Metabotropic glutamate receptor 1 internalization induced by muscarinic acetylcholine receptor activation: differential dependency of internalization of splice variants on nonvisual arrestins

In this study, we characterized the glutamate- or second-messenger kinase-dependent internalization of the rat metabotropic glutamate receptor 1 (mGluR1) splice variants 1a, 1b, and 1c, and assessed the arrestin and dynamin dependence of these processes. To facilitate this we inserted a hemagglutinin epitope tag in the extracellular N-terminal domain of the splice variants. Quantification of glutamate-induced mGluR1 splice variant internalization provided by enzyme-linked immunosorbent assay and confirmed by immunofluorescent microscopy indicated that each splice variant underwent rapid internalization, which was strongly inhibited by coexpression of dominant-negative mutant (DNM) arrestin or dynamin. In addition glutamate-induced rapid translocation of arrestin-2-green fluorescent protein (GFP) or arrestin-3-GFP from cytosol to membrane was observed in cells expressing mGluR1 splice variants. Glutamate-induced internalization of mGluR1a and mGluR1c was partially blocked by a selective inhibitor of protein kinase C (PKC), 2-[1-(3-dimethylamino-propyl)indol-3-yl]-3-(1H-indol-3-yl)maleimide (GF 109203X), whereas mGluR1b internalization was not significantly affected by this inhibitor. Similarly, inositol phosphate production after glutamate-induced activation of mGluR1a and mGluR1c was increased after PKC inhibition, whereas glutamate-induced mGluR1b stimulation was unaffected. Activation by carbachol of endogenously expressed M(1) muscarinic receptors in human embryonic kidney 293 cells, induced the internalization of mGluR1 splice variants, which was partially blocked by pretreatment with inhibitors of either PKC or Ca(2+) calmodulin-dependent kinase II (CaMKII). Expression of DNM-arrestin with mGluR1a or 1c strongly inhibited carbachol-induced internalization. However, coexpression of DNM-arrestin with mGluR1b was less effective in reducing carbachol-induced receptor internalization. In addition, arrestin-2-GFP or arrestin-3-GFP underwent significant carbachol-induced translocation from cytosol to membrane in cells coexpressing mGluR1a or 1c but not in cells coexpressing mGluR1b. This study demonstrates that the internalization of mGluR1 splice variants is subject to PKC and CaMKII regulation. In addition, regulation by these kinases confers differential arrestin dependence.     

Activities of daily living instruments:optimizing scales for neurologic assessments

The ability to perform activities of daily living (ADL) is an important part of assessment in neurologic patients. A literature search was carried out to identify multi-item ADL scales developed for the assessment of neurologic patients, comparing item content, range, and detail of ADL scales. Of the 113 ADL scales identified, 27 (24%) were designed for use in neurology. In the basic ADL (BADL) domains (basic mobility and self-care), individual items were present in 44% to 81% of instruments. In the extended ADL (EADL) domains (e.g., outdoor mobility, housekeeping), items were present in up to 67% of the instruments identified. A typical trade-off was observed between the range, the detail (number of items), and hence the practicality of a scale. In general, scales focus on either BADL or EADL domains or, on occasion, some of both, rather than measuring the full range of functioning. There are many ADL scales in neurology, with much overlap in item content, leading to redundancy. New scales developed with the traditional methods will not solve the existing difficulties associated with range and detail, ordinal scale scores, and cross-instrument comparability. The possibilities of a modern psychometric method known as item response theory that was designed to solve these problems are discussed.     

Ischemic preconditioning and Na+/H+ exchange inhibition improve reperfusion ion homeostasis

BACKGROUND: Intramyocyte sodium (Na+) increases during ischemia and reperfusion, which causes myocardial calcium (Ca2+) uptake and leads to myocyte injury or death. This study determines if ischemic preconditioning and myocyte sodium-hydrogen ion (Na+-H+) exchange (NHE) inhibition decreases Na+ gain that otherwise occurs with cardioplegic arrest and reperfusion. METHODS: Pigs had 1 hour of cardioplegic arrest followed by reperfusion. Group 1 had no intervention (controls). Group 2 received dimethyl amiloride (DMA, an NHE inhibitor), and group 3 had ischemic preconditioning before cardioplegic arrest. Precardioplegia to postreperfusion change in intramyocyte ion content was measured with atomic absorption spectrometry. The time to initial electrical activity and number of defibrillations needed to establish an organized rhythm postreperfusion were used as electrophysiologic variables to measure ischemia-reperfusion injury. RESULTS: Intramyocyte Na+ content for group 1 increased from 45.9+/-6.7 to 61.9+/-22.5 micromol/g (p = 0.02). Group 2 had an insignificant decrease in intramyocyte Na+ of 27.7+/-19.58 micromol/g (p = 0.06), and group 3 had an insignificant decrease of 10.8+/-46.33 micromol/g (p = 0.48). Interstitial water increased significantly in all groups, but there were no significant increases in intramyocyte water content. Electrophysiologic recovery was similar for all three groups. CONCLUSIONS: The NHE inhibition and ischemic preconditioning each eliminated the increase in intramyocyte Na+ content that otherwise occurred with cardioplegic arrest and reperfusion in this porcine model. Because their mechanisms are distinct, it is possible that an additive beneficial effect against ischemia-reperfusion injury can be achieved by using NHE inhibition together with a preconditioning stimulus as prereperfusion therapy.     

