141 with IGT and 32 of 74 with type 2 diabetes mellitus. DeltaGLP-1 did not predict CHD (HR 1.0, 95% CI 0.52-2.28). The prevalence of IGT was associated with DeltaGLP-1, lowest vs highest quartile (OR 0.3, 95% CI 0.12-0.58), with no such association for type 2 diabetes mellitus (OR 1.0, 95% CI 0.38-2.86). M/I was significantly associated with DeltaGLP-1 in the type 2 diabetes mellitus group (r = 0.38, p < 0.01), but not in the IGT (r = 0.11, p = 0.28) or NGT (r = 0.10, p = 0.16) groups. CONCLUSIONS/INTERPRETATION: Impaired GLP-1 secretion is associated with IGT, but not with type 2 diabetes mellitus. This finding in the latter group might be confounded by oral glucose-lowering treatment. GLP-1 does not predict CHD. Although DeltaGLP-1 was associated with insulin sensitivity in the type 2 diabetes mellitus group, GLP-1 does not seem to be a predictor of CHD in insulin-resistant patients.

Race and differences in breast cancer survival in a managed care population.

BACKGROUND: African-American women with breast cancer have poorer survival than European-American women. After adjustment for socioeconomic variables, survival differences diminish but do not disappear, possibly because of residual differences in health care access, biology, or behavior. This study compared breast cancer survival in African-American and European-American women with similar health care access. METHODS: We measured survival in women with breast cancer who are served by a large medical group and a metropolitan Detroit health maintenance organization where screening, diagnosis, treatment, and follow-up are based on standard practices and mammography is a covered benefit. We abstracted data on African-American and European-American women who had been diagnosed with breast cancer from January 1986 through April 1996 (n = 886) and followed these women for survival through April 1997 (137 deaths). RESULTS: African-American women were diagnosed at a later stage than were European-American women. Median follow-up was 50 months. Five-year survival was 77% for African-American and 84% for European-American women. The crude hazard ratio for African-American women relative to European-American women was 1.6 (95% confidence interval [CI] = 1.1-2.2). Adjusting only for stage, the hazard ratio was 1.3 (95% CI = 0.9-1.9). Adjusting only for sociodemographic factors (age, marital status, and income), the hazard ratio was 1.2 (95% CI = 0.8-1.9). After adjusting for age, marital status, income, and stage, the hazard ratio was 1.0 (95% CI = 0.7-1.5). CONCLUSION: Among women with similar medical care access since before their diagnoses, we found ethnic differences in stage of breast cancer at diagnosis. Adjustment for this difference and for income, age, and marital status resulted in a negligible effect of race on survival.

Automated, multiplex assay for high-frequency microsatellite instability in colorectal cancer.

PURPOSE: In a series of hereditary nonpolyposis colorectal cancer (HNPCC) patients, we evaluated the sensitivities of the individual microsatellites recommended by the National Cancer Institute (NCI) consensus workshop for detection of high-frequency microsatellite instability (MSI-H). On the basis of this evaluation, we developed a three-marker assay that assigns microsatellite instability (MSI) in a multiplex polymerase chain reaction. METHODS: Individual marker sensitivity was assessed in 18 HNPCC tumors. Multiplex and NCI assays were then assessed in a series of 120 patients with early-onset colon cancer. RESULTS: The sensitivity of microsatellite markers BAT25, BAT26, D2S123, D5S346, and D17S250 for ASI in HNPCC cancers was 100%, 94%, 72%, 50%, and 50%, respectively. The three most accurate markers were combined and optimized in a multiplex assay that assigned MSI-H whenever at least two of three markers revealed ASI. In early-onset colon cancers, the prevalence of MSI-H determined by the multiplex assay and by the NCI assay was 16% and 23%, respectively. The additional MSI-H tumors and patients with MSI-H identified by the NCI assay lacked the traits characteristic of MSI-H seen in tumors and patients identified by the multiplex assay: retention of heterozygosity (NCI additional 22% v multiplex 84%; P =.003), characteristic tumor morphology (0% v 64%; P =.006), and 5-year cancer survival rate (44% v 100%; P =.0003). CONCLUSION: The multiplex assay identifies colon cancers with MSI-H by assessing three highly accurate microsatellite markers. This assay identifies a smaller MSI-H cohort with more homogeneous clinical features and is superior as a marker of favorable prognosis. It merits prospective evaluation as a marker of prognosis and as a screening test for HNPCC.

