Search PubMed⌕ Search

Biomedical subjects

E J Beck

Publications and source records attributed to E J Beck.

At least 19 recordsLinked to original sources

Seasonal congestive heart failure mortality and hospitalisation trends, Quebec 1990-1998.

STUDY OBJECTIVE: To describe seasonal congestive heart failure (CHF) mortality and hospitalisations in Quebec, Canada between 1990-1998 and compare trends in CHF mortality and morbidity with those in France. DESIGN: Population cohort study. SETTING: Province of Quebec, Canada. PATIENTS: Mortality data were obtained from the Quebec Death Certificate Registry and hospitalisation from the Quebec Med-Echo hospital discharge database. Cases with primary ICD-9 code 428 were considered cases of CHF. RESULTS: Monthly CHF mortality was higher in January, declined until September and then rose steadily (p<0.05). Hospital admissions for CHF declined from May until September (moving averages analysis p<0.0001). Seasonal mortality patterns observed in Quebec were similar to those observed in France. CONCLUSION: CHF mortality in Quebec is highest during the winter and declines in the summer, similar to observations in France and Scotland. This suggests that absolute temperatures may not necessarily be that important but increased CHF mortality is observed once environmental temperatures fall below a certain "threshold" temperature. Alternatively better internal heating and warmer clothing required for survival in Quebec may ameliorate mortality patterns despite colder external environments.

Climate↗

Naively changing HAART.

BACKGROUND: Few UK studies have systematically investigated which antiretroviral therapy (ART) combinations HIV-infected people are commenced on, when they start and reasons for stopping or changing their regimens. OBJECTIVE: To describe when HIV-infected ART-naive patients started first-, second- or third-line triple ART, classes of drugs prescribed and whether stopping ART was associated with virological, immunological or clinical indicators of treatment failure. DESIGN: A multicentre prospective open cohort study, employing the National Prospective Monitoring System on the use, cost and outcome of HIV service provision in UK hospitals-HIV Health-economics Collaboration (NPMS-HHC). SETTING: Five hundred and eighty-five ART-naive patients seen in one London and two non-London HIV clinics between 1 January 1998 and 31 December 1999. RESULTS: Of 4,044 HIV-infected individuals seen, 585 (15%) were ART naive. Median time interval (interquartile range, IQR) between HIV diagnosis and starting triple ART was 800 (63-2,094) days. Median CD4 count when first diagnosed with HIV infection was 278 (IQR 127-481) cells/ micro L which dropped to 190 (IQR 86-297) cells/ micro L when starting triple ART. Of these 585 patients, 162 started second-line and 46 third-line ART during the study period. Of those patients who stopped ART, 51% did not have evidence of virological, immunological or clinical indicators of therapy failure. CONCLUSIONS: Reasons for the delay between diagnosis of HIV infection and starting ART are varied. The large proportion of individuals who stopped ART for reasons other than virological, immunological or clinical indicators of therapy failure, are most likely due to drug-associated toxicity. Both of these findings need to be elucidated in greater detail through prospective studies.

Adult↗

Changing trends in mortality and admissions to hospital for elderly patients with congestive heart failure in Montreal.

BACKGROUND: Congestive heart failure (CHF) is a common disease requiring admission to hospital among elderly people and is associated with a high mortality rate. The objective of this study was to examine trends in CHF mortality and admissions to hospital in Montreal between 1990 and 1997 for individuals aged 65 years or more. METHODS: We obtained information about deaths from the Quebec Death Certificate Registry database and information about admissions to hospital from the Quebec Med-Echo database. Patients with a primary diagnosis that was classified as ICD-9 code 428 were considered cases of CHF. RESULTS: Although age-adjusted rates of mortality from CHF did not change significantly between 1990 and 1997, the annual rate of admission to hospital for CHF increased from 92 per 10,000 population in 1990/91 to 124 per 10,000 population in 1997/98 (p < 0.01). Deaths due to CHF, expressed as a proportion of all cardiovascular deaths, increased among women from 5.6% in 1990 to 6.2% in 1997 (p = 0.01). The rate of readmission for all causes following a first admission for CHF during that year rose over the study period from 16.6% to 22.0% within one month (p < 0.001) and from 46.7% to 49.4% within 6 months (p = 0.03). Conversely, mean annual length of stay per admission decreased from 16.4 days in 1990/91 to 12.2 days in 1997/98. INTERPRETATION: The increase in rates of admission to hospital for CHF and the stable rates of CHF mortality suggest that the management of CHF and its antecedents has improved in recent years.

