Beta-catenin mutations and protein accumulation in all hepatoblastomas examined from B6C3F1 mice treated with anthraquinone or oxazepam.

The molecular pathogenesis of hepatoblastomas in the B6C3F1 mouse is unclear but may involve alterations in the beta-catenin/Wnt signaling pathway as was recently described for chemically induced hepatocellular neoplasms and human liver cancers. The objective of this study was to characterize the mutation frequency and spectrum of beta-catenin mutations and the intracellular localization of beta-catenin protein accumulation in chemically induced hepatoblastomas. In this study, beta-catenin mutations were identified in all 19 anthraquinone-induced hepatoblastomas and all 8 oxazepam-induced hepatoblastomas examined. Although several hepatoblastomas had multiple deletion and/or point mutations, the pattern of mutations in the hepatoblastomas did not differ from that identified in hepatocellular neoplasms. In a majority of the hepatoblastomas (six of seven) examined by immunohistochemical methods, both nuclear and cytoplasmic localization of beta-catenin protein were detected, whereas in hepatocellular adenomas, carcinomas, and normal liver only membrane staining was observed. Our data suggest that beta-catenin mutations and the subsequent translocation of beta-catenin protein from the cell membrane to the cytoplasm and nucleus may be critical steps in providing hepatocellular proliferative lesions with the growth advantage to progress to hepatoblastoma.

Is an osteotome necessary for pterygomaxillary dysjunction or dysjunction through the tuberosity during Le Fort I osteotomy? A systematic review.

Pterygomaxillary dysjunction with an osteotome is commonly used to mobilise the maxilla during Le Fort I osteotomy, despite the risk of serious complications. Different instruments and positions have been tried, including dysjunction through the tuberosity. Down fracture by digital pressure alone has also been advocated, but to our knowledge has not been widely adopted. We have therefore reviewed published papers to see if there is any clinical or anatomical evidence for the use of osteotomes to mobilise the maxilla vertically during a Le Fort I osteotomy for either pterygomaxillary dysjunction or dysjunction through the tuberosity. We found only one paper that analysed the anatomy of the pterygomaxillary fissure and described small bony bridges and syncondroses across the joint. We found no clinical or anatomical evidence for the use of osteotomes in pterygomaxillary separation or separation through the tuberosity. A large clinical trial on down fracture of the maxilla by digital pressure alone showed no serious complications, and we found no strong evidence to justify the use of osteotomes in pterygomaxillary dysjunction or dysjunction through the tuberosity. We have successfully used digital pressure alone in 138 consecutive Le Fort I osteotomies, and we encourage our colleagues to consider adopting this approach.

Trauma history as a predictor of psychologic symptoms in women with breast cancer.

PURPOSE: To identify predictors of psychiatric problems in women with early-stage breast cancer. PATIENTS AND METHODS: One hundred sixty women with early-stage breast cancer were recruited from three treatment centers. They filled out self-report questionnaires, including a medical history and demographic survey, the Trauma History Questionnaire, Life Event Questionnaire, Brief Symptom Inventory, Beck Depression Inventory, and Duke-UNC Functional Social Support Questionnaire, and were evaluated using the Structured Clinical Interview for DSM-III-R. RESULTS: Hierarchical regression analyses indicated that four of five variable sets made a significant incremental contribution to outcome prediction, with 35% to 37% of the variance explained. Outcomes were predicted by demographic variables, trauma history variables, precancer psychiatric diagnosis, recent life events, and perceived social support. Cancer treatment variables did not predict outcome. CONCLUSION: The findings highlight the important roles of trauma history and recent life events in adjustment to cancer and have implications for screening and treatment.

Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use.

