Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold.

Dengue and West Nile viruses (WNV) are mosquito-borne members of flaviviruses that cause significant morbidity and mortality. There is no approved vaccine or antiviral drugs for human use to date. In this study, a series of functionalized meta and para aminobenzamide derivatives were synthesized and subsequently screened in vitro against Dengue virus and West Nile virus proteases. Four active compounds were identified which showed comparable activity toward the two proteases and shared in common a meta or para(phenoxy)phenyl group. The inhibition constants (K(i)) for the most potent compound 7n against Dengue and West Nile virus proteases were 8.77 and 5.55 µM, respectively. The kinetics data support a competitive mode of inhibition of both proteases by compound 7n. This conclusion is further supported by molecular modeling. This study reveals a new chemical scaffold which is amenable to further optimization to yield potent inhibitors of the viral proteases via the combined utilization of iterative medicinal chemistry/structure-activity relationship studies and in vitro screening.

Hemorrhagic adenovirus cystitis after renal transplantation.

PURPOSE: Viral infections are a major cause of postoperative morbidity and mortality after renal transplantation. Although cytomegalovirus, Epstein-Barr virus, and polyoma virus infections are common, there have been only a few reports of adenovirus infections. MATERIALS AND METHODS: We report an unusual case of a patient with adenovirus-induced hemorrhagic cystitis (AHC). We also performed a comprehensive MEDLINE review to identify similar cases. We then compared the presentation, management, and outcome of all patients to identify patterns that may facilitate the diagnosis and management of AHC. RESULTS: Review of the literature revealed 36 other reported cases of AHC in renal transplant recipients. Thirty-six of the 37 cases occurred within 1 year of transplantation. These patients presented with fever, dysuria, hematuria, and graft dysfunction. Thirty-four received high-dose steroids for treatment of symptoms of acute rejection. Four patients received antiviral medications. The infection was self-limited with mean duration of symptoms being 20 days. In all cases, serum creatinine returned to baseline or near baseline levels with resolution of symptoms. CONCLUSIONS: Although uncommon, AHC usually presents within 1 year of renal transplantation with a consistent constellation of symptoms. The infection appears to be self-limited with full recovery in most patients within 4 weeks. The efficacy of antiviral medications could not be determined in this review.

Early discharge of infected patients through appropriate antibiotic use.

BACKGROUND: Patients with infections are usually discharged from the hospital with antibiotics when afebrile and clinically improved. OBJECTIVES: To compare outcomes of early vs conventionally discharged patients and to examine the role of antibiotic use in the discharge process. METHODS: One hundred eleven patients hospitalized with cellulitis, community-acquired pneumonia, or pyelonephritis (urinary tract infection) discharged from the hospital early in their clinical course before defervescence by an infectious diseases hospitalist (L.J.E.) were compared in a case-controlled study with 112 patients discharged from the hospital according to conventional standards of care by internal medicine (IM) hospitalists. Patients were matched for age, sex, diagnosis, and comorbidities. Outcomes were determined for average lengths of stay, readmission to the hospital within 30 days with the same diagnosis, satisfaction with their discharge program, and time to return to their normal activities of daily living. RESULTS: Patients cared for by the infectious diseases hospitalist had a shorter average length of stay (mean difference, 1.7 days), no readmissions, higher satisfaction scores, and a shorter time to return to their activities of daily living, compared with those cared for by the IM hospitalists. Analysis of the antibiotics that patients were discharged with revealed that the infectious diseases hospitalist used outpatient parenteral antibiotic therapy more frequently than IM hospitalists in the treatment of cellulitis, and switched from intravenous to oral antibiotics sooner than IM hospitalists for patients with community-acquired pneumonia and urinary tract infection. CONCLUSIONS: The infectious diseases hospitalist discharged patients from the hospital earlier than the IM hospitalists by more efficient use of antibiotics. The earlier discharge did not adversely affect outcomes.

Normative influences on aggression in urban elementary school classrooms.

We report a study aimed at understanding the effects of classroom normative influences on individual aggressive behavior, using samples of 614 and 427 urban elementary school children. Participants were assessed with measures of aggressive behavior and normative beliefs about aggression. We tested hypotheses related to the effects of personal normative beliefs, descriptive classroom norms (the central tendency of classmates' aggressive behavior), injunctive classroom normative beliefs (classmates' beliefs about the acceptability of aggression), and norm salience (student and teacher sanctions against aggression) on longitudinal changes in aggressive behavior and beliefs. injunctive norms affected individual normative beliefs and aggression, but descriptive norms had no effect on either. In classrooms where students and teachers made norms against aggression salient, aggressive behavior diminished over time. Implications for classroom behavior management and further research are discussed.

