PubMed Health⌕ Search

Biomedical subjects

Peter McIntyre

Publications and source records attributed to Peter McIntyre.

At least 19 recordsLinked to original sources
PubMed2006

The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif.

We have investigated the glycosylation, disulfide bonding, and subunit structure of mouse TRPM8. To do this, amino-terminal c-myc or hemagglutinin epitope-tagged proteins were incorporated and expressed in Chinese hamster ovary cells. These modifications had no obvious effects on channel function in intracellular calcium imaging assays upon application of agonists, icilin or menthol, and cold temperatures. Unmodified TRPM8 migrates with an apparent mass of 129 kDa and can be glycosylated in Chinese hamster ovary cells to give glycoproteins with apparent masses of 136 and 147 kDa. We identified two potential N-linked glycosylation sites in TRPM8 (Asn-821 and Asn-934) and mutated them to show that only the site in the putative pore region at position 934 is modified and that glycosylation of this site is not absolutely necessary for cell surface expression or responsiveness to icilin, menthol, and cool temperatures. Enzymatic cleavage of the carbohydrate chains indicated that they are complex carbohydrate. The glycosylation site is flanked in the pore by two cysteine residues that we mutated, to prove that they are involved in a conserved double cysteine motif, which is essential for channel function. Mutation of either of these cysteines abolishes function and forces the formation of a non-functional complex of the size of a homodimer. The double cysteine mutant is also non-functional. Finally, we showed in Perfluoro-octanoic acid-polyacrylamide gels that TRPM8 can form a tetramer (in addition to dimer and trimer forms), consistent with current thinking that functional TRP ion channels are tetrameric.

Amino Acid Motifs↗
PubMed2006

Higher pertussis hospitalization rates in indigenous Australian infants, and delayed vaccination.

This ecological study aimed to identify possible reasons for higher pertussis hospitalization rates in indigenous Australian infants. Two national datasets were analysed: the Hospital Morbidity Database and the Australian Childhood Immunisation Register (ACIR). Most (52%) pertussis hospitalizations in indigenous infants occurred at 0-2 months of age, and rates in these indigenous infants were significantly higher in remote areas. Indigenous infants had higher hospitalization rates and more frequently delayed vaccination than non-indigenous infants of the same age. These data suggest that residence in a remote area, as a proxy for poorer living conditions for indigenous people, and delayed vaccination, both contribute to higher pertussis hospitalization rates in indigenous infants.

Australia↗
PubMed2006

Vaccine preventable diseases and vaccination policy for indigenous populations.

Compared with nonindigenous people, indigenous people in first-world countries have experienced much higher rates of many vaccine preventable diseases. This systematic review of published scientific literature, government reports, and immunization guidelines from Australia, Canada, New Zealand, and the United States compares pre- and postvaccination disease rates and vaccination policy for indigenous people in these four countries. Nationally funded universal vaccination programs are clearly the most effective way of reducing disease in indigenous populations. Most successful have been programs for viral diseases in which strain variations are not important and herd immunity is high, such as measles and hepatitis B. For bacterial infections, strain variations (pneumococcal disease), heavy nasopharyngeal colonization of young infants (pneumococcal and Haemophilus influenzae type b disease), low vaccine effectiveness in adults with a high prevalence of risk factors (polysaccharide pneumococcal vaccine), and waning immunity (pertussis) have been associated with continuing or widening disparities between indigenous and nonindigenous populations. However, universal vaccination programs are not always possible. Geographic targeting of all persons in certain regions with high disease rates has been successful, as has targeting of indigenous populations in regions where they constitute larger proportions of the population. In national programs targeting only indigenous people, it has been difficult to achieve high coverage, particularly in urban areas. Innovative program approaches are particularly needed in these situations.

Australia↗
PubMed2006

Identification and biological characterization of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain.

Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.

Animals↗
PubMed2006

Vaccination for the paediatrician.

