Oestrogen-mediated phosphorylation and stabilization of BRCA2 protein in breast.

Disease-associated BRCA2 mutations typically result in protein truncations that delete the phosphorylation-regulated S3291 BRCA2 domain that interacts with Rad51. BRCA2 hereditary breast cancers are usually ER(+), differing from BRCA1 hereditary cancers, which are usually ER(-). We studied BRCA2 protein expression and S3291 phosphorylation in normal breast tissues and in sporadic breast cancers and observed that BRCA2 is expressed and phosphorylated in normal breast and 10 ER(+) breast cancers but not in 10 ER(-) breast cancers. In order to study this correlation between ER and BRCA2 expression, we studied ER(+) breast cancer cell lines. We found that a rapid increase in BRCA2 S3291 phosphorylation occurs following 17-beta-oestradiol (E2) treatment. This increase seen in BRCA2 total and phospho-S3291 protein levels was found to be unaffected with cycloheximide pre-treatment, but decreased following tamoxifen, ICI 182,780 or roscovitine treatment. This suggests a requirement for ER and cdk (cyclin-dependent kinase) in mediating the increased protein levels. MCF7 cell cycle distribution analysis following E2, in both the presence and absence of roscovitine (a cdk inhibitor), did not demonstrate any changes during an 8 h period, which further supports our hypothesis that mitogenic effects of E2 are not predominant at early time points. Studies with MG132 proteasome inhibitor and siRNA to skp2 support a model in which skp2-mediated proteasomal degradation of BRCA2 rapidly degrades BRCA2 protein in the absence of hormone treatment, which likely inhibits this pathway. E2 was shown to improve survival of MCF7 cells upon radiation treatment and roscovitine partially reversed this effect. We have demonstrated that BRCA2 protein is specifically expressed in ER(+) breast cancers and are investigating a pathway that may show a link between E2 action and BRCA2 protein function in breast cancer.

Sources of variability in repeated T-helper lymphocyte counts from human immunodeficiency virus type 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important.

The study objective was to determine the causes and magnitude of absolute CD4 (T4) count variation in human immunodeficiency virus type 1 (HIV-1)-infected (+) adult males. We conducted a prospective, blinded, and controlled study of 22 adult military male outpatients, including 16 HIV(+) [12 in Walter Reed stage (WR-) 1 through 5, 4 in WR-6 (AIDS)], and 6 HIV seronegative (-) healthy controls. Ten CD4+ cell counts were drawn within a 3-day interval from each patient at the following times: 0800, 1200, 1600, and 2200 h on day 1; and 0800, 1200, and 1600 h on days 2 and 3. A significant CD4+ cell count diurnal increase of 59 cells/mm3 was detected between 0800 h and 2200 h from the WR-1-5 patients (p = 0.018), although this diurnal change was significantly blunted (p = 0.028) as compared with the 506 cells/mm3 CD4+ cell count diurnal increase observed from the HIV(-) healthy controls. The coefficients of variation [CV = (standard deviation/average) x 100] of the three daily 0800 h CD4 cell counts from each patient were 15 (median) and 19 (average) for the WR-1-5 patient group. Blood leukocyte counts, differential fractions of lymphocytes, and total lymphocyte counts contributed more to the observed CD4+ cell count variability than did the CD4% measurements [CV = 7.5 (median), 11 (average)] obtained from flow cytometry. We conclude that the large fluctuations that we observed in repeated CD4+ cell counts in HIV(+) patients can be explained in part by CD4+ cell count diurnal cycle and in part by high variability in total lymphocyte counts.(ABSTRACT TRUNCATED AT 250 WORDS)

Syphilis and neurosyphilis in a human immunodeficiency virus type-1 seropositive population: evidence for frequent serologic relapse after therapy.