Aged↗

Kv4 channels exhibit modulation of closed-state inactivation in inside-out patches.

The mechanisms of inactivation gating of the neuronal somatodendritic A-type K(+) current and the cardiac I(to) were investigated in Xenopus oocyte macropatches expressing Kv4.1 and Kv4.3 channels. Upon membrane patch excision (inside-out), Kv4.1 channels undergo time-dependent acceleration of macroscopic inactivation accompanied by a parallel partial current rundown. These changes are readily reversible by patch cramming, suggesting the influence of modulatory cytoplasmic factors. The consequences of these perturbations were investigated in detail to gain insights into the biophysical basis and mechanisms of inactivation gating. Accelerated inactivation at positive voltages (0 to +110 mV) is mainly the result of reducing the time constant of slow inactivation and the relative weight of the slow component of inactivation. Concomitantly, the time constants of closed-state inactivation at negative membrane potentials (-90 to -50 mV) are substantially decreased in inside-out patches. Deactivation is moderately accelerated, and recovery from inactivation and the peak G--V curve exhibit little or no change. In agreement with more favorable closed-state inactivation in inside-out patches, the steady-state inactivation curve exhibits a hyperpolarizing shift of approximately 10 mV. Closed-state inactivation was similarly enhanced in Kv4.3. An allosteric model that assumes significant closed-state inactivation at all relevant voltages can explain Kv4 inactivation gating and the modulatory changes.

Allosteric Regulation↗

Assessing the cost-effectiveness of HAART for adults with HIV in England.

OBJECTIVE: To assess the cost-effectiveness of highly active antiretroviral therapy (HAART) compared with two nucleoside reverse transcriptase inhibitors (NRTIs) for HIV infected individuals. DESIGN: Different data sources on the clinical effects and costs of treatments were combined using a Markov model. SETTING: English HIV treatment centres. Perspective UK public finance. INTERVENTIONS: HAART - dual NRTI therapy plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor - vs. dual NRTI therapy. PARTICIPANTS: Hypothetical cohorts of 1000 individuals infected with HIV. Outcome measures Projected life expectancy, cost-effectiveness in UK pound per life-year saved and per quality-adjusted life-years (QALYs) saved. RESULTS: Assuming a 2-year additional treatment effect of therapy with HAART produced incremental cost-effectiveness ratios of pound14 602 per life-year saved and pound17 698 per QALY saved. CONCLUSIONS: The results were sensitive to a number of assumptions including the cost of HAART and the discount rate, but they suggest that the use of HAART in England is at least moderately cost-effective compared with treatment with two NRTIs alone.

Adult↗

The cost of HIV treatment and care. A global review.

This review of published studies on the costs of HIV treatment and care describes some of the recent developments that have influenced these costs in industrialised and industrialising countries, especially within the context of changing drug treatments. Some of the different approaches to estimating the economic impact of HIV infection are briefly presented. The methods used to review the literature are described, particularly the criteria of a scoring system that was specifically developed to systematically screen some of the studies identified. The mean review score for studies dealing with direct hospital costs increased significantly (p = 0.003) over the 3 periods analysed (before 1987, 1987 to 1995, and 1996 and beyond), indicating that the overall 'quality' of studies increased over time. All cost estimates, other than those from non-industrialised regions, were converted to 1996 US dollars using country-specific total health expenditure inflaters and country-specific Gross Domestic Product Purchasing Power Parity converters. A summary of hospital cost estimates over time and by region demonstrated that the costs of treating asymptomatic individuals and people with symptomatic non-AIDS increased over the period, but that the costs of treating individuals with AIDS appears to have stabilised since the late 1980s. As fewer studies could be identified on the costs of community and informal care, indirect productivity costs and population cost estimates, and costs of care for children with HIV infection, all of these studies were reviewed without the use of the scoring system. Finally, the discussion explores the evidence on the global costs of HIV in non-industrialised economies and the affordability of HIV treatment and care. Some suggestions for the direction of future HIV costing studies are also presented. A need remains for good quality cost data. Adequate research effort should be directed to improving the scope and quality of information on costs of HIV service provision around the world.

Adult↗

Cost effectiveness of expanded antenatal HIV testing in London.

