bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with sexual problems in HIV-positive gay men
Authors: Cove Jeff , Petrak Jenny
Published: May 2006

Our objective was to determine factors associated with sexual problems in a sample of HIV-seropositive gay male clinic patients. Using a cross-sectional survey design a volunteer sample of 78 outpatient HIV-seropositive gay male service users completed a self-report questionnaire. This examined sexual problems, their perceived causes and associated factors including demographics, health status, sexual behaviour, self-justifications for sexual risk-taking and mood state (Hospital Anxiety and Depression Scale). Fifty (69%) of 78 HIV-positive gay men reported one or more sexual problems. Erectile dysfunction (ED) was reported by 38% rising to 51% in the context of trying to use condoms. Loss of interest in sex was reported by 41% and 24% experienced delayed ejaculation. The presence of sexual problems affected condom use in that 33 (90%) of the 37 gay men who had ED associated with condom use were inconsistent condom users in insertive sex compared to 28% of those not having this type of ED ( P < 0.001). The presence of ED did not reduce the frequency of anal intercourse but those with ED associated with condoms were significantly more likely to have had receptive anal sex in the past three months (62%) compared to men without ED with condoms (38%) ( P = 0.05). Risk cognitions such as wanting to lose oneself in sex, leaving responsibility for condom use to the active partner and perceptions that condoms interfere with pleasure were significantly more likely to be endorsed by those who report ED with condoms. Other factors associated with sexual problems included low T-cell counts (i.e. < 200). Psychological explanations were the most frequently cited causes of sexual problems, whether alone or in interaction with HIV disease itself, and combination therapy. A high incidence of sexual problems was found amongst this sample of HIV-positive gay men. Untreated sexual dysfunctions may contribute to sexual risk-taking and therefore HIV clinics need to address both issues. Further research is required to better understand the role of psychological factors, HIV disease itself and combination therapy in the incidence and treatment of sexual problems.
Genital syndromes and syndromic management of vaginal discharge in a community setting
Authors: George R , Thomas K , Thyagarajan S P , Jeyaseelan L , Peedicayil A , Jeyaseelan V ,   George S and the STD Study Group
Published: May 2006

The objective of the study was to determine the community prevalence of genital syndromes in women and evaluate the syndromic management of vaginal discharge in this setting. A representative sample for the state of Tamilnadu was chosen using probability proportional to size cluster technique. Thirty clusters were selected from three districts. Demographic, sexual behaviour, risk factors, clinical and laboratory data were collected from the selected population using a structured questionnaire.

Direct smear examination for Trichomonas vaginalis, culture for Neisseria gonorrhoeae and Haemophilus ducreyi, serological tests for syphilis (RPR and TPHA), hepatitis B (Hbs Ag ELISA), IgM and IgG antibodies to HSV2 (Novum diagnostics, Germany) and PCR test for detection of C. trachomatis from urine were done.

There were 1157 women in the selected population. On examination, vaginal discharge was the most common genital syndrome (38.4%). The sensitivity, specificity, positive and negative predictive value of vaginal discharge as a marker for STD in women was found to be 43.3%, 61.6%, 10.7% and 91.1%, respectively.

We concluded that treatment on the basis of syndromic management would result in over-treatment of 90% of women with vaginal discharge.
Quality of primary care for sexually transmitted diseases in Durban, South Africa: influences of patient, nurse, organizational and socioeconomic characteristics
Authors: Bachmann M O , Colvin M S E , Nsibande D , Connolly C , Curtis B
Published: May 2006

Quality of sexually transmitted disease (STD) primary care in South Africa varies widely but reasons for this are poorly understood.

We investigated 37 randomly sampled clinics providing STD care, with simulated patients, and staff interviews and record review. Census data provided local socioeconomic indicators. Multiple regression identified independent predictors of quality. Of 271 simulated patient visits, 79% were correctly treated and 39% were correctly managed. Women received worse care, and care tended to be poorer in mainly African and mainly coloured (mixed race) areas. African and Indian nurses were more likely to provide correct treatment. Previous STD training was marginally associated with correct treatment. Quality assessments using simulated patients were not generally associated with assessments using staff interviews and record review.

There were frequent missed opportunities for STD prevention and treatment, and evidence of racial but not socioeconomic inequalities.
Interprofessional collaboration in the hospital: strategies and meanings
Authors: Reeves Scott , Lewin Simon
Published: May 2006

Objectives: Interprofessional collaboration is widely advocated in health and social care policies. However, existing research provides a relatively poor understanding of how professionals collaborate or the meanings they attach to their collaborative work. This paper aims to contribute to understanding of this activity by providing an in-depth account of interprofessional collaboration on medical wards in a large teaching hospital.

Methods: Ethnographic methods were used, including individual and group interviews with health and social care staff (i.e. doctors, nurses, therapists, social workers; n = 49) and participant observations of ward-based work.

Results: The organisation of medical teams, who cared for patients across a number of wards, and the task-oriented nature of medical work, limited opportunities for collaboration with other professionals (e.g. nurses, therapists) who were usually based on a single ward. Consequently, collaboration tended to be task-based, terse and formalistic. Staff employed a range of informal and formal communication strategies to overcome these constraints. Professionals also gave contrasting accounts of collaboration: doctors viewed collaboration primarily as an activity involving work with their medical colleagues, whereas other professionals saw it more as an interprofessional activity.

