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PubMed1991

Successful treatment of acquired immunodeficiency syndrome-related Mycobacterium avium complex disease with a multiple drug regimen including amikacin.

Disease due to Mycobacterium avium complex (MAC) in patients with the acquired immunodeficiency syndrome (AIDS) typically occurs late in the course of AIDS and is usually disseminated with evidence of multiorgan involvement. Most patients are persistently bacteremic. Previously published studies have noted a poor response to antimycobacterial chemotherapy. We describe successful treatment of MAC disease in an AIDS patient with a multiple drug regimen, including amikacin, clofazimine, rifampin, ethambutol, and ciprofloxacin. This patient, whose presentation and MAC disease course distinctly differ from most published experience, remains clinically and microbiologically MAC-disease free 25 months after initiation of therapy. We describe four additional AIDS patients with MAC disease who had a favorable clinical and microbiological response to this regimen without developing serious adverse effects after periods ranging from 4 to 12 months. We suggest a prospective, controlled clinical trial using this regimen for treatment of MAC disease in patients with AIDS may be warranted.

Acquired Immunodeficiency Syndrome↗
PubMed2006

[Clinical studies on the pathogenetic factors of cavitary and nodular bronchiectatic types in pulmonary Mycobacterium avium complex disease].

We investigated the clinical, laboratory and radiological findings of 273 newly diagnosed cases of pulmonary Mycobacterium avium complex (MAC) disease, who were diagnosed in our hospital during 7 years from January 1996 to December 2002. Radiological findings of all cases were classified at the time of diagnosis into 2 patterns, the cavitary (Cav) type and the nodular bronchiectasis (NB) type. Clinical and laboratory findings at the time of diagnosis of 44 death cases were compared with those of 273 newly diagnoses cases, to analyze the prognostic factors of this disease. MAC disease cases showed a marked increase in number in recent years, but only in women. Mean age at the first visit was 65.7 years in men and 63.2 years in women, and when limited to fatal cases, it was 72.3 years in men and 69.4 years in women. Low body weight in terms of body mass index (BMI) and moderately low serum albumin level were found at the time of the first hospital visit in all the newly diagnosed and death cases. In the fatal cases, the peripheral blood lymphocyte counts revealed a relatively smaller number than the normal range, and the PPD skin test showed a negative reaction in 57.7% of all cases, suggesting the presence of lowered cell-mediated immunity at the time of diagnosis. Whether malnutrition occurs as a result of MAC disease or the individuals with lower nutrition level are easy to develop to MAC disease remains to be clarified. In regard to radiological findings, many cavitary (Cav) type cases were found in men and nodular bronchiectasis (NB) type in women among newly diagnosed cases, while the cavitary type was observed in many in both men and women fatal cases. The mean duration period from diagnosis to death was 28.3 months in men and 60.2 months in women, showing a longer survival after diagnosis, perhaps due to earlier hospital visits by women. The average age at death was 74.4 years old in men and 73.8 years old in women, and the two radiological patterns did not change throughout the entire disease course.

Aged↗
PubMed2006

Histone deacetylase inhibitors: a novel therapeutic approach to Huntington's disease (complex mechanism of neuronal death).

Huntington's disease is an autosomal dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion. The onset of HD leads to problems with movement, cognition, and behavioral functioning and there is currently no effective treatment. The mechanism by which mutant huntingtin causes neuronal dysfunction is not known. However, multiple pathologic mechanisms have been discovered. Recent studies provide strong evidence for transcriptional dysregulation as a mechanism of HD pathogenesis. The control of eukaryotic gene expression depends on the modification of histone proteins associated with specific genes; acetylation and deacetylation of histones play a critical role in gene expression. Studies in numerous HD models have shown that mutant huntingtin expression leads to a change in histone acetyl transferase (HAT) activity and suggest that aberrant HAT activity may be an underlying mechanism of transcriptional dysregulation in HD. Furthermore, recent studies have shown a therapeutic role for histone deacetylase (HDAC) inhibitors in a number of HD models. In this review we discuss a number of studies that use HDAC inhibitors as therapeutic agents in HD models. These studies demonstrate that HDAC inhibitors are a promising therapeutic approach for the treatment of HD.

Acetylation↗
PubMed2005

Recursive partitioning analysis of complex disease pharmacogenetic studies. I. Motivation and overview.

Identifying genetic variation predictive of important phenotypes, including disease susceptibility, drug efficacy, and adverse events, is a challenging task, and theory and computer science work is being carried out in an attempt to tackle this issue. For many important diseases, such as diabetes, schizophrenia, and depression, the etiology is complex; either the disease is a result of several multiple mechanisms or is caused by an interaction among multiple genes or gene-environment interactions, or both. There is a need for statistical methods to deal with the large, complex data sets that will be used to disentangle these diseases. Each putative genetic polymorphism can be tested for association sequentially. The most difficult problem, however, is the identification of combinations of polymorphisms or genetic markers with increased predictive characteristics. Data from clinical trials, where patients with a particular disease are treated with certain drugs, can be retrospectively assembled using a case-control design. Such data will typically include treatment assignment, demographics, medical history, and genotypes for a large number of genetic markers. The number of variables in such data is expected to be much larger than the number of subjects. This report focuses on some of the methods being employed to deal with this complex data and covers, in some detail, a data-mining method--recursive partitioning--to analyze such data. The methods are demonstrated using a complex simulated data set, as there are few available public data sets. This explication of recursive partitioning should provide researchers with a better idea of the current available analysis techniques, in order to allow them to plan their experiments more effectively.