Targeting lurking pathogens in acute traumatic and chronic wounds.

The appropriate antimicrobial treatment for skin and soft tissue following acute trauma is determined by the mechanism of injury, time from injury to treatment, environmental wound contamination, pathogenicity of colonizing bacteria, and patient-specific issues. These factors can be used to predict the risk of secondary infection of wounds. Although common skin pathogens (such as Staphylococcus aureus and group A Streptococcus) cause most secondary wound infections, antibiotic therapy sometimes must be directed against unusual pathogens that are associated with atypical wounds, such as animal bites (amoxicillin with clavulanate for Pasteurella multocida) and plantar puncture wounds (ciprofloxacin for Pseudomonas aeruginosa). This customized treatment approach is also appropriate for chronic wounds, such as pressure and diabetic foot ulcers. In addition to antibiotic therapy, wound management may include surgical debridement. Active areas of investigation in wound management include the use of growth factors and hyperbaric oxygen.

Mupirocin cream is as effective as oral cephalexin in the treatment of secondarily infected wounds.

BACKGROUND: Topical antimicrobials have been considered for treatment of secondarily infected wounds because of the potential for reduced risk of adverse effects and greater patient convenience. We compared mupirocin cream with oral cephalexin in the treatment of wounds such as small lacerations, abrasions, or sutured wounds. METHODS: In 2 identical randomized double-blind studies, 706 patients with secondarily infected wounds (small lacerations, abrasions, or sutured wounds) received either mupirocin cream topically 3 times daily or cephalexin orally 4 times daily for 10 days. RESULTS: Clinical success at follow-up was equivalent in the two groups: 95.1% and 95.3% in the mupirocin cream and the cephalexin groups, respectively (95% confidence interval [CI], -4.0% to 3.6%; P = .89). The intention-to-treat success rate was 83% in both groups. Bacteriologic success at follow-up was also comparable: 96.9% in the mupirocin cream and 98.9% in the cephalexin groups (95% CI, -6.0% to 2.0%; P = .22). The occurrence of adverse experiences related to study treatment was similar for the 2 groups, with fewer patients in the mupirocin cream group reporting diarrhea (1.1% vs 2.3% for cephalexin). CONCLUSIONS: Mupirocin cream applied topically 3 times daily is as effective as oral cephalexin given 4 times daily for the treatment of secondarily infected wounds and was well tolerated.

Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus.

OBJECTIVE: To compare the safety and effectiveness of 5% and 1% imiquimod cream with vehicle cream in the treatment of external anogenital warts. DESIGN: Randomized, double-blind, placebo-controlled comparison that evaluated patients for total clearance of their warts. Patients who experienced total clearance were evaluated for recurrence in a 12-week follow-up. SETTING: Eleven ambulatory offices, including both private physician offices and referral medical centers. PATIENTS: Three hundred eleven healthy men and women aged 18 years or older with 2 to 50 external anogenital warts were recruited from the practices of investigators, referring physicians, and advertisements. Eighty-two additional patients were screened but did not qualify. Four patients discontinued use of the medication because of adverse effects. INTERVENTIONS: Five percent imiquimod (Aldara) cream, 1% imiquimod cream, or vehicle cream was applied to all external warts overnight 3 times each week for 16 weeks, or until all treated warts disappeared, whichever occurred first. MAIN OUTCOME MEASUREMENTS: The number of patients experiencing the elimination of all baseline warts and the recurrence rate of these warts. In addition, the reduction in baseline wart area the duration of therapy required to eliminate warts, and the frequency and severity of adverse reactions were principal measurements. RESULTS: In the intent-to-treat analysis, 54 (50%) of 109 patients who received 5% imiquimod cream, 21 (21%) of 102 of those who received 1% imiquimod cream, and 11 (11%) of 100 patients treated with vehicle cream experienced eradication of all treated baseline warts. The difference between the effectiveness of 5% imiquimod cream and the vehicle cream was statistically significant (P < .001). Of those patients whose warts cleared during therapy, 13% of patients who received 5% imiquimod experienced a recurrence of at least 1 wart. Recurrences occurred in none of the patients who used 1% imiquimod cream and in 10% of patients who used the vehicle cream. Local erythema was the most common adverse reaction, but the majority of patients in each group experienced no or only mild local inflammatory reactions. There were no differences in incidences of flulike symptoms among treatment groups. CONCLUSIONS: Five percent imiquimod cream is an effective and safe self-administered therapy for external anogenital warts when applied 3 times a week overnight for up to 16 weeks. The recurrence rate is low.