Conclusions: Temporospatial constraints and contrasting notions of 'collaboration' are important factors in shaping the nature of interprofessional collaboration. Policies that promote this activity cannot assume that shared understanding of collaboration exists. They also need to be mindful of the practical constraints that affect collaboration in hospital wards.
Will it make a difference if I show up and share? A citizens' perspective on improving public involvement processes for health system decision-making
Authors: Abelson Julia , Forest Pierre-Gerlier , Eyles John , Casebeer Ann , Mackean Gail ,   The Effective Public Consultation Project Team
Published: May 2006

Introduction: Health policy decision-makers are grappling with increasingly complex and ethically controversial decisions at a time when citizens are demanding more involvement in these decision processes.

Objectives: To assess and revise a set of guiding principles for the design of public involvement processes generated from a synthesis of public participation design and evaluation frameworks that can be used to inform the design and evaluation of future public participation processes in the health sector.

Methods: Six focus groups held in five Canadian provinces comprising citizens with considerable experience of public participation processes.

Results and discussion: Our findings suggest that citizen participants are highly critical of, and discerning about, their public participation experiences. Yet, they are optimistic and determined to contribute in meaningful ways to future public policy processes. They are clear about where improvements are needed and give top priority to what information is shared, and how, among participants and decision-makers. The views of experienced citizens mapped well onto most of the prior principles of public involvement with a few modifications. First, participants gave greater emphasis to the content and balance of information for the purposes of building trust and credibility between citizens and decision-makers. Second, participants viewed themselves, as well as decision-makers, as sources of information to be shared through the consultation process. Finally, participants stressed the importance of getting the information and communication principles right over addressing all other principles.
Do different types of nurses give different triage decisions in NHS Direct? A mixed methods study
Authors: O'Cathain Alicia , Nicholl Jon , Sampson Fiona , Walters Stephen , McDonnell Ann , Munro James
Published: May 2006

Objectives: To determine whether nurses with different clinical backgrounds make different triage decisions in NHS Direct, the 24-hour telephone helpline staffed by nurses.

Methods: Mixed methods including semistructured interviews with 24 nurses and a multilevel analysis of 60 794 calls triaged by 296 nurses.

Results: Nurse accounts helped to identify nurse characteristics that might affect decision-making. The proportion of calls triaged to self-care was 40% (24 049/60 794), varying by individual nurse from a 10th centile of 22% to a 90th centile of 60%, after adjustment for the age and sex of the patient and the time of the call. Variability was partly explained by the length of clinical experience of nurses and the type of software used: nurses with more than 20 years clinical experience were more likely to triage callers to self-care than those with less than ten years experience (42% versus 36%, respectively; odds ratio = 1.41, 95% confidence interval 1.13, 1.78). Proportions triaged to self-care differed by the type of clinical decision support software used: 31%, 37% and 44%. There was no evidence that the clinical background of nurses (hospital or community), their length of experience in NHS Direct, the range of their experience, or their gender affected triage decisions. Interviews identified that nursing characteristics affected individual nurses in different ways and helped to generate a hypothesis for future research – that individual nurses' approaches to risk may influence triage decisions.

Conclusion: There is no likely benefit in narrowing nurse recruitment to particular clinical backgrounds. The appropriateness of triage decisions still needs to be evaluated.
Bin Packing in Multiple Dimensions: Inapproximability Results and Approximation Schemes
Authors: Bansal Nikhil , Correa José R. , Kenyon Claire , Sviridenko Maxim
Published: May 2006

We study the following packing problem: Given a collection of d-dimensional rectangles of specified sizes, pack them into the minimum number of unit cubes. We show that unlike the one-dimensional case, the two-dimensional packing problem cannot have an asymptotic polynomial time approximation scheme (APTAS), unless P = NP. On the positive side, we give an APTAS for the special case of packing d-dimensional cubes into the minimum number of unit cubes. Second, we give a polynomial time algorithm for packing arbitrary two-dimensional rectangles into at most OPT square bins with sides of length 1 + ε, where OPT denotes the minimum number of unit bins required to pack these rectangles. Interestingly, this result has no additive constant term, i.e., is not an asymptotic result. As a corollary, we obtain the first approximation scheme for the problem of placing a collection of rectangles in a minimum-area encasing rectangle.
Average-Case and Smoothed Competitive Analysis of the Multilevel Feedback Algorithm
Authors: Becchetti Luca , Leonardi Stefano , Marchetti-Spaccamela Alberto , Schäfer Guido , Vredeveld Tjark
Published: May 2006

In this paper, we introduce the notion of smoothed competitive analysis of online algorithms. Smoothed analysis has been proposed by Spielman and Teng [25] to explain the behavior of algorithms that work well in practice while performing very poorly from a worst-case analysis point of view. We apply this notion to analyze the multilevel feedback algorithm (MLF) to minimize the total flow time on a sequence of jobs released over time when the processing time of a job is only known at time of completion.