OBJECTIVE: To describe clinical and treatment aspects of syphilis infection among patients seropositive for the human immunodeficiency virus (HIV). PATIENTS AND METHODS: Results of serologic tests for syphilis, CD4+ T-lymphocyte counts, and clinical response to therapy were retrospectively monitored in 100 HIV-infected adults with syphilis from a tertiary-care military HIV program. RESULTS: Of the 1,206 HIV-infected patients, 100 (8.3%) in the cohort had syphilis; 61 patients were treated for active syphilis. Serologic or clinical relapse eventually occurred in 10 of the 56 treated patients (17.9%) with follow-up available; 7 of the 10 who relapsed had previously received high-dose intravenous or procaine penicillin therapy. Relapse occurred more than 12 months after initial therapy in 6 of 10 patients (60%) who experienced relapse; 5 patients experienced multiple relapses. The mean CD4+ T-lymphocyte count was not predictive of relapse. Patients with reactive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test titers (4 of 7 patients [57%]) or the rash of secondary syphilis (4 of 14 patients [29%]) were at highest risk of subsequent relapse or treatment failure when monitored for an average of 2 years. CONCLUSION: Standard penicillin regimens, including high-dose intravenous penicillin, transiently lowered serum VDRL titers in nearly all cases, but were sometimes inadequate in preventing serologic and clinical relapse in patients infected with HIV type-1, especially among those with secondary syphilis and reactive CSF VDRL titers. Careful long-term follow-up is essential, and repeated courses of therapy may be needed for patients infected with HIV type-1 who have syphilis.

Corticosteroids for Pneumocystis carinii pneumonia with acute respiratory failure. Experience with rescue therapy.

Corticosteroids have proven effective as adjunctive therapy for the treatment of PCP in patients with AIDS, when begun within 72 h of conventional anti-Pneumocystis therapy. Their efficacy as rescue (or salvage) therapy in patients who have failed conventional therapy, however, remains unproven. Ths report presents our experience with 16 patients admitted to our MICU for acute respiratory failure (PaO2/FIO2 ratio less than or equal to 150) due to PCP. Five of six patients (83 percent) who received "primary" CS rescue (initial CS use prompted by acute respiratory failure after 72 h of conventional anti-Pneumocystis therapy) survived hospitalization. Our experience suggests that CSs may be effective even when started after 72 h of conventional therapy. Additional studies are needed to clarify the role of CS rescue therapy.

Epidemiology, preventive services, and illnesses of international travelers.

Medical preparation of travelers to overseas locations is an important part of military medical care. We reviewed pre-travel records of patients attending the travel clinic at the National Naval Medical Center (NNMC) and used a post-travel questionnaire to determine the most frequent medical problems associated with international travel. Among 1,416 individuals who received pre-travel care at NNMC, there were 760 (54%) males and 656 (46%) females, the median patient age was 48 years, the most common reason for travel was pleasure, and the median duration of travel was 21 days. The most common destinations were Asia (27%), Africa (15%), Europe (13%), Central America/Caribbean (12%), and South America (11%). The median number of immunizations prescribed was three. Malaria chemoprophylaxis was prescribed to 45%. The average cost of vaccines and medications to medically prepare a traveler was $67. Among 271 (82%) who returned the post-travel questionnaire, the most common illnesses reported were diarrhea (23%) and upper respiratory infections (19%); medical treatment was sought by 9%. Properly informed, military physicians can provide a valuable service at a reasonable cost to reduce the risk of travel-acquired medical problems and illnesses.

Syphilitic osteitis in a patient with secondary syphilis and concurrent human immunodeficiency virus infection.

Destructive bone disease is a well-recognized complication of congenital and tertiary syphilis. Clinically significant osteitis and osteomyelitis are rare complications of primary or secondary syphilis in patients who are not infected with human immunodeficiency virus (HIV). We report a case of an HIV-infected man who presented with symptomatic, left ulnar osteitis as the initial manifestation of secondary syphilis. The patient's clinical course was complicated by a pathological fracture, but he responded to high-dose intravenous penicillin G therapy and surgical intervention. Results of physical examination on follow-up at 15 months were normal, and a serofast (rapid plasma reagin [RPR]) titer of 1:4 and a markedly decreased uptake on bone scintigraphy were observed. Our case report suggests that bone disease can represent an atypical manifestation of early acquired syphilis and that HIV-positive patients who present with orthopedic complaints or bone lesions should be evaluated for the presence of syphilitic bone disease.