In most of Australia, general practitioners manage routine childhood vaccination schedules. However, paediatricians have an important role and need to have a thorough understanding of vaccination, particularly as it interfaces with other medical care. This is challenging as the Australian Standard Vaccination Schedule has undergone some substantial changes over the past 4 years, with the addition of meningococcal C conjugate, 7 valent pneumococcal conjugate, varicella and inactivated polio vaccines. Paediatricians are frequently the first port of call for advice on vaccination schedules for children with special needs, in relation to either vaccine efficacy or the risk of side effects. Categories include children with a range of chronic diseases, immunosuppression, premature infants and immigrant children. Advice about specific vaccines such as varicella, inactivated polio, influenza or multivalent vaccines and revaccination after adverse events is also often sought. The aim of this article is to update paediatricians on vaccination recommendations and relevant reference sources. The first part of this article discusses groups with special vaccination requirements. The second part discusses the use of individual vaccines in these children.

Adolescent↗
PubMed2006

Annual report: Surveillance of adverse events following immunisation in Australia, 2005.

This report summarises Australian passive surveillance data for adverse events following immunisation (AEFI) reported to the Adverse Drug Reactions Advisory Committee for 2005, and describes reporting trends over the six year period 2000 to 2005. There were 839 AEFI records for vaccines received in 2005. This is an annual AEFI reporting rate of 4.1 per 100,000 population, the lowest since 2000 and a 22 per cent decrease compared with 2004 (1,081 records; 5.4 AEFI records per 100,000 population). The decrease was not consistent across age groups. Reporting of AEFI increased for children aged <1 year in 2005 (60.7 versus 50.3 per 100,000 population) and decreased for the 7 to <20 year age group (0.9 versus 8.9 per 100,000 population). Dose-based AEFI reporting rates in 2005 were 11.0 per 100,000 doses of scheduled vaccines for children aged <7 years and 2.0 per 100,000 doses of influenza vaccine for adults aged >18 years. The majority of records described non-serious events while 9 per cent (n=72) described AEFIs defined as serious. There was one report of death in an older person following influenza vaccine and one of non-polio acute flaccid paralysis in an infant, both temporally associated with immunisation. The most frequently reported individual AEFI was injection site reaction in children following a fifth dose of diphtheria-tetanus-acellular pertussis vaccine (79 reports per 100,000 doses). The increase in the population-based AEFI reporting rate for children aged <1 year in 2005 coincided with the introduction of national immunisation programs for conjugate pneumococcal vaccine in January 2005 and inactivated poliovirus vaccine in November 2005. The fall in reporting rates for older children and adolescents follows the completion of the national meningococcal C catch-up program in early 2005. The consistently low reporting rate of serious AEFIs demonstrates the high level of safety of vaccines in Australia.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Should dexamethasone be part of routine therapy of bacterial meningitis in industrialised countries?

Two issues are clear from the data available regarding the current place of dexamethasone in routine management of suspected bacterial meningitis in industrialised countries. First, there is now good evidence of benefit from adjunctive dexamethasone therapy which is not confined to Hib meningitis, but in the case of pneumococcal meningitis probably requires that dexamethasone is given with or before, rather than after, parenteral antibiotics. In meningococcal meningitis, statistically significant benefit has not been demonstrated for any outcome, even in meta-analyses, but the point estimate is in the direction of benefit and failure to demonstrate an effect is more likely to be due to limited power from low event rates rather than no benefit; certainly there is no evidence of a detrimental effect. Most culture-negative cases of presumptive bacterial meningitis outside the neonatal period are likely to be due to one of the above 3 organisms. In the neonatal period or in some settings in developing countries, the spectrum of organisms is very different and extrapolation of these findings cannot be assumed. Second, the suggestion that dexamethasone is not applicable to certain subgroups in industrialised countries (such as cases not treated with cefuroxime, or some other sub-optimal therapy, or cases treated with vancomycin) (5) or that benefit only applies to hearing loss or Hib cases, either do not stand up to scrutiny or are not answerable from available data. What does this mean for clinical practice? The results of randomised controlled trials may not readily translate to clinical practice, particularly with respect to early commencement of steroids. The Sydney data show that in a representative developed country population with good access to services, after controlling for other prognostic variables, early corticosteroid therapy is associated with improved outcome. These data also show that deferred lumbar puncture is frequent and so criteria requiring presumptive identification of an organism are not practical to guide dexamethasone use, indeed those patients in whom lumbar puncture is deferred are more likely to have severe disease. This experience is an important addition to the findings from clinical trials of dexamethasone in pneumococcal meningitis in industrialised countries (5,6) as it demonstrates that adjunctive steroid therapy is beneficial in a 'real world' situation. In addition, the prospect of clinical trials in children, already limited by small case numbers, will be further reduced when the use of the conjugate pneumococcal vaccines is widespread. In Canada, a trend to decreasing use of corticosteroids was noted between 1991 and 1999, probably reflecting conflicting evidence. (16). Unless clear protocols are in place, the commencement of steroids before or with antibiotics will be difficult to implement in emergency situations, as illustrated by the data from Sydney.

