bluuebunny/crossref_metadata_2025 huggingface dataset:
RURAL AND REMOTE ORAL HEALTH, PROBLEMS AND MODELS FOR IMPROVEMENT: A WESTERN AUSTRALIAN PERSPECTIVE
Authors: Steele Lesley , Pacza Tom , Tennant Marc
Published: March 2003

Oral healthcare in rural communities shares many of the dilemmas faced by medicine in providing services to large geographical areas with dispersed populations. This study examined the population data and service provision data relevant to the geographical distribution of oral health care in Western Australia (WA). Of the 1.7 million people resident in WA, 72% were resident in the five major urban centres with only 13% in rural and remote regions. Of the 320 postcode regions, 186 had a population of less than 2500, 31 had a population from 2500 to 5000, 42 from 5000 to 10 000, 37 from 10 000 to 20 000, and 24 had a population greater that 20 000. Almost 80% of postcode regions with a population less than 2500 are in non‐urban regions. Of the total of 690 dentists who were analysed in this study, it was found that the vast majority (greater than 85%) worked in practices in postcode regions within metropolitan Perth or the major urban centres. A total of 43 postcode regions did not have a dental practice within their bounds. In order to address this disparity in service availability, strategies including the development of training for medical practitioners and auxiliaries, the use of modern technology, school‐based programs and the development of interdisciplinary links should be implemented. These strategies would also facilitate the development of closer links between medical and dental practitioners and the development of skills within the medical fraternity that would facilitate improved oral health in rural and remote communities.
Goal Attainment Scaling: An Effective Outcome Measure for Rural And Remote Health Services
Authors: Cox Ruth , Amsters Delena
Published: March 2003

Abstract: The aim of this paper is to demonstrate the utility of Goal Attainment Scaling (GAS) as an effective, multidisciplinary measure of client outcomes for rural and remote health services. Goal Attainment Scaling was adopted by the Spinal Outreach Team (SPOT) as a client‐focussed evaluation tool, as it is sensitive to the individual nature of clients’ presenting issues and the multidisciplinary focus of the team. It enables individualised goals to be set on a five‐point scale. Goal Attainment Scaling was introduced to the SPOT service after a pilot trial established guidelines for its effective implementation. An ongoing review process ensures that goal scaling remains realistic and relevant. Service outcomes can be effectively summarised using a frequency distribution of GAS scores. One of the important benefits of GAS is its facilitation of collaborative goal setting between clinician and client. Goal Attainment Scaling is recommended to rural and remote multidisciplinary health services because of its ability to summarise outcomes from heterogeneous service activities.
Demography and prognostic factors of ocular injuries in South India
Authors: Gothwal VK , Adolph S , Jalali S , Naduvilath TJ
Published: March 2003

Purpose: To evaluate the extent of visual recovery after multi‐disciplinary approach of treatment in serious ocular injuries; to determine the prognostic factors associated with poor final visual outcome and suggest adequate precautionary measures.

Methods: A retrospective analysis of 325 consecutive patients with direct ocular trauma who were examined and treated at a tertiary eye care centre in South India over a 3‐year period was undertaken.

Results: Males (86.8%) outnumbered the females (13.2%) and children (<16 years) constituted 46.8% of the total affected population. Anterior segment was involved in 51.1%, the posterior segment in 8.9% and both anterior and posterior segments were involved in 31.4% of patients. Prompt and meticulous surgical treatment restored useful vision (better than or equal to 6/18) in 60.5% of patients. Post‐treatment, a reduction in blindness and visual impairment rates in the affected eye with respect to WHO classification was 66.7 and 54.1% respectively (P < 0.0001). Two eyes needed prompt enucleation. The factors associated with visual impairment (visual acuity less than 6/18) were poor initial visual acuity, full chamber hyphema, endophthalmitis, retinal detachment, and vitreous haemorrhage.

Conclusions: Direct ocular trauma remains an important potentially preventable cause of ocular morbidity, but the advent of modern surgical techniques can often restore useful vision in such situations. Mandatory use of protective eye wear at work, public health education including awareness on the part of parents to the potential dangers of some childrens’ toys can to an extent help reduce ocular morbidity due to direct ocular trauma.
Predictors of 1-Year Outcome in Depression
Authors: Parker Gordon , Wilhelm Kay , Mitchell Philip , Gladstone Gemma
Published: March 2003

Objective: We compared several different methods for assessing depression ‘recovery’ over a 1-year review interval, to determine the utility of the contrasting approaches. Second, we assessed baseline predictors of 1-year outcome and recovery status. Third, we examined the extent to which predictors showed consistency across the variable definitions of outcome and recovery.

Methods: Twelve-month outcome was assessed in a sample of 182 subjects who at baseline assessment met DSM criteria for a major depressive episode. The contrasting methods involved a defined percentage reduction in Beck Depression Inventory self-rating scores, formalised change point definitions, no longer meeting DSM-IV major depression criteria, and clinical global improvement (CGI) ratings.

Results: Sixty-one per cent reached formalised change point criteria for full remission or recovery when trajectories across the 12-month interval were examined. Other measures quantified recovery rates ranging from 43% to 70%. Those with a psychotic or melancholic depression were more likely to have achieved recovery status in some analyses. Non-recovery at 12 months was predicted most consistently by higher baseline levels of anxiety and depression; high trait anxiety and a lifetime anxiety disorder; disordered personality function; and having reported exposure to acute and enduring stressors at baseline assessment.

