Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry.

T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT-PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.

Catastrophic visual loss due to Cryptococcus neoformans meningitis.

We have reviewed our experience with 17 of our own patients with cryptococcal meningitis and 32 cases from the literature. Although this complication is an uncommon event, patients with cryptococcal meningitis may develop visual loss in the absence of other ocular lesions (endophthalmitis or cryptococcomas in the visual pathway) that could explain the visual symptoms. There are 2 distinct patterns of visual loss: rapid visual loss and slow visual loss. Rapid visual loss is characterized by onset of profound visual loss over a period as short as 12 hours before or early in the course of therapy and a clinical syndrome that is strongly suggestive of optic neuritis. Direct invasion of the optic nerve by C. neoformans is demonstrated by cases in this and other reports. Slow visual loss is characterized by slow but progressive visual loss which typically begins later during therapy and may be due to the effects of increased intracranial pressure. While the initial deficit may be mild, patients with slow visual loss can progress to severe visual loss over weeks to months. The only factors that appear to predict either pattern of visual loss are the presence of papilledema, an elevated CSF opening pressure, and a positive CSF India ink preparation. In the 25 visual loss patients for whom data were available for all 3 items, 10 (40%) were positive for all 3, as opposed to only 4 of 114 (3.5%) from a reference group of cryptococcal meningitis patients without visual loss (p < 0.00001). The only therapeutic measures with any degree of consistent success were those directed at reducing intracranial pressure. When begun early and used aggressively, such therapy halted and sometimes even reversed the course of visual loss, particularly in the slow visual loss group. Corticosteroids did not appear to be of value in the small number of patients who received them.

Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group.

PURPOSE: The purpose of this study was to assess the tolerance and efficacy of itraconazole in the treatment of coccidioidomycosis. PATIENTS AND METHODS: Fifty-one patients with nonmeningeal coccidioidomycosis were considered for treatment with intraconazole. Forty-nine patients who met study criteria were treated with itraconazole given orally in doses of 100 to 400 mg/day for periods up to 39 months. Of these patients, 12 had osteoarticular disease, 23 had chronic pulmonary disease, and 14 had skin or soft tissue disease. Clinical response was evaluated using a scoring system accounting for lesion number and size, symptoms, culture, and serologic titer. Remission was defined as reduction of the pretreatment score by 50% or more. RESULTS: Patients with osteoarticular, chronic pulmonary, and soft tissue disease improved at similar rates. Because two patients had no scoring assessment for efficacy, they were considered inassessable for efficacy. Forty-seven patients are evaluable. Of these patients, 44 have completed therapy, and three are still receiving itraconazole. Of the 44 patients no longer receiving therapy, 25 (57%) achieved remission. Of the 25 patients achieving remission, four later experienced a relapse. Therapy failed in 19 patients (43%). Of these cases, 16 (36%) were clinical failures and three (7%) developed drug intolerance that precluded continuation of treatment. Evaluation of culture conversions was of limited value in the osteoarticular patients, fewer than half of whom had follow-up biopsies. However, culture conversions were a useful index of response in patients with chronic pulmonary disease. During the course of treatment, serologic titers declined in the two groups with extrapulmonary disease, but not in patients with pulmonary coccidioidomycosis. Possible toxicities were generally mild. CONCLUSION: Itraconazole appears efficacious and very well tolerated in patients with coccidioidomycosis.

Ketoconazole therapy of progressive coccidioidomycosis. Comparison of 400- and 800-mg doses and observations at higher doses.

One hundred and twelve patients with progressive pulmonary, skeletal, or soft tissue infections caused by Coccidioides immitis were randomly assigned to treatment with 400 or 800 mg per day dosages of ketoconazole. During therapy, if response was unsatisfactory, the protocol provided for treatment with higher doses. With 400 mg, ketoconazole resulted in 23.2 percent successes, which was similar to 32.1 percent successes with 800-mg treatments (p = 0.29). An additional six of 23 patients in whom initial therapy failed and who later received 1,200 or 1,600 mg per day of ketoconazole also showed improvement. However, among patients completing successful courses of therapy, relapses were more frequent in those requiring higher than 400-mg dosages for their success. From these studies, it is concluded that ketoconazole in doses above those currently recommended offer little or no benefit for most patients with non-meningeal forms of coccidioidomycosis.

Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis.

