Human lung microsomal cytochrome P4501A1 (CYP1A1) activities: impact of smoking status and CYP1A1, aryl hydrocarbon receptor, and glutathione S-transferase M1 genetic polymorphisms.

There are numerous conflicting epidemiological studies addressing correlations between cytochrome P450 1A1 (CYP1A1) genetic polymorphisms and lung cancer susceptibility, with associations plausibly linked to alterations in carcinogen bioactivation. Similarly, correlations between aryl hydrocarbon receptor gene (AHR) codon 554 genotype and CYP1A1 inducibility are controversial. The objective of this study was to determine whether smoking status, and CYP1A1, AHR, and glutathione S-transferase M1 gene (GSTM1) polymorphisms correlate with altered CYP1A1 activities. Lung microsomal CYP1A1-catalyzed 7-ethoxyresorufin O-dealkylation (EROD) activities were much higher in tissues from current smokers (n = 46) than in those from non-/former smokers (n = 24; 12.11 +/- 13.46 and 0.77 +/- 1.74 pmol/min/mg protein, respectively, mean +/- SD; P < 0.05). However, EROD activities in lung microsomes from current smokers CYP1A1*1/1 (n = 33) and heterozygous MspI variant CYP1A1*1/2A (n = 10) were not significantly different (12.23 +/- 13.48 and 8.23 +/- 9.76 pmol/min/mg protein, respectively, P > 0.05). Three current smokers were heterozygous variant CYP1A1*1/2B (possessing both *2A and *2C alleles), and exhibited activities similar to individuals CYP1A*1/1. One current smoker was heterozygous variant CYP1A1*4 and exhibited activities comparable with individuals CYP1A1*1/1 at that locus. EROD activities in microsomes from current smokers AHR(554)Arg/Arg (n = 41) and heterozygous variant AHR(554)Arg/Lys (n = 5) were not significantly different (12.13 +/- 13.56 and 12.01 +/- 14.23 pmol/min/mg protein, respectively; P > 0.05). Furthermore, microsomal EROD activities from current smokers with the GSTM1-null genotype (n = 28) were not significantly different from those (n = 18) carrying at least one copy of GSTM1 (12.61 +/- 14.24 and 11.34 +/- 12.53 pmol/min/mg protein, respectively; P > 0.05). Additionally, when genotypic combinations of CYP1A1, AHR, and GSTM1 were assessed, there were no significant effects on EROD activity. On the basis of microsomal enzyme activities from heterozygotes, CYP1A1*1/2A, CYP1A1*1/2B, CYP1A1*1/4, and AHR(554) Arg/Lys variants do not appear to significantly affect CYP1A1 activities in human lung, and we observed no association between CYP1A1 activity and the GSTM1-null polymorphism.

Use of cultured cells of kidney origin to assess specific cytotoxic effects of nephrotoxins.

During drug discovery, assessment of renal safety for a compound is important for further development of a candidate drug. In this study, we describe an in vitro cell-based assay capable of discerning nephrotoxicity. Three cell types, two of kidney origin and one of liver origin, were used to examine the effects of nephrotoxins. The cell types were the porcine normal kidney tubular epithelial cell line (LLC-PK1), the primary human renal proximal tubular epithelial cells (hRPTEC) and the human liver cell line (HepG2). Cytotoxicity was measured using a luciferin/luciferase assay that measures cellular ATP levels. Four known nephrotoxins, 4-aminophenol, cisplatin, cyclosporin A and paraquat, were tested in this cell-based assay to evaluate cytotoxicity on drug exposure. Kidney-derived LLC-PK1 cells and hRPTECs were found to be sensitive to selected nephrotoxins while liver-derived HepG2 cells were insensitive. Human RPTEC cells obtained from three individual donors demonstrated highly reproducible effects on drug exposure. With respect to drug discovery efforts, integration of the cell models described here are valuable for evaluation of nephrotoxic potentials during lead selection and optimization processes.

Intracranial fetus in fetu: report of a case.

A case of intracranial fetus found in a two-month-old Chinese girl is reported. She was born by cesarean section at term because of cephalopelvic disproportion. The infant was later admitted because of a progressive increase in head circumference. CT brain scan showed marked hydrocephalus and a huge heterogenous mass with multifocal calcification, cystic structures and soft tissue density occupying the left lateral ventricle and the third ventricle. The lesion was completely resected. The specimen obtained was a three-fetiform structure. Roentgenographic examination of the lesion showed the bony structure of three limbs and a vertebral axis, which distinguished the mass from a well-differentiated intraventricular teratoma.

Cholestatic hepatitis: a rare hepatic manifestation of systemic lupus erythematosus.