Anti-Inflammatory Agents↗
PubMed2005

The population and reproductive health programme in Brazil 1990-2002: lessons learned.

The story of Brazil's evolution in sexual and reproductive health and rights during the 1990s documents not only a decade of change in the population field, but the powerful role of social movements in a democracy. Between October and December 2002, 23 people were interviewed about where they believe progress has been made in Brazil and where there are still needs in relation to population trends, sexual and reproductive rights, and health policies. This paper contains excerpts from the full report and covers the economic and political background of Brazil; the role of non-governmental and women's organisations in influencing the national agenda; the intersection of national and international agendas on population and development, HIV/AIDS, human rights, racism and other issues; changes in sexual and reproductive health policies; HIV/AIDS policy progress, perhaps most importantly mandatory free treatment for people with HIV/AIDS; recent progress in women's health, especially in relation to antenatal and obstetric services, and services addressing violence against women. Finally it describes the role of policy accountability mechanisms that aim to ensure that the many excellent policies that have been passed since 1990 are implemented in a decentralised health system of national, state and local management and services.

Brazil↗
PubMed2005

Antihyperalgesic activity of a novel nonpeptide bradykinin B1 receptor antagonist in transgenic mice expressing the human B1 receptor.

We describe the properties of a novel nonpeptide kinin B1 receptor antagonist, NVP-SAA164, and demonstrate its in vivo activity in models of inflammatory pain in transgenic mice expressing the human B1 receptor. NVP-SAA164 showed high affinity for the human B1 receptor expressed in HEK293 cells (K(i) 8 nM), and inhibited increases in intracellular calcium induced by desArg10kallidin (desArg10KD) (IC50 33 nM). While a similar high affinity was observed in monkey fibroblasts (K(i) 7.7 nM), NVP-SAA164 showed no affinity for the rat B1 receptor expressed in Cos-7 cells. In transgenic mice in which the native B1 receptor was deleted and the gene encoding the human B1 receptor was inserted (hB1 knockin, hB1-KI), hB1 receptor mRNA was induced in tissues following LPS treatment. No mRNA encoding the mouse or human B1 receptor was detected in mouse B1 receptor knockout (mB1-KO) mice following LPS treatment. Freund's complete adjuvant-induced mechanical hyperalgesia was similar in wild-type and hB(1)-KI mice, but was significantly reduced in mB1-KO animals. Mechanical hyperalgesia induced by injection of the B1 agonist desArg10KD into the contralateral paw 24 h following FCA injection was similar in wild-type and hB1-KI mice, but was absent in mB1-KO animals. Oral administration of NVP-SAA164 produced a dose-related reversal of FCA-induced mechanical hyperalgesia and desArg10KD-induced hyperalgesia in hB1-KI mice, but was inactive against inflammatory pain in wild-type mice. These data demonstrate the use of transgenic technology to investigate the in vivo efficacy of species selective agents and show that NVP-SAA164 is a novel orally active B1 receptor antagonist, providing further support for the utility of B1 receptor antagonists in inflammatory pain conditions in man.

Administration, Oral↗
PubMed2005

Cough symptoms in children aged 5-14 years in Sydney, Australia: non-specific cough or unrecognized pertussis?

