Role of CD40 ligand signaling in defective type 1 cytokine response in human immunodeficiency virus infection.

The pathogenesis of defective interleukin (IL)-12 and interferon (IFN)-gamma production in human immunodeficiency virus (HIV)-infected patients remains to be elucidated. This study investigated the possibility that perturbations in CD40 ligand signaling are involved in this defect. CD40 ligand trimer (CD40LT) stimulated peripheral blood mononuclear cell (PBMC) production of IL-12 in response to Toxoplasma gondii and cytomegalovirus (CMV). Regardless of the CD4 cell count, CD40LT restored IL-12 secretion in response to T. gondii in HIV-infected patients. In the presence of CD40LT, PBMC from both HIV-infected patients and control subjects produced high levels of IL-12 in response to CMV. CD40LT restored T. gondii- and CMV-triggered IFN-gamma secretion by T cells and PBMC from HIV-infected patients with a CD4 cell count >200 cells/microL. CD4 cells from HIV-infected patients, even those with a CD4 cell count >500 cells/microL, had defective CD40L induction after T cell stimulation mediated by antigen-presenting cells. Together, impaired CD40L induction is likely to contribute to defective IL-12 and IFN-gamma production in HIV infection.

What can technology do to, and for, family medicine?

Medical technology can be divided into information technology, diagnostic technology, and therapeutic technology. These technologies can enhance the care of patients in a family practice; they also have the potential to diminish or fragment family practice when the technologies can only be provided by specialists. While some family physicians have an aversion to technological advances, we believe it is imperative that family physicians participate in the development of technologies that enhance family practice and improve patient outcomes in primary care practice. These include electronic medical records, decision support systems, tools for managing medical information, and others. Criteria are presented to help determine when these new technologies should be adopted into practice.

Screening for skin cancer.

CONTEXT: Malignant melanoma is often lethal, and its incidence in the United States has increased rapidly over the past 2 decades. Nonmelanoma skin cancer is seldom lethal, but, if advanced, can cause severe disfigurement and morbidity. Early detection and treatment of melanoma might reduce mortality, while early detection and treatment of nonmelanoma skin cancer might prevent major disfigurement and to a lesser extent prevent mortality. Current recommendations from professional societies regarding screening for skin cancer vary. OBJECTIVE: To examine published data on the effectiveness of routine screening for skin cancer by a primary care provider, as part of an assessment for the U.S. Preventive Services Task Force. DATA SOURCES: We searched the MEDLINE database for papers published between 1994 and June 1999, using search terms for screening, physical examination, morbidity, and skin neoplasms. For information on accuracy of screening tests, we used the search terms sensitivity and specificity. We identified the most important studies from before 1994 from the Guide to Clinical Preventive Services, second edition, and from high-quality reviews. We used reference lists and expert recommendations to locate additional articles. STUDY SELECTION: Two reviewers independently reviewed a subset of 500 abstracts. Once consistency was established, the remainder were reviewed by one reviewer. We included studies if they contained data on yield of screening, screening tests, risk factors, risk assessment, effectiveness of early detection, or cost effectiveness. DATA EXTRACTION: We abstracted the following descriptive information from full-text published studies of screening and recorded it in an electronic database: type of screening study, study design, setting, population, patient recruitment, screening test description, examiner, advertising targeted at high-risk groups or not targeted, reported risk factors of participants, and procedure for referrals. We also abstracted the yield of screening data including probabilities and numbers of referrals, types of suspected skin cancers, biopsies, confirmed skin cancers, and stages and thickness of skin cancers. For studies that reported test performance, we recorded the definition of a suspicious lesion, the "gold-standard" determination of disease, and the number of true positive, false positive, true negative, and false negative test results. When possible, positive predictive values, likelihood ratios, sensitivity, and specificity were recorded. DATA SYNTHESIS: No randomized or case-control studies have been done that demonstrate that routine screening for melanoma by primary care providers reduces morbidity or mortality. Basal cell carcinoma and squamous cell carcinoma are very common, but detection and treatment in the absence of formal screening are almost always curative. No controlled studies have shown that formal screening programs will improve this already high cure rate. While the efficacy of screening has not been established, the screening procedures themselves are noninvasive, and the follow-up test, skin biopsy, has low morbidity. Five studies from mass screening programs reported the accuracy of skin examination as a screening test. One of these, a prospective study, tracked patients with negative results to determine the number of patients with false-negative results. In this study, the sensitivity of screening for skin cancer was 94% and specificity was 98%. Several recent case-control studies confirm earlier evidence that risk of melanoma rises with the presence of atypical moles and/or many common moles. One well-done prospective study demonstrated that risk assessment by limited physical exam identified a relatively small (<10%) group of primary care patients for more thorough evaluation. CONCLUSIONS: The quality of the evidence addressing the accuracy of routine screening by primary care providers for early detection of melanoma or nonmelanoma skin cancer ranged from poor to fair. We found no studies that assessed the effectiveness of periodic skin examination by a clinician in reducing melanoma mortality. Both self-assessment of risk factors or clinician examination can classify a small proportion of patients as at highest risk for melanoma. Skin cancer screening, perhaps using a risk-assessment technique to identify high-risk patients who are seeing a physician for other reasons, merits additional study as a strategy to address the excess burden of disease in older adults.