Evaluating a cognitive/ecological program for the prevention of aggression among urban children.

The Metropolitan Area Child Study (MACS) is a multifaceted school- and family-based intervention and evaluation study designed to prevent and understand the development of aggressive behavior. The multifaceted interventions are grounded in combined social-cognitive and ecologic theories. Social-cognitive theories contend that cognitive scripts, attributions, and beliefs acquired early in life mediate the effects of ecological factors that influence the development of antisocial behavior. Prevention programs aimed at these cognitions must address multiple dimensions of the child's environment including family, peer, school, and community. The program has three levels of intervention delivered in two-year segments: (1) Level 1: a general enhancement classroom intervention that stresses culturally sensitive student and teacher interaction involving instructional and classroom management strategies and a social-cognitive curriculum that mitigates aggressive development; (2) Level 2: intensive small-group sessions designed to change children's cognitions and enhance peer relationship skills for at-risk children added to the general classroom enhancement program; and (3) Level 3: a one-year family relationship intervention that stresses parenting skill building and emotional responsiveness in family interactions added to the general enhancement and small-group training conditions. Sixteen Chicago-area schools are randomly assigned (four each) to a control group or one of the three intervention levels. Individual child assessment, peer assessments, classroom behavioral observations, and archival data are collected before the interventions begin, during the interventions, at the end of each intervention, and at a follow-up point. The pretests indicate that the children on average have higher levels of aggression than found nationally and elevated clinical levels of other psychopathologies. Across the four intervention levels there are no significant differences in ethnic composition, socio-economic status (SES), aggressive behavior, and normative beliefs about aggression.

Stressful events and individual beliefs as correlates of economic disadvantage and aggression among urban children.

This study examined 3 factors that were hypothesized to increase risk for aggression among urban children: economic disadvantage, stressful events, and individual beliefs. Participants were 1,935 African American, Hispanic, and White elementary-school boys and girls assessed over a 2-year period. The relation between individual poverty and aggression was only significant for the White children, with significant interactions between individual and community poverty for the other 2 ethnic groups. With a linear structural model to predict aggression from the stress and beliefs variables, individual poverty predicted stress for African American children and predicted beliefs supporting aggression for Hispanic children. For all ethnic groups, both stress and beliefs contributed significantly to the synchronous prediction of aggression, and for the Hispanic children, the longitudinal predictions were also significant. The findings are discussed in terms of their implications for preventive interventions in multiethnic, inner-city communities.

Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS.

BACKGROUND: Disseminated Mycobacterium avium complex infection eventually develops in most patients with the acquired immunodeficiency syndrome (AIDS). This infection results in substantial morbidity and reduces survival by about six months. METHODS: We conducted two randomized, double-blind, multicenter trials of daily prophylactic treatment with either rifabutin (300 mg) or placebo. All the patients had AIDS and CD4 cell counts < or = 200 per cubic millimeter. The primary end point was M. avium complex bacteremia as assessed monthly by blood culture. The secondary end points were signs and symptoms associated with disseminated M. avium complex infection, adverse events, hospitalization, and survival. RESULTS: In the first trial, M. avium complex bacteremia developed in 51 of 298 patients (17 percent) assigned to placebo and 24 of 292 patients (8 percent) assigned to rifabutin (P < 0.001). In the second trial, bacteremia developed in 51 of 282 patients in the placebo group (18 percent) and 24 of 274 patients in the rifabutin group (9 percent) (P = 0.002). Rifabutin significantly delayed fatigue, fever, decline in the Karnofsky performance score (by > or = 20 percent), decline in the hemoglobin level (by more than 10 percent), elevation in alkaline phosphatase, and hospitalization. The incidence of adverse events was similar with rifabutin and placebo. Overall survival did not differ significantly between the two groups, although there were fewer deaths with rifabutin (33) than with placebo (47) during the double-blind phase (P = 0.086). The distribution of minimal inhibitory concentrations of rifabutin among the isolates of M. avium complex did not differ significantly between the treatment groups. CONCLUSIONS: Rifabutin, given prophylactically, reduces the frequency of disseminated M. avium complex infection in patients with AIDS and CD4 counts < or = 200 per cubic millimeter.