Measles seroprevalence and vaccine response in HIV-infected adults.

Measles in HIV-infected patients can be a severe, even fatal, illness. The prevalence of measles seropositivity in HIV-infected adults and the durability of these antibody levels are uncertain. A prospective survey of 210 HIV-infected adults found that 95% of the adults had demonstrable antibodies using a standard ELISA technique. Seropositivity was no different in patients with CD4 counts over 400, from those with more advanced disease and CD4 counts under 200 (p = 0.8). Six seronegative patients were vaccinated and had serial antibody determinations: two of six (33%) patients had a durable positive antibody response at 1 year, and none had any observed toxicity. Vaccination of the identified measles-seronegative HIV-infected adults who are at high risk for measles is recommended, but a measurable antibody response may be expected in only a minority of cases.

Neuropsychological effects of Interferon Alfa-n3 treatment in asymptomatic human immunodeficiency virus-1-infected individuals.

Eighteen asymptomatic HIV-1-infected (HIV+) individuals were evaluated neuropsychologically before and during Interferon Alfa-n3 treatment. All 18 were evaluated twice, and 9 were evaluated three times. Analyses revealed few significant effects of treatment on cognitive, motor, and affective function. Improvements occurred over visits on measures of attention and appeared to reflect practice effects. Decrements occurred over visits on measures of procedural and supraspan learning. Examination of the data suggested that decrements were due to procedural artifacts and were not medication effects. In contrast to prior studies reporting significant neuropsychiatric side effects of interferon alpha treatment, few such effects occurred when HIV+ individuals were treated with Interferon Alfa-n3 and were evaluated neuropsychologically in a systematic manner.

Varicella immunity and clinical disease in HIV-infected adults.

Varicella is an infrequent but potentially severe infection in adult HIV-infected patients. We reviewed five cases of varicella in HIV-seropositive men; two were complicated by severe headache and meningismus, and one of these patients also had hepatitis and thrombocytopenia. All five patients responded well to acyclovir therapy, but one patient had dermatomal zoster 2 years later, and another failed to have detectable antibody after infection. We also performed a serosurvey on 181 consecutive HIV-infected patients presenting themselves for evaluation. A total of 95% of these patients had demonstrable antibody to varicella-zoster virus. Immune status to varicella did not correlate with the declining CD4 count, which was well preserved even in patients with fewer than 200 CD4 cells/mm3.

Recombinant immunoblot assays for hepatitis C in human immunodeficiency virus type 1-infected US Navy personnel.

The prevalence of hepatitis A, B, C, and D viruses was studied in 467 military personnel with human immunodeficiency virus type 1 (HIV-1) infection. Antibody to hepatitis C virus (anti-HCV) by first-generation ELISA was found in 136 (29%). Of sera repeatedly reactive for anti-HCV by first-generation ELISA, two-antigen recombinant immunoblot assay (RIBA) was positive in 41 (32%) and four-antigen RIBA was positive in 55 (41%). Four-antigen RIBA was positive in 33 (30%) of the 109 with an OD on ELISA of < or = 2.0 compared with 22 (81%) of the 27 with an OD > 2.0 (P < .001). Anti-HCV detected by four-antigen RIBA was associated with increasing age, black or Hispanic race, and antibody to hepatitis B core antigen. When patients with hepatitis B surface antigen were excluded, elevated alanine aminotransferase was found in 5 (8%) of 63 with a negative RIBA and 13 (28%) of 47 with a positive RIBA (P = .006). While RIBA was negative in more than half of those with anti-HCV by ELISA, 55 (12%) of these HIV-1 infected personnel had anti-HCV detected by RIBA, which was associated with a strong reaction by ELISA, elevated liver enzymes, coinfection with hepatitis B, minority race, and older age.