Conclusions: While the CGI was the superior system in terms of number of significant discriminating predictors of outcome, the change point definitional approach provides much greater information across the follow-up interval, arguing for their complementary utility. As several currently identified baseline predictors of outcome (i.e. anxiety, disordered personality function) also predicted onset of depression, their relevance as both depression-inducing and depression-propagating variables is suggested.
PRIMARY MUCOSAL AND GLANS PENIS MELANOMAS: THE SYDNEY MELANOMA UNIT EXPERIENCE
Authors: Larsson K. B. M. , Shaw H. M. , Thompson J. F. , Harman R. C. , Mccarthy W. H.
Published: March 2003

Background: Melanomas that arise on mucosal surfaces and the glans penis are rare.

Methods: A retrospective study of the Sydney Melanoma Unit experience with 69 patients treated since 1956 for these types of melanomas was undertaken to determine primary lesion site, sex, age at diagnosis, symptoms, clinical stage at first presentation, histopathology, treatment and outcome.

Results: Primary lesion sites were: nasal cavity (n = 9), oral cavity (n = 16), vulva/vagina (n = 25), anus/rectum (n = 13) and glans penis (n = 6). At diagnosis, 55 patients had local disease only, eight had regional lymph node metastases and six had widespread disease. Local recurrence as the first sign of relapse developed in 15 of the 55 stage I patients (three‐stage system). Prognosis for the entire group was poor, only 10% being disease free 3 years after diagnosis and overall 3‐ and 5‐year actuarial survival being 40% and 23%, respectively. The only statistically significant factor influencing survival was stage of disease at diagnosis (P = 0.002).

Conclusions: Possible reasons for poor survival include: (i) non‐specific symptoms resulting in late presentation; (ii) locally advanced disease not being recognized by a clinician as a rare form of melanoma, resulting in a delay in treatment; (iii) anatomical constraints precluding surgery with generous margins and consequently resulting in a high incidence of local recurrence. Also, rich vascularity and multiple lymphatic drainage pathways may mean a predisposition to early dissemination. Prompt diagnosis and referral to a specialist unit for treatment and follow up are essential. Adequate surgery remains the cornerstone of treatment for these types of melanoma until more effective systemic therapies become available.
CLINICAL PATHWAY MANAGEMENT OF TOTAL KNEE ARTHROPLASTY: A RETROSPECTIVE COMPARATIVE STUDY
Authors: Pearson Sue , Moraw Irene , Maddern Guy J.
Published: March 2003

Background: Clinical pathways facilitate the management of defined patient groups using interdisciplinary plans of care. The aim of the present study was to evaluate the effectiveness of a clinical pathway in improving a range of selected outcome measures in patients who have undergone total knee arthroplasty (TKA).

Methods: The present study was conducted at Queen Elizabeth Hospital, Adelaide. Using a retrospective comparative study design, 119 TKA patients who were managed on a clinical pathway from July 1997 to January 1998 (group 2) were compared with a retrospective group of 58 patients who underwent the same procedure from July 1996 to January 1997 (group 1) prior to the pathway’s implementation. The following outcomes were measured: length of hospital stay; postoperative complications; readmissions and emergency service visits within 6 months of discharge; day of transfer to the convalescent unit; convalescent unit utilization and admission and discharge times.

Results: There was a significant reduction in the median length of stay in group 2 patients (9 vs 7 days; P < 0.0001). In addition there was a 66% increase in the proportion of patients in group 2 who were admitted on the day of surgery (P < 0.0001) and a 19.6% increase in the number of patients discharged within 8 postoperative days (P < 0.01). There were no significant differences between the groups with respect to the occurrence of postoperative complications. Although there was a trend toward a reduction in emergency service utilization and readmissions within 6 months of discharge for patients managed on the pathway, this was not significant.

Conclusions: The development and implementation of a TKA clinical pathway resulted in a significant reduction in length of stay and improved streamlining of admission, discharge and transfer processes without adversely affecting patient outcomes.
Jack Smyth: A major contribution to surgery
Authors: Wright J. E.
Published: March 2003

This personal comment records the contributions of the late Dr John Smyth and Royal Newcastle Hospital to surgical audit and surgical training. Smyth introduced surgical audit to this country against considerable professional opposition. The first publication on the subject appeared in The Medical Journal of Australia in 1959.
Surgical resection for pulmonary metastases from colorectal cancer
Authors: Moore K. H. , Mccaughan B. C.
Published: March 2003

Background: Isolated pulmonary metastases from colorectal cancer are rare. The present study reports on the 15‐year experience of the Royal Prince Alfred Unit and discusses means of improving survival outcomes.

Methods: This was a retrospective review, over a 15‐year period, of 41 patients who had resectable pulmonary metastases of colorectal origin.

Results: Most were asymptomatic at the time of diagnosis. Seventy‐two per cent had solitary metastases. The most common procedure performed was a lobectomy. Median follow up was 21 months. Five‐year survival was 24%. There were no significant prognostic indicators except for the ability to achieve clear surgical margins.