Biomedical Research↗
PubMed1994

Disseminated Mycobacterium avium complex disease in patients with AIDS.

Disseminated Mycobacterium avium complex (MAC) infection is a common complication of advanced HIV disease that is associated with significant morbidity. After diagnosis of MAC by recovery of organisms from blood or other normally sterile sites, specific treatment with multiple-drug regimens is appropriate and may reduce morbidity. Multiple-drug regimens with agents active against MAC should be employed to reduce the development of drug resistance. Unfortunately, as most clinical trials of anti-MAC agents have lasted 12 weeks or less and have not compared specific agents, the most effective multiple-drug regimen has not been established. The U.S. Public Health Service Task Force on Prophylaxis and Therapy of MAC recommends treatment of disseminated disease with at least two antimycobacterial agents, one of which should be clarithromycin or possibly azithromycin. Ethambutol, which may have an additive or synergistic effect in combination with other anti-MAC agents, is a reasonable second drug. Other agents with activity include rifampin or rifabutin, clofazimine, ciprofloxacin, or parenteral amikacin. A microbiological response may require up to 2 to 8 weeks. The clinical response generally parallels the microbiological response. Rifabutin, which is licensed for prophylaxis of MAC, reduces the incidence of and delays the time to MAC bacteremia. Individuals at highest risk of MAC bacteremia (i.e., CD4+ cell counts of < 75-100 cells/microliters) had the most benefit from rifabutin prophylaxis. Tuberculosis must be ruled out before rifabutin prophylaxis is initiated. Careful observation without prophylaxis is an acceptable alternative for those who are not able to take rifabutin or alternative agents.

AIDS-Related Opportunistic Infections↗
PubMed1998

Pulmonary Mycobacterium avium complex disease without dissemination in HIV-infected patients.

Pulmonary disease due to Mycobacterium avium complex (MAC) without evidence of dissemination is uncommon in HIV-infected patients. Five cases were observed over a 2-year period. All patients had AIDS and the median CD4 cell count at the time of presentation was 90 x 10(6)/L. Radiographic patterns included unilobar alveolar infiltrates or diffuse alveolar densities. All patients had a favorable clinical response to antimycobacterial chemotherapy with a median follow-up period of 10 months. MAC should be considered in HIV-infected patients with positive respiratory samples for acid-fast bacilli and pulmonary infiltrates. Patients with such findings in whom presumptive therapy for tuberculosis has failed should receive broad-spectrum antimycobacterial chemotherapy until final identification is available.

AIDS-Related Opportunistic Infections↗
PubMed2006

A double-blind randomized study of aminoglycoside infusion with combined therapy for pulmonary Mycobacterium avium complex disease.

A prospective study of the clinical efficacy of an aminoglycoside antibiotic (streptomycin, SM) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease was carried out. In a multicenter trial, patients with pulmonary MAC disease received protocol-guided combined chemotherapy with or without SM. SM was given to the patients intramuscularly 15 mg/kg three times per week for the initial 3 months and three other antibiotics (rifampicin, ethambutol, and clarithromycin) were added and administered for over 24 months after the conversion of MAC strains. From April 1998 to December 2004, 160 HIV-negative patients were enrolled in this trial. Fourteen patients were found to be ineligible because they could not continue the treatment, and they were excluded from the analysis after randomization. Seventy-three patients were assigned to receive combined chemotherapy with SM (group A) and 73 were assigned to receive combined chemotherapy without SM (group B). The median durations of treatment were 27.6 months in group A and 28.4 months in group B. The difference in the backgrounds of the groups was not statistically significant. There were no differences in microbiological and radiological findings between the groups, but the sputum conversion rate for pulmonary MAC disease at the completion of treatment was significantly higher in group A than that in group B. Although, there were no significant differences in the sputum relapse rate and clinical improvement including both clinical symptoms and radiological findings, group A showed better initial microbiological response than group B. As for adverse reactions and abnormal laboratory findings, there were no significant differences between the groups. Based on the results of this double-blind randomized study, we support treatment including SM according to both the American Thoracic Society (ATS) and the Japanese Society for Tuberculosis (JST) guidelines for patients with pulmonary MAC disease without HIV infection.

Aged↗
PubMed2002

[Pulmonary Mycobacterium avium complex disease showing nodular bronchiectasis--: pathological findings in two cases].

Histopathological examinations were carried out on 2 cases of Mycobacterium avium complex (MAC) disease of nodular bronchiectasis (NB) type on radiograms. The removed lung specimens revealed histological findings of granulomatous bronchiolopneumonia, consisting of epithelioid cell granulomas with lymphocytic infiltrations without exudation in the alveolar areas surrounding the respiratory bronchiole. The central bronchiolar walls were also affected by epithelioid cell granulomas with lymphocytic infiltration, occasionally showing polypoid protrusion into the bronchiolar lumen accompanying emphysema in the peripheral alveolar area. Bronchial lesions seemed to progress from peripheral to central airway with consequent atrophy and disappearance of intramural smooth muscles, resulted in bronchioloectasis. These histological findings well correspond to radiographical 'nodular bronchiectasis'. Large histiocytic granulomas without caseous necrosis developed in some area, which are not usually found in tuberculosis lesions. Epithelioid cell granulomas were occasionally found in the hilar lymph nodes as well as in the walls of lymphatic vessel in the pulmonary interlobular tissues, indicating intrapulmonary lymphatic spread of the mycobacteria.

Bronchi↗