Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo

We previously used Gene Expression Signature technology to identify methazolamide (MTZ) and related compounds with insulin sensitizing activity in vitro. The effects of these compounds were investigated in diabetic db/db mice, insulin-resistant diet-induced obese (DIO) mice, and rats with streptozotocin (STZ)-induced diabetes. MTZ reduced fasting blood glucose and HbA1c levels in db/db mice, improved glucose tolerance in DIO mice, and enhanced the glucose-lowering effects of exogenous insulin administration in rats with STZ-induced diabetes. Hyperinsulinemic-euglycemic clamps in DIO mice revealed that MTZ increased glucose infusion rate and suppressed endogenous glucose production. Whole-body or cellular oxygen consumption rate was not altered, suggesting MTZ may inhibit glucose production by different mechanism(s) to metformin. In support of this, MTZ enhanced the glucose-lowering effects of metformin in db/db mice. MTZ is known to be a carbonic anhydrase inhibitor (CAI); however, CAIs acetazolamide, ethoxyzolamide, dichlorphenamide, chlorthalidone, and furosemide were not effective in vivo. Our results demonstrate that MTZ acts as an insulin sensitizer that suppresses hepatic glucose production in vivo. The antidiabetic effect of MTZ does not appear to be a function of its known activity as a CAI. The additive glucose-lowering effect of MTZ together with metformin highlights the potential utility for the management of type 2 diabetes.

Cross-sectional analysis of association between socioeconomic status and utilization of primary total hip joint replacements 2006-7 : Australian orthopaedic association national joint replacement registry

Background The utilization of total hip replacement (THR) surgery is rapidly increasing, however few data examine whether these procedures are associated with socioeconomic status (SES) within Australia. This study examined primary THR across SES for both genders for the Barwon Statistical Division (BSD) of Victoria, Australia.

Methods Using the Australian Orthopaedic Association National Joint Replacement Registry data for 2006–7, primary THR with a diagnosis of osteoarthritis (OA) among residents of the BSD was ascertained. The Index of Relative Socioeconomic Disadvantage was used to measure SES; determined by matching residential addresses with Australian Bureau of Statistics census data. The data were categorised into quintiles; quintile 1 indicating the most disadvantaged. Age- and sex-specific rates of primary THR per 1,000 person years were reported for 10-year age bands using the total population at risk.

Results Females accounted for 46.9% of the 642 primary THR performed during 2006–7. THR utilization per 1,000 person years was 1.9 for males and 1.5 for females. The highest utilization of primary THR was observed in those aged 70–79 years (males 6.1, and females 5.4 per 1,000 person years). Overall, the U-shaped pattern of THR across SES gave the appearance of bimodality for both males and females, whereby rates were greater for both the most disadvantaged and least disadvantaged groups.

Conclusions Further work on a larger scale is required to determine whether relationships between SES and THR utilization for the diagnosis of OA is attributable to lifestyle factors related to SES, or alternatively reflects geographic and health system biases. Identifying contributing factors associated with SES may enhance resource planning and enable more effective and focussed preventive strategies for hip OA.

Gaze behavior among experts and trainees during optic disc examination : does how we look affect what we see?

Purpose. The authors compared the visual gaze behaviors of glaucoma subspecialists with those of ophthalmology trainees during optic disc and retinal nerve fiber layer (RNFL) examination.

Methods. Seven glaucoma subspecialists and 23 ophthalmology trainees participated in the project. Participants were shown eight glaucomatous optic disc images with varied morphology. Eye movements during examination of the optic disc photographs were tracked. For each disc image, graders were asked to assign a presumptive diagnosis for probability of glaucoma. There was no time restriction.

