In Vitro inhibitory potential of decursin and decursinol angelate on the catalytic activity of cytochrome P-450 1A1/2, 2D15, and 3A12 isoforms in canine hepatic microsomes

Danggui is one of the most popular herbal medicines consumed by patients in different clinical settings in Asian countries. In this study, the two major pyranocoumarin compounds extracted from the Korean Angelica gigas root decursin (DC) and decursinol angelate (DA) were examined in vitro with regard to their abilities to inhibit hepatic CYP1A1/2, CYP2D15, and CYP3A12 catalytic activities in canine liver microsomes. The two components were capable of inhibiting CYP1A1/2, CYP2D15, and CYP3A12 catalytic activities, but the potencies varied. DC and DA selectively and noncompetitively inhibited CYP1A1/2 activity, with K _i values of 90.176 and 67.560 μM, respectively. On the other hand, they exhibited slight inhibitory effects on CYP2D15 and CYP3A12 with K _i values of 666.180 and 872.502 μM, 990.500 and 909.120 μM (1’hydroxymidazolam, MDZ1’H), and 802.800 and 853.920 μM (4-hydroxymidazolam, MDZ4H), respectively. Additionally, they showed increased inhibition after preincubation, which suggests the involvement of a mechanism-based inhibition. In sum, this in vitro data should be heeded as a signal of possible in vivo interactions. The use of human liver preparations would considerably strengthen the practical impact of the data generated from this study. The two authors contributed equally to this paper.     

Addressing the workforce crisis: the professional aspirations of pharmacy students in Ghana

Objective A lack of skilled health professionals, and net migration from developing to more developed countries, are widely recognised as barriers to the delivery of effective health care. However, few studies have investigated this issue from the perspective of pharmacists, although they are increasingly viewed as a potentially valuable and underexploited health care resource. The objectives of this study were to examine the professional aspirations and perceived opportunities of final year pharmacy students in a developing country; and consider what developments may encourage them to remain in, and contribute to, health care in their home country. Method Final year pharmacy students from the Faculty of Pharmacy, KNUST, Kumasi, Ghana, were randomly selected and invited to participate in in-depth interviews. These were audio-recorded (with permission of respondents) and transcribed verbatim to enable a qualitative analysis. Main outcome measure: professional aspirations, and perceived opportunities and barriers to their achievement in Ghana and abroad. Results Participants viewed themselves, and wished to be viewed by others, as health professionals. They described a commitment to applying their clinical knowledge and to education beyond their first degree. However, they identified significant barriers to the achievement of professional aspirations in Ghana, which would diminish their opportunities to contribute to health care. Whilst most students expressed the expectation or desire to travel at some point, usually early, in their career, they all demonstrated a commitment to their country and stated a wish to return. Conclusion Overall the study highlighted prospective pharmacists in Ghana as ambitious, committed potential health professionals. The study indicates that a lack of attention by policy makers and professional bodies to ways of exploiting the contribution of pharmacists to public health, may represent a lost potential human resource for health in developing countries.     

Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications

PURPOSE: More than 1,300,000 prostate needle biopsies are done annually in the United States with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer on subsequent needle biopsies in prostate-specific antigen-screened populations. In contemporary series, prostate cancer is detected in approximately 20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histologic subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG gene fusion that has recently been described in prostate cancer has also been shown to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion prostate cancer is associated with a more aggressive clinical course. EXPERIMENTAL DESIGN: In this study, we assessed a series of HGPIN lesions and paired prostate cancer for the presence of TMPRSS2-ERG gene fusion. RESULTS: Fusion-positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances, the matching cancer shared the same fusion pattern. Sixty percent of TMPRSS2-ERG fusion prostate cancer had fusion-negative HGPIN. CONCLUSIONS: Given the more aggressive nature of TMPRSS2-ERG prostate cancer, the findings of this study raise the possibility that gene fusion-positive HGPIN lesions are harbingers of more aggressive disease. To date, pathologic, molecular, and clinical variables do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies.     