A multicenter prospective randomized trial of four versus six weeks of amphotericin B, 0.3 mg/kg per day, plus flucytosine, 150 mg/kg per day, was performed with 194 patients with cryptococcal meningitis. One or more toxic drug reactions developed in 103 patients: azotemia (51), renal tubular acidosis (two), leukopenia (30), thrombocytopenia (22), diarrhea (26), nausea/vomiting (10), and hepatitis (13). The four- and six-week regimens were complicated by toxicity in 44 percent and 43 percent of cases, respectively. Toxicity appeared during the first two weeks of therapy in 56 percent and during the first four weeks in 87 percent. Azotemia did not occur more frequently in renal transplant recipients or diabetic patients. Cytopenias did not appear more often in patients with hematologic malignancies or those receiving immunosuppressive therapies. Toxic reactions that contributed to death developed in five patients (two with azotemia, one with pancytopenia, one with hepatitis, one with ileus). Amphotericin B-induced azotemia was not a significant risk factor for the subsequent development of bone marrow, gastrointestinal, or hepatic toxicity attributable to flucytosine. Flucytosine toxicity was associated with peak serum flucytosine levels of 100 micrograms/ml or more during two or more weeks of therapy (p = 0.005). Peak 5-fluorouracil levels were not predictive of toxicity. An initial dose of flucytosine is recommended based on the creatinine clearance: 150 mg/kg per day at a creatinine clearance above 50 ml/minute, 75 mg/kg per day at a creatinine clearance of 26 to 50 ml/minute, and 37 mg/kg per day at a creatinine clearance of 13 to 25 ml/minute. The serum creatinine level should be monitored twice weekly and the creatinine clearance weekly during therapy in order to anticipate changes in serum flucytosine concentration. In addition, it is recommended that the serum flucytosine level be determined two hours after an oral dose once a week, and that the dose be adjusted to maintain a level of 50 to 100 micrograms/ml.

Heterogeneity of natural killer lymphocyte abnormalities in colon cancer patients.

p6e monoclonal antibody HNK-1 reacts exclusively with human granular lymphocytes that comprise 16 +/- 1.4% of blood mononuclear cells. In normal individuals, almost all natural killer (NK) and killer (K) cell function resides in this lymphocyte subset. The level of HNK-1+ granular lymphocytes, their stage of differentiation, and NK cell function were examined in 70 colon cancer patients and the results compared with data for 114 age-matched normal individuals. Median levels of granular lymphocytes were significantly depressed in colon cancer patients compared to controls (9% versus 16.5%, P less than 0.0001). Despite the depressed numbers of circulating HNK-1+ cells, NK cell function in the colon cancer patients was essentially the same as in normals (P = 0.78). The HNK-1+ lymphocyte level correlated exactly with NK cell function in about two thirds of normal individuals but only one third of colon cancer patients (P = 0.025). Three possible mechanisms for this dichotomy were examined. First, lymphoid cell subpopulations purified with a fluorescence-activated cell sorter (FACS) were examined for altered NK cell functional activity. HNK-1+ cells from the colon cancer patients exhibited significantly less NK functional activity compared to normals (796 versus 1046 lytic units, P = 0.04). Interestingly, the HNK-1- fraction (predominantly T lymphocytes) had increased NK cell functional activity in the colon cancer patients compared to normals (373 versus 218 lytic units, P = 0.0001). Purified monocytes did not contribute to NK cell functional activity. Second, the functional maturity of the HNK-1+ lymphocytes was correlated with NK activity. Two subsets of HNK-1+ cells were identified by surface membrane markers and purified with the FACS. The more mature HNK-1+ subset (i.e., HNK+Leu-4-M1+) exhibited almost ten times more NK cell functional activity than did the less mature cell fraction (i.e., HNK+Leu-4+M1-) cells in normal individuals (2230 versus 286 lytic units/10(7) cells). Further analysis demonstrated that the ratio of mature to immature HNK+ cells in normal individuals was 3:1, while it was decreased to a 1:1 ratio in colon cancer patients P = 0.005). Third, the influence of prostaglandin-mediated suppression on NK cell activity was examined. PGE2 did not appear to influence NK cell function, since NK cell function was unchanged in vitro in the presence of a prostaglandin synthesis inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)

Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients.