Conclusion: Morbidity and mortality have not altered significantly over time. But an improved selection process such as the use of preoperative positron emission tomography will potentially improve survival outcomes.
Arthroscopic subacromial decompression with a holmium:YAG laser: Review of the literature
Authors: Boult Maggi , Wicks Malcolm , Watson David I. , Macdougal Graeme , Shimmin Andrew , Maddern Guy J.
Published: March 2003

Background: The Australian Safety and Efficacy Register of New Interventional Procedures–Surgical (ASERNIP‐S) undertook to systematically review the literature regarding arthroscopic subacromial decompression (ASD) using a holmium:YAG laser for patients with impingement syndrome, with respect to the safety and efficacy of the procedure.

Methods: Studies on ASD with a holmium:YAG laser were identified using MEDLINE (1984 to July 2000), EMBASE (1974 to August 2000) and Current Contents (1993 to week 33 2000). A number of search terms were used: (laser and shoulder) and (surgery or arthroscop* or acromioplasty or orthopaed* or orthoped* or subacromial decompression or impingement syndrome). The Cochrane Library was searched from 1966 to issue 3 2000, using the search terms ‘shoulder and surgery’. Human studies were included for patients with impingement syndrome but without full‐thickness rotator cuff tears or rheumatological disorders, and where shoulder pain had been experienced for more than 3 months. A surgeon and reviewer independently assessed the retrieved articles for their inclusion in the review.

Results: Seven papers were identified that related to ASD with a holmium:YAG laser. None of the papers for review offered high‐quality evidence. There were no properly designed randomized controlled studies. The highest level of evidence came from time series studies. No quantitative analysis could be undertaken for this review.

Conclusions: Given the extremely low level of evidence available for this procedure it was recommended that further research be conducted to establish the safety and efficacy of the technique. This reinforces the conclusion reached in the Cochrane review of interventions for shoulder pain where insufficient evidence was found to either support or refute the efficacy of other interventions for shoulder pain.
Internal pancreatic fistulas with pancreatic ascites and pancreatic pleural effusions: Recognition and management
Authors: Kaman Lileswar , Behera Arunanshu , Singh Rajinder , Katariya Rabindra Nath
Published: March 2003

Background: Internal pancreatic fistulas are well recognized complications of chronic pancreatitis.

Methods: Six patients with internal pancreatic fistulas were treated over a period of 5 years from 1995 to 1999. Four patients presented with ascites, one patient presented with ascites and bilateral pleural effusion and the sixth patient presented with left‐sided pleural effusion. Five patients were chronic alcoholics and in one patient the cause of pancreatitis was not clear. Although the serum amylase was mildly elevated the levels of amylase in the aspirated fluid were consistently elevated (more than 800 Somogyi units/100 mL), along with the level of proteins (> 3 g/100 mL), and on this basis the diagnosis was made. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated pancreatic ductal disruption in four cases. Initial treatment was conservative, consisting of nasogastric aspiration, nil per oral, antisecretory drugs, repeated paracentesis or thoracocenthesis and total parenteral nutrition (TPN). In two patients nasopancreatic drains (NPD) were placed across the disrupted pancreatic duct.

Results: In one patient conservative treatment with NPD was successful, and the remaining five patients required surgical intervention. There was no mortality. Two patients developed surgery‐related complications that were successfully managed, but they required an extended hospital stay.

Conclusion: Internal pancreatic fistulas should be treated initially non‐operatively; if this is not effective, operative therapy should be considered without delay.
Determinants of pancreaticoenteric anastomotic leak following pancreaticoduodenectomy
Authors: Srivastava Sanjai , Sikora Sadiq S. , Pandey Chandra M. , Kumar Ashok , Saxena Rajan
Published: March 2003

Background: The purpose of the present paper was to study the incidence, presentation and management of pancreaticoenteric anastomotic (PEA) leak following pancreaticoduodenectomy (PD) and to identify risk factors associated with PEA leak.

Methods: One hundred and twenty patients underwent PD for benign and malignant pancreatic and periampullary lesions from 1989 to 1998. Prospectively collected data were analysed for incidence and outcome of PEA leak. Four clinical, three laboratory parameters, preoperative biliary drainage (PBD), perioperative octreotide use, nine intraoperative parameters, site of tumour and stage of malignant tumours were analysed by univariate and multivariate logistic regression analysis to identify factors influencing PEA leak.

Results: Pancreatic leak developed in 15 (12.5%) patients. Nine patients (60%) had a PEA leak that manifested as controlled leak through the drain. All were managed conservatively and the leak stopped after a mean duration of 17 days (range: 6–32 days). Six (40%) patients had associated intra‐abdominal complications, and three (50%) died in the postoperative period. Pancreatic fistula healed in the three remaining patients after a mean duration of 18 days (range: 15–25 days). Diabetes (P = 0.02; odds ratio (OR) = 4.60; 95% confidence interval (CI): 1.23–17.18), PBD (P = 0.03; OR = 4.82; 95% CI: 1.21–19.24), sequence of reconstruction (bilioenteric anastomosis as first anastomosis; P = 0.01; OR = 6.25; 95% CI: 1.45–26.83) and duration of surgery > 8 h (P = 0.01; OR: 5.61; 95% CI: 1.54–20.39) were associated with a significantly higher incidence of PEA leak.