Effects of MSH/ACTH 4-10 on the classically-conditioned rabbit nictitating membrane.

Subjects were conditioned/extinguished under four experimental conditions using either MSH/ACTH 4-10(A) or diluent (D): D/D, D/A, A/D, and A/A. The major question investigated was whether or not the peptide has an effect on this classically-conditioned behavior similar to that reported for instrumental conditioning paradigms. The results indicated that it does not. An effect was seen on performance, not on learning or attentional processes. Animals treated with the peptide performed more poorly (i.e., displayed fewer conditioned responses) during both acquisition and extinction. In addition, there was an apparent residual effect of the peptide that lasted 24 but not 48 hours.

A new model of partial status epilepticus based on kindling.

In this experiment, a new model of partial status epilepticus (SE) is described which is based on the antecedent development of a kindled focus. Following kindling, the amygdala was stimulated continuously for 60 min with the previous kindling stimulus (60 Hz sine wave, 50 microA peak-to-peak). This treatment provoked SE in 22 of 35 rats. Without drug intervention, rats spontaneously recovered (SR group) from the seizure between 10 and 24 h. After recovery from SE, after discharge (AD) thresholds were elevated and remained so for the 2 weeks before sacrifice. The histologies of these SR rats indicated massive gliosis and degeneration of the ipsilateral hemisphere, extending from the medial olfactory bulb, through the amygdala-pyriform cortex to the ventral hippocampus. Damage was observed frequently in the midline thalamic nuclei and hippocampal CA1 fields. Interruption of the SE with Nembutal 30 min after the stimulation offset (30 Min group) was occasionally associated with slight gliosis at the kindled electrode, whereas interruption after 4 h of SE (4 Hr group) resulted in more extensive cell loss. The AD thresholds of the 30 Min group, like those of the rats which did not develop SE (NSE group), returned to near-normal values by 2 weeks after SE; only the NSE rats exhibited generalized seizures to their AD threshold stimulus. This model of SE results in brain pathology similar to that found in other models, but has the advantage of being uncontaminated by exogenous chemicals and toxins.

Shear strength of the composite bond to etched porcelain.

The shear bond strength of composite resin to porcelain was investigated to optimize variables for bonding porcelain laminate veneers. Scanning electron microscopy was initially used to examine the surface configuration of porcelain prepared under various conditions. A factorial experiment was undertaken to determine the effects of three different bonding methods on both etched and non-etched porcelain. Composite resin was bonded to the porcelain groups using (a) unfilled resin, (b) silane, and (c) silane with dentin adhesive. The results indicated a significant difference in shear bond strength for the three bonding groups, depending on the porcelain surface condition. For the unetched samples, significant differences in bond strength were obtained for all three bonding conditions. However, for the etched group, there were no differences between the silane and silane-with-dentin-adhesive groups. Porcelain etching significantly increased bond strength across all three bonding methods and was the main contributor to the obtained values.

An SEM study of posts cemented with an unfilled resin.