OBJECTIVE: The aim of this study was to estimate the community prevalence of coughing symptoms, consistent with surveillance definitions for pertussis, and doctor-diagnosed pertussis in children aged 5-14 years. METHODOLOGY: A telephone survey of a cross-sectional community sample of parents regarding their child's cough symptoms in the previous 12 months was undertaken in a representative Australian urban region. RESULTS: In 2020 interviews, parents reported that 22% of children had a cough lasting 2 weeks or longer in the preceding 12 months, and 14% (283) had additional symptoms meeting the Centers for Disease Control (CDC) case definition for pertussis. A cough meeting the case definition was significantly more commonly reported by parents of children aged 5-9 years (17%; P < 0.001) but reported exposure to diagnosed pertussis in such cases was significantly more common in children aged 10-14 years (4.3%; odds ratio 12.8; P < 0.01). Parents of 90% of children meeting the CDC case definition sought medical advice. A diagnosis of pertussis was reported in only 1.2% of cases, which extrapolates to an annual incidence of doctor-diagnosed pertussis of 347/100,000 (95% confidence interval, 140-714 per 100,000). This contrasts with 29/100,000 notified cases in the same age group, time period and geographic area. CONCLUSION: Cough episodes meeting a clinical case definition for pertussis commonly used in surveillance are reported by a high proportion of carers of school-aged children in Australia. The majority of children who met the CDC and Australian case definitions for pertussis and sought medical attention were not identified as potentially having pertussis, suggesting underdiagnosis of pertussis. Even if less than half of this is true pertussis, the potential impact in terms of transmission of pertussis in the community is likely to be high. The reported incidence of doctor-diagnosed disease estimated from this survey was at least five and up to 20 times the official notification rate. More work needs to be done in raising awareness among medical practitioners of pertussis as a differential diagnosis in older children and adolescents with cough.

Adolescent↗
PubMed2004

Potent and orally bioavailable non-peptide antagonists at the human bradykinin B(1) receptor based on a 2-alkylamino-5-sulfamoylbenzamide core.

The bradykinin B(1) receptor is rapidly induced after inflammation or tissue trauma and appears to play an important role in the maintenance of hyperalgesia in inflammatory conditions. Here, we describe the optimization process to identify novel, potent non-peptide human B(1) receptor antagonists based on a 2-alkylamino-5-sulfamoylbenzamide core. Optimized derivatives are selective, functional B(1) antagonists with low nanomolar affinity and exhibit oral bioavailability in animals.

Administration, Oral↗
PubMed2004

Using computer simulations to compare pertussis vaccination strategies in Australia.

High levels of notified pertussis in adolescents and adults, persisting severe disease (hospitalization and deaths) in infants despite high childhood immunization coverage, together with the availability of adult-formulated pertussis vaccines, have made alternate strategies for vaccine control of pertussis an important issue in Australia. An age-structured computer simulation model was used to compare the likely effects of adopting different vaccination strategies in Australia on pertussis transmission by age group over a 50 year time period. Epidemiological parameters and vaccination coverage in Australia were estimated from previous pertussis modeling studies and existing data. In the simulations, replacing the pertussis booster at 18 months with a booster dose for adolescents at an age between 12 and 17 years, assuming 80% coverage, led to decreases in pertussis cases of 30% in children of ages 0-23 months (who have the highest complication rates) and of 25% in adolescents, but an increase of 15% in cases in 2-4-year-old children. The simulations did not suggest any shift of pertussis cases into the adult child-bearing years. Varying parameter values in the simulations in a series of sensitivity analyses showed the model predictions to be robust over a plausible range. The results of these simulations suggest that the recent change in the Australian pertussis vaccination schedule, replacing the 18 month dose with a pertussis booster in 15-17-year-old adolescents, is very likely to reduce overall pertussis incidence in Australia without increasing the cost of the current vaccine program.

Adolescent↗
PubMed2004

The cost-effectiveness of pneumococcal conjugate vaccination in Australia.

