The Australian mortality decline: cause-specific mortality 1907-1990

This review describes the changes in composition of mortality by major attributed cause during the Australian mortality decline this century. The principal categories employed were: infectious diseases, nonrheumatic cardiovascular disease, external causes, cancer,'other' causes and ill-defined conditions. The data were age-adjusted. Besides registration problems (which also affect all-cause mortality) artefacts due to changes in diagnostic designation and coding-are evident. The most obvious trends over the period are the decline in infectious disease mortality (half the decline 1907-1990 occurs before 1949), and the epidemic of circulatory disease mortality which appears to commence around 1930, peaks during the 1950s and 1960s, and declines from 1970 to 1990 (to a rate half that at the peak). Mortality for cancer remains static for females after 1907, but increases steadily for males, reaching a plateau in the mid-1980s (owing to trends in lung cancer); trends in cancers of individual sites are diverse. External cause mortality declines after 1970. The decline in total mortality to 1930 is associated with decline in infection and 'other' causes, Stagnation of mortality decline in 1930-1940 and 1946-1970 for males is a consequence of contemporaneous movements in opposite directions of infection mortality (decrease) and circulatory disease and cancer mortality (increase). In females, declines in infections and 'other' causes of death exceed the increase in circulatory disease mortality until 1960, then stability in all major causes of death to 1970. The overall mortality decline since 1970 is a consequence of a reduction in circulatory disease,'other' cause, external cause and infection mortality, despite the increase in cancer mortality (for males).

Targeting of a cholecystokinin-DNA complex to pancreatic cells in vitro and in vivo

The carboxy terminal octapeptide of cholecystokinin (CCK8) is a hormone that binds high affinity receptors in a number of tissues including pancreas and pancreatic tumours. As part of our studies to develop effective gene therapy for the treatment of pancreatic cancers, we have investigated various gene delivery systems that depend on CCK8 receptor targeting. In this paper,we describe the synthesis of a CCK8-DNA complex designed to deliver foreign DNA to cholecystokinin receptor-positive cells. CCK8 was ligated to avidin and then complexed to linearis biotinylated DNA (pSV-CAT). The uptake of P-32-labelled CCK8-DNA complex by rat pancreatic acini was linear with time over 4 h with 65-70% of uptake inhibited by 100 nM CCK8. The complex appeared to be internalised since it could not be removed by acid wash. When administered intra-arterially, the complex was rapidly removed from the circulation with no evidence of targeted delivery to the pancreas, However, following a single intraperitoneal dose, the pancreas accumulated-5- 8% of the total administered complex by 24 h. These results suggest that peptide-dependent gene delivery to CCK receptor positive cells in vivo is feasible but, when administered directly into the circulation, diffusional barriers across the endothelium may limit distribution to peripheral tissues. Intraperitoneal administration therefore may be a useful alternative for targeting the pancreas.

Sequence heterogeneity in Parkinsonian speech

Parkinson's disease (PD) is a neurodegenerative movement disorder primarily due to basal ganglia dysfunction. While much research has been conducted on Parkinsonian deficits in the traditional arena of musculoskeletal limb movement, research in other functional motor tasks is lacking. The present study examined articulation in PD with increasingly complex sequences of articulatory movement. Of interest was whether dysfunction would affect articulation in the same manner as in limb-movement impairment. In particular, since very Similar (homogeneous) articulatory sequences (the tongue twister effect) are more difficult for healthy individuals to achieve than dissimilar (heterogeneous) gestures, while the reverse may apply for skeletal movements in PD, we asked which factor would dominate when PD patients articulated various grades of artificial tongue twisters: the influence of disease or a possible difference between the two motor systems. Execution was especially impaired when articulation involved a sequence of motor program heterogeneous in terms of place of articulation. The results are suggestive of a hypokinesic tendency in complex sequential articulatory movement as in limb movement. It appears that PD patients do show abnormalities in articulatory movement which are similar to those of the musculoskeletal system. The present study suggests that an underlying disease effect modulates movement impairment across different functional motor systems. (C) 1998 Academic Press.