Refractory mucosal candidiasis in advanced human immunodeficiency virus infection.

We conducted a multicenter, prospective study of the risk factors, natural history, and outcome of fluconazole-refractory mucosal candidiasis (FRMC) in 832 persons with advanced human immunodeficiency virus (HIV) infection (median CD4 cell count, 14/mm3) during 1994-1996. FRMC was defined as mucosal candidiasis that failed to resolve despite 14 days of therapy with daily doses (> or =200 mg) of fluconazole. Thirty-six persons (4.3%) had FRMC (35, oral; 1, esophageal), for an incidence of 4.2 per 100 person-years (859.7 total years of follow-up). In a multivariate model, the use of trimethoprim-sulfamethoxazole within 6 months of enrollment (relative risk [RR], 2.39; P=.04) and the use of fluconazole daily or every other day (RR, 5.64; P=.004) were significantly associated with the development of FRMC. The median survival after the development of FRMC was 32.6 weeks. In conclusion, the annual incidence of FRMC was <5%. Refractory candidiasis was a poor prognostic indicator. Daily or every-other-day use of fluconazole was associated with the development of refractory infection.

A randomized trial of interferon alpha therapy for HIV type 1 infection.

The immunologic and virologic efficacy and safety of interferon a (IFN-alpha) administered in combination with zidovudine (ZDV) and zalcitabine (ddC) was evaluated in HIV-infected subjects with CD4+ cell counts between 300 and 500 cells/ml and no more than 14 weeks of prior antiretroviral therapy. A total of 256 subjects enrolled in an open-label, randomized controlled trial. Subjects were randomized equally into treatment groups. All subjects received ZDV and ddC, while half also receive IFN-alpha (3 MU subcutaneously every 24 hr). At 48 weeks the median average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA for the two-drug group was -0.68 versus -0.75 log10 copies/ml for the IFN-alpha group (p = 0.046). Mean HIV-1 RNA changes from baseline to 48 weeks for these groups were -0.65 and -1.12 log10 copies/ml, respectively (p = 0.010). The median AAUCMB for CD4+ cell count for the two-drug group was 28 versus -1 cells/mm3 for the IFN-alpha group (p = 0.011). Neutropenia, anemia, and drug intolerance were more common in the IFN-alpha group. This study demonstrates that IFN-alpha inhibits HIV-1 replication but attenuates the CD4+ cell response to dual therapy with ZDV and ddC.

Preventive dentistry: practitioners' recommendations for low-risk patients compared with scientific evidence and practice guidelines.

INTRODUCTION: The purpose of this article is to compare published evidence supporting procedures to prevent dental caries and periodontal disease, in low-risk patients, with the actual preventive recommendations of practicing dentists. METHODS: Methods included (1) a survey questionnaire of general dentists practicing in western New York State concerning the preventive procedures they would recommend and at what intervals for low-risk children, young adults, and older adults; and (2) review of the published, English-language literature for evidence supporting preventive dental interventions. RESULTS: The majority of dentists surveyed recommended semiannual visits for visual examination and probing to detect caries (73% to 79%), and scaling and polishing to prevent periodontal disease (83% to 86%) for low-risk patients of all ages. Bite-wing radiographs were recommended for all age groups at annual or semiannual intervals. In-office fluoride applications were recommended for low-risk children at intervals of 6 to 12 months by 73% of dentists but were recommended for low-risk older persons by only 22% of dentists. Application of sealants to prevent pit and fissure caries was recommended for low-risk children by 22% of dentists. Literature review found no studies comparing different frequencies of dental examinations and bite-wing radiographs to determine the optimal screening interval in low-risk patients. Two studies of the effect of scaling and polishing on the prevention of periodontal disease found no benefit from more frequent than annual treatments. Although fluoride is clearly a major reason for the decline in the prevalence of dental caries, there are no studies of the incremental benefit of in-office fluoride treatments for low-risk patients exposed to fluoridated water and using fluoridated toothpaste. CONCLUSIONS: Comparative studies using outcome end points are needed to determine the optimal frequency of dental examinations and bite-wing radiographs for the early detection of caries, and of scaling and polishing to prevent periodontal disease in low-risk persons. There is no scientific evidence that dental examinations, including scaling and polishing, at 6 month intervals, as recommended by the dentists surveyed in this study, is superior to annual or less frequent examinations for low-risk populations. There is also no evidence that in-office fluoride applications offer incremental benefit over less costly methods of delivering fluoride for low-risk populations.