Systemic lupus erythematosus is a multi-system inflammatory disease. The clinical manifestations are diverse. Hepatic manifestation is a rarely seen complication of systemic lupus erythematosus. We report a case of complication of systemic lupus erythematosus presenting as cholestatic hepatitis in a 56-year-old Chinese woman. The cholestatic hepatitis progressed as part of the lupus activity and responded to steroid therapy.

Pyrexia of unknown origin--approach to management.

Pyrexia of unknown origin (PUO) remains one of the major diagnostic challenges for the clinician. Although infection, malignancy and collagen vascular disease remain the 3 most important causes of PUO, the relative importance of different disease entities within each of these major categories has changed because of improvements in serodiagnosis, culture techniques and radiologic imaging modalities. A detailed clinical history and meticulous physical examination remain the mainstay of the approach to management of patients with PUO. There is no set of "routine" investigations that patients with PUO should be subjected to. Instead, diagnostic testing should be individualised and guided by abnormalities found on clinical examination and simple laboratory testing. In patients in whom the diagnosis remains obscure in spite of extensive investigations and in whom the disease process is clearly progressive, judicious use of narrow spectrum anti-microbial therapy may be warranted. In the majority of the other patients who remain stable, careful clinical observation for new symptoms and signs are advised in the place of multiple courses of antimicrobials.

Case report and review of Chromobacterium sepsis--a gram-negative sepsis mimicking melioidosis.

Chromobacterium violaceum has recently been recognised as a pathogen which can cause life-threatening disease. It is the only Chromobacterium species which is pathogenic to humans. Due to its unfamiliarity, clinicians often do not appreciate its importance when it is isolated in sterile cultures and may dismiss it as a "containment". It is therefore important for us to be aware of this infection and its clinical spectrum since it is a disease of the tropics. We report a paediatric case of documented Chromobacterium sepsis in Singapore who presented like septicaemic melioidosis associated with diminished T-cell numbers. A review of both fatal and non-fatal Chromobacterium, infections is also included.

Foodborne diseases.

Foodborne diseases continue to cause significant morbidity and mortality both in developing and developed countries. Its spectrum has vastly expanded in recent years with the recognition of new foodborne pathogens and clinical syndromes. The increase in international travel and demand for exotic and raw food underscore the importance of traveller's diarrhoea. The emergence of day care centres and residential institutions predispose to an environment that enhances the transmission of foodborne pathogens. Last but not least, our greying population, the AIDS pandemic and increasing use of immunosuppressive chemotherapy have produced a special population that is easily susceptible to the microbial contamination of food. Diseases in these individuals are usually more chronic, severe or life-threatening. This article seeks to address the above issues as well as to present a practical approach to the diagnosis and management of foodborne diseases.

Use of prophylactic antibiotics in the prevention of infective endocarditis and prosthesis infection.

In the field of antimicrobial therapy, few areas have created more debate and controversy than the subject of antibiotic prophylaxis for infective endocarditis. Firstly, there still exists considerable controversy about the efficacy of prophylactic antibiotics for prevention of bacterial endocarditis. Secondly, dental surgeons, orthopaedic surgeons, cardiologists and endoscopists have differing opinions regarding indications for pre-procedural prophylactic antibiotics against infective endocarditis. The British have a different set of recommendations from the Americans although the basic tenets on which these recommendations are founded are similar. This article summarises the updated recommendations issued by the American Heart Association (AHA) as well as those from the British Society for Antimicrobial Chemotherapy. A short discussion of the use of prophylactic antibiotics prior to endoscopy and surgery for patients with non-valvular prosthetic devices has been included in this paper. Practitioners should also be reminded that these recommendations are issued as guidelines and clinical judgement must be exercised when dealing with individual patients.

Cryptococcal meningitis resulting in irreversible visual impairment in AIDS patients--a report of two cases.

Cryptococcus neoformans is the leading cause of meningitis in patients with Acquired Immune Deficiency Syndrome (AIDS) and is associated with high mortality rate. Presenting symptoms include fever, nausea and vomiting, altered mentation, headache and meningismus. Cryptococcal meningitis is not infrequently complicated by raised intracranial pressure and visual sequelae (sometimes by blindness). In patients who survive the infection, the most debilitating outcome appears to be visual impairment or blindness. Management of impending visual complication combines medical and surgical treatment modalities. We report two cases of cryptococcal meningitis associated with visual impairment.

Fatal varicella infections in Singapore.

Varicella (chickenpox) is common in Singapore. The annual incidence of reported cases for the period 1977-1990 ranged from 790 to 18,934, with a mean of 4,747. Mortality from chickenpox is rare. However, failure to recognise the severity and the potential complications of the disease, especially in immunocompetent patients, exists because of the common knowledge that chickenpox is a mild and self-limiting illness. We report six cases of fatal varicella in immunocompetent patients during the period 1988 to 1990.