The initial processing times are integers in the range [1, 2K]. We use a partial bit randomization model, i.e., the initial processing times are smoothed by changing the k least significant bits under a quite general class of probability distributions. We show that MLF admits a smoothed competitive ratio of O((2k/σ)3+ (2k/σ)22K-k), where σ denotes the standard deviation of the distribution. In particular, we obtain a competitive ratio of O(2K-k) if σ = Θ(2k). We also prove an Ω(2K-k) lower bound for any deterministic algorithm that is run on processing times smoothed according to the partial bit randomization model. For various other smoothing models, including the additive symmetric smoothing one, which is a variant of the model used by Spielman and Teng [25], we give a higher lower bound of Ω(2K).

A direct consequence of our result is also the first average-case analysis of MLF. We show a constant expected ratio of the total flow time of MLF to the optimum under several distributions including the uniform one.
An Incremental Method for Solving Convex Finite Min-Max Problems
Authors: Gaudioso Manlio , Giallombardo Giovanni , Miglionico Giovanna
Published: May 2006

We introduce a new approach to minimizing a function defined as the pointwise maximum over finitely many convex real functions (next referred to as the “component functions”), with the aim of working on the basis of “incomplete knowledge” of the objective function. A descent algorithm is proposed, which need not require at the current point the evaluation of the actual value of the objective function, namely, of all the component functions, thus extending to min-max problems the philosophy of the incremental approaches, widely adopted in the nonlinear least squares literature. Given the nonsmooth nature of the problem, we resort to the well-established machinery of “bundle methods.” We provide global convergence analysis of our method, and in addition, we study a subgradient aggregation scheme aimed at simplifying the problem of finding a tentative step. This paper is completed by the numerical results obtained on a set of standard test problems.
The Impossible Case of Japan
Authors: Leonardsen Dag
Published: May 2006

If increasing crime seems to be an unavoidable concomitant of rapid urbanisation, Japan might be an interesting exception. Both statistics and research tell us that Japan is a modern, rapidly urbanised society with little crime. This article raises the question if, and eventually in which way, one may talk about Japan as a low crime nation. Is there anything of criminological interest to learn from Japan? After describing the Japanese society along five analytical dimensions the answer to this question is that while in the West we can talk about “community lost”, in Japan we should rather talk about “individual lost”. At the individual level the obliteration of the self is the price to be paid for less crime. However, at the collective level Japan might teach the West a lesson. If crime is regarded as actions committed by outsiders, then Japanese society has succeeded in linking the individual to a group context which most likely functions in a crime preventive way. Instead of endless crime preventive programs of “social engineering”, the West should pay more attention to basic sociological insights concerning collective obligations and identities. In this regard we might look to Japan.
The Process of Attrition in Child Sexual Assault Cases: A Case Flow Analysis of Criminal Investigations and Prosecutions
Authors: Parkinson Patrick N. , Shrimpton Sandra , Swanston Heather Y. , O'Toole Brian I. , Oates R. Kim
Published: May 2006

As part of a prospective study which tracked 183 child sexual abuse cases referred to two Child Protection Units in Sydney, NSW, a search of court records was conducted to obtain criminal justice outcomes. Of the 183 cases, there were 117 cases where the name of the offender was known. Forty-five cases reached trial. Thirty-two cases resulted in a conviction. A sub-cohort of 84 of the children and their families was interviewed in detail to determine reasons why many cases did not proceed down the track of criminal investigation and prosecution and why other cases dropped out of the criminal justice system. Among this sub-cohort of 84 children, there were 67 cases where the offender was identifiable and could have been charged. There were 25 convictions. Reasons for not proceeding to trial included: the offence was not reported to police; parents wished to protect children, the perpetrator or other family members; evidence was not strong enough to warrant proceeding; the child was too young; the offender threatened the family; or the child was too distressed. The implications for criminal prosecution as a child protection strategy are considered in the light of this evidence of attrition.
The Abusive Society: A Review Essay
Authors: Pratt John
Published: May 2006

This essay reviews a recent book on a New Zealand child abuse case which has become well-known in that country. It uses the review to explore broader issues associated with the differing and controversial forms of child sexual abuse that have come into focus in some English speaking societies over the last 20 years and the social context which has made their emergence possible.
Reduction in Mitochondrial Superoxide Dismutase Modulates Alzheimer's Disease-Like Pathology and Accelerates the Onset of Behavioral Changes in Human Amyloid Precursor Protein Transgenic Mice
Authors: Esposito Luke , Raber Jacob , Kekonius Lisa , Yan Fengrong , Yu Giu-Qiu , Bien-Ly Nga , Puoliväli Jukka , Scearce-Levie Kimberly , Masliah Eliezer , Mucke Lennart
Published: May 2006