Drug susceptibility of Mycobacterium tuberculosis isolates from recent Haitian migrants: correlation with clinical response.

Between November 1991 and June 1993, approximately 11,000 Haitian migrants were screened for active tuberculosis and human immunodeficiency virus type 1 (HIV-1) infection at the U.S. Naval Base in Guantánamo Bay, Cuba. Cultures of specimens from 37 of these patients yielded Mycobacterium tuberculosis; eight (22%) of these isolates were resistant to standard medications, including isoniazid (22%), rifampin (0), ethambutol (3%), and streptomycin (3%). Two isolates (5.4%) were resistant to two drugs simultaneously. All but one of 340 patients who were treated for presumptive active tuberculosis and who were followed up for about 1 month had a favorable initial clinical response to a standard four-drug regimen. Among 259 HIV-1-infected patients who had normal findings on screening chest radiographs and who received prophylaxis with isoniazid, there were 1.8 incident cases of active tuberculosis per 100 person-years; this rate was 76% lower than that (reported by others) among HIV-1-infected Haitian patients who were not treated with isoniazid. No serious toxic effects due to standard four-drug regimens or to prophylaxis with isoniazid were observed. These data suggest that standard empirical therapeutic interventions for tuberculosis are adequate and well tolerated in Haitian migrants.

Phase I trial of interferon alfa-n3 in early-stage human immunodeficiency virus type 1 disease: evidence for drug safety, tolerance, and antiviral activity.

The safety and tolerance of interferon alfa-n3 (IFN-alpha n3) was tested in 20 adults with asymptomatic human immunodeficiency virus type 1 (HIV-1) infection (> 400 CD4 lymphocytes/mm3). IFN-alpha n3 was self-injected three times per week for 3-6 months: 5 patients received 1 mega-IU (MIU)/dose, 10 received 5 MIU/dose, and 5 escalated to their maximum tolerated dose. Subjects were evaluated every 2-4 weeks through 2 months after cessation of treatment. Neuropsychological tests were given at 3-month intervals. Markers of IFN activity, anti-IFN neutralizing antibodies, and antiviral response were measured monthly. IFN-alpha n3 was safe and well tolerated: influenza-like symptoms were uncommon, laboratory toxicity was minimal, no adverse neurobehavioral side effects were evident, and no patient developed neutralizing antibodies against IFN. IFN-alpha n3 induced IFN-specific biologic responses and dose-related antiviral activity against HIV-1. Subjects showed stabilization of CD4 cells for > 20 months. IFN-alpha n3 should be studied in combination with other antiretroviral agents and in persons with more advanced HIV-1 infection.

Neurocognitive impairment in human immunodeficiency virus infection is correlated with sexually transmitted disease history.

BACKGROUND AND OBJECTIVES: Neurocognitive impairment is common in human immunodeficiency virus (HIV)-infected subjects. The relationship of sexually transmitted diseases to neurocognitive changes is unknown. GOAL: To establish whether HIV-infected patients with a history of syphilis or gonorrhea have a higher rate of neurocognitive dysfunction. STUDY DESIGN: Neurocognitive function was measured by a battery of quantitative tests in a 453-person HIV-infected cohort and a 219-person HIV-seronegative control group. Neurocognitive function was then correlated with histories of either syphilis or gonorrhea to assess for possible relationships between these sexually transmitted diseases and neurologic impairment. RESULTS: Human immunodeficiency virus-infected subjects with a history of either syphilis or gonorrhea tended to perform worse on neurocognitive testing than their counterparts. This difference could not be explained by educational attainment, age, race or CD4 cell count, and was not noted in the HIV-uninfected control subjects. CONCLUSIONS: Sexually transmitted diseases in HIV-infected subjects are correlated with neurocognitive impairment through an unidentified mechanism.