After the grant runs out. Long-term provider health maintenance compliance using a computer-based tracking system.

OBJECTIVE: To measure long-term provider (physicians and physician's assistants) health maintenance compliance 4 years after the completion of a grant-funded project to improve provider compliance by using a computer-based health maintenance tracking system. DESIGN: Cross-sectional comparison of provider health maintenance compliance for patients receiving computer-based health maintenance tracking in 1992 and 1996. SETTING: Rural, multiple-office, nonprofit, fee-for-service family practice. MAIN OUTCOME MEASURES: Overall provider compliance with the common elements of the health maintenance protocols in 1992 and 1996. Provider compliance with specific, individual preventive interventions was compared. RESULTS: Overall provider compliance was 83% in 1996, compared with 80% in 1992. This difference was statistically significant (P = .05) but not clinically significant. Provider compliance was significantly higher in 1996 for 3 procedures: blood pressure determination, tetanus-diphtheria immunization, and weight. It was unchanged for 5 procedures: clinical breast examination, mammography, Papanicolaou smears, cholesterol determination, and fecal occult blood testing for colon cancer. Provider compliance with obtaining a history of tobacco use declined. CONCLUSION: Improvements in provider health maintenance compliance associated with installation of a computer-based health maintenance tracking system were maintained 4 years after cessation of the formal research intervention.

Use of colchicine to treat severe constipation in developmentally disabled patients.

BACKGROUND: Patients with severe developmental disabilities often have concurrent decreased neuromuscular tone of the gastrointestinal tract, which can lead to a weak gag reflex, esophageal reflux, aspiration, and severe intractable constipation. High doses of multiple laxatives are frequently needed to maintain bowel motility in these patients. Colchicine, a natural alkaloid that is primarily used for the treatment of acute attacks of gout, causes an increase in gastrointestinal motility by neurogenic stimulation. The purpose of this study was to determine whether daily colchicine administration can improve bowel function and reduce laxative use in profoundly disabled patients with severe, intractable constipation who currently require large doses of multiple laxatives. METHODS: Twelve developmentally disabled patients who required three or more different laxatives to manage their chronic constipation were selected to participate in a double-blind, crossover study. Eleven patients who completed the study received placebo treatment for 8 weeks and colchicine treatment for 8 weeks. The total number of bowel movements and the total number of laxatives used during each of the two 8-week periods were compared. RESULTS: Eight of 11 patients experienced an improved bowel pattern while on colchicine compared with placebo, as defined by an increase in total number of bowel movements or a decrease in total number of rectal laxatives used. No clinically important complications were related to use of colchicine. CONCLUSIONS: Colchicine appears to be a valuable adjunct in the management of severe intractable constipation. Larger, long-term studies are needed to confirm these preliminary results.

Determinants of cancer screening frequency: the example of screening for cervical cancer.

BACKGROUND: Cancer screening frequency should be based on the rate of progression of the disease and the sensitivity of the screening test. A common misconception is that a person's risk of getting the disease determines how often they should be screened. METHODS: We describe algebraically the theoretical interaction of disease progression rate and screening test sensitivity determining the portion of invasive cancers prevented by screening. After discussing the assumptions and limitations of the model, we apply this model to the example of screening for cervical cancer. Actual data from large screening programs assembled by the International Agency for Research on Cancer (IARC) are used to test the assumptions of the model. RESULTS: A simple formula can express the relation between disease progression rate, sensitivity of the screening test, screening frequency, and screening error. Disease prevalence does not figure in this equation. The IARC data suggest that, at least for cervical cancer, as screening frequency increases, incremental sensitivity of the test decreases or remaining undetected cases progress more rapidly so that anticipated benefits from more frequent screening are not realized. CONCLUSIONS: Rate of disease progression and sensitivity of the screening test are the proper determinants of cancer screening frequency. Because these factors can vary depending on screening frequency, however, the optimal screening interval for a particular cancer must be determined by clinical trials.