Post preparations in two groups of endodontically treated anterior teeth were completed. In Group I, the preparation was rinsed with 2 ml of 5.25% NaOCL. In Group II, the preparation was rinsed with 1 ml of 17% EDTA, followed by 1 ml of 5.25% NaOCl. A plastic post was fitted and cemented with an unfilled resin. After polymerization, the teeth were decalcified in 5% nitric acid. The decalcified structured was dissolved away with 5.25% NaOCl, leaving a model of the cemented post. This was examined by SEM to determine the extent of resin penetration into the dentinal tubules. In Group I, most of the post was smooth, and there was penetration only in small, random areas. In Group II, there was penetration into the tubules the full length and circumference of the post. Such penetration provides a very strong mechanical lock that enhances the tensile strength of the cemented post. Removing the smeared layer and then cementing a post with a Bis-GMA resin results in greatly increased tensile strength, even with shorter posts.

Measurement of in vivo corrosion rates in baboons, and correlation with in vitro tests.

The Lineal Polarization Technique was used to determine the polarization resistances and corrosion currents of various dental restorative and implant alloys and amalgams placed in the teeth of animals, and as laboratory samples in artificial saliva. Gold- and chromium-containing alloys corroded the least, and amalgams generated the highest corrosion currents. There was good agreement between measurements made in vivo and in vitro. This is the first time that corrosion current have been measured in the mouth repeatedly over a long time span. These methods may be developed into useful predictive tests of in vivo corrosion.

Shame, compassion, and the "borderline" personality.

This article focuses on the emotionality of the individual diagnosed as "borderline." There may be no clinical condition characterized by so wide a range of affective expression. The author points out that both Kernberg and Kohut view this cohort from the standpoint of drive theory, in which all emotion is traced to drive forces gone awry. Viewed from the perspective of affect theory, it becomes possible to explain this otherwise puzzling cluster of symptoms as the expression of and defenses against the painful emotion of shame. The very concept of a "borderline" illness may prove to be a construction made necessary by previous misunderstanding of shame psychology, and the symptoms themselves perhaps an artifact of a wider, societal misunderstanding of shame.

Understanding what is hidden. Shame in sexual abuse.

Competence in treating the victims of sexual abuse and exploitation requires an understanding of shame, the complex and multilayered emotion triggered when we have been exposed or when our self-esteem has been reduced. The experience of shame is initially physiologic, involving a cortical shock momentarily halting higher cognitive function, but followed immediately by a host of associations to previous experiences of shame. Acutely, the affect itself impels hiding, while defenses against it include anger, humor, silence, and a wide range of behaviors. In our culture, all sexuality involves an interplay between exposure and privacy, between control and release. The sexual abuse of adults and the sexual exploitation of children must produce shame, study of the interaction between abuser and abused suggests that shame conflict figures prominently in the genesis of such activity. To the extent that psychotherapy itself involves exposure, it must trigger shame; thus, it is likely that the therapist unskilled in the recognition of shame in all its disguises will overlook or misunderstand many of the issues that should form the core of our treatment of those whose sexual selves have been abused or exploited.

The role of calcium and cellular membrane dysfunction in experimental trauma and subarachnoid hemorrhage.

Acute subarachnoid hemorrhage (SAH) and intraparenchymal hematoma (IPH) in cats are accompanied by massive cellular depolarization. This depolarization, characterized by potassium (K+) efflux and calcium (Ca++) influx, results in membrane destabilization, osmotic imbalance, and a decrease in electrical conduction. The Ca++ influx appears to initiate a chain reaction that, in some instances, may result in delayed cell destruction. The ionic dysequilibrium probably contributes to both brain engorgement and spasm in large vessels. The cellular depolarization and calcium-induced cell membrane injury at the moment of impact may play a greater role in the pathophysiology of head trauma than previously thought.

Periodontal splinting with wire and composite resin. A revised approach.

A method for periodontal splinting of anterior teeth with wire and composite resins is described. The method combines the use of a double wire reinforcement shallow tooth preparation, and acid etching to obtain good strength and sealing properties. The sequence of steps are exclusively designed to suit the properties of composite resins. The technique has the advantages of conservatism and simplicity, good esthetics and strength that surpasses that of conventional wire and acrylic or composite splints.

Effects of moisture content and endodontic treatment on some mechanical properties of human dentin.