BACKGROUND: Pneumococcal conjugate vaccine, 7 valent (PCV7) is the most costly vaccine yet considered for publicly funded programs. In mid 2001, Australia funded PCV7 for high-risk groups only (indigenous children and children with certain underlying medical conditions). World wide, non-industry-funded studies and studies using cost-utility measures are sparse. We undertook an independent economic analysis of PCV7 compared with no vaccination in the non high-risk Australian childhood population using cost-utility and cost-effectiveness measures. METHODS: The incidence of invasive pneumococcal disease (IPD), non-bacteraemic pneumonia and otitis media was estimated using representative urban Australian data, or by extrapolation from comparable industrialised countries. A decision-analytic model was developed for a hypothetical birth cohort using the age-specific vaccine coverage from the Californian randomised controlled trial of PCV7. Health outcomes were measured by life-years saved and deaths and disability-adjusted life-years (DALYs) averted. In line with government guidelines, only direct costs were considered in 1997-1998 Australian dollars. RESULTS: For a birth cohort of 250,000, the gross cost of vaccination is $ 78.6 million. Subtracting treatment cost savings, the net cost (discounted) is $ 61.7 million. In undiscounted terms, vaccination prevents 13.7 deaths, 11.2 (82%) from IPD and the remainder from non-bacteraemic pneumonia. The discounted cost per death avoided is $ 5.0 million, per life-year saved $ 230,130 and per DALY averted $ 121,100, giving a break-even vaccine price of $ 15.40 per dose. These estimates are most sensitive to the unit cost per dose of vaccine, estimates of incidence and vaccine efficacy against non-bacteraemic pneumonia and the discount rate. The cost per DALY reduced to $ 81,000 with a discount rate of 3% rather than 5% and to $ 90,000 with the most favourable assumptions concerning pneumonia reduction. DISCUSSION: With a vaccine price of $ 90 per dose, mid-range estimates of impact against non-bacteraemic pneumonia, and discount rate of 5%, a PCV7 program for infants not at high risk of IPD is at the upper limit of cost per DALY previously approved under Australian pharmaceutical funding guidelines. The impact of PCV7 against non-bacteraemic pneumonia is poorly defined, but its importance to cost-effectiveness in resource rich and resource poor settings warrants further studies or analysis to give greater precision to this outcome.

Australia↗
PubMed2004

Identification of species-specific determinants of the action of the antagonist capsazepine and the agonist PPAHV on TRPV1.

The vanilloid receptor 1 (VR1 or TRPV1) ion channel is activated by noxious heat, low pH and by a variety of vanilloid-related compounds. The antagonist, capsazepine is more effective at inhibiting the human TRPV1 response to pH 5.5 than the rat TRPV1 response to this stimulus. Mutation of rat TRPV1 at three positions in the S3 to S4 region, to the corresponding human amino acid residues I514M, V518L, and M547L decreased the IC(50) values for capsazepine inhibition of the pH 5.5 response from >10,000 nm to 924 +/- 241 nm in [Ca(2+)](i) assays and increased capsazepine inhibition of the capsaicin response to levels seen for human TRPV1. We have previously noted that phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) is a strong agonist of rat TRPV1 but not human TRPV1 in [Ca(2+)](i) assays (1). Mutation of methionine 547 in S4 of rat TRPV1 to leucine, found in human TRPV1 (M547L), reduced the ability of PPAHV to activate TRPV1 by approximately 20-fold. The reciprocal mutation of human TRPV1 (L547M) enabled the human receptor to respond to PPAHV. These mutations did not significantly affect the agonist activity of capsaicin, resiniferatoxin (RTX) or olvanil in [Ca(2+)](i) assays. Introducing the equivalent mutation into guinea pig TRPV1 (L549M) increased the agonist potency of PPAHV by > 10-fold in the [Ca(2+)](i) assay and increased the amplitude of the evoked current. The rat M547L mutation reduced the affinity of RTX binding. Thus, amino acids within the S2-S4 region are important sites of agonist and antagonist interaction with TRPV1.

Amino Acid Sequence↗
PubMed2004

Phase 2 evaluation of parainfluenza type 3 cold passage mutant 45 live attenuated vaccine in healthy children 6-18 months old.