The immune regulation of phytohemagglutinin (PHA) and concanavalin A (Con A) mitogen responses by prostaglandin (PG)-producing suppressor monocytes was examined in 57 patients with colorectal cancer and 55 normal individuals. The blood lymphocyte responses to either PHA or Con A were significantly depressed in 74% of patients compared to normal controls. The mean PHA response for the patients was significantly lower than that for controls (17,649 versus 25,549 cpm, P = 0.02), while the mean Con A response for the patients was also depressed but not as significantly (13,551 versus 18,623 cpm, P = 0.09). The depression of immune competence was greatest in older patients and those with metastatic disease. The addition of indomethacin (1 microgram/ml) to cell cultures of both patients and normal individuals enhanced the mitogen response, suggesting that PGE-producing suppressor cells were operative in both groups. Among the patient group, however, a differential modulation of the immune response by indomethacin was observed. Thus, the addition of indomethacin restored the PHA response in patients almost to normal levels, while the Con A increase was less pronounced. Even after indomethacin treatment, the Con A proliferative response by lymphocytes was significantly depressed in patients as compared to controls (P = 0.002). To prove that indomethacin was blocking excessive PG production by suppressor monocytes in colon cancer patients, we directly measured PGE2 production by peripheral blood mononuclear cells (PBMCs) using a radioimmunoassay. PBMCs from the patients produced significantly greater amounts of PGE2 compared to controls (10.1 versus 5.1 ng/ml, P = 0.0001). This comparison was still significant after adjustment for age and sex. The increased PGE2 production appeared to be selective, since the levels of two other arachidonic acid metabolites, PGF1 alpha and thromboxane B2, were the same or less than control levels. PG-mediated immune suppression of mitogenesis thus appears to be abnormally increased in colon cancer patients, particularly for the PHA response. This abnormality was partially corrected in vitro by incubation of the PBMCs with indomethacin, a prostaglandin synthetase inhibitor.

Effect of labor on the postpartum bladder.

Urodynamic investigations were performed on 20 patients at 48 hours and at four weeks after delivery to assess the effect of modern obstetric practice on the postpartum bladder. Although there were significant differences in some values over this period, the mean urodynamic measurements on both occasions were within normal limits. It is concluded that the current management of labor does not predispose women to bladder hypotonia, the chief factors responsible being avoidance of prolonged labor and early catheterization after delivery.

Sonographic measurements and ratios in fetuses with Down syndrome.

Ultrasound measurements of 15 fetuses with trisomy 21 detected during the 17th week of gestation were matched retrospectively to those of 45 normal controls. We compared nine standard ultrasound measurements of the fetal head, abdomen, and femur in these two groups. The fetuses with trisomy 21 had significantly shorter mean femur lengths, narrower occipitofrontal diameters, and increased biparietal diameter (BPD)/femur length and abdominal circumference/femur length ratios. An increased BPD/femur length ratio was the ultrasound finding that best predicted a fetus with Down syndrome. A BPD/femur length ratio of 1.80 or higher was 40% sensitive and 97.8% specific in predicting Down syndrome, and had a false-positive rate of only 2.2%. An increased second-trimester BPD/femur length ratio measured by ultrasound may prove beneficial as an additional screening test for Down syndrome.

Risk for gonococcal and chlamydial cervicitis in adolescent females: incidence and recurrence in a prospective cohort study.

PURPOSE: This study attempted to determine the incidence and risk for gonococcal and chlamydial cervicitis among sexually active urban adolescent females. METHODS: The study design is a prospective cohort study. A cohort of 216 sexually active females were followed with repeat sexually transmitted diseases screening for 12-24 months. Subjects positive on any retest (FU) were compared with those who remained negative on all FU. Subjects were interviewed for history and screened for endocervical gonococcal and chlamydial infection. RESULTS: The number of visits per patient ranged from 2 to 9 (median, 3). The initial Chlamydia trachomatis and Neisseria gonorrhoeae rates were 23.2 and 11.6%, respectively. The cumulative FU positive rates were 20.8% for C. trachomatis and 17.1% for N. gonorrhoeae. Although the initial gonococcal infection was a significant risk for a subsequent infection by C. trachomatis (p = .05) and N. gonorrhoeae (p = .001), the initial C. trachomatis status was not predictive of subsequent infections. The number of partners was not predictive of subsequent infections with either. In the entire study period, 86 patients had at least one episode of C. trachomatis and N. gonorrhoeae infection was confirmed in 52; 20 patients had recurrent cervicitis. During the study, 101 episodes of C. trachomatis and 68 episodes of N. gonorrhoeae infections were identified. Those with recurrent cervicitis (9.3%) were responsible for 33% of all cervicitis episodes identified during the study. CONCLUSIONS: Adolescents in our study were at high risk for cervicitis, particularly as a result of C. trachomatis. Risk for subsequent C. trachomatis cervicitis was the same among initially positive and negative groups. Our data underscore the importance of repeat screening for sexually transmitted infections and treatment of contacts of adolescent females.