Although there are reports of cases of acute renal failure occurring in cystic fibrosis (CF) patients, usually in association with the use of nephrotoxic antibiotic therapy, there have been no studies of renal function in this patient group. We hypothesized that long-term use of intravenous (IV) nephrotoxic antibiotics (aminoglycosides and colistin sulphomethate) may contribute to renal disease in CF patients. In a prospective study, we assessed creatinine clearance as an index of renal function with two techniques (24-hr urine collections and the Cockroft-Gault formula) in a group of 80 stable adult CF outpatients chronically infected with Pseudomonas aeruginosa but with no history of preceding renal disease. Using a multiple linear regression model, we evaluated their renal function in terms of their lifetime IV use of aminoglycosides and colistin. Between 31% (Cockroft-Gault formula method) and 42% (24-hr urine collection method) of patients had a creatinine clearance below normal range. Using either method, there was a strong correlation between aminoglycoside use and diminishing renal function (r=- 0.32, P=0.0055), which was potentiated by the coadministration of colistin (r=- 0.42, P <0.0002). However, there was no correlation with colistin when used in combination with other antibiotics alone (r=0.18, P=NS). Repeated IV aminoglycoside use in CF is associated with long-term renal damage. Although this effect is potentiated by colistin, colistin on its own in moderate doses does not appear to be nephrotoxic. IV aminoglycosides should be used cautiously in CF patients, with regular monitoring of renal function.

Detection of HIV-1 gene sequences in hippocampal neurons isolated from postmortem AIDS brains by laser capture microdissection.

We employed laser capture microdissection to remove individual pyramidal neurons from the CA1, CA3, and CA4 regions of formalin-fixed, paraffin-embedded hippocampus from 8 AIDS brains and 2 HIV-1-seronegative normal brains. We amplified HIV-1 gag and nef gene sequences using separate, double round PCR reactions for each of the primer sets. In all 3 hippocampal regions, amplification efficiency was best with sequence length between 284 and 324 bp; HIV-1 nef gene sequences were more common than HIV-1 gag sequences; and rank order for percent positive amplification was CA3 > CA4 > CA1 samples. These results are the first to detect HIV-1 gene sequences in microdissected human tissue. They indicate that brain neurons in vivo contain HIV-1 DNA sequences consistent with latent infection by this virus, and suggest that neurons display a selective vulnerability for HIV infection. Neuronal HIV infection could contribute to neuronal injury and death or act as a potential viral reservoir if reactivated.

K-ras and p53 in pancreatic cancer: association with medical history, histopathology, and environmental exposures in a population-based study.

Pancreatic cancer is a highly fatal cancer with few identified risk factors. Increased risk of pancreatic cancer in tobacco smokers and among diabetic patients is well established, and some reports have suggested associations with coffee consumption and occupational exposure to organochlorines. At present, there is little information regarding the possible association of these risk factors with the known genetic alterations found in pancreatic cancers, such as activation of the K-ras oncogene and inactivation of the p53 tumor suppressor gene. Knowledge of such relationships may help to understand the molecular pathways of pancreatic tumorigenesis. We investigated the association between these molecular defects and risk factors for pancreatic cancer in 61 newly diagnosed patients identified through an ongoing study of pancreatic cancer in the San Francisco Bay Area. Interview information was obtained regarding environmental exposures, medical history, and demographic factors. Serum levels of dichlorodiphenyltrichloroethylene (DDE) and polychlorinated biphenyls were available on a subset of 24 patients. Tumor blocks were located from local hospitals and used for K-ras mutational analysis at codon 12 and for p53 protein immunohistochemistry. The molecular analyses were facilitated through the use of laser capture microdissection, which provides a reliable method to obtain almost pure populations of tumor cells. Mutations in K-ras codon 12 were found in 46 (75%) of 61 pancreatic cancers. A prior diagnosis of diabetes was significantly associated with K-ras negative tumors (P = 0.002, Fisher's exact test). The absence of this mutation was also associated with increased serum levels of DDE, although this association was not statistically significant (P = 0.16, Wilcoxon's test). There was no difference in polychlorinated biphenyl levels between the K-ras wild-type and mutant groups. Immunohistochemical staining for p53 protein did not differ by patient characteristics or clinical history, but significant associations were found with poor glandular differentiation (P = 0.002, chi2 trend test), severe nuclear atypia (P = 0.0007, chi2 trend test), and high tumor grade (P = 0.004, chi2 trend test). Our results are suggestive of the presence of K-ras codon 12 mutation-independent tumorigenesis pathways in patients with prior diabetes and possibly in patients with higher serum levels of DDE. Our results also support a role for the p53 tumor suppressor protein in the maintenance of genomic integrity.

Bronchoscopic insertion of Gianturco stents for the palliation of malignant lung disease: 10 year experience.