Alzheimer's disease (AD) is associated with accumulations of amyloid-β (Aβ) peptides, oxidative damage, mitochondrial dysfunction, neurodegeneration, and dementia. The mitochondrial antioxidant manganese superoxide dismutase-2 (Sod2) might protect against these alterations. To test this hypothesis, we inactivated oneSod2allele (Sod2+/−) in human amyloid precursor protein (hAPP) transgenic mice, reducing Sod2 activity to ∼50% of that inSod2wild-type (Sod2+/+) mice. A reduction in Sod2 activity did not obviously impair mice without hAPP/Aβ expression. In hAPP mice, however, it accelerated the onset of behavioral alterations and of deficits in prepulse inhibition of acoustic startle, a measure of sensorimotor gating. In these mice, it also worsened hAPP/Aβ-dependent depletion of microtubule-associated protein 2, a marker of neuronal dendrites. Sod2 reduction decreased amyloid plaques in the brain parenchyma but promoted the development of cerebrovascular amyloidosis, gliosis, and plaque-independent neuritic dystrophy. Sod2 reduction also increased the DNA binding activity of the transcription factor nuclear factor κB. These results suggest that Sod2 protects the aging brain against hAPP/Aβ-induced impairments. Whereas reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit.
Suppressor of Cytokine Signaling 1 Expression Protects Oligodendrocytes from the Deleterious Effects of Interferon-γ
Authors: Balabanov Roumen , Strand Krystal , Kemper April , Lee Ji Yeon , Popko Brian
Published: May 2006

Interferon-γ (IFN-γ) is a pleiotropic cytokine produced by T cells and natural killer cells that has been implicated as a deleterious factor in the immune-mediated demyelinating disorder multiple sclerosis.In vitro, purified developing and mature oligodendrocytes have been shown to die in the presence of IFN-γ by apoptosis and necrosis, respectively. Moreover, transgenic expression of IFN-γ in the CNS of mice during development results in tremor, hypomyelination, and oligodendrocyte cell loss, and IFN-γ expression in adult animals after demyelinating insults inhibits remyelination. To examine the molecular mechanisms of IFN-γ-induced oligodendrocyte injury, we generated a transgenic mouse line [PLP/SOCS1(proteolipid protein/suppressor of cytokine signaling 1)] that exhibits diminished oligodendrocyte responsiveness to IFN-γ attributable to the targeted expression of SOCS1 in these cells. We demonstrate that oligodendrocytes in thePLP/SOCS1transgenic mice are protected against the injurious effect of IFN-γ. Our data indicate that IFN-γ exerts a direct deleterious effect on developing oligodendrocytes. The capacity of SOCS1 to inhibit the effects of IFN-γ suggests a therapeutic approach toward protection of myelinating oligodendrocytes against the harmful effects of inflammation.
Psychostimulant-Induced Attenuation of Hyperactivity and Prepulse Inhibition Deficits inAdcyap1-Deficient Mice
Authors: Tanaka Kazuhiro , Shintani Norihito , Hashimoto Hitoshi , Kawagishi Naofumi , Ago Yukio , Matsuda Toshio , Hashimoto Ryota , Kunugi Hiroshi , Yamamoto Akiko , Kawaguchi Chihiro , Shimada Takeshi , Baba Akemichi
Published: May 2006

Psychostimulants, including amphetamine, act as antihyperkinetic agents in humans with hyperkinetic disorder such as attention-deficit hyperactivity disorder and are known to be effective in enhancing attention-related processes; however, the underlying mechanisms have not been adequately addressed. Mice lacking theAdcyap1gene encoding the neuropeptide pituitary adenylate cyclase-activating polypeptide (Adcyap1−/−) display psychomotor abnormalities, including increased novelty-seeking behavior and hyperactivity. In this study,Adcyap1−/−mice showed sensory-motor gating deficits, measured as deficits in prepulse inhibition (PPI), and showed normal PPI in response to amphetamine. Amphetamine also significantly decreased hyperlocomotion inAdcyap1−/−mice, and this paradoxical antihyperkinetic effect depended on serotonin 1A (5-HT1A) receptor signaling. c-Fos-positive neurons were increased in the prefrontal cortex in amphetamine-treatedAdcyap1−/−mice, suggesting increased inhibitory control by prefrontal neurons. Additionally, amphetamine produced an antihyperkinetic effect in wild-type mice that received the 5-HT1Aagonist 8-hydroxy-2-(di-n-propylamino)tetralin. These results indicate thatAdcyap1−/−mice act as a model of hyperlocomotion and PPI deficits and suggest that 5-HT1A-mediated pathways are important determinants of the psychostimulant-elicited, rate-dependent effects that are in a negative function of the baseline rate of activity.
Asymmetric Localization of Vangl2 and Fz3 Indicate Novel Mechanisms for Planar Cell Polarity in Mammals
Authors: Montcouquiol Mireille , Sans Nathalie , Huss David , Kach Jacob , Dickman J. David , Forge Andrew , Rachel Rivka A. , Copeland Neal G. , Jenkins Nancy A. , Bogani Debora , Murdoch Jennifer , Warchol Mark E. , Wenthold Robert J. , Kelley Matthew W.
Published: May 2006