Long-term suppression of recurrent genital herpes with acyclovir. A 5-year benchmark. Acyclovir Study Group.

BACKGROUND AND DESIGN: This multicenter trial (19 sites) was initiated in 1984 in more than 1100 immunocompetent individuals with a history of frequently recurring genital herpes (mean, > or = 12 episodes per year). The first year of this suppressive therapy trial was placebo controlled, with acyclovir being provided for episodic treatment in both groups. Thereafter, patients were treated with open-label acyclovir suppressive therapy on a long-term basis (400 mg twice daily) to continue to assess its long-term safety and efficacy. Complete data are available on 389 of the 430 patients who began the fifth year of the study. RESULTS: Patients were seen quarterly for review of diaries and clinical laboratory evaluations. The percentage of patients recurrence free for any 3-month quarter of the fifth year ranged from 86% to 90%. The mean annual number of recurrences per patient declined from 1.7 during the first year to 0.8 during the fifth year of suppressive therapy. The frequency of false prodromes has also decreased over time. More than 20% of the patients receiving suppressive therapy for 5 years have been recurrence free the entire time. The duration of herpetic outbreaks during suppressive therapy has not changed. CONCLUSION: This study extends the safety and efficacy profile of oral acyclovir in the suppression of genital herpes to 5 years. The majority of the patients were recurrence free on an annual basis during suppressive therapy. Therapy was well tolerated. Acyclovir usage was not associated with serious side effects or cumulative toxicity.

Recurrence of condylomata acuminata following cryotherapy is not prevented by systemically administered interferon.

OBJECTIVE: To determine whether interferon alpha-2a, when utilised as adjuvant chemotherapy following ablation of condylomata acuminata (genital warts) by cryotherapy, is effective in the prevention of recurrences. DESIGN: Randomised, placebo-controlled, double-blind study. Statistical analysis was by 2-tailed Fisher's Exact Test. PATIENTS: 97 patients with recurrent condylomata acuminata. INTERVENTION: 49 patients were treated with cryotherapy plus subcutaneously administered interferon alpha-2a, and 48 received cryotherapy plus placebo. Of these, 36 and 37 patients, respectively, completed the study and were evaluable. MAIN OUTCOME MEASURE: Clinical eradication of condylomata for six months following adjuvant chemotherapy. RESULTS: By completion of the adjuvant chemotherapy, 10 (28%) interferon recipients and 16 (43%) placebo recipients experienced recurrences. At six months follow-up, 25 (69%) interferon and 27 (73%) placebo recipients experienced recurrences. In the six months following interferon therapy, only 31% of interferon and 27% of placebo recipients remained free of recurrences (p = 0.99). CONCLUSIONS: Interferon alpha-2a administered subcutaneously offers no benefit as a chemotherapeutic adjuvant to cryotherapy when used alone in the therapy of genital warts in this population of patients with recurrent condylomata.

Continuous five-year treatment of patients with frequently recurring genital herpes simplex virus infection with acyclovir.

This study presents data relative to the efficacy and safety following the continuous use of oral acyclovir in the treatment of genital herpes over a 5-year period. In this study, 1,146 patients (53% males; 47% females) were originally enrolled. These included patients with a history of frequently recurring genital herpes (mean > 12 episodes per year). During the first year, patients were randomized between those receiving 400 mg of acyclovir twice daily and an equal number receiving placebo. Additionally, acyclovir was utilized for episodic treatment (ES) in both groups. Thereafter, patients received open-label acyclovir suppressive therapy for the remainder of the study period. Complete data are available on 389 patients who completed the fifth year of therapy. All the participants who completed the fifty year of the study had completed either 4 or 5 years of daily suppressive acyclovir therapy. During the first year, a significant decrease in the frequency of recurrences in patients receiving continuous acyclovir (SS) was noted as compared to the placebo group (1.7 vs. 12.5 recurrences; P < 0.0001). From year one to the end of year three, a progressive decrease in the frequency of recurrences was noted in both groups. Yet, those patients who had received SS for the full 3 years had significantly fewer recurrences than those who had received ES in the first year (P = 0.05). During years four and five, the decrease in frequency of recurrences between the ES and SS groups was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)