Conclusion: Pancreaticoenteric anastomotic leak occurred in 12% of patients undergoing PD for pancreatic and periampullary tumours. The majority of these were uncomplicated and healed with conservative treatment. Complicated leaks were associated with high mortality. Diabetes mellitus, PBD, prolonged surgery and the sequence of reconstruction were risk factors associated with an increased incidence of PEA leak.
Measuring the outcome of occupational therapy: Tools and resources
Authors: Unsworth Carolyn
Published: March 2003

Current pressures to document outcomes and demonstrate the efficacy of occupational therapy intervention arise from fiscal restraints as much as from the humanitarian desire to provide the best quality health care to consumers. However, measuring outcomes is important in facilitating mutual goal setting, increasing the focus of therapy on the client, monitoring client progress, as well as demonstrating that therapy is valuable. The aims of this article are to provide the reader with an overview of what outcomes research is and to provide resources to aid the selection of outcomes assessments in a variety of practice areas. This article adopts the latest version of the World Health Organisation’s health classification system (International Classification of Impairments, Activities and Participation), as an organizing framework, and promotes the use of this framework when undertaking outcomes research.
Value of magnetic resonance myelography in the diagnosis of disc herniation and spinal stenosis
Authors: Pui Margaret H , Husen Yousuf A
Published: March 2003

Magnetic resonance imaging provides a good‐quality image over the entire length of the spine and can assess the morphology of the discs and cord. It is the imaging modality of choice in the investigation of spinal diseases. Magnetic resonance myelography (MRM) is non‐invasive, has comparable sensitivity to conventional myelography in visualizing lumbar nerve roots and allows overall assessment of the spinal canal even in the presence of cerebrospinal fluid block. Seventy‐two patients with pre‐surgical diagnosis of disc herniation were prospectively investigated prior to surgery to determine the value of MRM in the diagnosis of disc herniation and spinal stenosis. The difference between the sensitivity and accuracy of MRI (89.0–95.6%, 89.1–95.7%) and MRM (82.4–89.0%, 82.6–89.1%) was not significant for both observers. There was no significant improvement with the addition of MRM to MRI (91.2–97.8%, 91.3–97.8%). Although MRM did not significantly improve the diagnostic accuracy of MRI, it allowed a better overall view of the dural sac and root sleeves, therefore making it easier to diagnose spinal stenosis and disc herniation in a minority of cases.
Acute disseminated encephalomyelitis and multiple sclerosis: Magnetic resonance imaging differentiation
Authors: Singh Surendra , Prabhakar Subhashini , Korah Ipeson P , Warade Sanjay S , Alexander Mathew
Published: March 2003

The study was undertaken to compare the MR imaging features of acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) in a country with a high prevalence of ADEM. Magnetic resonance scans from 33 patients diagnosed clinically with MS (14 patients) or ADEM (19 patients) were reviewed concurrently by two radiologists blinded to the clinical diagnosis. The size, site, morphology and pattern of brain and spinal cord involvement were recorded and the MR imaging diagnosis was compared with the clinical diagnosis. The MR imaging findings matched with the clinical diagnosis in 11 of 14 patients with MS (sensitivity = 78.6%), and with the clinical diagnosis in 15 of 18 patients with ADEM (sensitivity = 78.9%). Three patients had non‐specific findings and in a further three patients discordant imaging features were present. One patient with imaging features typical of Balo’s concentric sclerosis was diagnosed clinically as suffering from ADEM. In a country with a high prevalence of ADEM, the majority of patients with ADEM and MS can be differentiated on MR imaging.
Atypical magnetic resonance imaging findings of craniopharyngioma
Authors: Wang Yi‐Xiang J , Jiang Hao , He Guo‐Xiang
Published: March 2003

Three cases of craniopharyngiomas with atypical MRI findings are reported. The first patient had a nasopharyngeal craniopharyngioma. Its unusual location made diagnosis difficult. The second patient had a massive craniopharyngioma with extensive cystic expansion, involving the anterior, middle and posterior cranial fossae, and extending into the foramen magnum. The tumour of the third patient involved the suprasellar region with a large extension into the third ventricle, and demonstrated a predominantly high signal intensity on all T1‐weighted, proton‐weighted and T2‐weighted images. These patients further stressed the complexity of MRI findings in craniopharyngiomas.
Small ureterocele‐like Gartner’s duct cyst associated with ipsilateral renal aplasia: A case report
Authors: Kalva S P , Rammurti S , Subbarao D , Chittibabu N , Murthy V Subbalakshmi
Published: March 2003

Gartner’s duct cyst associated with ipsilateral renal aplasia is a rare anomaly and fewer than 40 cases have been reported in the literature. A case of Gartner’s duct cyst presenting like an ureterocele on sonography, intravenous pyelography and CT are described.
Preoperative diagnosis of bilateral tuberculous epididymo‐orchitis following intravesical Bacillus Calmette–Guerin therapy for superficial bladder carcinoma
Authors: Muttarak Malai , Lojanapiwat Bannakij , Chaiwun Benjaporn , Wudhikarn Supot
Published: March 2003

We report a case of bilateral tuberculous epididymo‐orchitis following intravesical Bacillus Calmette–Guerin (BCG) therapy for superficial bladder carcinoma in which the diagnosis was made by ultrasonography prior to surgery. The US findings include heterogeneous enlargement of the epididymis and testis, associated with scrotal‐skin thickening and scrotal sinus track. Patients with bladder carcinoma treated with intravesical BCG therapy, the presence of scrotal swelling with scrotal‐skin thickening and epididymal involvement suggests tuberculous epididymo‐orchitis rather than testicular tumour. It is important to be aware of this rare complication and to be familiar with the ultrasonographic features so that appropriate treatment can be given.
2002 Australian Radiology Workforce Report
Authors: Jones DN
Published: March 2003