Malignant large airway obstruction is life threatening and may not be amenable to urgent radiotherapy. Palliative airway stenting is difficult and traditionally carried out under general anaesthesia and fluoroscopy. We have shown that self expanding Gianturco metal stents can be placed under local anaesthesia using fibreoptic bronchoscopy and direct vision for the treatment of malignant airway tumours, and report our 10 year experience. All referrals for stenting referred to our unit between 1990 and 1999 were included, looking for histological type, number and site of stents, complications of the procedure, other interventions, and survival. One hundred and sixty two patients (average age 64 years, (range 21-89)) had 307 stents inserted during 167 procedures (144 primary lung tumours, 18 secondary malignancy). There were no operative deaths, but three patients developed a pneumothorax, one requiring intercostal drain insertion. Average survival following stent insertion was less for primary lung cancer than for secondary disease (103 vs. 431 days, P<0.001). There were no excess complications in a subgroup of 64 patients treated locally by oncologists, even when stenting was the primary procedure. This technique is useful in palliating life threatening airway obstruction, particularly for secondary cancer, and can be used in any centre undertaking fibreoptic bronchoscopy.

Organizational approaches to the HIV/AIDS crisis.

The Centers for Disease Control and Prevention (CDC) has played a major role in controlling the HIV/AIDS epidemic in the United States. After implementation of perinatal zidovudine therapy in 1994, the efforts of the CDC and others produced a dramatic decline in perinatal HIV transmission. However, in recent years, approximately 300 perinatally infected infants have been born annually in the United States. To further reduce this number, the CDC has identified four prevention goals: improve prenatal care, recommend HIV testing, ensure treatment for HIV-infected pregnant women, and ensure follow-up care. To address these goals, the CDC launched a prevention plan consisting of surveillance, research, outreach strategies, grant programs, evaluation efforts, and policy development. Globally, the CDC tailors this plan to meet the needs of developing countries. The CDC provides technical assistance to international organizations to help develop, implement, and evaluate global prevention programs. Specific international sites are targeted for new research and programs to reduce perinatal HIV transmission.

Nurses in the community: a manpower study.

High priority is at present being given to the expansion of health visiting and home nursing services as part of the change of emphasis from institutional to community care. The aim of this study was to provide nurse managers in two regional health authorities with basic information about community nurses with could be used for service planning and development. The results of the study emphasise the particular problems of staffing the community nursing service in inner London, where home nurse and health visitors are younger, more recently appointed, and relatively less experienced than staff in other parts of the regions. High turnover rates and chronic recruitment difficulties in inner London prevent nurse managers from maintaining both the level and the quality of the services they aim to provide. Until these problems are remedied there is little prospect of achieving any significant shift in the balance of care in inner London.

Functioning and well-being of patients in a consultation-liaison psychiatry clinic.

Outpatient consultation-liaison (C-L) psychiatry clinics are valuable settings for research and teaching endeavors. However, little is known about psychiatric symptoms and health status of persons treated in such settings. In this study, 80 persons seen in an outpatient C-L psychiatry clinic were compared with 100 persons seen in a mood disorder clinic on a variety of self-report instruments. Outpatient C-L clinic patients were found to have significantly poorer health status than mood clinic patients on the following domains as measured by the RAND instrument: general health perception, pain, physical functioning, and role functioning due to physical problems. Both groups had poor role functioning due to emotional problems and poor social functioning. The groups did not differ in depressive symptoms but C-L patients were significantly less anxious. Thus, it appears that patients in an outpatient C-L setting not only have significant medical comorbidity, as expected, but have levels of psychiatric distress comparable to that seen in a traditional psychiatry outpatient setting. These findings indicate that such a clinic is a fertile area for research and training in the diagnosis and treatment of persons with comorbid physical and mental disorders.

A world-wide internet survey of public knowledge about tuberculosis.

