HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct-acting antiviral regimens.

Multiple direct-acting antiviral (DAA)-based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post-treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer.

The potent vasoconstrictor endothelin-1 (ET-1) is at its highest concentration in the normal human ejaculate and is associated with the progression of metastatic prostate cancer. ET-1 protein expression is detected in situ in 14 of 14 primary cancers and 14 of 16 metastatic sites of human prostatic carcinoma. Exogenous ET-1 induces prostate cancer proliferation directly and enhances the mitogenic effects of insulin-like growth factor I, insulin-like growth factor II, platelet-derived growth factor, basic fibroblast growth factor, and epidermal growth factor in serum-free conditions in vitro. The ETA-selective receptor antagonist A-127722 inhibits ET-1-stimulated growth, but the ETB-selective receptor antagonist BQ-788 does not. ET-3, an ETB-selective agonist, also had no effect on prostate cancer growth. No specific ETB-binding sites could be demonstrated in any established human prostate cancer cell line tested, and ETB mRNA, detected by reverse transcription PCR, was reduced. The predominance of ETB binding on human benign prostatic epithelial tissue is not present in metastatic prostate cancer by autoradiography. In human prostate cancer progression to metastases, ET-1 and ETA expression are retained, whereas ETB receptor expression is reduced.

Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate.

Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.

E-cadherin expression as a marker of tumor aggressiveness in routinely processed radical prostatectomy specimens.

OBJECTIVES: Approximately 30% of clinically localized prostate adenocarcinomas treated by radical prostatectomy (RP) will recur within 10 years. To prevent recurrence, new adjuvant therapies are in development that seek to treat high-risk patients after surgery. To identify patients as candidates for these treatments, improved biomarkers for predicting prognosis are needed. Reduced expression of E-cadherin has been proposed as a new marker for predicting prognosis in prostate adenocarcinoma. Since few studies have examined the relation between risk factors for disease progression and E-cadherin expression using routinely processed RP specimens, we used RP specimens to correlate downregulation of E-cadherin and pathologic stage at RP. METHODS: Primary adenocarcinomas (n = 76) from formalin-fixed and paraffin-embedded RP specimens were evaluated by immunohistochemistry against E-cadherin (HECD-1) using heat-induced epitope retrieval and automated staining (BioTek Solutions). Normal appearing prostate epithelium was used as an internal control for each specimen. Staining was scored as an estimate of the percentage of tumor cells in each specimen that showed strong plasma membrane staining. RESULTS: Specimens were divided into three categories with respect to Gleason score: intermediate (score 5 to 6, n = 31), intermediate to high (score 7, n = 25), and high (score 8 to 9, n = 20). For pathologic stage, specimens were divided into three categories: low stage/organ confined (pT2, n = 30), intermediate stage/limited extraprostatic extension (pT3a, n = 25), and high stage/seminal vesicle-pelvic lymph node metastases (pT3b-any pTN1, n = 21). In univariate analysis, reduced levels of E-cadherin correlated with advanced Gleason score (P = 0.003) and advanced pathologic stage (P = 0.008). In multivariate analysis, E-cadherin, preoperative prostate-specific antigen, and Gleason score all contributed independently to the prediction of high-stage disease (P<0.0001). Ten pelvic lymph node metastases from this same patient cohort were stained for E-cadherin. All were positive and 9 of 10 were moderately to strongly positive. CONCLUSIONS: Since essentially all patients in the high-stage category have a very high likelihood of disease recurrence, we conclude that the study of E-cadherin in a prospective manner as a potential biomarker of disease progression in patients with clinically organ-confined prostate cancer who undergo RP is warranted. Additionally, our finding that most metastatic tumor cells in pelvic lymph nodes express E-cadherin supports the notion that the establishment of the distant colonization and growth of metastatic tumor cells may be facilitated by expression or re-expression of previously downregulated E-cadherin. This would strongly suggest that irreversible genetic inactivation through mutation or allelic loss at 16q2.3 is probably not the mechanism of E-cadherin downregulation in most abnormally expressing primary prostate carcinomas.

Domestic violence.