Th2-type CD4(+) cells neither enhance nor suppress antitumor CTL activity in a mouse tumor model

Many cervical cancers express the E7 protein of human papillomavirus 16 as a tumor-specific Ag (TSA). To establish the role of E7-specific T cell help in CD8(+) CTL-mediated tumor regression, C57BL/6J mice were immunized with E7 protein or with a peptide (GF001) comprising a minimal CTL epitope of E7, together with different adjuvants, Immunized mice were challenged with an E7-expressing tumor cell line, EL4.E7. Growth of EL4.E7 was reduced following immunization with E7 and Quil-A (an adjuvant that induced a Th1-type response to E7) or with GF001 and Quil-A, Depletion of CD8(+) cells, but not CD4(+) cells, from an immunized animal abrogated protection, confirming that E7-specific CTL are necessary and sufficient for TSA-specific protection in this model. Immunization with E7 and Algammulin (an alum-based adjuvant) induced a Th2-like response and provided; no tumor protection. To investigate whether a Th2 T helper response to E7 could prevent the development of an E7-specific CTL-mediated protection, mice were simultaneously immunized with E7/Algammulin and GF001/Quil-A or, alternatively, were immunized with GF011/Quil-A 8 wk after immunization with E7/Algammulin, Tumor protection was observed in each case. We conclude that an established Th2 response to a TSA does not prevent the development of TSA-specific tumor protective CTL.

Simplifying the molecular mechanisms of human papillomavirus

The human papillomaviruses (HPVs) are associated with several human epithelial diseases. These diseases are confined to cutaneous and mucosal epithelia and comprise papillomas (warts) and benign or malignant neoplasms. Globally, infection by HPVs presents a considerable health problem given that at any one time approximately 10% of the population may have warts of one form or another. Of more serious concern is the prevalence of HPV-associated cervical carcinoma. It is estimated that 500,000 new cases of cervical neoplasia are diagnosed per year (primarily squamous carcinomas). Thus, HPV-associated cancer represents one of the most common cancers afflicting women and is one of the three most common causes of cancer death among women globally.(15) Although some genotypes of human papillomaviruses are clearly associated with the development of cancer (in particular, HPVs 16 and 18) these viruses share significant structural and functional similarity to the nononcogenic genotypes, and one of the puzzles of HPV biology is why essentially similar viruses vary so widely in their oncogenic potential.

Predictors of local recurrence after treatment of ductal carcinoma in situ - A meta-analysis

lBACKGROUND. Management of patients with ductal carcinoma in situ (DCIS) is a dilemma, as mastectomy provides nearly a 100% cure rate but at the expense of physical and psychologic morbidity. It would be helpful if we could predict which patients with DCIS are at sufficiently high risk of local recurrence after conservative surgery (CS) alone to warrant postoperative radiotherapy (RT) and which patients are at sufficient risk of local recurrence after CS + RT to warrant mastectomy. The authors reviewed the published studies and identified the factors that may be predictive of local recurrence after management by mastectomy, CS alone, or CS + RT. METHODS. The authors examined patient, tumor, and treatment factors as potential predictors for local recurrence and estimated the risks of recurrence based on a review of published studies. They examined the effects of patient factors (age at diagnosis and family history), tumor factors (sub-type of DCIS, grade, tumor size, necrosis, and margins), and treatment (mastectomy, CS alone, and CS + RT). The 95% confidence intervals (CI) of the recurrence rates for each of the studies were calculated for subtype, grade, and necrosis, using the exact binomial; the summary recurrence rate and 95% CI for each treatment category were calculated by quantitative meta-analysis using the fixed and random effects models applied to proportions. RESULTS, Meta-analysis yielded a summary recurrence rate of 22.5% (95% CI = 16.9-28.2) for studies employing CS alone, 8.9% (95% CI = 6.8-11.0) for CS + RT, and 1.4% (95% CI = 0.7-2.1) for studies involving mastectomy alone. These summary figures indicate a clear and statistically significant separation, and therefore outcome, between the recurrence rates of each treatment category, despite the likelihood that the patients who underwent CS alone were likely to have had smaller, possibly low grade lesions with clear margins. The patients with risk factors of presence of necrosis, high grade cytologic features, or comedo subtype were found to derive the greatest improvement in local control with the addition of RT to CS. Local recurrence among patients treated by CS alone is approximately 20%, and one-half of the recurrences are invasive cancers. For most patients, RT reduces the risk of recurrence after CS alone by at least 50%. The differences in local recurrence between CS alone and CS + RT are most apparent for those patients with high grade tumors or DCIS with necrosis, or of the comedo subtype, or DCIS with close or positive surgical margins. CONCLUSIONS, The authors recommend that radiation be added to CS if patients with DCIS who also have the risk factors for local recurrence choose breast conservation over mastectomy. The patients who may be suitable for CS alone outside of a clinical trial may be those who have low grade lesions with little or no necrosis, and with clear surgical margins. Use of the summary statistics when discussing outcomes with patients may help the patient make treatment decisions. Cancer 1999;85:616-28. (C) 1999 American Cancer Society.