Planar cell polarity (PCP) is a process in which cells develop with uniform orientation within the plane of an epithelium. To begin to elucidate the mechanisms of PCP in vertebrates, the localization of the protein Vangl2 (Van Gogh-like) was determined during the development of the mammalian cochlea. Results indicate that Vangl2 becomes asymmetrically localized to specific cell–cell boundaries along the axis of polarization and that this asymmetry is lost in PCP mutants. In addition, PDZ2 (postsynaptic density/Discs large/zona occludens 1), PDZ3, and PDZ4 of the PCP protein Scrb1 (Scribble) are shown to bind to the C-terminal PDZ binding domain of Vangl2, suggesting that Scrb1 plays a direct role in asymmetric targeting of Vangl2. Finally, Fz3 (Frizzled), a newly demonstrated mediator of PCP, is also asymmetrically localized in a pattern that matches that of Vangl2. The presence and asymmetry of Fz3 at the membrane is shown to be dependent on Vangl2. This result suggests a role for Vangl2 in the targeting or anchoring of Fz3, a hypothesis strengthened by the existence of a physical interaction between the two proteins. Together, our data support the idea that protein asymmetry plays an important role in the development of PCP, but the colocalization and interaction of Fz3 and Vangl2 suggests that novel PCP mechanisms exist in vertebrates.
Bone Cave: A Severely Disturbed Cave Site in Central Oregon
Authors: Ferguson Jeffrey R. , Skinner Craig E.
Published: May 2006

The presence of obsidian artifacts available for hydration and sourcing analysis, a high concentration of well-preserved faunal remains, a limited time span of occupation, and a wealth of obsidian research in the region, make Bone Cave an ideal example of an often ignored class of archaeological site. Although highly disturbed, analysis of the excavation results allowed us to determine that Bone Cave served as a probable pre-Mazama (prior to 6850 B.P.) rabbit processing site during the Early Holocene. The disturbed site of Bone Cave shows that field research is possible even in a region or political environment in which the excavation of intact sites is not.
Using Investment Data to Assess the Importance of Price Mismeasurement
Authors: Comin Diego A
Published: May 2006

This paper presents a new approach to assess the role of price mismeasurement in the productivity slowdown. I invert the firm’s investment decision to identify the embodied and disembodied components of productivity growth. With a Cobb-Douglas production function, output price mismeasurement only should affect the latter. Contrary to the mismeasurement hypothesis, I find that in the Post-War period, disembodied productivity grew faster in the hard-to-measure than in the non-manufacturing easy-to-measure sectors, and that disembodied productivity slowed down less in the hard-to-measure than in the easy-to-measure sectors since the 70’s. These results hold a fortiori when capital and labor are complements.
Kinetics of H2S Sorption on Manganese Oxide and Mn-Fe-Cu Mixed Oxide Prepared by the Complexation Technique
Authors: Caglayan Pinar , Yasyerli Sena , Ar Irfan , Dogu Gulsen , Dogu Timur
Published: May 2006

Hydrogen sulfide sorption activities of manganese oxide and Mn-Fe-Cu mixed oxide sorbents were examined in a fixed bed reactor. Sulfur retention capacity of Mn-O sorbent was found to be quite high at 600 °C both in the absence and presence of hydrogen gas (0.17 and 0.14 g S/g sorbent, respectively). This sorbent has a high porosity and a relatively high surface area. Best regeneration temperature of this sorbent was found as 700 °C, with a gas stream containing 6% oxygen in nitrogen. Mn-Fe-Cu mixed oxide sorbent had a lower sulfur retention capacity (0.07 g S/g sorbent). However, both of these sorbents gave quite high initial sorption rate constants, resulting very sharp breakthrough curves. Deactivation model was shown to give good agreement with the experimental H2S breakthrough curves.
Phosphatidylinositol 3-Kinase–Dependent Activation of Akt, an Essential Signal for Hyperthermia-Induced Heat-Shock Protein 72, Is Attenuated in Streptozotocin-Induced Diabetic Heart
Authors: Shinohara Tetsuji , Takahashi Naohiko , Ooie Tatsuhiko , Hara Masahide , Shigematsu Sakuji , Nakagawa Mikiko , Yonemochi Hidetoshi , Saikawa Tetsunori , Yoshimatsu Hironobu
Published: May 2006

We tested the hypothesis that phosphatidylinositol 3-kinase (PI 3-kinase)-dependent activation of Akt is essential for the expression of cardiac heat-shock protein 72 (HSP72) and that this pathway is impaired in the streptozotocin (STZ)-induced diabetic heart. STZ-induced male diabetic rats were treated with insulin (STZ-insulin group, n = 26) or vehicle (STZ-vehicle group, n = 61) for 3 weeks. Whole-body hyperthermia (43°C for 20 min) was applied, and the heart was isolated 24 h later. Compared with control heart, hyperthermia-induced HSP72 expression and phosphorylation of Akt were attenuated in the STZ-vehicle heart. Pretreatment with wortmannin attenuated hyperthermia-induced HSP72 expression and phosphorylation of Akt. In isolated perfused heart experiments, the hyperthermia-treated STZ-vehicle heart showed poor left ventricular functional recovery during reperfusion after no-flow global ischemia compared with hyperthermia-treated control heart. Insulin treatment restored HSP72 expression and reperfusion-induced functional recovery. In cultured neonatal rat cardiomyocytes, hyperthermia-induced HSP72 expression was enhanced by insulin, together with tolerance against hypoxia-reoxygenation injury. Wortmannin and LY294002 inhibited hyperthermia-induced HSP72 expression and phosphorylation of Akt. Our results indicate that activation of Akt, in a PI 3-kinase–dependent manner, is essential for hyperthermia-induced HSP72 expression in association with cardioprotection, suggesting impairment of this signaling pathway in the STZ-induced diabetic heart, probably due to insulin deficiency.
Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module
Authors: Li Ming V. , Chang Benny , Imamura Minako , Poungvarin Naravat , Chan Lawrence
Published: May 2006

