Retinoic acid synergistically enhances the melanocytotoxic and depigmenting effects of monobenzylether of hydroquinone in black guinea pig skin

Monobenzylether of hydroquinone (MBEH) has long been utilized for the depigmentation therapy of patients with extensive vitiligo. In this approach, the normally pigmented areas surrounding vitiligo lesions are depigmented to achieve a uniform skin tone. One of the important disadvantages of MBEH therapy, however, is the resistance of a considerable number of vitiligo patients against the depigmenting effect of this agent. We have previously proposed that the glutathione-dependent cytoprotection of melanocytes can be impaired through the inhibition of the enzyme glutathione S-transferase by retinoic acid (RA). The combination of RA with melanocytotoxic agents could thus lead to increased susceptibility of melanocytes to such compounds. In this study we have shown, for the first time, that the melanocytotoxic and depigmenting effects of MBEH are synergistically enhanced when it is combined with RA. The treatment of black guinea pig skin with RA (0.025%) alone induced no significant changes in the number of epidermal melanocytes and no skin depigmentation. On the other hand, MBEH (10%) produced mild to moderate skin depigmentation and reduced the average number of melanocytes from 76 (+/-5)/field (magnification: x 40) in control sites, to 42 (+/-6)/field in the depigmented skin. The RA (0.025%)-MBEH (10%) combination, however, produced a complete degree of depigmentation in the majority of treated sites after 10 days of application and reduced the average number of melanocytes to only 6 (+/-6)/field. RA-MBEH combination serves as a very potent skin depigmenting formula and now awaits future assessments of its potential use for the treatment of extensive vitiligo.     

High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients.

PURPOSE: Prostate cancer is a highly prevalent malignancy and constitutes a major cause of cancer-related morbidity and mortality. Owing to the limitations of current clinical, serologic, and pathologic parameters in predicting disease progression, we sought to investigate the prognostic value of promoter methylation of a small panel of genes by quantitative methylation-specific PCR (QMSP) in prostate biopsies. EXPERIMENTAL DESIGN: Promoter methylation levels of APC, CCND2, GSTP1, RARB2, and RASSF1A were determined by QMSP in a prospective series of 83 prostate cancer patients submitted to sextant biopsy. Clinicopathologic data [age, serum prostate-specific antigen (PSA), stage, and Gleason score] and time to progression and/or death from prostate cancer were correlated with methylation findings. Log-rank test and Cox regression model were used to identify which epigenetic markers were independent predictors of prognosis. RESULTS: At a median follow-up time of 45 months, 15 (18%) patients died from prostate cancer, and 37 (45%) patients had recurrent disease. In univariate analysis, stage and hypermethylation of APC were significantly associated with worse disease-specific survival, whereas stage, Gleason score, high diagnostic serum PSA levels, and hypermethylation of APC, GSTP1, and RASSF1A were significantly associated with poor disease-free survival. However, in the final multivariate analysis, only clinical stage and high methylation of APC were significantly and independently associated with unfavorable prognosis, i.e., decreased disease-free and disease-specific survival. CONCLUSIONS: High-level APC promoter methylation is an independent predictor of poor prognosis in prostate biopsy samples and might provide relevant prognostic information for patient management.     

The importance of central corneal thickness measurements and decision making in general ophthalmology clinics: a masked observational study

Background  

To assess the impact of knowing central corneal thickness (CCT) on glaucoma management in a United Kingdom district general hospital.     

Immunohistochemical p53 expression patterns in sarcomatoid carcinomas of the upper respiratory tract

Sarcomatoid carcinoma of the upper respiratory tract is a phenotypically complex neoplasm that has triggered much thoughtful discussion regarding histogenic origin and morphologic classification. In particular, its putative epithelial lineage and distinction from a pseudosarcomatous reaction are sometimes questioned. Little is known about the genetic alterations underlying sarcomatoid carcinoma. Although about 45% of conventional squamous cell carcinomas of the upper respiratory tract harbor p53 mutations, the p53 status of sarcomatoid carcinomas is not well established. p53 immunohistochemical analysis using the monoclonal antibody D07 was performed on 23 sarcomatoid carcinomas of the upper respiratory tract. Twenty tumors were biphasic, having dual epithelial and spindled components. In four of these biphasic tumors, the epithelial and spindled components were separately analyzed for p53 gene mutations by sequence analysis. p53 immunohistochemistry was also performed on 19 cases of postradiation stromal atypia. Strong and diffuse p53 staining was detected in 18 (78%) of the 23 sarcomatoid carcinomas. When the spindled component was compared with its corresponding epithelial component, identical patterns of p53 protein expression were noted in 19 (95%) of the 20 biphasic tumors. Weak p53 staining was observed in one (5%) of the 19 cases of postradiation stromal atypia. In the four biphasic tumors evaluated by DNA sequence analysis, p53 status was always the same in the paired epithelial and spindle cell components. These findings help further dispel the notion that sarcomatoid carcinoma represents a reactive spindle cell proliferation (pseudosarcoma) or a collision between a carcinoma and a sarcoma (collision tumor). Instead, the epithelial and spindled components share a common pathway of tumorigenesis despite their conspicuous divergence at the phenotypic level.     

Activity of antimicrobial-impregnated silicone tissue expanders

Because bacterial colonization of medical devices may result in clinical infection, it is conceivable that antimicrobial impregnation of tissue expanders may reduce the rate of infection. The objective of this in vitro study was to examine the spectrum, durability, and shelf-life antimicrobial activity of minocycline/rifampin-impregnated silicone tissue expander shells. The impregnated devices exhibited zones of inhibition at baseline against Staphylococcus epidermidis, Staphylococcus aureus, and Escherichia coli. The impregnated devices exhibited strong residual activity against S. epidermidis and S. aureus after suspension in serum at 37 degrees C for 4 weeks. There was no significant decrease in the size of zones of inhibition after storing the impregnated devices at room temperature for 1 year. These results indicate that minocycline/rifampin-impregnated tissue expander shells provide broad-spectrum and durable antimicrobial activity and that the shelf-life antimicrobial activity exceeds 1 year. These findings prompt future exploration of the anti-infective efficacy of these antimicrobial-impregnated devices.     