Sexual contact tracing outcome in adolescent chlamydial and gonococcal cervicitis cases.

BACKGROUND AND OBJECTIVE: Treatment of sex partners is an essential part of sexually transmitted diseases (STD) control. This study examined the efficacy of contact tracing via patient self-referral in gonococcal and chlamydial cervicitis cases among adolescents, compared with the effectiveness of provider-referral. STUDY DESIGN: Adolescent females with culture-proven chlamydial or gonococcal cervicitis were the study subjects. This cohort study was done in an urban non-STD clinic setting. The subjects chose either provider-notification or self-notification method to inform their sex partner(s) in 2 months preceding the interview date. RESULTS: Two hundred and sixty-five eligible subjects (91% African-American, 9% white) were identified. One hundred and ninety-eight sex contacts were reported by 165 (62%) cases; no contact was elicited in the remaining 100 (38%). The follow-up data revealed that 129/198 (66%) contacts were informed: 63 contacts by 61 index cases, 54 contacts of 47 cases by the case manager, 9 by both methods, and 3 by unspecified means. History of treatment was obtained in 54 contacts, including 37% (23/63) of patient-notified contacts and 50% (27/54) of provider-notified contacts; these 54 contacts constituted 42% of informed contacts, or 27% of all named contacts. The mean number of sexual contacts treated per index case was 0.58 (27/47) for the provider-referral groups and 0.38 (23/61) for the self-referral groups. Successful contact tracing was documented in 19.3% (51/265) of all index cases, resulting in treatment of 54 contacts. CONCLUSION: This study demonstrates the need for more effective partner treatment strategies in adolescent STD cases.

Fetal myelomeningocele. Is antenatal ultrasound useful in predicting neonatal outcome?

The objective of this study was to determine if an ultra-sound examination, when performed in the third trimester immediately preceding delivery, is useful in predicting outcome in infants with a myelomeningocele. A retrospective review was undertaken of prenatal ultrasound records and pediatric outcome data on fetuses with isolated myelomeningocele referred to our institution after 28 weeks' gestation during a three-year period. Macrocephaly proved to be the one antenatal ultrasound finding that most correlated with later poor outcomes in infants with myelomeningocele. Macrocephalic fetuses had a longer mean hospital stay after birth and were more likely to have significant respiratory and feeding difficulties. No fetus with macrocephaly had a normal mental score, and all had severe motor deficits on later follow-up testing. The ultrasound diagnosis of macrocephaly identified a group of fetuses with myelomeningocele, who were at highest risk of neonatal problems and developmental delay. Cesarean delivery and aggressive medical treatment of complications did not improve the outcome in these infants. This finding will be useful when counseling patients regarding route of delivery and in pediatric decisions regarding treatment of complications.

Invasive fungal infections in low-risk liver transplant recipients: a multi-center prospective observational study.

Prevention of invasive fungal infections (IFIs) in orthotopic liver transplant (OLT) recipients utilizing postoperative systemic antifungal prophylaxis, typically with fluconazole, is justified among those at high risk for IFI. Use of postoperative antifungal prophylaxis for low-risk OLT recipients is widely practiced but not universally accepted nor supported by data. We conducted a prospective observational study among 200 OLT recipients who were at low risk for IFI and did not receive postoperative antifungal prophylaxis. Patients were considered low risk if they had /=units of 40 blood products or return to the operating room for intra-abdominal bleeding; return to the operating room for anastomotic leak or vascular insufficiency; preoperative serum creatinine of >/=2 mg/dL; and perioperative Candida colonization. Patients were followed 100 d post-transplantation for evidence of IFI. Of 193 eligible patients, 7 (4%) developed an IFI. Three (2%) IFIs were due to Candida spp. and potentially preventable by standard fluconazole prophylaxis. Three patients developed invasive aspergillosis; one developed late onset disseminated cryptococcosis. Liver transplant recipients at low risk for IFI can be identified utilizing pre-determined criteria, and post-transplantation antifungal prophylaxis can be routinely withheld in these patients.

The koilocyte and cervical intraepithelial neoplasia: time-trend analysis of a recent decade.