The objective of this study was to determine whether significant differences exist between the mechanical properties of human dentin from treated pulpless teeth and dentin from normal vital teeth. Dentin specimens (n = 262) were obtained from 54 freshly extracted normal vital human teeth and 24 treated human pulpless teeth. These specimens were subjected to different experimental conditions (wet, air dried, desiccated, and rehydrated). Compression, indirect tensile, and impact tests were conducted to measure the mechanical properties of those specimens. All data obtained were analyzed with t tests. The results showed that the dehydration of dentin increases the Young's modulus, proportional limit (in compression), and especially the ultimate strength (in both compression and tension). Substantial dehydration changes the fracture characteristics of dentin specimens under static compressive and indirect tensile loadings. The measurements of impact-breaking energies of desiccated dentin were not found to be significantly decreased. The compressive and tensile strengths of dentin from treated pulpless teeth obtained in this study do not appear to be significantly different from those of normal dentin (p > 0.05), while the mean values of Young's modulus and proportional limit in compression tests appear to be lower. Fifty percent of the dentin specimens from treated pulpless teeth exhibit greater plastic deformation than normal dentin in compression. The results of this study do not support the theory that dehydration after endodontic treatment per se weakens dentin structure in terms of compressive and tensile strengths. Other mechanical properties of treated pulpless teeth, however, may not be the same as those of normal vital teeth.

Survival rate and fracture strength of incisors restored with different post and core systems and endodontically treated incisors without coronoradicular reinforcement.

This in vitro study evaluated the survival rate and fracture resistance of maxillary central incisors restored with different post and core systems. The post and core systems investigated were a prefabricated high precious metal post with cast core (group A), zirconia post with a prefabricated bonded ceramic core (group B), and a resin-ceramic interpenetrating phase composite post (experimental) with a prefabricated bonded ceramic core (group C). The all-ceramic copings were cemented using Panavia 21 TC. In the group without coronoradicular reinforcement, the access cavity was closed with a light-cured composite in combination with a dentine-bonding agent (group D). Each specimen was intermittently loaded and thermocycled before final stress tests in a Zwick machine. The survival rates after 1,200,000 cycles in the artificial mouth were 90% (group A), 80% (group B), 60% (group C), and 100% (group D). Statistically significant differences were found between all groups with the exception of A and B, when failure during cyclic loading was included (Kruskal-Wallis multiple comparisons test). Samples restored with a cast post and core demonstrated more vertical root fractures. It was concluded that the preservation of both internal and external tooth structure is of utmost importance when restoring endodontically treated teeth.

Splenectomy in a child with chronic Mycobacterium avium complex infection and splenic sequestration.

Mycobacterium avium complex infections (MAC) are being reported with increasing frequency in immunocompromised patients. When these infections become resistant to standard antibiotic therapy, treatment with interferon-gamma (IFN-gamma) can be helpful. Pain, fever, splenic enlargement, and cytopenias caused by splenic sequestration developed during IFN-gamma treatment in a 9-year-old boy and were successfully treated by splenectomy. The development of IFN-gamma-induced splenic sequestration and cytopenias in MAC-infected patients represents a new indication for splenectomy.

Vital tooth bleaching: sensitivity and pulpal considerations.

For some patients, sensitivity and discomfort follow vital tooth bleaching. Clinical observations, however, suggest these are reversible episodes with no irreversible long-term effects. Using milder peroxide formulations or gels diminishes postoperative discomfort. The author recommends careful treatment when patients have large restorations, cervical erosion or enamel cracks. Fluoride treatment, sealing restorations and premedication may lessen discomfort.

Indications for orthodontic-prosthodontic collaboration in dental treatment.

In dental practice, combined plans of orthodontic and prosthodontic treatment are underused. Indications for a collaborative effort include preservation of integrity of the dental arch, biomechanical factors, limitations in design of prostheses, esthetic appearance, periodontal considerations, prevention of malocclusion, and better retention of position of teeth.