This paper describes the current status of radiologist provision in Australia, and explores issues relating to its current adequacy, as well as analysing projections of supply and requirements, and their balancing. Data are drawn from several sources including the results of the Royal Australian and New Zealand College of Radiologists Workforce Survey 2000, and the report of the Australian Medical Workforce Advisory Committee Radiology Working Party 2001. The main conclusions to be drawn are that: (i) there is a current shortfall of radiologist supply in Australia; (ii) future requirements (taking all factors into consideration) are expected to grow at a greater rate than projected supply (based on the status quo); and (iii) supply of radiologists should therefore be increased. These conclusions are roughly in line with those from other countries, such as the UK, Canada and USA. Radiologists practising in Australia also appear to have relatively high productivity, including by some international comparisons. These findings are presented in the context of current issues in Australian medical imaging, including provider consolidation and corporatization, globalization and funding.
Detection of aortoenteric fistula with helical CT
Authors: Puvaneswary M , Cuganesan R
Published: March 2003

We describe a case of a patient with symptoms suggestive of secondary aortoenteric fistula (AEF). Extravasation of contrast medium from the aorta into the lumen of the small bowel was definitive evidence of AEF. The role of abdominal CT performed without oral contrast is discussed.
LIVING IN THE COLD: FREEZE‐INDUCED GENE RESPONSES IN FREEZE‐TOLERANT VERTEBRATES
Authors: Storey Kenneth B
Published: March 2003

1. Winter survival for numerous cold‐blooded animals includes freeze tolerance: the ability to endure the conversion of as much as 65% of total body water into extracellular ice. Selected molecular adaptations underlying freeze tolerance (e.g. cryoprotectants, ice nucleating proteins) have been widely studied, but the full range of metabolic adjustments needed for freeze endurance remains unknown.

2. Recent studies using gene screening techniques are providing a different approach to the search for biochemical responses that support freezing survival by identifying genes and proteins that are up‐regulated by freezing or thawing in freeze‐tolerant amphibians and reptiles.

3. Screening of a cDNA library from wood frog liver revealed the freeze‐induced up‐regulation of genes coding for the α‐ and γ‐subunits of fibrinogen (a plasma clotting protein), the mitochondrial ADP/ATP translocase and a novel 10 kDa protein containing a nuclear exporting sequence.

4. Northern blotting revealed that these genes were differentially responsive to two of the component stresses of freezing (dehydration and anoxia), indicating that different genes are induced by signals radiating either from cell volume change or oxygen deprivation during freezing.

5. Freeze up‐regulation of fibrinogen synthesis in liver and other organs appears to be a damage repair response that anticipates a need for enhanced plasma clotting capacity to deal with ice crystal damage to capillary beds.

6. Up‐regulation of ADP/ATP translocase in frog liver is linked with ischaemia resistance and studies with freeze‐ tolerant turtles have shown that other genes encoding proteins involved in mitochondrial energetics (NADH‐ubiquinone oxidoreductase subunit 5, cytochrome C oxidase subunit 1) are also up‐regulated by both anoxia and freezing exposures.

7. These studies are making major advances in our understanding of freeze tolerance as a natural phenomenon and also highlight new key areas that can be targeted by applied interventions for the optimization of medical cryopreservation techniques for cells, tissues and organs.
ACUTE EXPOSURE TO A LOW LEVEL OF TESTOSTERONE IMPAIRS RELAXATION IN PORCINE CORONARY ARTERIES
Authors: Quan ADRIAN , Teoh HWEE , Man RICKY YK
Published: March 2003

1. While the gender bias associated with coronary artery disease has been suggested to be partially accounted for by the protective effects of oestrogens, the role of testosterone remains unclear. The aim of the present study was to determine whether vasorelaxation could be affected by acute administration of testosterone with and without 17β‐oestradiol.

2. Precontracted porcine coronary artery rings were relaxed with sodium nitroprusside (SNP), levcromakalim, bradykinin (BK) or A23187. At 1 nmol/L, testosterone impaired relaxations to BK and A23187, while the same concentration of 17β‐oestradiol potentiated levcromakalim‐ and SNP‐induced relaxations. The impairment of relaxation responses by testosterone was reduced in the presence of 17β‐oestradiol, while the enhancement by 17β‐oestradiol was decreased by testosterone.

3. We demonstrate that a low level of testosterone can impair agonist‐induced relaxation, an effect that is reduced by 17β‐oestradiol. This further supports evidence indicating a detrimental role for testosterone in coronary artery disease and suggests that circulating levels of testosterone may undermine the beneficial effects of oestrogen in women.
A Short History Of Nitroglycerine And Nitric Oxide In Pharmacology And Physiology
Authors: Marsh Neville , Marsh Alexander
Published: March 2003

1. Nitroglycerine (NG) was discovered in 1847 by Ascanio Sobrero in Turin, following work with Theophile‐Jules Pelouze. Sobrero first noted the ‘violent headache’ produced by minute quantities of NG on the tongue.

2. Constantin Hering, in 1849, tested NG in healthy volunteers, observing that headache was caused with ‘such precision’. Hering pursued NG (‘glonoine’) as a homeopathic remedy for headache, believing that its use fell within the doctrine of ‘like cures like’.