Travel medicine: a perspective on the emerging problem of travel-related infections.

Travel Medicine has come a long way since it was started in the 1980s. Today, with the advances in electronic communications and efficient international travel, the demand for up-to-date information on international health situation is more urgent than before. Disease outbreaks can be updated and be available immediately across to the whole world in a matter of hours via the Internet. Travel medicine specialists no longer can give the excuse that they are unaware of such a situation because it is posted all over the net. Advances in vaccine development and the work of international agencies like the World Health Organization and the Centres for Disease Control have helped further the strategies and the knowledge we have in travel health risks. For the traveller, this means that they should no longer be travelling to a destination without knowing the health hazards and without taking the appropriate prophylaxis and precautions.

A knowledge, attitudes, beliefs and practices (KABP) survey on HIV infection and AIDS among doctors and dental surgeons in Singapore.

An anonymous postal questionnaire survey studying the knowledge, attitudes, beliefs and practices on human immunodeficiency virus (HIV) infection was conducted among all registered medical and dental practitioners in Singapore in 1996. In all, 1523 replies were received, yielding a response rate of 29.3%. The level of knowledge regarding transmission and prevention was generally good, although there were a number who believed that HIV could be transmitted by the respiratory and oral routes. However, knowledge regarding diagnosis and medical management was unsatisfactory. Although a large majority felt they had the ethical obligation to treat HIV patients, only half of them indicated their willingness to do so if they were given the choice. The majority (62.3%) supported the idea of routine preoperative HIV testing for patients, but fewer (40%) supported mandatory HIV testing for health care workers. Dentists seemed more sensitive to issues involving transmission in the workplace, and 95% of them practised universal precautions. Continuing medical education on HIV infection is required to improve and maintain the level of knowledge and competency of doctors and dentists in Singapore.

PIP: In September 1996, a questionnaire covering HIV-related knowledge, attitudes, beliefs, and practices was mailed to all 5248 registered medical and dental practitioners in Singapore. 1523 replies (29.3%) were received. Although a number of respondents believed HIV could be transmitted by the orofecal and respiratory routes (21% and 12.5%, respectively) and 22.1% did not know latex condoms are an effective preventive method, overall knowledge of prevention and transmission was good. Knowledge regarding diagnosis and medical management of HIV-infected patients was unsatisfactory, however. Only 57.5% were aware of the availability of anonymous HIV testing in Singapore, the CD4 count was correctly identified as the most useful diagnostic measure by just 46%, and only 24.3% could list all the anti-HIV medications used in Singapore. 82.9% believed medical professionals have an ethical obligation to treat people with AIDS, but only 61.5% were willing to do so. 81.3% supported mandatory HIV testing of high-risk groups and 62.3% were in favor of routine preoperative HIV testing without the patient's consent. 30.6% of respondents had ever treated an HIV-positive patient and 71.8% reported use of universal precautions with all patients. These findings indicate a need for continuing medical education on HIV infection to improve the level of knowledge of physicians and dentists in Singapore and to impart clear guidelines on the need to obtain consent before an HIV test is administered.

Three new cases of leishmaniasis: implications for the Singapore medical community.

Although visceral and cutaneous leishmaniasis are important clinical and public health problems worldwide, these diseases are not endemic in Singapore and the medical profession here has little opportunity to diagnose and manage these conditions. We report our experience with two patients with culture-proven visceral leishmaniasis and one with histologically-proven cutaneous leishmaniasis. The patients with kala-azar were migrant workers from countries in which the disease is endemic. The patient with proven cutaneous leishmaniasis (and another who was diagnosed to have the condition clinically) had entered the jungles of an endemic area. With increasing travel on the part of Singaporeans along less well-trodden paths to exotic destinations as well as the burgeoning traffic of migrant workers from less developed countries, doctors in Singapore will continue to see diseases such as leishmaniasis.

Case reports of nocardiosis in patients with human immunodeficiency virus (HIV) infection.

INTRODUCTION: We present 4 local cases of nocardiosis in HIV-infected patients and discuss the diagnosis, clinical syndromes and therapy of nocardiosis. CLINICAL PICTURE: Two cases presented with pulmonary nocardiosis, one had a cervical lymph node abscess and one had disseminated nocardiosis with pulmonary, cerebral and soft tissue involvement. TREATMENT: Combination therapy is often employed. Sulphonamides or co-trimoxazole, amikacin, imipenen, minocycline and ceftriaxone are some of the drugs that could be used. OUTCOME: Outcome hinges on the early recognition and optimal treatment of this infection. CONCLUSIONS: Clinical presentations vary and diagnosis is difficult and frequently delayed. Nocardiosis should be suspected in patients who present with pulmonary lesions with soft tissue and/or cerebral abscesses.