We report here a novel mechanism for glucose-mediated activation of carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper (bHLH/ZIP) transcription factor of Mondo family that binds to carbohydrate response element in the promoter of some glucose-regulated genes and activates their expression upon glucose stimulation. Structure-function analysis of ChREBP in a highly glucose-sensitive system using GAL4-ChREBP fusion constructs revealed a glucose-sensing module (GSM) that mediates glucose responsiveness of ChREBP. GSM is conserved among Mondo family members; MondoA, a mammalian paralog of unknown function, and the GSM region of a Drosophila homolog were also found to be glucose responsive. GSM is composed of a low-glucose inhibitory domain (LID) and a glucose-response activation conserved element (GRACE). We have identified a new mechanism accounting for glucose responsiveness of ChREBP that involves specific inhibition of the transactivation activity of GRACE by LID under low glucose concentration and reversal of this inhibition by glucose in an orientation-sensitive manner. The intramolecular inhibition and its release by glucose is a regulatory mechanism that is independent of changes of subcellular localization or DNA binding activity, events that also appear to be involved in glucose responsiveness. This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation.
Human Vascular Smooth Muscle Cells From Diabetic Patients Are Resistant to Induced Apoptosis Due to High Bcl-2 Expression
Authors: Ruiz Emilio , Gordillo-Moscoso Antonio , Padilla Eugenia , Redondo Santiago , Rodriguez Enrique , Reguillo Fernando , Briones Ana M. , van Breemen Cornelis , Okon Elena , Tejerina Teresa
Published: May 2006

An emerging body of evidence suggests that vascular remodeling in diabetic patients involves a perturbation of the balance between cell proliferation and cell death. Our aim was to study whether arteries and vascular smooth muscle cells (VSMCs) isolated from diabetic patients exhibit resistance to apoptosis induced by several stimuli. Internal mammary arteries (IMAs) were obtained from patients who had undergone coronary artery bypass graft surgery. Arteries from diabetic patients showed increasing levels of Bcl-2 expression in the media layer, measured by immunofluorescence and by Western blotting. Human IMA VSMCs from diabetic patients showed resistance to apoptosis, measured as DNA fragmentation and caspase-3 activation, induced by C-reactive protein (CRP) and other stimuli, such as hydrogen peroxide and 7β-hydroxycholesterol. The diabetic cells also exhibited overexpression of Bcl-2. Knockdown of Bcl-2 expression with Bcl-2 siRNA in cells from diabetic patients reversed the resistance to induced apoptosis. Consistent with the above, we found that pretreatment of nondiabetic VSMCs with high glucose abolished the degradation of Bcl-2 induced by CRP. Moreover, cell proliferation was increased in diabetic compared with nondiabetic cells. This differential effect was potentiated by glucose. We conclude that the data provide strong evidence that arterial remodeling in diabetic patients results from a combination of decreased apoptosis and increased proliferation.
Imaging of Insulin Signaling in Skeletal Muscle of Living Mice Shows Major Role of T-Tubules
Authors: Lauritzen Hans P.M.M. , Ploug Thorkil , Prats Clara , Tavaré Jeremy M. , Galbo Henrik
Published: May 2006

Insulin stimulates glucose transport in skeletal muscle by glucose transporter GLUT4 translocation to sarcolemma and membrane invaginations, the t-tubules. Although muscle glucose uptake plays a key role in insulin resistance and type 2 diabetes, the dynamics of GLUT4 translocation and the signaling involved are not well described. We have now developed a confocal imaging technique to follow trafficking of green fluorescent protein–labeled proteins in living muscle fibers in situ in anesthetized mice. Using this technique, by imaging the dynamics of GLUT4 translocation and phosphatidylinositol 3,4,5 P3 (PIP3) production in response to insulin, here, for the first time, we delineate the temporal and spatial distribution of these processes in a living animal. We find a 10-min delay of maximal GLUT4 recruitment and translocation to t-tubules compared with sarcolemma. Time-lapse imaging of a fluorescent dye after intravenous injection shows that this delay is similar to the time needed for insulin diffusion into the t-tubule system. Correspondingly, immunostaining of muscle fibers shows that insulin receptors are present throughout the t-tubule system. Finally, PIP3 production, an early event in insulin signaling, progresses slowly along the t-tubules with a 10-min delay between maximal PIP3 production at sarcolemma compared with deep t-tubules following the appearance of dye-labeled insulin. Our findings in living mice indicate a major role of the t-tubules in insulin signaling in skeletal muscle and show a diffusion-associated delay in insulin action between sarcolemma and inner t-tubules.
A Functional Tyr1306Cys Variant in LARG Is Associated With Increased Insulin Action in Vivo
Authors: Kovacs Peter , Stumvoll Michael , Bogardus Clifton , Hanson Robert L. , Baier Leslie J.
Published: May 2006