Four simple multiple-choice questions about tuberculosis (TB) were posted on a non-medical internet site for a 2-month period. A total of 564 responses were received. Sixty-two were excluded as individuals had made multiple attempts at the questions. Sixty-five per cent of responses were from North America, 14.5% from Europe and 12% from Australia and New Zealand, with only a small number of responses from Africa, the Indian subcontinent and South America. Of the respondents 49.5% correctly answered that cough is the commonest symptom of TB, 45% knew that TB was transmitted mainly by air-borne droplets, 37.8% knew that TB was caused by a bacterium. Only 19.5% knew that the most important risk factor for developing TB was HIV infection and only 4% answered all questions correctly. This survey suggests that knowledge about tuberculosis is limited in computer-literate individuals throughout the world.

Loss of E-cadherin expression in gastric intestinal metaplasia and later stage p53 altered expression in gastric carcinogenesis.

Gastric cancers are commonly subdivided into intestinal and diffuse subtypes on a morphologic basis, supported by corollary evidence of differences at the pathogenetic and molecular levels. Chronic atrophic gastritis with intestinal metaplasia is a common precursor lesion for the intestinal type of carcinoma. To identify early molecular changes, in this study we have examined 13 surgical specimens both for the expression of E-cadherin, p53 and beta-catenin by immunohistochemistry and for methylation of the CDH1 promoter (E-cadherin) by bisulfite genomic sequencing of laser capture microdissected samples. Each specimen examined contained areas of normal (nonmetaplastic) gastric mucosa, as well as areas of intestinal metaplasia and/or carcinoma. Reduced or absent E-cadherin and partial to complete methylation of one to multiple CpG sites examined in the CDH1 promoter were observed in all of the metaplasia samples. Thus, the methylation status of the CDH1 promoter and expression of E-cadherin together provide strong evidence that loss of E-cadherin is an early event in intestinal type gastric carcinogenesis. In contrast, expression of p53, assumed to be mutant p53, was generally not detected (except for isolated cells) until the carcinoma stage in tissues from these patients. These results suggest that mutation of p53 is a late event in intestinal type gastric cancer. The level of beta-catenin expression did not appear to change between normal, metaplastic and carcinoma cells of intestinal type, and no nuclear staining was visible in any of the tissues. These results suggest that the Wnt signaling pathway is not upregulated in this type of cancer.

Risk factors for Nipah virus transmission, Port Dickson, Negeri Sembilan, Malaysia: results from a hospital-based case-control study.

A hospital-based case-control study of viral encephalitis was carried out at Port Dickson Hospital, in the state of Negeri Sembilan, Malaysia. Between March and May 1999, 69 clinically diagnosed viral encephalitis cases and 31 controls were interviewed. Job histories on pig farming activities were assessed by a group of epidemiologists and veterinary surgeons. Results show that among clinical cases of viral encephalitis, 52 (75.4%) cases were diagnosed to have Nipah virus infection based on positive serology for antibodies to the cross-reacting Hendra virus antigen. The Nipah virus encephalitis was significantly associated with a history of working in pig farms (p < 0.001, OR = 196.0, 95% CI = 20.4-4741.6), history of contact with animals (p < 0.001, OR = 38.3, 95% CI = 8.2-209.0) and with history of direct contact with pigs (p = 0.002, OR = 34.4, 95% CI = 2.6-1,024.4). The Nipah virus infection was also significantly associated with history of feeding/cleaning pigs (p < 0.001, OR = 102, 95% CI = 11.9-2,271.5). These results provide evidence that involvement in pig farming activities is significantly associated with the risk of getting Nipah virus infection. They are potential risk factors for Nipah virus transmission in the major pig-producing area of Bukit Pelandok, Port Dickson Negeri Sembilan.

Clinical predictors of outcome of acute episodes of low back pain.

In this prospective study, predictors of outcome were identified for patients (n = 116) who presented to their family physician with acute mechanical low back pain. Short-term outcome was measured by the number of days lost from work and longer term outcome was measured by disability at the six-week follow-up. Unlike other published work, this study did not find obesity or a history of previous back problems to be related to a poorer outcome from acute episodes of low back pain. Among those patients not involved in manual labor, a history of anxiety or depression was a significant predictor of both greater work loss and longer term disability. Among this same group, cigarette smoking was also found to be related to greater long-term disability from acute low back pain. Further study of this relationship is needed. The number of hours of manual labor performed daily was a strong predictor of poor outcome (both short- and long-term) of acute episodes of low back pain. Among both manual laborers and professional-technical workers, the number of days off work (at bed rest) prescribed by the physician was significantly related to greater absenteeism from work; the physician's diagnosis of an actual or possible disc problem was also related (P less than .05) to greater work loss among manual laborers. Neither of these factors, however, was related to longer term disability.