Dysmorphogenesis in psychosis: Quantitative and qualitative measures involving the head and face

In this study, we examined qualitative and quantitative measures involving the head and face in a sample of patients and well controls drawn from the Brisbane Psychosis Study. Patients with psychosis (n=310) and age and sex-matched controls (n=303) were drawn from a defined catchment area. Features assessed involved hair whorls (position, number, and direction), eyes (epicanthus), supraorbital ridge, ears (low set, protrusion, hypoplasia, ear lobe attachment, asymmetry, helix width), and mouth (palate height and shape, palate ridges, furrowed and bifid tongue). Quantitative measures related to skull size (circumference, width and length) selected facial heights and depths. The impact of selected risk factors (place and season of birth, fathers' occupation at time of birth, selfreported pregnancy and birth complications, family history) were examined in the entire group, while the association between age of onset and dysmorphology was assessed within the patient group. Significant group (cases versus controls) differences included: patients had smaller skull bases, smaller facial heights, larger facial depths, lower set and protruding ears, different palate shape and fewer palate ridges. In the entire sample significant associations included: (a) those with positive family history of mental illness bad smaller head circumference, cranial length and facial heights; (b) pregnancy and birth complications was associated with smaller facial beights: (c) larger head circumference was associated with higher ranked fathers' occupations at birth. Within the patient group, age of onset was significantly lower in those with more qualitative anomalies or with larger facial heights. The group differences were not due to outliers or distinct subgroups, suggesting that the factors responsible for the differences may be subtle and widely dispersed in the patient group. The Stanley Foundation supported this project.

Localization of N-acetyltransferases NAT1 and NAT2 in human tissues

Human acetyl coenzyme A-dependent N-acetyltransferase (EC 2.3.1.5) (NAT) catalyzes the biotransformation of a number of arylamine and hydrazine compounds. NAT isozymes are encoded at 2 loci; one encodes NAT1, formerly known as the monomorphic form of the enzyme, while the other encodes the polymorphic NAT2, which is responsible for individual differences in the ability to acetylate certain compounds. Human epidemiological studies have suggested an association between the acetylator phenotype and particular cancers such as those of the bladder and colon. In the present study, NAT1- and NAT2-specific riboprobes were used in hybridization histochemistry studies to localize NAT1 and NAT2 mRNA sequences in formalin-fixed, paraffin-embedded human tissue sections. Expression of both NAT1 and NAT2 mRNA was observed in liver, gastrointestinal tract tissues (esophagus, stomach, small intestine, and colon), ureter, bladder, and lung. In extrahepatic tissues, NAT1 and NAT2 mRNA expression was localized to intestinal epithelial cells, urothelial cells, and the epithelial cells of the respiratory bronchioles. The observed heterogeneity of NAT1 and NAT2 mRNA expression between human tissue types may be of significance in assessing their contribution to known organ-specific toxicities of various arylamine drugs and carcinogens.

The effect of mammographic screening on invasive breast cancer in Western Australia

Objective: To determine whether mammographic screening has affected the presentation of invasive breast cancer in Western Australia. Design: Population-based reviews of the presentation of all invasive breast cancers diagnosed in Western Australia in 1989 and 1994. Setting: Western Australia (population 1.8 million), Active recruitment of women aged 50-69 years for mammographic screening began in 1989. Main outcome measures: Size and stage of invasive breast cancers at diagnosis. Results: From 1989 to 1994, the age-standardised incidence rose from 109 to 123 per 100 000 woman-years, based on 584 and 750 cases, respectively. The proportion of all invasive breast cancers detected as a result of a mammogram increased from 9.2% in 1989 to 34.5% in 1994. Among the cases where relevant information was recorded, the proportion of impalpable tumours increased from 7.7% in 1989 to 27.6% in 1994, and the average size of palpable tumours fell. There was an unexpected increase in the proportion of tumours that were negative on assays for oestrogen and progesterone receptors. Conclusions: A relatively simple and inexpensive clinical review has boosted confidence that the outlay of public monies required to establish and conduct screening in Australia appears likely to yield the reductions in mortality from breast cancer that would be predicted on the basis of the earlier controlled trials of mammography.