Domestic violence is alarmingly prevalent, yet medical students, residents, and experienced physicians are often handicapped by insufficient knowledge and expertise in the diagnosis and care of these patients. This article reviews the epidemiology of domestic violence, highlights risk factors, discusses current obstacles in the diagnosis and treatment of domestic violence, identifies history taking and physical examination skills to increase diagnosis of this condition, and outlines treatment plans for victims.

Influenza and pneumococcal immunization rates among a high-risk population.

BACKGROUND: Influenza and pneumococcal infections are the most vaccine-preventable infectious diseases among the elderly population. Elderly patients (65 years and older) with chronic diseases derive substantial benefit from having current immunization status due to their high risk for respiratory diseases. However, immunization levels for influenza and pneumococcus remain suboptimal. This study sought to determine the immunization rates in a high-risk geriatric population. METHODS: Charts of consecutive patients seen in a geriatric clinic from November 1999 to February 2000 were obtained. Medical records were reviewed to assess their influenza and pneumococcal immunization status. RESULTS: Of 200 patients who qualified for the study, all had at least two indications for vaccination, yet only 34% were current with influenza immunization, and 26% were current with pneumococcus immunization. CONCLUSIONS: In a high-risk elderly population, influenza and pneumococcal immunization rates were low. Patients who received pneumococcus vaccination were more likely to receive influenza immunization as well.

Subclavian steal syndrome: a rare but important cause of syncope.

An elderly woman came to our emergency room for evaluation of a syncopal episode. While climbing a flight of stairs, she had turned her head to the left and abruptly passed out. Positive physical findings included blood pressure of 141/65 mm Hg (right arm) and 80/43 mm Hg (left arm), as well as nonpalpable left radial and brachial pulses that were detectable only by Doppler ultrasonography. Carotid duplex ultrasonography showed reverse flow in the left vertebral artery and an abnormal, stenotic distal left subclavian artery. Magnetic resonance angiography confirmed complete occlusion of the left subclavian artery with classic subclavian steal. The patient had percutaneous transluminal angioplasty with stenting of the left subclavian artery and has remained asymptomatic through 2 years of follow-up with aggressive risk-factor modification.

Changing antibiotic sensitivity patterns at a university hospital, 1992 through 1999.

BACKGROUND: The emergence of antibiotic-resistant organisms is of great concern in the medical community. Antibiotic sensitivity patterns were studied at a large university hospital. METHODS: From 1992 through 1999, susceptibility testing was done and results recorded for all isolates of Streptococcus pneumoniae, Enterococcus sp, Staphylococcus aureus, coagulase-negative Staphylococcus, Eshcherichia coli, Haemophilus influenzae, and Pseudomonas aeruginosa. Microbiologic and sensitivity data were reviewed and compiled. RESULTS: Over the 8-year period, several common bacterial pathogens declined in susceptibility to various antimicrobial agents. Most notable were the decreased sensitivities of S pneumoniae to penicillin (96% to 63%), coagulase-negative Staphylococcus to oxacillin (50% to 38%), and P aeruginosa to aminoglycosides [(gentamicin (85% to 64%), tobramycin (96% to 83%), amikacin (92% to 74%)] and ciprofloxacin (85% to 69%). CONCLUSIONS: These decreased antibiotic sensitivities reflect increased bacterial selection pressure as a result of widespread antibiotic use. A combined approach involving infection-control specialists, infectious disease physicians, and hospital administrators is necessary to address this increasingly difficult problem.

Neuroleptic malignant syndrome due to promethazine.

A 42-year-old man came to our emergency room hyperthermic (oral temperature, 42.4 degrees C), diaphoretic, and delirious. Other findings included labile blood pressure, sinus tachycardia (heart rate, 138/min), tachypnea (respiratory rate 34/min), muscle rigidity, and incontinence. Two days earlier, he had gone to a local clinic with complaints of abdominal pain, nausea, and vomiting. Promethazine was prescribed, and this was the patient's only medication on admission. Laboratory studies showed leukocytosis, hypernatremia, metabolic acidosis, elevated creatinine phosphokinase level, elevated transaminase levels, azotemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and myoglobulinuria. The clinical and laboratory findings were characteristic of the neuroleptic malignant syndrome, with promethazine as the offending agent.