Results. Overall, trainees spent more time looking at disc images than glaucoma subspecialists (21.3 [13.9–37.7] vs. 16.6 [12.7–19.7]) seconds; median [interquartile range (IQR)], respectively; P < 0.01) and had no systematic patterns of gaze behavior, and gaze behavior was unaltered by disc morphology or topographic cues of pathology. Experienced viewers demonstrated more systematic and ordered gaze behavior patterns and spent longer times observing areas with the greatest likelihood of pathology (superior and inferior poles of the optic nerve head and adjacent RNFL) compared with the trainees. For discs with focal pathology, the proportion of total time spent examining definite areas of pathology was 28.9% (22.4%–33.6%) for glaucoma subspecialists and 13.5% (12.2%–19.2%) for trainees (median [IQR]; P < 0.05). Furthermore, experts adapted their viewing habits according to disc morphology.

Conclusions. Glaucoma subspecialists adopt systematic gaze behavior when examining the optic nerve and RNFL, whereas trainees do not. It remains to be elucidated whether incorporating systematic viewing behavior of the optic disc and RNFL into teaching programs for trainees may expedite their acquisition of accurate and efficient glaucoma diagnosis skills.

Glaucoma and on-road driving performance

PURPOSE. To investigate the on-road driving performance of patients with glaucoma.

METHODS. The sample comprised 20 patients with glaucoma and 20 subjects with normal vision, all licensed drivers, matched for age and sex. Driving performance was tested over a 10-km route incorporating 55 standardized maneuvers and skills through residential and business districts of Halifax, Nova Scotia, Canada. Testing was conducted by a professional driving instructor and assessed by an occupational therapist certified in driver rehabilitation, masked to participant group membership and level of vision. Main outcome measures were total number of satisfactory maneuvers and skills, overall rating, and incidence of at-fault critical interventions (application of the dual brake and/or steering override by the driving instructor to prevent a potentially unsafe maneuver). Measures of visual function included visual acuity, contrast sensitivity, and visual fields (Humphrey Field Analyzer; Carl Zeiss Meditec, Inc., Dublin, CA; mean deviation [MD] and binocular Esterman points).

RESULTS. There was no significant difference between patients with glaucoma (mean MD = −1.7 dB [SD 2.2] and −6.5 dB [SD 4.9], better and worse eyes, respectively) and control subjects in total satisfactory maneuvers and skills (P = 0.65), or overall rating (P = 0.60). However, 12 (60%) patients with glaucoma had one or more at-fault critical interventions, compared with 4 (20%) control subjects (odds ratio = 6.00, 95% CI, 1.46–24.69; higher still after adjustment for age, sex, medications and driving exposure), the predominant reason being failure to see and yield to a pedestrian. In the glaucoma group, worse-eye MD was associated with the overall rating of driving (r = 0.66, P = 0.002).

CONCLUSIONS. This sample of patients with glaucoma with slight to moderate visual field impairment performed many real-world driving maneuvers safely. However, they were six times as likely as subjects with normal vision to have a driving instructor intervene for reasons suggesting difficulty with detection of peripheral obstacles and hazards and reaction to unexpected events.

Risk of falls and motor vehicle collisions in glaucoma

PURPOSE. To investigate the risk of falls and motor vehicle collisions (MVCs) in patients with glaucoma.

METHODS. The sample comprised 48 patients with glaucoma (mean visual field mean deviation [MD] in the better eye = −3.9 dB; 5.1 dB SD) and 47 age-matched normal control subjects, who were recruited from a university-based hospital eye care clinic and are enrolled in an ongoing prospective study of risk factors for falls, risk factors for MVCs, and on-road driving performance in glaucoma. Main outcome measures at baseline were previous self-reported falls and MVCs, and police-reported MVCs. Demographic and medical data were obtained. In addition, functional independence in daily living, physical activity level and balance were assessed. Clinical vision measures included visual acuity, contrast sensitivity, standard automated perimetry, useful field of view (UFOV), and stereopsis. Analyses of falls and MVCs were adjusted to account for the possible confounding effects of demographic characteristics, medications, and visual field impairment. MVC analyses were also adjusted for kilometers driven per week.