Measuring the functional status of patients in clinical trials using modern clinimetric methods

In clinical medicine numerous measurement instruments have been developed to assess the functional outcome of patients in clinical trials. The majority are questionnaires with multiple-choice items. The responses of the patients are used to calculate a sum score. However, there are some disadvantages associated with the use of sum scores. Modern clinimetric methods, based on item response theory (IRT) in combination with a calibrated item bank, can overcome these problems. When using this measurement technique, it is possible to arrange both the item difficulty and the patient's ability on a single, hierarchical linear scale. This allows the user to obtain a sufficiently detailed clinical picture using a small number of items. In addition to being efficient, this method makes it possible to present different sets of items to different groups of patients. Since all of the items are calibrated, the measurements remain comparable. The application of this innovative method of measuring is being studied in the ongoing 'Amsterdam linear disability score' (ALDS) project.     

Testosterone therapy in late-life major depression in males

BACKGROUND: Major depression associated with aging in males may improve with anabolic/androgenic steroid therapy. The efficacy and safety of testosterone therapy in the treatment of depression in elderly hypogonadal males is inconclusive. The following study identifies a subgroup of elderly depressed males who may benefit from testosterone therapy. METHOD: Participants included 16 elderly eugonadal males with major depressive disorder (DSM-IV criteria) and a Hamilton Rating Scale for Depression (HAM-D) score > 18. Following a single-blind 2-week placebo lead-in, patients were randomly assigned to treatment with either a physiologic dose of testosterone cypionate (TC), 100 mg/week, or supraphysiologic dose of 200 mg/week IM for 6 weeks. Psychometric testing was carried out at entry into the study, at the TC injection baseline, and every 2 weeks thereafter. Tests included an objective measurement, the HAM-D, and the Buss-Durkee Hostility Inventory. RESULTS: One patient meeting inclusion criteria responded during the placebo lead-in; thus, 15 patients were randomly assigned to treatment (100 mg/week, N = 8; 200 mg/week, N = 7). There was a 42% decrease in the mean HAM-D scores from 20.1 to 11.9 (p <.0001). However, the majority of the change was due to improvement in the 10 late-onset (< or = 45 years old) depression patients, whose mean HAM-D score decreased from 19.8 to 9.3 (53%), versus the 5 early-onset depression patients, whose mean HAM-D score decreased from 20.8 to 17.0 (18%) (p =.0110). The TC dose did not affect the response. Similar HAM-D decreases of 43% and 41% occurred for the respective 100- and 200-mg/week doses. The HAM-D responder analysis found that none of 5 early-onset patients had HAM-D response, whereas 6 (60%) of 10 late-onset patients responded (p =.025). Similarly, none of the early-onset patients experienced a remission whereas 5 (50%) of the late-onset patients were categorized as remitters (p =.053). Correlations between the peak and mean total testosterone concentrations and HAM-D change scores suggested that only minimal TC doses were required to produce an antidepressant effect. CONCLUSION: These data suggest that testosterone therapy would best be limited to men with late-onset depression. The findings suggest that short-term therapy with TC is safe. Long-term treatment safety is unknown. Psychiatrists using testosterone therapy should ascertain that patients have been recently valuated for prostate cancer. If testosterone therapy is initiated, serial serum prostate-specific antigen sampling should be used for monitoring patients' prostate status.     

Patient self-management of chronic disease in primary care

Thomas Bodenheimer, MD; Kate Lorig, RN, DrPH; Halsted Holman, MD; Kevin Grumbach, MD

JAMA. 2002;288:2469-2475.