BACKGROUND: Recently the Department of Health announced the introduction in England of voluntary universal HIV screening in early pregnancy to prevent vertical transmission. New data have shown the importance of HIV infection in infants born to mothers who were HIV-negative in early pregnancy and who acquired HIV later in pregnancy or during lactation. This requires consideration of repeat testing in late pregnancy and testing of partners of pregnant women (expanded antenatal HIV testing). OBJECTIVE: To estimate cost effectiveness of expanded antenatal HIV testing in London (England) within the framework of universal voluntary HIV screening in early pregnancy. DESIGN: Incremental cost-effectiveness analysis. METHODS: Cost estimates of service provision for HIV-positive children and adults by stage of HIV infection were combined with estimates of health benefits for infants and parents and with costs of counselling and testing (testing costs). In a pharmacoeconomic model cost effectiveness was estimated for expanded antenatal HIV testing in London for universal and selective strategies. RESULTS: Testing costs in the plausible range of pounds sterling 4 to pounds sterling 40 translate into favourable incremental cost-effectiveness estimates for expanded antenatal HIV testing in London which is already at low numbers of vertical transmissions averted per 100000 pregnant women who test HIV-negative in early pregnancy. Favourable cost effectiveness for universal expanded testing would require testing costs in the lower range, whereas selective expanded testing may produce favourable cost effectiveness at testing costs close to pounds sterling 40. CONCLUSION: Based on pharmaco-economic considerations, the authors believe that implementation of expanded HIV testing in London should be considered.

Adult↗

[Pharmaco-economic evaluation of mandatory HIV-screening in pregnancy; a cost-efficacy analysis in Amsterdam].

OBJECTIVE: To estimate the cost effectiveness of universal screening for HIV of pregnant women in Amsterdam. DESIGN: Pharmaco-economic model calculation. METHOD: An estimate was made of the minimal and maximal prevalences of undiagnosed HIV infection during pregnancy for the whole of Amsterdam, based on epidemiological data from observation among pregnant women in two Amsterdam hospitals and one obstetrical practice. The calculation was based on universal screening with an ELISA test. The interventions after screening comprised pharmacotherapy during pregnancy, delivery by caesarean section and breast-milk substitution. The issues of pharmaco-economic analysis were whether or not costs were reduced and net costs per year of life gained; the question was also studied at what lifetime costs of care for HIV infected children the net costs would be nil (costs equal benefits). RESULTS: Universal HIV screening in Amsterdam required a total investment of about Dfl 300,000.-per annum. In many of the analysed options for HIV screening the financial profits exceeded the investment. Variation of assumptions showed that the net costs of HIV screening under all conditions investigated would remain below Dfl 1,200.-per life year gained. CONCLUSION: Universal HIV screening of pregnant women in Amsterdam showed a favourable cost effectiveness. The calculations indicated a possibility of reducing costs.

Adult↗

Indirect cost of HIV infection in England.

BACKGROUND: Few studies have estimated the indirect costs of care for HIV infection in England by stage of infection at a population level. OBJECTIVE: This study estimated annual indirect costs of the HIV epidemic in England in 1997-1998 from both a public-sector and societal perspective. METHODS: Service costs for HIV-infected individuals were indexed to 1997-1998 English prices. Average annual indirect costs included the costs of statutory, community, and informal services; disability payments; and lost economic productivity by stage of HIV infection. Disability payments were excluded from the societal perspective, whereas the degree of lost economic productivity was varied for the sensitivity analyses. Total average annual indirect costs by stage of HIV infection were calculated, as were population-based costs by stage of HIV infection and overall population costs. RESULTS: Annual indirect costs from the public-sector and societal perspectives, respectively, ranged from pound sterling 3169 (dollars 5252) to pound sterling 3931 (dollars 6515) per person-year for asymptomatic individuals, pound sterling 5302 (dollars 8787) to pound sterling 7929 (dollars 13,140) for patients with symptomatic non-AIDS, and pound sterling 9956 (dollars 16,499) to pound sterling 21,014 (dollars 34,825) for patients with AIDS. Estimated population-based indirect costs from the public-sector perspective varied between pound sterling 109 million (dollars 181 million) and pound sterling 145 million (dollars 241 million) for 1997-1998, respectively, comprising between 58% and 124% of direct treatment costs for triple drug therapy in England during 1997. From the societal perspective, estimated population-based costs varied between pound sterling 84 million (dollars 138 million) and pound sterling 119 million (dollars 198 million) in 1997-1998, comprising between 45% and 102% of direct treatment costs and cost of care, respectively, during 1997. CONCLUSIONS: Average indirect costs increase as HIV-infected individuals' illness progresses. Whether one takes a public-sector or societal perspective, indirect costs add a considerable amount to the cost of delivering health care to HIV-infected individuals. Both direct and indirect costs, when obtainable, should be used to assess the economic consequences of HIV infection and treatment interventions.