RESULTS. There were no significant differences between patients with glaucoma and control subjects with respect to number of systemic medical conditions, body mass index, functional independence, and physical activity level (P > 0.10). At baseline, 40 (83%) patients with glaucoma and 44 (94%) control subjects were driving. Compared with control subjects, patients with glaucoma were over three times more likely to have fallen in the previous year (odds ratio [OR]adjusted = 3.71; 95% CI, 1.14–12.05), over six times more likely to have been involved in one or more MVCs in the previous 5 years (ORadjusted = 6.62; 95% CI, 1.40–31.23), and more likely to have been at fault (ORadjusted = 12.44; 95% CI, 1.08–143.99). The strongest risk factor for MVCs in patients with glaucoma was impaired UFOV selective attention (ORadjusted = 10.29; 95% CI, 1.10–96.62; for selective attention >350 ms compared with ≤350 ms).

CONCLUSIONS. There is an increased risk of falls and MVCs in patients with glaucoma.

The letter contrast sensitivity test : clinical evaluation of a new design

PURPOSE. To compare the reliability, validity, and responsiveness of the Mars Letter Contrast Sensitivity (CS) Test to the Pelli-Robson CS Chart.

METHODS. One eye of 47 normal control subjects, 27 patients with open-angle glaucoma, and 17 with age-related macular degeneration (AMD) was tested twice with the Mars test and twice with the Pelli-Robson test, in random order on separate days. In addition, 17 patients undergoing cataract surgery were tested, once before and once after surgery.

RESULTS. The mean Mars CS was 1.62 log CS (0.06 SD) for normal subjects aged 22 to 77 years, with significantly lower values in patients with glaucoma or AMD (P < 0.001). Mars test-retest 95% limits of agreement (LOA) were ±0.13, ±0.19, and ±0.24 log CS for normal, glaucoma, and AMD, respectively. In comparison, Pelli-Robson test-retest 95% LOA were ±0.18, ±0.19, and ±0.33 log CS. The Spearman correlation between the Mars and Pelli-Robson tests was 0.83 (P < 0.001). However, systematic differences were observed, particularly at the upper-normal end of the range, where Mars CS was lower than Pelli-Robson CS. After cataract surgery, Mars and Pelli-Robson effect size statistics were 0.92 and 0.88, respectively.

CONCLUSIONS. The results indicate the Mars test has test-retest reliability equal to or better than the Pelli-Robson test and comparable responsiveness. The strong correlation between the tests provides evidence the Mars test is valid. However, systematic differences indicate normative values are likely to be different for each test. The Mars Letter CS Test is a useful and practical alternative to the Pelli-Robson CS Chart.

Glaucomatous visual field progression with frequency-doubling technology and standard automated perimetry in a longitudinal prospective study

PURPOSE. To compare frequency-doubling technology (FDT) perimetry with standard automated perimetry (SAP) for detecting glaucomatous visual field progression in a longitudinal prospective study.

METHODS. One eye of patients with open-angle glaucoma was tested every 6 months with both FDT and SAP. A minimum of 6 examinations with each perimetric technique was required for inclusion. Visual field progression was determined by two methods: glaucoma change probability (GCP) analysis and linear regression analysis (LRA). For GCP, several criteria for progression were used. The number of locations required to classify progression with FDT compared with SAP, respectively, was 1:2 (least conservative), 1:3, 2:3, 2:4, 2:6, 2:7, 3:6, 3:7, and 3:10 (most conservative). The number of consecutive examinations required to confirm progression was 2-of-3, 2-of-2, and 3-of-3. For LRA, the progression criterion was any significant decline in mean threshold sensitivity over time in each of the following three visual field subdivisions: (1) all test locations, (2) locations in the central 10° and the superior and inferior hemifields, and (3) locations in each quadrant. Using these criteria, the proportion of patients classified as showing progression with each perimetric technique was calculated and, in the case of progression with both, the differences in time to progression were determined.