Utility of urine and leukocyte cultures and plasma DNA polymerase chain reaction for identification of AIDS patients at risk for developing human cytomegalovirus disease.

Urine and blood leukocyte cultures and qualitative plasma polymerase chain reaction (PCR) and quantitative competitive (QC) PCR were evaluated for their ability to identify AIDS patients at risk for human cytomegalovirus (HCMV) disease. AIDS patients were followed with urine and blood specimens every 3 months. During a mean follow-up of 12 months, 26 (28%) developed HCMV disease. The sensitivity, specificity, positive predictive value, and negative predictive value for urine culture were 85%, 29%, 31%, and 83%; for leukocyte culture were 38%, 74%, 69%, and 81%; for qualitative plasma PCR were 89%, 75%, 58%, and 94%; for QC-PCR (>1000 copies/microL) were 35%, 100%, 100%, and 80%; and for QC-PCR (>100 copies/microL) were 73%, 90%, 73%, and 90%, respectively. Of 41 patients identified by qualitative PCR to have HCMV DNA in plasma, the 24 who developed HCMV disease had 1510 +/- 448 (mean +/- SE) peak copies of HCMV DNA/microL by QC-PCR, versus 161 +/- 52 for the 17 patients who did not develop disease (P = .0007). Thus, plasma PCR is superior to culture for identification of AIDS patients at risk for HCMV disease, and quantitation of plasma DNA further identifies high-risk persons.

U.S. Preventive Services Task Force: highlights of the 1996 report.

The recent report of the U.S. Preventive Services Task Force is a compendium of the scientific evidence supporting clinical preventive services that might be offered by primary care physicians. Pediatric recommendations include height, weight and blood pressure measurements, neonatal screening for hemoglobinopathies and counseling about injury prevention, diet and exercise, sexual behavior, substance abuse and dental health. Lead screening is recommended in communities with a high prevalence of elevated lead levels. Adult recommendations include measurement of blood pressure and weight, selective screening for elevated total cholesterol level, screening persons over age 50 for colorectal cancer, screening women for cervical cancer at least every three years, and screening women 50 to 69 years of age for breast cancer with mammography every one to two years. Counseling patients about substance abuse, diet and exercise, injury prevention, sexual behavior and dental health is recommended. Women of childbearing age should receive folic acid supplementation to prevent neural tube defects if they should become pregnant. Multiple marker testing is recommended for women over age 35 to screen for Down syndrome. Immunization recommendations are similar to those of other national groups.

Serum chemokine levels in patients with non-progressing HIV infection.

OBJECTIVE: To evaluate serum chemokines, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and RANTES, concentrations in non-progressing HIV-infected patients and AIDS patients. SETTING: University Hospital-based AIDS Clinical Trials Unit. DESIGN/METHODS: Serum MIP-1 alpha, MIP-1 beta and RANTES levels were determined by enzyme-linked immunosorbent assay using archived serum specimens obtained on two occasions at least 1.8 years apart. PATIENT SELECTION: Long-term non-progressing HIV-infected adult patients were identified from clinic records. For each non-progressing patient two adult AIDS patients with initial documentation of seropositivity the same year and the same length of follow-up were selected. RESULTS: Four long-term non-progressing patients and eight AIDS patients were studied. Neither the duration of known HIV positivity at the time of specimen collection nor the length of time between specimen collections differed significantly between non-progressing patients and AIDS patients. Serum levels of MIP-1 alpha, MIP-1 beta and RANTES in specimens obtained either early or later in the course of HIV infection did not differ significantly between non-progressing patients and AIDS patients. In the two patient subsets, significant differences in serum chemokine levels over time were not observed. The rate of change of serum chemokine concentration over time also did not differ between non-progressing patients and AIDS patients. Serum MIP-1 alpha and MIP-1 beta levels did not reach levels reported to suppress HIV proliferation in vitro. When expressed as a quantity per peripheral blood CD8+ lymphocyte, AIDS patients exhibited significantly greater levels of MIP-1 alpha, MIP-1 beta and RANTES than non-progressing HIV patients (P < 0.05). These values did not exhibit a significant variation over time. CONCLUSIONS: Serum MIP-1 alpha, MIP-1 beta and RANTES levels do not distinguish patients with AIDS from patients with non-progressing HIV infection. Variations in levels of these chemokines do not explain individual variation in the natural history of HIV infection.