Lack of apoptosis in the hypoxic brain of a rat model mimicking cyanotic heart disease

OBJECTIVE: To assess the effect of chronic hypoxia on brain neuronal apoptosis, an animal model mimicking cyanotic heart disease was utilized. METHODS: Rats were placed in an hypoxic environment at birth and oxygen levels were maintained at 10% in an air-tight Plexiglass chamber. Controls remained in room air. Animals were sacrificed and the brains were harvested at 1 and 4 weeks, respectively. RESULTS: Significant polycythemia developed in the hypoxic rats at 1 and 4 weeks. Indexed brain mass to body weight was significantly increased in the hypoxic groups by 18% (p < 0.01) and 38% (p < 0.01) as compared to controls at 1 and 4 weeks, respectively. There was no difference in the number of apoptotic neurons between the chronically hypoxic rats and controls, as assayed by TUNEL labelling and Hoechst staining. The role of the sphingolipid ceramide was then examined because of its reported role in stress response, growth suppression and apoptosis. It was found that the brain ceramide accumulation was not significantly different in the hypoxic and control groups at 1 and 4 weeks. CONCLUSION: A protective adaptive response to chronic hypoxia in the neonatal brain may exist.     

Short report: Crimean-Congo hemorrhagic fever outbreak in Rawalpindi, Pakistan, February 2002

A nosocomial outbreak of Crimean-Congo hemorrhagic fever occurred in Rawalpindi, Pakistan in February 2002. The identified index case died shortly after admission to a hospital. Two of the health care workers became secondary cases; one of them died on day 13 after coming in contact with the index case. The other secondary case was successfully treated with oral ribavirin.     

Contribution of ionotropic glutamate receptors and voltage-dependent calcium channels to the potentiation phenomenon induced by transient pentylenetetrazol in the CA1 region of rat hippocampal slices

The role of ionotropic glutamate receptors and voltage-dependent calcium channels (VDCCs) in potentiation phenomenon and epileptic activity induced by a transient pentylenetetrazol (PTZ) application in the CA1 region of rat hippocampal slices was investigated. Also we examined whether adenosine as an inhibitory neuromodulator would interact with expression of the long-lasting effect of transient PTZ. Population spikes (PS) were recorded in the CA1 cell body layer of the hippocampal slices following stratum radiatum stimulation. Changes in the PS amplitude potentiation and number of extra PS, which induced by transient PTZ were used as indices to quantify the effects of drugs. PS input-output curve was significantly increased 10 min after PTZ application and persisted at least for 60 min after PTZ washout. Polyspikes also appeared, but did not persist. Both ketamine and APV reduced the extent of potentiation of PS amplitude but had no effect on number of extra PS. The selective non-NMDA receptor antagonist CNQX prevented the amplitude potentiation and the generation of extra PS. The blocker of VDCCs, verapamil, prevented the amplitude potentiation and inhibited polyspike activity. Co-application of adenosine and PTZ produced a rapid and reversible decrease in the PS amplitude, but PTZ-induced potentiation phenomenon was observed after washout. It is concluded that ionotropic glutamate receptors as well as VDCCs involve in the PTZ-induced LTP of PS amplitude. PTZ-induced LTP is also insensitive to adenosine. The epileptiform activity induced by a transient PTZ application could be attributed to VDCCs. The polyspikes mediated by VDCCs are dependent on prior activation of AMPA receptors.     

Physical and hormonal profile of male sexual development in epilepsy

PURPOSE: This study was designed to investigate the effect of epilepsy and antiepileptic drugs (AEDs) on both the physical and hormonal aspects of the sexual development of male patients with epilepsy. METHODS: One hundred thirty male subjects with epilepsy, their age ranging between 8 and 18 years (mean, 14 +/- 2.9 years), entered the study; all were taking AEDs. Anthropometric measurements [height, weight, and body mass index (BMI)], testicular volume, penile length, and pubarche were assessed in the studied groups, as well as measurement of the levels of testosterone (T), free testosterone (FT), estradiol (E2), lutenizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL), and the results were compared with those of a control group. RESULTS: In this study, male patients older than 16 years were significantly shorter than their matched controls. The mean values of testicular volume and penile length were significantly lower in the patients in the different age subgroups, and the pubic hair staging (pubarche) was delayed in the patients older than 16 years. The mean values of total testosterone, estradiol, LH, and FSH serum levels were significantly higher, whereas the mean values of free testosterone, total-T/E2, total. T/LH, and FT/E2 ratios were lower in the patient subgroups compared with their age-matched controls. There were no significant changes in the mean basal PRL serum levels in the patients compared with the controls. The present study demonstrated a reduction in the testicular volume and penile length, significantly lower mean values of free testosterone and total-T/E2, and a higher mean value of E2 in the patients receiving polytherapy in the age subgroup older than 16 years compared with those on monotherapy; however, there was no demonstrable effect of seizure control or the duration of illness in any of the studied parameters. CONCLUSIONS: There is a delay in the sexual development of male patients with epilepsy in the different age subgroups, with endocrine changes in the form of increase in the total testosterone, but the free testosterone is lower, and an increase in estradiol, with lower T/LH levels. Patients receiving polytherapy, especially those older than 16 years, were more likely to have delayed gonadarch and disturbances in their hormonal profile.