Conformational selection of inhibitors and substrates by proteolytic enzymes: Implications for drug design and polypeptide processing

Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such as AIDS and viral infections, cancers, inflammatory disorders, and Alzheimer's disease. Generic approaches to the design of protease inhibitors are limited by the unpredictability of interactions between, and structural changes to, inhibitor and protease during binding. A computer analysis of superimposed crystal structures for 266 small molecule inhibitors bound to 48 proteases (16 aspartic, 17 serine, 8 cysteine, and 7 metallo) provides the first conclusive proof that inhibitors, including substrate analogues, commonly bind in an extended beta-strand conformation at the active sites of all these proteases. Representative superimposed structures are shown for (a) multiple inhibitors bound to a protease of each class, (b) single inhibitors each bound to multiple proteases, and (c) conformationally constrained inhibitors bound to proteases. Thus inhibitor/substrate conformation, rather than sequence/composition alone, influences protease recognition, and this has profound implications for inhibitor design. This conclusion is supported by NMR, CD, and binding studies for HIV-1 protease inhibitors/ substrates which, when preorganized in an extended conformation, have significantly higher protease affinity. Recognition is dependent upon conformational equilibria since helical and turn peptide conformations are not processed by proteases. Conformational selection explains the resistance of folded/structured regions of proteins to proteolytic degradation, the susceptibility of denatured proteins to processing, and the higher affinity of conformationally constrained 'extended' inhibitors/substrates for proteases. Other approaches to extended inhibitor conformations should similarly lead to high-affinity binding to a protease.

Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma

Immune surveillance by cytotoxic lymphocytes against cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is dependent on the pore-forming protein perforin (pfp), we examined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lymphoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was accentuated by simultaneous lack of expression of the p53 gene, mutations in which also commonly predispose to human malignancies, including lymphoma. In contrast, the incidence and age of onset of sarcoma was unaffected in p53-deficient mice. Pfp-deficient mice were at least 1,000-fold more susceptible to these lymphomas when transplanted, compared with immunocompetent mice in which tumor rejection was controlled by CD8(+) T lymphocytes. This study is the first that implicates direct cytotoxicity by lymphocytes in regulating lymphomagenesis.

Analysis of Mouse Keratin 6a Regulatory Sequences in Transgenic Mice Reveals Constitutive, Tissue-Specific Expression by a Keratin 6a Minigene

The analysis of keratin 6 expression is complicated by the presence of multiple isoforms that are expressed constitutively in a number of internal stratified epithelia, in palmoplantar epidermis, and in the companion cell layer of the hair follicle. In addition, keratin 6 expression is inducible in interfollicular epidermis and the outer root sheath of the follicle, in response to wounding stimuli, phorbol esters, or retinoic acid. In order to establish the critical regions involved in the regulation of keratin 6a (the dominant isoform in mice), we generated transgenic mice with two different-sized mouse keratin 6a constructs containing either 1.3 kb or 0.12 kb of 5' flanking sequence linked to the lacZ reporter gene. Both constructs also contained the first intron and the 3' flanking sequence of mouse keratin 6a. Ectopic expression of either transgene was not observed. Double-label immunofluorescence analyses demonstrated expression of the reporter gene in keratin 6 expressing tissues, including the hair follicle, tongue, footpad, and nail bed, showing that both transgenes retained keratinocyte-specific expression. Quantitative analysis of beta -galactosidase activity verified that both the 1.3 and 0.12 kb keratin 6a promoter constructs produced similar levels of the reporter. Notably, both constructs were constitutively expressed in the outer root sheath and interfollicular epidermis in the absence of any activating stimulus, suggesting that they lack the regulatory elements that normally silence transcription in these cells. This study has revealed that a keratin 6a minigene contains critical cis elements that mediate tissue-specific expression and that the elements regulating keratin 6 induction lie distal to the 1.3 kb promoter region.