Cost of Illness↗

Use and cost of hospital and community service provision for children with HIV infection at an English HIV referral centre.

OBJECTIVE: To describe the use of hospital and community services for children infected with HIV and estimate the cost per patient-year by stage of HIV infection during the era of antiretroviral monotherapy. DESIGN: Data on the use of hospital services were collected from case notes; the use of statutory and nonstatutory community services was recorded through diaries and interviews. Total cost estimates were calculated from unit costs from relevant hospital departments and community organisations. SETTING: Children managed at St. Mary's Hospital (London, England) between 1 January 1986 and 31 December 1994, some of whom used statutory and nonstatutory community services in South East England between 1 November 1994 and 31 May 1996. PATIENTS AND PARTICIPANTS: 118 children with positive HIV antibody status. MAIN OUTCOME MEASURES AND RESULTS: Mean inpatient days, outpatient visits, tests and procedures performed, drugs prescribed, community services used, associated unit costs and average cost estimates per patient-year by stage of HIV infection (1995/1996 values), and lifetime costs. Service provision during the study period was predominantly hospital-based. The use of services increased for different stages of HIV infection and increased with increasing severity of HIV infection. A shift from an inpatient-based to an outpatient-based service was seen between the periods 1986 to 1991 and 1992 to 1994. As symptoms evolved, children used more hospital inpatient services, with an accompanying shift in the use of community services from general services, such as schooling, to increased use of nurses, social care and home help. The estimated total cost of hospital and community care was 18,600 Pounds per symptomatic non-AIDS patient per year and 46,600 Pounds per AIDS patient per year. Similar estimates for children with indeterminate HIV infection and asymptomatic infection amounted to 8300 Pounds and 4800 Pounds per patient-year, respectively. Nondiscounted lifetime costs for hospital care amounted to 152,400 Pounds (44,300 Pounds to 266,800 Pounds) compared with discounted lifetime costs of 122,700 Pounds (42,000 Pounds to 182,200 Pounds); nondiscounted lifetime costs for community care amounted to 24,300 Pounds (7900 Pounds to 41,600 Pounds) compared with discounted lifetime costs of 21,000 Pounds (6800 Pounds to 32,000 Pounds). CONCLUSIONS: The continued emphasis on the use of hospital services may be due to the small number of children infected with HIV, most of whom lived in the London metropolitan area where specialist care was concentrated in a few centres. A shift from an inpatient- to an outpatient-based service was observed over time; the advent of the use of combination antiretroviral therapy in this population may further facilitate a shift in service provision and promote shared care between specialist centres, local hospital and community-based services.

Anti-HIV Agents↗

Decreased morbidity and use of hospital services in English HIV-infected individuals with increased uptake of anti-retroviral therapy 1996-1997. National Prospective Monitoring System Steering Group.

OBJECTIVE: To investigate the relationship between changing morbidity patterns, the use of hospital services by HIV-infected patients and the uptake of antiretroviral therapy (ART) in England. DESIGN: Prospective serial cross-sectional analyses based on data collected through the National Prospective Monitoring System (NPMS), a multi-centre prospective monitoring system. SETTING: HIV-infected patients seen in 10 clinics, five London and five non-London, during the three semesters, 1 January 1996 to 30 June 1997. MAIN OUTCOME MEASURES: The mean use of hospital services per patient-year, mean new HIV-related opportunistic illnesses per 1000 patient-years and percentage uptake of ART. RESULTS: The use of inpatient services changed particularly among AIDS patients. The mean number of inpatient days for AIDS patients decreased from 19.7 [95% confidence interval (CI) 13.7-25.7] in 1996 to 11.2 (95% CI 6.1-15.6) per patient-year in 1997. Concurrently the number of new AIDS-defining events decreased significantly from 567 (95% CI 529-607) to 203 (95% CI 183-225) per 1000 patient-years. The overall uptake of ART increased significantly from 33% (95% CI 31-35%) to 50% (95% CI 48-52%), and a switch from mono or dual to triple therapy or quadruple or more therapy was observed. However, by mid-1997 only 29% (95% CI 26-32%) of asymptomatic patients and 51% (95% CI 49-54%) of patients with symptomatic non-AIDS were on ART, compared with 69% (95% CI 66-71%) of AIDS patients. CONCLUSION: The observed reduction in new AIDS-defining events has led to a reduction in the need for inpatient hospital care and has been associated with an increased uptake of ART, including a switch to triple therapy. All of these factors are likely to have contributed to the observed reduction in mortality among English AIDS patients. As the overall uptake of ART remained relatively low in English centres further improvements can be anticipated. However, the medium to long-term effects of these treatment regimens will need to be closely monitored.