Cancer occurrence and screening in family practice. A 20-year experience.

BACKGROUND: This article is a sequel to a previously published article describing the occurrence of cancer in a rural family practice and the contribution of screening to the diagnosis of breast, colorectal, and cervical cancer. Together, the two articles describe a 20-year family practice experience in diagnosing and screening for cancer. METHODS: The study is a retrospective chart review of all cancers diagnosed in a family practice from January 1985 through December 1994. Records of a regional tumor registry were reviewed to validate and ensure completeness of the cancer diagnoses. RESULTS: One hundred twenty-one cancers were identified during the 10-year study period in a population of approximately 4000 patients. Screening by fecal occult blood testing identified 11 of 20 colorectal cancers, mammography and physician examination identified 9 of 12 breast cancers, and a program of biannual Papanicolaou smears resulted in the diagnosis of 3 of 3 cervical cancers. Only 3 melanomas, 3 ovarian cancers, and 1 testicular cancer were diagnosed in this practice during the entire 20 years of the combined studies. CONCLUSIONS: The five most common cancers--skin, colorectal, lung, breast, and prostate--accounted for 71% of the cancers diagnosed. A high rate of provider and patient compliance with screening was achieved. Screening detected a majority of breast and colorectal cancers. Annual Papanicolaou smear screening would have provided no incremental benefit over the biannual screening used in this practice.

Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group.

OBJECTIVE: To compare the tolerability and efficacy of three oral regimens for the treatment of patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia. DESIGN: A randomized, double-blind study. SETTING: 24 U.S. academic medical centers. PATIENTS: 181 patients with morphologically confirmed P. carinii pneumonia and alveolar-arterial oxygen differences (PAO2-PaO2) of 45 mm Hg or less. INTERVENTION: Patients were randomly assigned to receive trimethoprim-sulfamethoxazole, dapsone-trimethoprim, or clindamycin-primaquine for 21 days. Patients with a PAO2-PaO2 of 35 to 45 mm Hg at study entry also received prednisone. MEASUREMENTS: Serial clinical and laboratory evaluations for therapeutic response and toxicity. Therapeutic failure at day 21 was defined by any of the following: increase in PAO2-PaO2 of greater than 20 mm Hg; no remission of baseline signs and symptoms; and change in antipneumocystis therapy for reasons other than toxicity, intubation, or death. Dose-limiting toxicity was defined as discontinuation of therapy by the primary physician because of one or more adverse reactions. RESULTS: No statistically significant differences were seen among treatment groups in the proportions of patients who had dose-limiting toxicity (P=0.2), therapeutic failure (P>0.2), or a complete course of therapy (P>0.2). Survival during therapy or for 2 months thereafter did not differ among the three groups (P>.02). However, elevation of serum aminotransferase levels to more than five times the baseline levels was more frequent in the trimethoprim-sulfamethoxazole group (P=0.003), and one or more serious hematologic toxicities (neutropenia, anemia, thrombocytopenia, or methemoglobinemia) occurred more frequently in the clindamycin-primaquine group (P=0.01). CONCLUSIONS: The rates of dose-limiting toxicity, therapeutic failure, and survival did not differ among patients with AIDS who were receiving oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, or clindamycin-primaquine for mild to moderate P. carinii pneumonia. However, the limited sample size prevents the unequivocal demonstration of the equality of these three regimens. Differences in expected categories of toxicities associated with each regimen should guide the clinician in choosing first-line therapy, particularly for patients with baseline hepatic insufficiency or myelosuppression.

Radioactivity: conception to birth. The Health Physics Society 1995 Radiology Centennial Hartman Oration.

Röntgen's description of his discovery of x rays was convincing and comprehensive. The response of the scientific community and public was immediate and intense. In contrast, the discovery of radioactivity was a muddled affair that excited little interest. While it would prove far more revolutionary than that of x rays, the discovery of radioactivity began, in the words of Alfred Romer, as something of a dead horse. There it lay, too big to ignore, but what did you do with it? Even the discoverer, Henri Becquerel, left it to decay and went on to pursue other interests. For various reasons, others chose to investigate: Marie and Pierre Curie in France, William Crookes in England, and Ernest Rutherford in Canada. But it was Frederick Soddy, a young chemist with a fascination for alchemy, who, together with Rutherford, revealed the true nature of radioactivity: transmutation.