RESULTS. Sixty-five patients were followed for a median of 3.5 years (median number of examinations, 9). For the least conservative GCP criterion, 32 (49%) patients were found to have progressing visual fields with FDT and 32 (49%) patients with SAP. Only 16 (25%) patients showed progression with both methods, and in most of those patients, FDT identified progression before SAP (median, 12 months earlier). The majority of GCP progression criteria (15/27), classified more patients as showing progression with FDT than with SAP. Contrary to this, more patients showed progression with SAP than FDT, when analysed with LRA; e.g., using quadrant LRA 20 (31%) patients showed progression with FDT, 23 (35%) with SAP, and only 10 (15%) with both.

CONCLUSIONS. FDT perimetry detected glaucomatous visual field progression. However, the proportion of patients who showed progression with both FDT and SAP was small, possibly indicating that the two techniques identify different subgroups of patients. Using GCP, more patients showed progression with FDT than with SAP, yet the opposite occurred using LRA. As there is no independent qualifier of progression, FDT and SAP progression rates vary depending on the method of analysis and the criterion used.

The development of the Melbourne low vision ADL index : a measure of vision disability

PURPOSE. To develop a new test of activities of daily living (ADLs) appropriate for the low-vision population: the Melbourne Low-Vision ADL Index (MLVAI).

METHODS. The MLVAI was designed as a desk-based clinical assessment, comprising 18 observed items on complex ADLs in part (a) and 9 questions on broad self-care ADLs in part (b). Each item was rated on a five-level descriptive scale from 0 to 4, based on independence, speed, and accuracy of performance. It was designed to be administered under standardized conditions with regard to the instructions, illumination, and working distances. The validity and reliability of the new MLVAI was determined for 122 subjects who were representative of the general low-vision population, in a cross-sectional study.

RESULTS. Two items were found to be redundant and were eliminated from the test. Thus, the final test comprised 25 items, with 100 being the highest possible score. Cronbach’s α indicated an internal reliability of 0.96, and an intraclass correlation coefficient indicated an overall reliability of 0.95. The SE of measurement was 4.5. According to Spearman’s correlation coefficient, the test–retest reliability was 0.94 (P < 0.001), and the interpractitioner reliability for five different pairs of practitioners was 0.90 or higher (P < 0.001). With regard to validity, there was a moderately high correlation with vision impairment (r = −0.68, P < 0.001). Using Rasch analysis, content validity was also demonstrated by good separation indexes (4.70 and 9.88) and high reliability scores (0.96 and 0.99) for the person and items parameters, respectively. Separate calculation of indexes and reliability scores for parts (a) and (b) indicated high content validity and reliability of each part. However, the separation indexes and reliability scores were higher for part (a) than for part (b). The correlation coefficient for part (a) and part (b) was 0.68.

CONCLUSIONS. The MLVAI is a highly valid and reliable standardized test of ADL performance for the general low-vision population. It may be used to assess patients with low vision and has the potential to be used as a measure of low-vision rehabilitation outcomes.

HIV-1 down-modulates γ signaling chain of FcγR in human macrophages : a possible mechanism for inhibition of phagocytosis