Reappraisal of the role of human chorionic gonadotropin in the diagnosis and treatment of the nonpalpable testis: a 10-year experience.

PURPOSE: We retrospectively evaluated the ability of human chorionic gonadotropin (HCG) to make the nonpalpable cryptorchid testis become palpable and promote testicular descent. MATERIALS AND METHODS: Through surgical bookings we identified 94 patients younger than 11 years who received HCG between 1984 and 1994 for the diagnosis or treatment of a nonpalpable undescended testis. The dose of HCG was 1,500 IU/m.2 intramuscularly 2 times weekly for 4 weeks. Testis location was determined by physical examination before and after hormone administration, and confirmed at surgical exploration. RESULTS: Of the 99 nonpalpable testes identified in 94 patients 39 (39%) became palpable following HCG administration and only 2 (2%) completely descended. A total of 60 testes remained nonpalpable with the most common reason being an absent or severely atrophic testis (40, 67%). Of the testes remaining nonpalpable after hormonal stimulation 73% were surgically located at or distal to the internal ring. CONCLUSIONS: HCG is preoperatively efficacious in causing the nonpalpable undescended testis to become palpable. For patients failing to respond to hormonal stimulation we recommend preliminary inguinal exploration, since most testes or testicular remnants are located within the inguinal canal or immediately below the internal ring.

Paecilomyces lilacinus fungemia in an adult bone marrow transplant recipient.

Paecilomyces lilacinus is a rare fungal pathogen in humans. We report a case of fungemia caused by P. lilacinus in a non-neutropenic adult, 120 days after bone marrow transplant. The patient's primary risk factor was the presence of an indwelling vascular catheter. Her initial clinical course was characterized by fever, chills, and rigors. Blood cultures from the central line and peripheral veins were positive, as was a peripheral specimen drawn after removal of the catheter. Two initial peripheral specimens were positive for P. lilacinus only by blind subculture and/or sustained incubation. She developed peripheral pulmonary nodules following the fungemia, thus raising the possibility of disseminated disease, but definitive diagnosis was confounded by Pseudomonas bacteremia. The nodules cleared and she recovered following removal of the central line and treatment with amphotericin B and 5-fluorocytosine, despite in vitro resistance to these antifungal drugs. This case underscores the increasing importance of P. lilacinus as a human pathogen capable of producing disease in immunocompetent, as well as in immunocompromised hosts. Also of note is that blood culture systems may require extended incubation or subcultures in order to detect fungi.

HIV-1 DNA shedding in genital ulcers and its associated risk factors in Pune, India.

HIV infection status was determined in 302 consecutive patients with genital ulcer disease (GUD) presenting to two sexually transmitted disease (STD) clinics in Pune, India. Of the 71 (24%) individuals with HIV infection, 67 (94%) were HIV antibody-positive, and 4 (6%) were HIV antibody-negative but p24 antigen-positive at the time of presentation. HIV-1 DNA was detected in 24 (34%) specimens. The genital ulcers of all four acutely infected p24-antigenemic subjects were HIV-1 DNA-positive by polymerase chain reaction (PCR) assay, compared with 20 of 67 (30%) seropositive patients (p = .01). Presence of chancroid, GUD symptoms for > 10 days, and concurrent diagnosis of cervicitis or urethritis were significantly associated risk factors for HIV-1 DNA shedding in ulcers. Early GUD diagnosis and aggressive treatment of HIV-infected patients may significantly reduce secondary transmission of HIV to other sex partners.