Evaluation of a human papillomavirus assay in cervical screening in Zimbabwe

Objective To determine the utility of an assay for high risk genital human papillomavirus (HPV) in cervical screening in Zimbabwe, Africa.
Design Cross-sectional study.
Setting Harare, Zimbabwe.
Population Zimbabwe women (   n = 2140  ), 25 to 55 years old, recruited in clinics in Chitungwiza and Greater Harare.
Methods Genital specimens were assessed for HPV, using the HPV DNA test Hybrid Capture II (probe B). Further assessment of the women was conducted using colposcopy and biopsy as indicated. High grade squamous intraepithelial lesions were diagnosed in 215 women. Colposcopy and/or biopsy showed low grade lesions in 346 women.
Results The overall prevalences were: 42.7% for HPV, 10% for high grade squamous intraepithelial lesions and 16% for low grade lesions. Prevalence for HPV decreased significantly with increase in age (   P for trend < 0.0001  ) and increased significantly with increasing disease severity, from 35% in normal women, to 53% in women with low grade lesions and 81% in women with high grade lesions (   P for trend < 0.001  ). In specimens positive for HPV, the amount was 14-fold higher in women with high grade lesions compared with normal women. In screening for high grade lesions the assay for HPV had a sensitivity of 81% (CI 75%–86%); sensitivity for low grade lesions was 64% (CI 60%–68%). Specificity was 62% (CI 59%–64%) for high grade lesions and 65% (CI 62%–67%) for low grade lesions. The positive predictive value was 19% (CI 17%–22%) for high grade lesions and 39% (CI 36%–42%) for low grade lesions.
Conclusion For high grade squamous intraepithelial lesions the sensitivity of the Hybrid Capture II HPV DNA test was high, but the specificity was relatively low. The test may therefore be most useful in conjunction with other screening tests.     

Effect of acute and long-term oral tobacco use on oesophageal motility

BACKGROUND AND AIMS: Nicotine administration is known to decrease lower oesophageal sphincter (LOS) pressure. Although a few studies have assessed the effect of tobacco on the LOS, the effect of acute and long-term oral tobacco use on oesophageal motility is not known. The study was designed to investigate the effect of acute and long-term oral tobacco use on LOS and distal oesophageal motility. METHODS: Thirty-six healthy men (aged 18-65 years, median 34 years; 18 oral tobacco users, 18 non-tobacco users) underwent oesophageal manometry using a water-perfusion system. After baseline manometry, tobacco users were asked to keep 0.5 g tobacco in their mouth for 10 min; non-users of tobacco were kept in quiet surroundings for a similar period. Manometry was then repeated. RESULTS: The LOS basal pressures were similar in tobacco users and non-tobacco users (mean +/- SD 15.4 +/- 6.3 vs 13.4 +/- 5.3 mmHg). In the distal oesophageal body, the velocity (4.4 +/- 3.1 vs 4.9 +/- 2.6 cm/s), amplitude (92.7 +/- 38.3 vs 84.8 +/- 33.2 mmHg) and duration of contraction (2.1 +/- 0.7 vs 1.7 +/- 0.9 s) were similar in tobacco users and non-users. Acute tobacco use did not affect these parameters. The numbers of abnormal waves (triple peaks and non-transmitted contractions) were also similar in the two groups. CONCLUSION: Oral tobacco use does not appear to affect LOS pressures and distal oesophageal motility acutely or in the long term.     

Lesions simulating retinoblastoma.

Of 500 consecutive patients referred to the Ocular Oncology Service at Wills Eye Hospital with the diagnosis of possible retinoblastoma, 288 (58%) were found on clinical evaluation to have retinoblastoma and 212 (42%) had lesions that simulated retinoblastoma. A total of 23 different conditions accounted for the 212 pseudoretinoblastomas. Three most common pseudoretinoblastomas were: persistent hyperplastic primary vitreous (28%), Coats' disease (16%), and presumed ocular toxocariasis (16%). Congenital cataract and retinopathy of prematurity accounted for a much lower percent of pseudoretinoblastomas in this series as compared to a previously reported series. The pertinent clinical features that serve to differentiate these simulating lesions from retinoblastoma are reviewed.     