3. Alfred Nobel joined Pelouze in 1851 and recognized the potential of NG. He began manufacturing NG in Sweden, overcoming handling problems with his patent detonator. Nobel suffered acutely from angina and was later to refuse NG as a treatment.

4. During the mid‐19th century, scientists in Britain took an interest in the newly discovered amyl nitrite, recognized as a powerful vasodilator. Lauder Brunton, the father of modern pharmacology, used the compound to relieve angina in 1867, noting the pharmacological resistance to repeated doses.

5. William Murrell first used NG for angina in 1876, although NG entered the British Pharmacopoeia as a remedy for hypertension. William Martindale, the pharmaceutical chemist, prepared ‘. . . a more stable and portable preparation’: 1/100th of a grain in chocolate.

6. In the early 20th century, scientists worked on in vitro actions of nitrate‐containing compounds although little progress was made towards understanding the cellular mode of action.

7. The NG industry flourished from 1900, exposing workers to high levels of organic nitrites; the phenomena of nitrate tolerance was recognized by the onset of ‘Monday disease’ and of nitrate‐withdrawal/overcompensation by ‘Sunday Heart Attacks’.

8. Ferid Murad discovered the release of nitric oxide (NO) from NG and its action on vascular smooth muscle (in 1977). Robert Furchgott and John Zawadski recognized the importance of the endothelium in acetylcholine‐induced vasorelaxation (in 1980) and Louis Ignarro and Salvador Moncada identified endothelial‐derived relaxing factor (EDRF) as NO (in 1987).

9. Glycerol trinitrate remains the treatment of choice for relieving angina; other organic esters and inorganic nitrates are also used, but the rapid action of NG and its established efficacy make it the mainstay of angina pectoris relief.
AM424: History Of A Novel Drug Candidate
Authors: Kurek John
Published: March 2003

1. Leukaemia inhibitory factor (LIF) is a 180 amino acid single‐chain protein, named after its effect on haematopoietic cells. Leukaemia inhibitory factor belongs to a group of cytokines that includes ciliary neurotrophic factor, interleukin (IL)‐6, IL‐11, cardiotrophin‐1 and oncostatin M. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect.

2. Research over the past 6–8 years has shown LIF to have potent neuromuscular activity. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in enhancing the survival of both motor and sensory neurons, while reducing denervation‐induced muscle atrophy. In models of both axotomy induced neuronal death and in the wobbler mouse, LIF is active at doses as low as 1 μg/kg delivered systemically.

3. In muscle, LIF will increase the rate of muscle regeneration in vivo when applied exogenously after injury and will stimulate intrinsic muscle repair following its targeted release to dystrophic muscle in the mdx mouse. Leukaemia inhibitory factor may also have a role as an adjunct to myoblast transfer therapy, with studies showing that the transplantation of genetically competent myoblasts into mdx mouse muscle is enhanced when cells are injected with LIF.

4. Distribution and pharmacokinetic studies have been conducted in primates with doses of 20 μg/kg recombinant human LIF given subcutaneously over 2 weeks tolerated without major side effects.

5. A pharmaceutical form of recombinant human LIF (AM424; AMRAD Operations, Richmond, Victoria, Australia) entered human clinical trials during 1997 and a phase I clinical trial in healthy volunteers has been completed. A phase I repeat dose study has also been completed in cancer patients undergoing chemotherapy. The primary indication for a phase II study is the treatment of chemotherapy induced peripheral neuropathy. Other potential indications include muscle wasting diseases, acute nerve trauma and motor neuron disease.

6. The role of LIF in modulating nerve loss should make it an ideal candidate for the treatment of a number of neurological conditions. The phase I study represents the first trial in a programme for the clinical development of AM424.
Effects Of Tachykinin Receptor Agonists And Antagonists On The Guinea‐Pig Isolated Oesophagus
Authors: Kerr Karen P
Published: March 2003

1. Vagal nerve stimulation of the guinea‐pig isolated oesophagus produced a triphasic tetrodotoxin (TTX)‐sensitive contractile response. The third phase, which was resistant to ganglion blocking drugs, was selectively abolished by capsaicin, suggesting the involvement of one or more neuropeptides released from afferent neurons. Receptors on cholinergic neurons were subsequently activated because the response was atropine sensitive. Contractile responses resulting from exogenous substance P were abolished by atropine and TTX and enhanced by physostigmine. These findings suggest that the third phase may be mediated by the action of a substance P‐like neuropeptide released from sensory nerve endings that subsequently activated cholinergic neurons.

2. The tachykinin receptors in the body of the guinea‐pig oesophagus were characterized by determining the relative agonist potencies of natural tachykinins as well as tachykinin receptor‐selective analogues. Antagonist affinities were also determined. The results indicated the presence of both NK2 and NK3 receptors. In addition, the effects of a cocktail of peptidase inhibitors (captopril, thiorphan and amastatin) on responses to various tachykinins and synthetic analogues were determined. The results indicate that one or more peptidases are present in this preparation.