The burden of mental disorders in Victoria, 1996

Background: Between 1998 and 1999, a burden of disease assessment was carried out in Victoria, Australia applying and improving on the methods of the Global Burden of Disease Study. This paper describes the methods and results of the calculations of the burden due to 22 mental disorders, adding 14 conditions not included in previous burden of disease estimates, Methods: The National Survey of Mental Health and Wellbeing provided recent data on the occurrence of the major adult mental disorders in Australia. Data from international studies and expert advice further contributed to the construction of disease models, describing each condition in terms of incidence, average duration and level of severity, with adjustments for comorbidity with other mental disorders. Disability weights for the time spent in different states of mental ill health were borrowed mainly from a study in the Netherlands, supplemented by weights derived in a local extrapolation exercise. Results: Mental disorders were the third largest group of conditions contributing to the burden of disease in Victoria, ranking behind cancers and cardiovascular diseases. Depression was the greatest cause of disability in both men and women. Eight other mental disorders in men and seven in women ranked among the top twenty causes of disability. Conclusions: Insufficient information on the natural history of many of the mental disorders, the limited information on the validity of mental disorder diagnoses in community surveys and considerable differences between ICD-10 and DSM-IV defined diagnoses were the main concerns about the accuracy of the estimates. Similar and often greater concerns have been raised in relation to the estimation of the burden from common non-fatal physical conditions such as asthma, diabetes and osteoarthritis. In comparison, psychiatric epidemiology can boast greater scientific rigour in setting standards for population surveys.

Targeting c-Myb expression in human disease

c-Myb is a transcription factor employed in the haematopoietic system and gastrointestinal tract to regulate the exquisite balance between cell division, differentiation and survival. In its absence, these tissues either fail to form, or show aberrant biology. Mice lacking a functional c-myb gene die in utero by day 15 of development. When inappropriately expressed, as is common in leukaemia and epithelial cancers of the breast, colon and gastro-oesophagus, c-Myb appears to activate gene targets of key importance to cancer progression and metastasis. These genes include cyclooxygenase-2 (COX-2), Bcl-2, Bcl-X-L and c-Myc, which influence diverse processes such as angiogenesis, proliferation and apoptosis. The clinical potential for blocking c-Myb expression in malignancies is based upon strong preclinical data and some trial-based evidence. The modest clinical experience to date has been with haematopoietic malignancies, but other disease classes may be amenable to similar interventions. The frontline agents to achieve this are nuclease-resistant oligodeoxynucleotides (ODNs), which are proving to be acceptable therapeutic reagents in terms of tolerable toxicities and delivery. Nevertheless, further effort must be focused on improving their efficacy, eliminating non-specific toxicity and optimising delivery. Optimisation issues aside, it would appear that anti-c-Myb therapies will be used with most success when combined with other agents, some of which will be established cytotoxic and differentiation-inducing drugs. This review will explore the future strategic use of ODNs in vivo, focusing on a wide spectrum of diseases, including several beyond the haematopoietic malignancies, in which c-Myb appears to play a role.

Evaluating curriculum changes in undergraduate cancer education

Background. Previous studies have indicated that Australian medical schools have not adequately prepared our graduating doctors to care for patients with cancer. The University of Western Australia (UWA) introduced a two-week clinical attachment in cancer medicine for fifth-year students in 2000 and a four-day clinical attachment in palliative care for sixth-year students in 2001. This article evaluates the introduction of these dedicated clinical attachments in cancer and palliative care. Method. The Australian Cancer Society's Cancer Education Survey was administered to the UWA graduates starting their intern year in teaching hospitals in Perth, Western Australia, in 2002. Their responses were compared with data collected in a similar national survey of Australian and New Zealand interns in 2001. Results. The response rate was 56% (n = 70). When compared with the national data for 2001, more UWA interns (2002) would refer a newly diagnosed breast cancer patient to a multidisciplinary breast clinic (97% vs. 74%, P<.001). Fewer UWA 2002 interns rated their training as poor or very poor in the management of patients with incurable cancer (19% vs. 35%, P=.008) and the management of symptoms in patients dying from cancer (10% vs. 37%, P<.001), but they were more likely to rate their training in assisting a patient to stop smoking as poor or very poor (54% vs. 21%, P<.001). Only a quarter of the UWA 2002 interns had examined a patient with a cancer of the mouth or tongue (25% vs. 49%, P<.001), and only two thirds had examined a patient with lymphoma (64% vs. 83%, P<.001). Conclusions. Our data reflect changes in the final two years of the medical course at UWA and suggest that the introduction of dedicated attachments in cancer and palliative care has better prepared graduating doctors to care for patients with cancer.