Prediction of blood pressure from plasma renin activity in reflux nephropathy.

As there is a 10% risk of hypertension developing in children with reflux nephropathy and the renin-angiotensin system has been implicated in its aetiology, a long term prospective study has been undertaken to explore the relationship between plasma renin activity (PRA) and blood pressure in such patients. In 1978, of 100 normotensive children with reflux nephropathy 8% were shown to have PRA above normal. Five years later of 85 subjects suitable for analysis 13% had increased PRA and it was shown that PRA and blood pressure SD scores significantly increased. The present study refers to the 10 year follow up in which 95 of the original group were traced but eight of these were unavailable for study and 28 others were excluded from analysis because of extraneous factors that might influence blood pressure or PRA. Results therefore on 59 have been analysed. PRA was above normal in 13/59 (20%) subjects, and PRA and blood pressure SD scores had further increased. The data continue to support the role of the renin-angiotensin system in the observed rise of blood pressure in reflux nephropathy, but individual PRA measurements do not appear so far to predict reliably the onset of hypertension in affected patients.     

Probable nonpapillomavirus etiology of squamous cell carcinoma of the vulva in older women: a clinicopathologic study using in situ hybridization and polymerase chain reaction.

A clinical, pathologic, and molecular virologic analysis of 30 cases of invasive squamous cell carcinoma of the vulva was undertaken to investigate the relationship of human papillomavirus (HPV) to this neoplasm. The presence of the virus was detected by the polymerase chain reaction and localized in the tumor and in the adjacent epithelium by in situ hybridization of paraffin sections of vulvectomy specimens. Specimens were examined for nucleic acid sequences of HPVs 6, 11, 16, and 18 were detected by in situ hybridization utilizing 35S-labeled antisense RNA probes and by polymerase chain reaction using HPV type-specific primers for a segment of the E6 gene followed by Southern hybridization of the amplified products. The cases were classified as typical squamous cell carcinoma, basaloid carcinoma, and warty carcinoma. Typical squamous cell carcinoma shows varying degrees of squamous maturation, whereas basaloid carcinoma is characterized by immature basal-type cells showing minimal or no squamous maturation. Warty carcinoma displays an exophytic condylomatous appearance. The squamous cells of this tumor are mature, and many show koilocytotic atypia characterized by a variable degree of nuclear atypia and cytoplasmic vacuolization. The adjacent epithelium was classified as squamous hyperplasia, lichen sclerosus, or vulvar intraepithelial neoplasia (VIN). VIN was subdivided into basaloid or warty VIN using similar criteria as for the invasive carcinomas. Overall, HPV 16 was detected in 11 cases and HPV 18 in two; none of the cases were positive for HPVs 6/11. HPV was detected in four (21%) of 19 squamous cell carcinomas, six (75%) of eight basaloid carcinomas, and three (100%) of three warty carcinomas. The adjacent epithelial lesions also showed a close correlation with the tumor type and presence of HPV. Fourteen (74%) squamous cell carcinomas had adjacent squamous hyperplasia; all of these squamous hyperplasias were negative for HPV. In contrast, seven (87%) of the basaloid carcinomas had adjacent basaloid-VIN and HPV 16 was detected within the VIN in three. Three warty carcinomas (100%) had adjacent warty VIN or basaloid VIN, and HPV was detected within VIN in two. The mean age of women with squamous cell carcinoma was 77 years, for women with basaloid carcinoma 54 years, and for those with warty carcinoma 47 years. The mean age of women with HPV-negative tumors was 77 years compared with 55 years for women with HPV-positive tumors (p less than 0.01). Thus, there appears to be a close correlation between the presence of HPV, specific subsets of invasive carcinoma and VIN, and age.(ABSTRACT TRUNCATED AT 400 WORDS)