Diminished insulin sensitivity is a characteristic feature of type 2 diabetes. Inhibition of insulin action, resulting in reduced skeletal muscle glucose uptake, is mediated in part through stimulation of RhoA activity. One regulator of RhoA activity is leukemia-associated Rho guanine nucleotide exchange factor (LARG). The LARG gene maps to a region on chromosome 11q23-24 that shows genetic linkage to BMI and type 2 diabetes in Pima Indians. Because of its role in RhoA activation, the LARG gene was analyzed as a positional candidate gene for this linkage. Sequencing of the LARG gene and genotyping of variants identified several polymorphisms that were associated with in vivo rates of insulin-mediated glucose uptake, at both physiological and maximally stimulating insulin concentrations, among 322 nondiabetic Pima Indians who had undergone a hyperinsulinemic-euglycemic clamp. The strongest association with rate of glucose uptake was found with a Tyr1306Cys polymorphism (P < 0.0001, adjusted for age, sex, percent body fat, and nuclear family membership). In transient transfection studies in NIH3T3 cells, the LARG(Cys1306) protein had reduced activity compared with LARG(Tyr1306) protein (P < 0.05). We propose that the Tyr1306Cys substitution in LARG, through its differential activation of RhoA, increases insulin sensitivity in nondiabetic Pima Indians.
Improvement of Glucose Tolerance and Hepatic Insulin Sensitivity by Oligofructose Requires a Functional Glucagon-Like Peptide 1 Receptor
Authors: Cani Patrice D. , Knauf Claude , Iglesias Miguel A. , Drucker Daniel J. , Delzenne Nathalie M. , Burcelin Rémy
Published: May 2006

Nondigestible fermentable dietary fibers such as oligofructose (OFS) exert an antidiabetic effect and increase the secretion of glucagon-like peptide 1 (GLP-1). To determine the importance of GLP-1 receptor-dependent mechanisms for the actions of OFS, we studied high-fat-fed diabetic mice treated with OFS for 4 weeks in the presence or absence of the GLP-1 receptor antagonist exendin 9-39 (Ex-9). OFS improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, and insulin-sensitive hepatic glucose production and reduced body weight gain. Ex-9 totally prevented the beneficial effects of OFS. Furthermore, GLP-1 receptor knockout mice (GLP-1R−/−) were completely insensitive to the antidiabetic actions of OFS. At the molecular level, the effects of OFS on endogenous glucose production correlated with changes of hepatic IRS (insulin receptor substrate)-2 and Akt phosphorylation in an Ex-9-dependent manner. As inflammation is associated with diabetes and obesity, we quantified nuclear factor-κB and inhibitor of κB kinase β in the liver. The activity of both intracellular inflammatory effectors was reduced by OFS but, importantly, this effect could not be reverted by Ex-9. In summary, our data show that the antidiabetic actions of OFS require a functional GLP-1 receptor. These findings highlight the therapeutic potential of enhancing endogenous GLP-1 secretion for the treatment of type 2 diabetes.
Aldose Reductase Pathway Inhibition Improved Vascular and C-Fiber Functions, Allowing for Pressure-Induced Vasodilation Restoration During Severe Diabetic Neuropathy
Authors: Demiot Claire , Tartas Maylis , Fromy Bérengère , Abraham Pierre , Saumet Jean Louis , Sigaudo-Roussel Dominique
Published: May 2006

Pressure-induced vasodilation, a neurovascular mechanism relying on the interaction between mechanosensitive C-fibers and vessels, allows skin blood flow to increase in response to locally nonnociceptive applied pressure that in turn may protect against pressure ulcers. We expected that severe neuropathy would dramatically affect pressure-induced vasodilation in diabetic mice, and we aimed to determine whether pressure-induced vasodilation alteration could be reversed in 8-week diabetic mice. Control and diabetic mice received no treatment or sorbinil, an aldose reductase inhibitor, or alagebrium, an advanced glycation end product breaker, the last 2 weeks of diabetes. Laser Doppler flowmetry was used to evaluate pressure-induced vasodilation and endothelium-dependent vasodilation after iontophoretic delivery of acetylcholine (ACh). We assessed the nervous function with measurements of motor nerve conduction velocity (MNCV) as well as the C-fiber-mediated nociception threshold. Pressure-induced vasodilation, endothelial response, C-fiber threshold, and MNCV were all altered in 8-week diabetic mice. None of the treatments had a significant effect on MNCV. Although sorbinil and alagebrium both restored ACh-dependent vasodilation, sorbinil was the sole treatment to restore the C-fiber threshold as well as pressure-induced vasodilation development. Therefore, the inhibition of aldose reductase pathway by sorbinil improved vascular and C-fiber functions that allow pressure-induced vasodilation restoration that could limit neuropathic diabetic cutaneous pressure ulcers.
Metabolic Sensors Mediate Hypoglycemic Detection at the Portal Vein
Authors: Matveyenko Aleksey V. , Donovan Casey M.
Published: May 2006