A phase 2 evaluation of live attenuated parainfluenza type 3 (PIV3)-cold passage mutant 45 (cp45) vaccine was conducted in 380 children 6-18 months old; 226 children (59%) were seronegative for PIV3. Of the 226 seronegative children, 114 received PIV3-cp45 vaccine, and 112 received placebo. No significant difference in the occurrence of adverse events (i.e., runny nose, cough, or temperature > or =38 degrees C) was noted during the 14 days after vaccination. There was no difference between groups in the occurrence of acute otitis media or serous otitis media. Paired serum samples were available for 109 of the seronegative vaccine recipients and for 110 of the seronegative placebo recipients; 84% of seronegative vaccine recipients developed a > or =4-fold increase in antibody titers. The geometric mean antibody titer after vaccination was 1 : 25 in the vaccine group and <1 : 4 in the placebo group. PIV3-cp45 vaccine was safe and immunogenic in seronegative children and should be evaluated for efficacy in a phase 3 field trial.

Acute Disease↗
PubMed2004

Steroids in adults with acute bacterial meningitis: a systematic review.

Bacterial meningitis is uncommon but causes significant mortality and morbidity, despite optimum antibiotic therapy. A clinical trial in 301 patients showed a beneficial effect of adjunctive steroid treatment in adults with acute community-acquired pneumococcal meningitis, but data on other organisms or adverse events are sparse. This led us to do a quantitative systematic review of adjunctive steroid therapy in adults with acute bacterial meningitis. Five trials involving 623 patients were included (pneumococcal meningitis=234, meningococcal meningitis=232, others=127, unknown=30). Overall, treatment with steroids was associated with a significant reduction in mortality (relative risk 0.6, 95% CI 0.4-0.8, p=0.002) and in neurological sequelae (0.6, 0.4-1, p=0.05), and with a reduction of case-fatality in pneumococcal meningitis of 21% (0.5, 0.3-0.8, p=0.001). In meningococcal meningitis, mortality (0.9, 0.3-2.1) and neurological sequelae (0.5, 0.1-1.7) were both reduced, but not significantly. Adverse events, recorded in 391 cases, were equally divided between the treatment and placebo groups (1, 0.5-2), with gastrointestinal bleeding in 1% of steroid-treated and 4% of other patients. Since treatment with steroids reduces both mortality and neurological sequelae in adults with bacterial meningitis, without detectable adverse effects, routine steroid therapy with the first dose of antibiotics is justified in most adult patients in whom acute community-acquired bacterial meningitis is suspected.

Acute Disease↗
PubMed2004

National study of infants hospitalized with pertussis in the acellular vaccine era.

BACKGROUND: In Australia in 1999 acellular pertussis vaccine (DTPa) replaced locally manufactured whole cell vaccine given at 2, 4 and 6 months of age with coverage of about 95% by 12 months of age. Few data are available on pertussis hospitalizations or sources of infection in countries exclusively using DTPa. METHODS: In 2001 national active monthly surveillance of infant hospitalizations for pertussis was conducted through the Australian Pediatric Surveillance Unit, which surveys all child health specialists monthly. A standard questionnaire was completed for notified cases. RESULTS: There were 140 infants reported (median age at diagnosis, 8 weeks). The rate of hospitalization in indigenous infants was significantly higher than in nonindigenous infants (P < 0.01). Of 97 (69%) infants who had not been vaccinated for pertussis, 63 (65%) were <8 weeks old (before the first scheduled dose of DTPa vaccine). Of 76 infants age > or =8 weeks, only 28 (37%) were appropriately immunized for age. Of 68 coughing contacts whose ages were known, 46 (68%) were adults, usually one of the infant's parents. Of 32 child contacts 16 (50%) were siblings. Four infants <6 weeks old died. CONCLUSION: Despite universal vaccination with DTPa in Australia, pertussis remains an important cause of hospitalization, morbidity and death in infants, most of whom were too young to be vaccinated or had missed vaccinations. The most common source of infection was a parent. Strategies to improve pertussis control in countries with high DTPa coverage could include adult-formulated booster pertussis vaccines for adolescents and recent parents and/or accelerated pertussis vaccine schedules for infants.

Australia↗