PIP: Genital ulcer disease (GUD) has been associated with an increased risk of HIV infection and transmission. The present study investigated HIV status in 302 consecutive patients with GUD presenting to two sexually transmitted disease (STD) clinics in Pune, India, in a 3-month period in 1994. 71 patients (24%) were HIV-positive; 4 (6%) of these patients were HIV-antibody negative but p24 antigen-positive. HIV-1 DNA was present in 24 specimens (34%). The genital ulcers of all 4 acutely infected p24 antigenemic subjects were HIV-1 DNA-positive by polymerase chain reaction assay compared with 20 (30%) of HIV antibody-positive patients. Significant risk factors for HIV-1 DNA shedding in ulcers were presence of chancroid (adjusted odds ratio (OR), 4.78; 95% confidence interval (CI), 1.15-19.9), GUD symptoms for more than 10 days (adjusted OR, 4.54; 95% CI, 1.19-17.3), and concurrent diagnosis of cervicitis or urethritis (adjusted OR, 9.35; 95% CI, 2.30-38.0). The finding of HIV-1 DNA in all 4 patients with acute primary HIV infection may be related to the high degree of circulating viremia present in acute infection. Early GUD diagnosis and aggressive treatment, especially of chancroid, in HIV-infected patients may significantly reduce secondary transmission of HIV to sexual partners.

The etiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India.

OBJECTIVES: To determine the etiology of genital ulcer disease (GUD) among patients attending sexually transmitted disease (STD) clinics in Pune, India, and to examine the relationship to HIV infection and compare the clinical diagnosis of GUD with the results of a multiplex polymerase chain reaction (M-PCR) assay for Treponema pallidum, herpes simplex virus (HSV), and Hemophilus ducreyi infection. METHODS: Between June 20, 1994, and September 26, 1994, 302 patients with a genital ulcer were evaluated. Clinical etiology of GUD was based on physical appearance and microbiologic evaluations which included darkfield microscopy and serology for syphilis. Swabs of each genital ulcer were tested for HSV antigen by enzyme immunoassay (Herpchek; Dupont, Wilmington, DE) and processed in a multiplex PCR assay (M-PCR; Roche, Branchburg, NJ) for simultaneous detection of HSV, Treponema pallidum, and Hemophilus ducreyi. RESULTS: Two hundred seventy-seven men and 25 women with a median age of 25 were evaluated. The seroprevalence of HIV was 22.2%. The etiology of GUD as determined by M-PCR was HSV (26%), H. ducreyi (23%), T. pallidum (10%), and multiple infections (7%); no etiology was identified in 34%. HIV seroprevalence was higher among those patients positive for HSV compared with other etiologies (OR = 2.1, CI: 1.2-3.7; p = 0.01). When compared with M-PCR, the Herpchek test was 68.5% sensitive and 99.5% specific. Darkfield detection for T. pallidum was 39% sensitive and 82% specific, in contrast to rapid plasma reagin and fluorescent treponemal antibody absorption test, which was 66% sensitive and 90% specific. Clinical diagnosis alone or in combination with basic laboratory tests showed poor agreement with M-PCR.

PIP: The etiology of genital ulcer disease (GUD) and the relationship between GUD and HIV infection were investigated in 302 patients presenting to a sexually transmitted disease clinic in Pune, India, in a 3-month period in 1994. Swabs of each genital ulcer were tested for herpes simplex virus (HSV) antigen by enzyme immunoassay and processed in a multiplex polymerase chain reaction (M-PCR) assay for simultaneous detection of HSV, Treponema pallidum, and Haemophilus ducreyi. The seroprevalence of HIV in this series was 22.2%. Clinical diagnosis of GUD was undermined when HIV infection was present. The etiology of GUD according to M-PCR was HSV in 26%, chancroid in 23%, primary syphilis in 10%, and multiple infections in 7%; no etiology could be identified in the remaining 34% of cases. Attempts to differentiate the etiology of GUD based solely on clinical grounds resulted in many inaccurate diagnoses. Chancroid was the most common clinical diagnosis (40%), followed by HSV (24%), syphilis (20%), and multiple infections (3%). HIV seroprevalence was significantly higher in patients with HSV compared with other etiologies (odds ratio, 2.1; 95% confidence interval, 1.2-3.7), presumably as a result of HIV-induced immunosuppression and consequent HSV reactivation. Until rapid, inexpensive, and sensitive assays become available, syndromic treatment with antibiotics should be provided to patients with GUD in order to reduce the risk of acquiring HIV infection.