The current study sought to ascertain whether portal vein glucose sensing is mediated by a metabolic fuel sensor analogous to other metabolic sensors presumed to mediate hypoglycemic detection (e.g., hypothalamic metabosensors). We examined the impact of selectively elevating portal vein concentrations of lactate, pyruvate, or β-hydroxybutyrate (BHB) on the sympathoadrenal response to insulin-induced hypoglycemia. Male Wistar rats (n = 36), chronically cannulated in the carotid artery (sampling), jugular vein (infusion), and portal vein (infusion), underwent hyperinsulinemic-hypoglycemic (∼2.5 mmol/l) clamps with either portal or jugular vein infusions of lactate, pyruvate, or BHB. By design, arterial concentrations of glucose and the selected metabolite were matched between portal and jugular (NS). Portal vein concentrations were significantly elevated in portal versus jugular (P < 0.0001) for lactate (5.03 ± 0.2 vs. 0.84 ± 0.08 mmol/l), pyruvate (1.81 ± 0.21 vs. 0.42 ± 0.03 mmol/l), or BHB (2.02 ± 0.1 vs. 0.16 ± 0.03 mmol/l). Elevating portal lactate or pyruvate suppressed both the epinephrine (64% decrease; P < 0.01) and norepinephrine (75% decrease; P < 0.05) responses to hypoglycemia. In contrast, elevating portal BHB levels failed to impact epinephrine (P = 0.51) or norepinephrine (P = 0.47) levels during hypoglycemia. These findings indicate that hypoglycemic detection at the portal vein is mediated by a sensor responding to some metabolic event(s) subsequent to the uptake and oxidation of glucose.
Role of Genetic Polymorphism Peroxisome Proliferator–Activated Receptor-γ2 Pro12Ala on Ethnic Susceptibility to Diabetes in South-Asian and Caucasian Subjects
Authors: Radha Venkatesan , Vimaleswaran Karani S. , Babu Hunsur Narayan S. , Abate Nicola , Chandalia Manisha , Satija Pankaj , Grundy Scott M. , Ghosh Saurabh , Majumder Partha P. , Deepa Raj , Rao Sathyanarayana M.R. , Mohan Viswanathan
Published: May 2006

OBJECTIVE—To determine whether the peroxisome proliferator–activated receptor (PPAR)-γ Pro12ala polymorphism modulates susceptibility to diabetes in South Asians.

RESEARCH DESIGN AND METHODS—South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-γ Pro12Ala was determined using restriction fragment–length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects.

RESULTS—The Caucasian diabetic subjects had significantly lower prevalence of PPAR-γ 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-γ Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 ± 68 and 54 ± 33 μU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-γ Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas.

CONCLUSIONS—Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-γ Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.
Parent Perceptions of Caring for Adolescents With Type 2 Diabetes
Authors: Mulvaney Shelagh A. , Schlundt David G. , Mudasiru Eniola , Fleming Mary , Vander Woude Ann M. , Russell William E. , Elasy Tom A. , Rothman Russell
Published: May 2006

OBJECTIVE—No studies have been performed to examine parent perceptions of caring for adolescents with type 2 diabetes. In this qualitative study, we examined parent perceptions of barriers and strategies to address barriers to self-care in adolescents with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Families of adolescents with type 2 diabetes were recruited from a pediatric diabetes clinic. Focus groups were used to elicit parent experiences and perceptions of diabetes management of their adolescents with type 2 diabetes. Questions concerning barriers to self-care behaviors were asked by trained group facilitators. Transcripts were coded into themes by three reviewers. Qualitative analyses were conducted using NVIVO software.

RESULTS—Between 2003 and 2005, six focus groups were conducted with a total of 27 parents or guardians. Parents identified many barriers to and practical strategies for positive adolescent self-management. Five domains that influence self-management were identified: the role of others with diabetes, parenting skills, perceived lack of normalcy, environment, and adolescent development. Parents identified many barriers to dietary and exercise habits that were unique to the circumstances of adolescents with type 2 diabetes.

CONCLUSIONS—Parents identified many barriers to self-management that may be unique to adolescents with type 2 diabetes. The importance of others and environmental influences in the self-management behavior of adolescents with type 2 was evident. Interventions that are designed to improve self-management should include components that address multiple influences such as peers, school professionals, parents, siblings, and/or family systems.
A Clinical Screening Tool Identifies Autoimmune Diabetes in Adults
Authors: Fourlanos Spiros , Perry Christine , Stein Mark S. , Stankovich Jim , Harrison Leonard C. , Colman Peter G.
Published: May 2006

OBJECTIVE—Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing.

RESEARCH DESIGN AND METHODS—Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA−) (aged 30–75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a “LADA clinical risk score,” based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA.

RESULTS—In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset <50 years (P < 0.0001), 2) acute symptoms (P < 0.0001), 3) BMI <25 kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score ≥2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score ≤1 of 99%.

CONCLUSIONS—At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.