To determine whether the role of the human papillomavirus in the development of cervical intraepithelial neoplasia has changed recently, cervical biopsy specimens from the years 1972 and 1982 were reviewed to compare the frequency of diagnosis of human papillomavirus-associated koilocytosis in patients with suspected cervical intraepithelial neoplasia. No significant difference was found in the frequency of koilocytosis in biopsy specimens with cervical intraepithelial neoplasia between the years, koilocytosis being present in about half of the cases of cervical intraepithelial neoplasia during both years. In each year koilocytosis was more common in grades 1 and 2 lesions. Koilocytotic atypia without cervical intraepithelial neoplasia also was present in a relatively constant proportion of cases over the decade (8.0% and 6.5%). The average patient age was younger in 1982 than in 1972 (27.6 versus 32.6 years), but analysis of patients by age groups again showed no significant difference in the occurrence of koilocytosis. This study suggests that the relative importance of human papillomavirus in the evolution of cervical intraepithelial neoplasia has remained unchanged in the recent past.

Working parents: the impact of day care and breast-feeding on cytomegalovirus infections in offspring.

The increase in the popularity of breast feeding and utilization of child care arrangements are having a major effect on the epidemiology of cytomegalovirus infections. The impact is greater for women of upper socioeconomic background who send their toddlers to day-care centers and for day-care workers. If primary cytomegalovirus infections occur during pregnancy it is logical to anticipate more cases of severe congenital infections.

Malpractice in pediatric radiology: a survey in the United States and Canada.

A survey of the chairmen of pediatric radiology departments in children's hospitals in Canada and the United States was undertaken to gain data on the subject of malpractice in pediatric radiology. Sixty-two members of the Society of Chairmen of Radiology in Children's Hospitals (SCORCH) were surveyed. Forty-two surveys (65%) were returned for analysis. Malpractice premiums paid per pediatric radiologist per year ranged from $499-$29,000 (mean $8,630). Twenty-eight malpractice claims were reported from 1980 to 1992. The largest number of claims involved gastrointestinal/abdomen and chest examinations, areas that were perceived as low risk by the respondents. The incidence of lawsuits against pediatric radiologists in the midwest was statistically higher compared to Canada (p < 0.05). Private practice models had a statistically greater incidence of malpractice suits compared to university practice models (p < 0.04). No statistical difference between the number of malpractice suits and the number of examinations performed per year or the number of pediatric radiologists in the group was found. We concluded that pediatric radiologists run the risk of malpractice claims. This data may aid in lessening this risk in the future.

Increased rate of cytomegalovirus infection among parents of children attending day-care centers.

We screened parents of children from three previously studied day-care centers where children have maintained high rates of cytomegalovirus (CMV) excretion, as well as parents of children not in day-care centers (controls), for antibody to CMV. Longitudinal serologic follow-up of seronegative parents revealed that 14 of 67 with children in the day-care centers acquired CMV, as compared with none of 31 controls (P less than 0.003). All 14 parents who seroconverted had a child who was shedding CMV in saliva or urine. Among the day-care group, acquisition of CMV occurred in 14 of 46 parents of children who shed CMV, as compared with none of 21 whose children did not excrete the virus (P less than 0.0001). There was no correlation between parental seroconversion and sex, race, age, number of years of education, marital status, occupation, or number of children in the home. CMV infection occurred in 9 of 20 parents (45 percent) with a child shedding CMV who was 18 months of age or less at enrollment. We conclude that children often transmit CMV to parents and could be an important source of maternal CMV infection during pregnancy.

In vitro natural killer and lymphokine-activated killer activity in patients with bronchogenic carcinoma.

The authors examined peripheral blood mononuclear cells from 45 patients with bronchogenic carcinoma to determine natural killer (NK) and lymphokine-activated killer (LAK) activity after in vitro incubation with media alone or media plus interferon gamma (IFN, 200 U/ml) and/or interleukin-2 (IL-2, 100 U/ml). Our results show that lymphocytes from patients with bronchogenic carcinoma can acquire LAK activity, but the level of activity acquired was significantly lower compared with lymphocytes from 25 control subjects when IL-2 cultures were supplemented with 10% autologous human serum (AHS) (15.6% +/- 2.1% specific release versus 26.0% +/- 2.9% specific release, P = 0.004). The LAK activity, defined as cytotoxicity of an NK-resistant cell line, of the patients' lymphocytes was augmented when cells were cultured with both IL-2 and IFN compared with IL-2 alone (P = 0.0001, paired t-test). Control subjects were unchanged (P = 0.09). There was no significant difference between groups of patients with different histologic types of tumor or different stages of disease. The NK activity, defined as killing of NK-sensitive K-562 target cells, of the patients' lymphocytes was not significantly different from that of the controls' lymphocytes (42.8% +/- 3.0% specific release versus 49.3% +/- 3.3% specific release, P = 0.16). These studies indicate the feasibility of IL-2 and IFN therapy in patients with bronchogenic carcinoma.