Anti-HIV Agents↗

Universal HIV screening of pregnant women in England: cost effectiveness analysis.

OBJECTIVE: To estimate the cost effectiveness of universal, voluntary HIV screening of pregnant women in England. DESIGN: Cost effectiveness analysis. Cost estimates of caring for HIV positive children were based on the stage of HIV infection and calculated using data obtained from a London hospital between 1986 and 1996. These were combined with estimates of the health benefits and costs of antenatal screening so that the cost effectiveness of universal, voluntary antenatal screening for HIV infection in England could be estimated. MAIN OUTCOME MEASURES: Lifetime, direct costs of medical care of childhood HIV infection; life years gained as a result of the screening programme; net cost per life year gained for different pretest counselling costs; and different prevalence rates of pregnant women who were unaware that they were HIV positive. RESULTS: Estimated direct lifetime medical and social care costs of childhood HIV infection were pound178 300 using a 5% discount rate for time preference (1995-6 prices). In high prevalence areas screening pregnant women for HIV is estimated to be a cost effective intervention with a net cost of less than pound4000 for each life year gained. For areas with comparatively low prevalence rates, cost effectiveness could be less than pound20 000 per life year gained, depending on the number of pregnant women who are unaware that they are infected and local screening costs. CONCLUSIONS: Our results confirm recent recommendations that universal, voluntary antenatal HIV screening should be implemented in the London area. Serious consideration of the policy should be given for other areas in England depending on local prevalence and screening costs.

AIDS Serodiagnosis↗

Changing sexual attitudes and behaviour in China: implications for the spread of HIV and other sexually transmitted diseases.

In Imperial China sexual behaviour was regarded as an indispensable activity to reach harmony with the universe, through the unity of the interaction of two opposing forces: yin and yang. Sexual intercourse was accepted when linked to procreation within a family context, while an individual's sexuality was not considered important. Homosexuality was tolerated although not advocated, while masturbation was denounced. Since the One Child Family and Open Door policies in the 1970s and the economic reforms of the 1980s, attitudes towards sexuality in China have changed. Premarital sex has become widely accepted among young people and people in China are now more tolerant toward extramarital sex. Nowadays young people consider that love should dominate marriage and the quality of an individual's sex life is currently more valued than it used to be. Attitudes towards masturbation have become more tolerant and though homosexuality has been hidden by society for a long time, in recent years it has begun to be considered as a legitimate lifestyle choice. Attitudes towards sex and sexual behaviour have become recognized as an individuals' responsibility as long as no offence occurs against society or the interests of other individuals, resulting in the recognition of diversity of sexual behaviour. As part of the changing attitudes to sex and sexual behaviour, heterosexual transmission is becoming the most important route of HIV transmission in China. This is complicated by the internal migration of an estimated 120 million labourers moving from the countryside to the cities as the result of economic reforms, most of whom are sexually active young men. Unless addressed directly, these factors may add to the estimated 300,000 HIV-infected Chinese, further fuelling an already rapidly spreading epidemic. The ramifications of the Chinese HIV epidemic will not only be felt within China, but also within the surrounding Asian countries thereby fuelling the HIV pandemic.

Attitude to Health↗

Patient satisfaction with HIV service provision in NPMS hospitals: the development of a standard satisfaction questionnaire. NPMS Steering Group.

A self-completion satisfaction questionnaire evaluating the standard of care of HIV outpatient services was developed as part of the National Prospective Monitoring System on the Use, Cost and Outcome of HIV Service Provision in English Hospitals (NPMS). The questionnaire was designed in conjunction with service users and health care professionals, and piloted in three London and three non-London HIV clinics. In addition to testing alternative methods of administering the questionnaire, the pilot provided satisfaction scores on a variety of aspects of service provision for participating clinics. The questionnaire was completed by 548 respondents and was most effectively collected using a sealed box in the clinic waiting area. Mean satisfaction scores for the attitude and skills of staff members was 4.7 (95% CI 4.6-4.7) but satisfaction scores were significantly lower for the clinic environment with a mean of 4.1 (95% CI 4.1-4.2). Satisfaction scores did not differ significantly by gender, age, sexual orientation, ethnic group, employment status or severity of symptoms. London respondents were more satisfied with the clinic environment and seeing preferred members of staff than their non-London counterparts, however there were no other differences between clinics. The questionnaire functioned well in practice and provided meaningful and useful information for individual clinics as well as at aggregate level.