3. Experiments using various tachykinin receptor antagonists were performed to determine whether the activation of tachykinin receptors played a role in the mediation of the third phase of the response to vagal nerve stimulation. While this response was unaffected by NK1 and NK2 receptor‐selective antagonists, it was only partially inhibited (23%) by the NK3 receptor antagonist SR 142801. Thus, in the guinea‐pig oesophagus, it appears that NK3 receptors play only a minor role in mediating a contractile response when afferent neurons are excited by vagal nerve stimulation.
Proceedings of the Australian Physiological and Pharmacological Society Symposium: Ion Channels PREDICTING CHANNEL FUNCTION FROM CHANNEL STRUCTURE USING BROWNIAN DYNAMICS SIMULATIONS
Authors: Chung Shin‐Ho , Kuyucak Serdar
Published: March 2003

1. The transport process of ions across the potassium channel is studied using computer simulations. The shape of the model channel corresponds closely to that deduced from crystallography.

2. We first give an intuitive account of how the motion of ions experiencing an applied electric force and interacting with a dielectric boundary and charge residues on the channel wall can be simulated accurately by using a powerful supercomputer.

3. We then show how some of the salient features of ion channels can be deduced by following the positions of ions at each discrete step over many millions of time steps.
Effect Of Anti‐Oxidant Treatment And Cholesterol Lowering On Resting Arterial Tone, Metabolic Vasodilation And Endothelial Function In The Human Forearm: A Randomized, Placebo‐Controlled Study
Authors: Duffy Stephen J , O'Brien Richard C , New Gishel , Harper Richard W , Meredith Ian T
Published: March 2003

1. The aim of the present study was to determine whether anti‐oxidant therapy with vitamin E and/or cholesterol‐lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia.

2. Endothelium‐dependent and ‐independent, nitric oxide (NO)‐mediated vasodilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies suggest that vascular function may be improved with anti‐oxidant or cholesterol‐ lowering therapy, although these treatments may be synergistic.

3. We compared FBF at rest, in response to isotonic exercise, the endothelium‐dependent vasodilator acetylcholine (ACh), the endothelium‐independent vasodilator sodium nitroprusside (SNP) and the NO synthase inhibitor NG‐monomethyl‐L‐arginine (L‐NMMA) in 26 young, otherwise healthy volunteers (mean (±SD) age 29±7 years; 14 female, 12 male) with hypercholesterolaemia, before and after 6 months treatment with vitamin E, simvastatin and/or placebo. Treatment was randomized, double‐blinded in a 2 × 2 factorial design. Forearm blood flow was measured using venous occlusion plethysmography.

4. Vitamin E therapy increased plasma α‐tocopherol from 39.5±9.6 to 75.7±33.8 μmol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9±1.7 to 4.9±0.8 mmol/L and low‐ density lipoprotein (LDL) from 4.8±1.7 to 3.0±0.7 mmol/L (both P < 0.001), although total and LDL–cholesterol also decreased slightly in the placebo group. Vitamin E increased resting FBF from 2.1±0.3 to 2.4±0.3 mL/100 mL per min (P = 0.04) and decreased resting forearm vascular resistance from 42.1±4.2 to 36.1±3.4 units (P = 0.01), but the reduction in resting FBF with L‐NMMA was not affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin and in the combined vitamin E–simvastatin groups. NG‐Monomethyl‐L‐arginine infusion reduced resting FBF and functional hyperaemia in response to exercise and these responses were not altered by treatment.

5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subjects, these effects may not be via NO‐dependent pathways. Metabolic vasodilation and responses to the NO‐mediated vasodilators ACh and SNP were not favourably affected by anti‐oxidant or cholesterol‐lowering therapy, either alone or in combination.
Role Of Angiotensin Type 2 Receptors In Human Forearm Vascular Responses Of Normal Volunteers
Authors: Phoon Stephen , Howes Laurence Guy
Published: March 2003

1. It has been hypothesized that the expression of angiotensin (Ang) II type 2 (AT2) receptors may become important in vascular disease; however, the functional existence of AT2 receptors in normal adult humans remains to be established.

2. Vascular responses to AngII after the administration of the specific AT2 receptor antagonist PD 123319 were determined in the forearm circulation of normal volunteers.

3. PD 123319 (8 μg/min) did not alter basal forearm blood flow, or forearm blood flow or forearm vascular resistance responses to AngII.

4. These results suggest that AT2 receptors do not play a significant role in the regulation of forearm blood flow or forearm vascular resistance of normal volunteers, but do not preclude a role for AT2 receptors in other vascular beds or in patients with cardiovascular disease.
Involvement Of B‐50 (GAP‐43) Phosphorylation In The Modulation Of Transmitter Release By Protein Kinase C
Authors: Iannazzo L
Published: March 2003

1. Protein kinase C (PKC) is a family of enzymes that is activated by diacylglycerol (DAG) following phospholipase (PL) C activation. Protein kinase C may also be activated by metabolites and arachidonic acid generated by breakdown of membrane phospholipids by PLD and PLA2, respectively. Subsequent to PKC activation, key protein substrates are phosphorylated, resulting in the facilitation of transmitter release.

2. Phorbol esters are compounds that mimic the actions of DAG on PKC and have been shown to facilitate stimulation‐induced (S‐I) transmitter release in rat brain. However, some phorbol esters that have a high affinity for PKC have no effect on transmitter release, whereas others with a lower affinity for PKC markedly elevate S‐I transmitter release.

3. The structure and, more importantly, the lipophilicity of the phorbol esters determines their ability to access and activate the intraneuronal pools of PKC that are involved with transmitter release. In studies in which cell membranes were intact, phorbol esters did not display the characteristics expected based on their affinities for PKC in contrast with studies in disrupted synaptosomes. This supports the hypothesis that the membrane plays a critical role in determining the effects of phorbol esters on PKC.