Growth and change in the funding and provision of home care for the elderly.

Home care has been promoted as an alternative to acute and long-term care in hospitals and nursing homes in the interests of controlling the high and rising costs of institutional care. This has resulted in legislative and regulatory changes to public programs, of which the elderly are the main beneficiaries. Consequently, there has been major growth and change in the home care industry with Medicare being the largest third-party payor and primary income source for many home care agencies. The industry is now coming under closer scrutiny as a result of the increasing public expenditures, and concerns regarding public accountability and the cost-effectiveness of care delivered by this fragmented and relatively unregulated sector have been expressed. There is now increasing evidence that industry expectations of future growth may not be met from publicly funded home care programs for the elderly as currently conceived, regulated, and reimbursed. Changes are likely to result in an expanded role for the physician in home health care planning and supervision.

Medication use by the elderly.

Medication use is correlated with the age-associated onset of chronic diseases for which drug therapy offers symptomatic relief, and assists in preventing the onset of disabling and life-threatening complications. However, high rates of medication use by older people raise a number of issues, ranging from concerns with rising expenditures for individuals and third-party insurers; increased risk of adverse drug reactions; toxic or interaction effects from concomitant use of multiple pharmaceutical agents, both physician and self-prescribed; and poor compliance with complex medication regimens by the more physically and mentally impaired. Although existing data do not support the theory of age as an independent predictor of drug-specific adverse reactions, older people have typically been excluded from clinical trials in the dynamic and changing field of pharmacotherapy. Furthermore, ingestion of a greater number of different agents clearly exposes individuals to higher risk of adverse reactions and interactions. Recent advances in information technology have facilitated multicenter clinical trials and post-marketing epidemiological surveillance studies of specific and concomitant medication use by individuals of all ages. The employment of such technology by insurers to determine appropriate prescribing or to control costs in the present limited state of knowledge is, however, premature. Furthermore, such techniques will not replace the need for careful clinical review of symptoms and total drug therapy by prescribing physicians, with modification of regimens and provision of appropriate information and instructions to older individuals and their caregivers.

Mycobacterial culture results of smear-positive patients with suspected pulmonary tuberculosis in Liverpool.

The aim of this study was to assess the final mycobacterial culture results of patients with smear-positive sputum or bronchial washings and to investigate the efficiency of local tuberculosis (TB) contact-tracing. Retrospective analysis of mycobacterial cultures and contact-tracing was performed in every patient with smear-positive sputum or bronchoalveolar lavage (BAL) in two Liverpool teaching hospitals (1996-1998). Of these patients 116 with smear-positive sputum or BAL were identified. Mycobacterium tuberculosis (M. tuberculosis) was cultured in 57 (49%), environmental mycobacteria in 37 (32%) and cultures were negative in 22 (19%) of the patients. Contact-tracing information was available in 107 of the 116 (92%) patients. A total number of 1,357 contacts were screened for possible tuberculosis. Of these, 420 (31%) were contacts of patients who cultured environmental organisms or had negative cultures. In this study, 51% of smear-positive patients in Liverpool did not have tuberculosis. Inefficiencies in current contact-tracing procedures have been identified which result from screening contacts of index cases that are subsequently found not to have cultured Mycobacterium tuberculosis. The authors believe that there are clear grounds for using rapid tests to identify and type mycobacteria more quickly than current solid or liquid media methods. It is also suggested that regional variations in the frequency of infection with environmental mycobacteria should be considered when formulating tuberculosis contact-tracing procedures.

Mental status change in older surgical patients. Cognition, depression, and other comorbidity.

The authors studied patients age 60 and over to assess the effect of elective surgery as a precipitating factor for cognitive decline over the postoperative year. They found an association between change in test performance and age, physical disability, and number of depressive symptoms. However, persistent decline in Mini-Mental State Exam scores was associated with identifiable factors related to the initial surgery in only 3/ 251 (1 percent of cases). Depression and new onset of acute illness were confounding factors in the assessment of cognitive decline.