Clinical characteristics and natural history of human immunodeficiency virus infected patients seen at a general hospital in Singapore.

The number of patients with human immunodeficiency virus (HIV) infection in Singapore has risen over the years. A considerable proportion of them present with acquired immunodeficiency syndrome (AIDS). In this study, we document the clinical characteristics and natural history of a consecutive series of 50 patients who were found to have HIV infection when they were seen at a tertiary care hospital. The majority were in the 30 to 49 age group and the most common mode of acquisition was heterosexual contact. The patients presented with a variety of symptoms to 11 different clinical departments. Fifty-eight per cent of the patients had AIDS-defining illnesses at presentation, with Pneumocystis carinii pneumonia being the most common. On follow-up, the most frequently occurring opportunistic infection that developed was Cytomegalovirus retinitis. Most patients had multiple subsequent admissions--for both AIDS-defining and non AIDS-defining conditions. The median CD4 count of the cohort at presentation was 72/mm3. The median survival was 399 and 822 days in those who had and those who did not have an AIDS-defining illness at presentation, respectively. Mortality was most commonly attributed to pneumonia. HIV infection has protean manifestations and patients may present to various specialty departments; hence, doctors need to be aware of the spectrum of disease in order to make a diagnosis.

Vibrio vulnificus infections: case reports and literature review.

Vibrio vulnificus is an emerging opportunistic pathogen that is responsible for one of the most fulminant food-borne diseases in immunocompromised hosts. The infection should be suspected in patients with underlying liver disorders who present with a prominent skin rash, hypotension and septic parameters especially if they give a history of seafood or shellfish ingestion. Awareness and early recognition of this infection will result in a better outcome for the patient.

Decision-making within the social course of dementia: accounts by Chinese-American caregivers.

The goal of this retrospective pilot study was to provide a naturalistic description of the decision-making process regarding dementia, a chronic illness. The hypothesis was that in-depth descriptions by caregivers in a community setting would provide a more comprehensive and realistic representation of decision-making in the case of chronic illness than has been provided by most models. Data were gathered from in-depth, qualitative interviews with seven Chinese-American families living in the Boston area and caring for an elderly family member with dementia. These were supplemented with interviews with medical professionals and ethnography done in the community regarding the care of elders with dementia. Based on the findings, this paper proposes a dynamic, more comprehensive model for the social process of decision-making which is particularly applicable to clinical and life situations of decision-making in the case of chronic illness. The model describes: 1) the decision-maker constellation, including multiple family members, professionals and service systems; 2) relationships between decision-makers as "allies" or "competitors"; 3) variations in the nature of the decision-making process; and 4) the interaction of decision-making with larger social, economic and cultural forces. Decision-making in the case of dementia is placed within the conceptual framework of the "social course" of chronic illness.

Vibrio cholerae fur mutations associated with loss of repressor activity: implications for the structural-functional relationships of fur.

We used the Vibrio cholerae Fur protein as a model of iron-sensitive repressor proteins in gram-negative bacteria. Utilizing manganese mutagenesis, we isolated twelve independent mutations in V. cholerae fur that resulted in partial or complete loss of Fur repressor function. The mutant fur genes were recovered by PCR and sequenced; 11 of the 12 contained point mutations (two of which were identical), and one contained a 7-bp insertion that resulted in premature truncation of Fur. All of the mutants, except that containing the prematurely truncated Fur, produced protein by Western blot (immunoblot) analysis, although several had substantially smaller amounts of Fur and two made an immunoreactive protein that migrated more rapidly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Nine of the 11 point mutations altered amino acids that are identical in all of the fur genes sequenced so far, suggesting that these amino acids may play important structural or functional roles in Fur activity. Eight of the point mutations occurred in the amino-terminal half of Fur, which is thought to mediate DNA binding; most of these mutations occurred in conserved amino acids that have been previously suggested to play a role in the interaction between adjacent alpha-helices of the protein. Three of the point mutations occurred in the carboxy-terminal half of Fur, which is thought to bind iron. One mutation at histidine-90 was associated with complete loss of Fur function; this amino acid is within a motif previously suggested as being involved in iron binding by Fur. The fur allele mutant at histidine-90 interfered with iron regulation by wild-type fur in the same cell when the mutant allele was present at higher copy number; wild-type fur was dominant over all other fur mutant alleles studied. These results are analyzed with respect to previous models of the structure and function of Fur as an iron-sensitive repressor.