Acquired Immunodeficiency Syndrome↗

What is the cost of getting the price wrong?

BACKGROUND: The objective of this study was to compare differences in cost estimates for paediatric HIV hospital service provision based on hospital prices with cost estimates obtained through a research-based service-specific costing exercise. METHODS: Activity data on the use of hospital services of children by stage of HIV infection were collected from case-notes for 118 HIV antibody positive children, managed at St Mary's Hospital NHS Trust, London, 1 January 1986-31 December 1994. Hospital unit prices were obtained from the Hospital Trust Finance Department; unit cost estimates were obtained from relevant hospital departments through a research-based service-specific costing exercise. Financial data related to the 1993-1994 financial year, and were indexed to 1995-1996 prices. The main outcome measures were cost estimates per patient-year by stage of HIV infection. Three cost scenarios were calculated: first by linking activity data with hospital prices (Trust Prices); second by linking activity data with routinely available hospital prices plus units costs from the costing exercise where no relevant hospital prices existed (Supplemented Trust Prices); third, by linking activity data exclusively with unit costs from the hospital-specific costing exercise (Unit Costs). RESULTS: There were substantial differences between unit cost estimates per patient-year based on Trust Prices and Supplemented Trust Prices compared with those based on Unit Costs. Differences increased with more intense use of services. The deficit based on Trust Prices compared with Unit Costs ranged from Pound Sterling 432 per patient-year for HIV negative children, Pound Sterling 574 for asymptomatic HIV-infected children, Pound Sterling 1288 for indeterminate children, Pound Sterling 1814 for children with symptomatic non-AIDS to Pound Sterling 7418 per patient-year for children with AIDS. CONCLUSIONS: In this hospital, reliance on generic hospital prices to derive cost estimates for paediatric HIV services produced considerable underestimates of the cost of service provision compared with data derived through the costing exercise. If this occurs across all or most areas of service provision, this can lead to substantial financial deficits, which in turn may mean that the needs of specific client populations may not be met.

Bias↗

Interactions between multiple phosphorylation sites in the inactivation particle of a K+ channel. Insights into the molecular mechanism of protein kinase C action.

Protein kinase C inhibits inactivation gating of Kv3.4 K+ channels, and at least two NH2-terminal serines (S15 and S21) appeared involved in this interaction (. Neuron. 13:1403-1412). Here we have investigated the molecular mechanism of this regulatory process. Site-directed mutagenesis (serine --> alanine) revealed two additional sites at S8 and S9. The mutation S9A inhibited the action of PKC by approximately 85%, whereas S8A, S15A, and S21A exhibited smaller reductions (41, 35, and 50%, respectively). In spite of the relatively large effects of individual S --> A mutations, simultaneous mutation of the four sites was necessary to completely abolish inhibition of inactivation by PKC. Accordingly, a peptide corresponding to the inactivation domain of Kv3.4 was phosphorylated by specific PKC isoforms, but the mutant peptide (S[8,9,15,21]A) was not. Substitutions of negatively charged aspartate (D) for serine at positions 8, 9, 15, and 21 closely mimicked the effect of phosphorylation on channel inactivation. S --> D mutations slowed the rate of inactivation and accelerated the rate of recovery from inactivation. Thus, the negative charge of the phosphoserines is an important incentive to inhibit inactivation. Consistent with this interpretation, the effects of S8D and S8E (E = Glu) were very similar, yet S8N (N = Asn) had little effect on the onset of inactivation but accelerated the recovery from inactivation. Interestingly, the effects of single S --> D mutations were unequal and the effects of combined mutations were greater than expected assuming a simple additive effect of the free energies that the single mutations contribute to impair inactivation. These observations demonstrate that the inactivation particle of Kv3.4 does not behave as a point charge and suggest that the NH2-terminal phosphoserines interact in a cooperative manner to disrupt inactivation. Inspection of the tertiary structure of the inactivation domain of Kv3.4 revealed the topography of the phosphorylation sites and possible interactions that can explain the action of PKC on inactivation gating.

Amino Acid Sequence↗