4. B‐50, a PKC substrate thought to be involved in transmitter release, also appears to be differentially phosphorylated by various phorbol esters. The effects on B‐50 phosphorylation in intact synaptosomes, but not disrupted synaptosomes, are well correlated with the effects of phorbol esters on S‐I transmitter release.

5. B‐50 is colocalized with actin, which has also been suggested to play an important role in facilitating the movement of reserve pools of transmitter vesicles to the readily releasable state. Therefore, it is possible that the phosphorylation status of B‐50 directly influences the organization of actin filaments, thereby allowing transmitter output to be sustained under high levels of stimulation.
Role Of Arterial Smooth Muscle Tone And Geometry In The Regulation Of Peripheral Conduit Artery Mechanics By Shear Stress
Authors: Joannides Robinson , Costentin Agathe , Iacob Michaela , Bakkali El‐Hassan , Richard Marie‐Odile , Thuillez Christian
Published: March 2003

1. Although arterial blood flow is recognized as an important modulator of vascular tone and geometry, the effect of acute changes in shear‐stress on conduit artery mechanics has not been fully investigated in humans because of technical limitations.

2. To assess, respectively, the effects of decreases and increases in flow and shear stress on radial artery tone and mechanics, arterial pressure (photoplethysmography), total blood viscosity, radial artery internal diameter, wall thickness (echotracking) and blood flow (Doppler) were measured in healthy volunteers (mean (±SEM) age 25 ± 1 years) during a distal flow arrest (n = 12) and hand skin heating (n = 18).

3. Radial artery flow decreased from 31 ± 4 to 7 ± 1 10–3 L/min during distal flow arrest (P < 0.001) and increased from 10 ± 2 to 22 ± 4 and 69 ± 6 10–3 L/min during heating (P < 0.001). At mean arterial pressure, these changes in flow were respectively associated with a parallel flow‐dependent reduction and increase in diameter and midwall stress. There was no significant modification in mean elastic modulus. Compliance did not change when flow decreased and only increased at the highest level of flow. Finally, the cross‐sectional compliance and incremental modulus were fitted as functions of midwall stress. The decrease in flow was associated with an upward shift of the modulus–midwall stress curve and a downward shift of the compliance–midwall stress curve. The increase in flow was associated with a downward shift of the modulus–midwall stress curve and an upward shift of the compliance–midwall stress curve at each level of wall shear stress.

4. By using two different procedures, we obtained similar results concerning the direct effects of increases and decreases in flow on stiffness of the arterial wall and on arterial compliance and demonstrated the presence of a flow‐dependent regulation of arterial smooth muscle tone of peripheral conduit arteries in humans.
Protective Effect Of α‐LIPOIC Acid Against Ischaemic Acute Renal Failure In Rats
Authors: Takaoka Masanori , Ohkita Mamoru , Kobayashi Yutaka , Yuba Mikihiro , Matsumura Yasuo
Published: March 2003

1. In the present study, we investigated whether treatment with α‐lipoic acid (LA), a powerful and universal anti‐oxidant, has renal protective effects in rats with ischaemic acute renal failure (ARF).

2. Ischaemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Blood urea nitrogen (BUN), plasma concentrations of creatinine (Pcr) and urinary
osmolality (Uosm) were measured for the assessment of renal dysfunction.
Creatinine clearance (Ccr) and fractional excretion of Na+
(FENa) were used as indicators of glomerular and tubular function, respectively.

3. Renal function in ARF rats decreased markedly 24 h after reperfusion. Intraperitoneal injection of LA at a dose of 10 mg/kg before the occlusion tended to attenuate the deterioration of renal function. A higher dose of LA (100 mg/kg) significantly (P
< 0.01) attenuated the ischaemia/reperfusion‐induced increases in BUN (19.1 ±
0.7 vs 7.2 ± 0.7 mmol/L before and after treatment, respectively),
Pcr (290 ± 36 vs 78.1 ± 4.2 μmol/L
before and after treatment, respectively) and FENa (1.39 ±
0.3 vs 0.33 ± 0.09% before and after treatment, respectively).
Treatment with 100 mg/kg LA significantly (P < 0.01) increased Ccr
(0.70 ± 0.13 vs 2.98 ± 0.27 mL/min per kg before
and after treatment, respectively) and Uosm (474 ± 39 vs
1096 ± 80 mOsmol/kg before and after treatment, respectively).

4. Histopathological examination of the kidney of ARF rats revealed severe lesions. Tubular necrosis (P < 0.01), proteinaceous casts in tubuli (P <
0.01) and medullary congestion (P < 0.05) were significantly suppressed by the higher dose of LA.

5. A marked increase in endothelin (ET)‐1 content in the kidney after ischaemia/reperfusion was evident in ARF rats (0.43 ± 0.02 ng/g tissue) compared with findings
in sham‐ operated rats (0.20 ± 0.01 ng/g tissue). Significant attenuation
(P < 0.01) of this increase occurred in ARF rats treated with the higher
dose of LA (0.24 ± 0.03 ng/g tissue).

6. These results suggest that administration of LA to rats prior to development of ischaemic ARF prevents renal dysfunction and tissue injury, possibly through the suppression of overproduction of ET‐1 in the postischaemic kidney.