Patients with chronic conditions make day-to-day decisions about—self-manage—their illnesses. This reality introduces a new chronic disease paradigm: the patient-professional partnership, involving collaborative care and self-management education. Self-management education complements traditional patient education in supporting patients to live the best possible quality of life with their chronic condition. Whereas traditional patient education offers information and technical skills, self-management education teaches problem-solving skills. A central concept in self-management is self-efficacy—confidence to carry out a behavior necessary to reach a desired goal. Self-efficacy is enhanced when patients succeed in solving patient-identified problems. Evidence from controlled clinical trials suggests that (1) programs teaching self-management skills are more effective than information-only patient education in improving clinical outcomes; (2) in some circumstances, self-management education improves outcomes and can reduce costs for arthritis and probably for adult asthma patients; and (3) in initial studies, a self-management education program bringing together patients with a variety of chronic conditions may improve outcomes and reduce costs. Self-management education for chronic illness may soon become an integral part of high-quality primary care.

     

Gender differences in survival of 234 patients referred to a psychogeriatric service

OBJECTIVE: To explore the survival characteristics of psychogeriatric patients.Participants and settingAn historical cohort of 234 patients consecutively referred to a specialized psychogeriatric service proximal to a general health service in Perth, Western Australia. METHODS: Linked health service data were analysed using relative survival analysis and actuarial methods. RESULTS: Relative survival of the cohort after 40 months was significantly lower than the general population of the same age, sex and calendar period (0.78; 95% CI=0.70-0.86). Male patients experienced twice the mortality rate of female patients after adjustment for age (MRR=2.10; 95% CI=1.37-3.20). Age, dementia, mood disorder and ethnicity had no independent effects on mortality in male patients. Female patients with a diagnosis of dementia experienced twice the mortality of female patients without this diagnosis. The distribution of major underlying causes of death was similar in males and females. CONCLUSIONS: Gender-specific factors appear to affect survival in psychogeriatric patients. Male patients are younger on average, but experience higher mortality than female patients. Ethnic background does not influence mortality in either male or female patients.     

Population-based outcomes after 28,246 in-hospital vasectomies and 1,902 vasovasostomies in Western Australia

OBJECTIVES: To examine trends in vasectomy and vasovasostomy, and the surgical complications and factors associated with reversal after vasectomy, and paternity after vasovasostomy. PATIENTS AND METHODS: Procedure rates were estimated from 1980 to 1996 in the population of Western Australia. Linked hospital morbidity records were used in the follow-up of men after vasectomy to estimate the risks of complications and reversals. Records of vasovasostomies were linked to the paternity field on birth registrations. Independent effects of the study factors were examined using Cox regression. RESULTS: There was little net change in vasectomy rates, whereas vasovasostomy rates increased in men aged 30-49 years. Risks of surgical complications were low and decreased for vasovasostomy. At 12-15 years after vasectomy, the risk of reversal levelled at 2. 4% in the total cohort and at 11.1% in men aged 20-24 years. The risk of vasovasostomy was 69% greater after vasectomy performed in 1994-96 than in 1980-84 (P = 0.011). The factors strongly associated with reversal were age < 30 years and being single, divorced or separated at the time of vasectomy. Paternity was achieved after an estimated 53% of vasovasostomies. Successful reversal was more likely if the man was younger at vasectomy and the time elapsed was comparatively short. Compared with vasovasostomies performed in 1980-84, the success rate of those in 1994-96 was almost four times higher. CONCLUSION: Population rates of vasectomy are stable but the risk of seeking a reversal has increased. Outcomes after vasovasostomy have improved. Care should be taken during the counselling of men before vasectomy, and especially in those aged <30 years.     

A decision to end a periodic syphilis-screening program in the Kimberley region

Syphilis rates in the Kimberley region of far-northern Western Australia are among the highest in the nation. In 1986, a formal program of periodic syphilis screening was established. Decreasing syphilis rates since the early 1990s prompted, in 1999, re-evaluation of the value of periodic screening. All confirmed cases of syphilis identified in the Kimberley between January 1996 and early December 1999 as a result of syphilis serology were classified by reason for the test and staged according to disease progression. During the study period, 196 cases of syphilis (117 male, 79 female) were diagnosed; 14 (7.1%) were primary, 32 (16.3%) secondary and 150 (76.5%) latent. The periodic screening program contributed only about 10 per cent of cases, whereas testing as a result of sexually transmitted disease symptoms, sexually transmitted disease contact, institutional screening and other screening contributed the remaining cases. In January 2000, the periodic syphilis-screening program was discontinued. The effect of this policy change will be closely monitored using indicators to ensure that, should the decision not to screen prove to have been misjudged, any increase in syphilis incidence is detected early and managed appropriately.