HIV-1 infection impairs a number of macrophage effector functions, thereby contributing to development of opportunistic infections and the pathogenesis of AIDS. FcγR-mediated phagocytosis by human monocyte-derived macrophages (MDM) is inhibited by HIV-1 infection in vitro, and the underlying mechanism was investigated in this study. Inhibition of phagocytosis directly correlated with the multiplicity of HIV-1 infection. Expression of surface FcγRs was unaffected by HIV-1 infection, suggesting that inhibition of phagocytosis occurred during or after receptor binding. HIV-1 infection of MDM markedly inhibited tyrosine phosphorylation of the cellular proteins, which occurs following engagement of FcγRs, suggesting a defect downstream of initial receptor activation. FcγR-mediated phagocytosis in HIV-infected MDM was associated with inhibition of phosphorylation of tyrosine kinases from two different families, Hck and Syk, defective formation of Syk complexes with other tyrosine-phosphorylated proteins, and inhibition of paxillin activation. Down-modulation of protein expression but not mRNA of the γ signaling subunit of FcγR (a docking site for Syk) was observed in HIV-infected MDM. Infection of MDM with a construct of HIV-1 in which nef was replaced with the gene for the γ signaling subunit augmented FcγR-mediated phagocytosis, suggesting that down-modulation of γ-chain protein expression in HIV-infected MDM caused the defective FcγR-mediated signaling and impairment of phagocytosis. This study is the first to demonstrate a specific alteration in phagocytosis signal transduction pathway, which provides a mechanism for the observed impaired FcγR-mediated phagocytosis in HIV-infected macrophages and contributes to the understanding of how HIV-1 impairs cell-mediated immunity leading to HIV-1 disease progression.

Early events of HIV-1 infection : can signalling be the next therapeutic target?

Intracellular signaling events are signposts of biological processes, which govern the direction and action of biological activities. Through millions of years of evolution, pathogens, such as viruses, have evolved to hijack host cell machinery to infect their targets and are therefore dependent on host cell signaling for replication. This review will detail our current understanding of the signaling events that are important for the early steps of HIV-1 replication. More specifically, the therapeutic potential of signaling events associated with chemokine coreceptors, virus entry, viral synapses, and post-entry processes will be discussed. We argue that these pathways may represent novel targets for antiviral therapy.

Shared care for chronic eye diseases : perspectives of ophthalmologists, optometrists and patients

Objective: To report the perspectives of optometrists, ophthalmologists and patients on a model of shared care for patients with chronic eye diseases.

Design, setting and participants: Qualitative study of a model of shared care between optometrists and ophthalmologists for patients with stable age-related macular degeneration, diabetic retinopathy and glaucoma, trialled by the Royal Victorian Eye and Ear Hospital in Melbourne during 2007–2009. Semi-structured interviews were conducted with optometrists, ophthalmologists and patients at completion of the project to obtain their perspectives on this model.

Results: Seventeen optometrists submitted expressions of interest to participate, and 12 completed web-based training modules and clinical observerships and adhered to specified examination and reporting protocols. All five participating ophthalmologists and 11 of the optometrists were interviewed. Ninety-eight patients participated and 37 were interviewed. Optometrists not only met ophthalmologists’ expectations but exceeded them, appropriately detecting and referring patients with additional, previously undetected conditions. Patients reported savings in travel time and were satisfied with the quality of care they received. Optometrists, ophthalmologists and patients indicated a general acceptance of shared care arrangements, although there were some issues relating to interprofessional trust.

Conclusions: Shared care between local optometrists and hospital-based ophthalmologists can help to reduce patient waiting time for review and offers an opportunity for these two groups of eye care professionals to collaborate in providing localised care for the benefit of patients. However, trust and relationship building need to be further developed.

Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton

Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the persistence of long-lived, latently infected resting memory CD4+ T cells. We now show that HIV-1 latency can be established in resting CD4+ T cells infected with HIV-1 after exposure to ligands for CCR7 (CCL19), CXCR3 (CXCL9 and CXCL10), and CCR6 (CCL20) but not in unactivated CD4+ T cells. The mechanism did not involve cell activation or significant changes in gene expression, but was associated with rapid dephosphorylation of cofilin and changes in filamentous actin. Incubation with chemokine before infection led to efficient HIV-1 nuclear localization and integration and this was inhibited by the actin stabilizer jasplakinolide. We propose a unique pathway for establishment of latency by direct HIV-1 infection of resting CD4+ T cells during normal chemokine-directed recirculation of CD4+ T cells between blood and tissue.