Antibacterial activity and mode of action of tert-butylhydroquinone (TBHQ) and its oxidation product, tert-butylbenzoquinone (TBBQ).

OBJECTIVES: The antioxidant tert-butylhydroquinone (TBHQ) is a food additive reported to have antibacterial activity, and may therefore have application in the healthcare setting. This study sought to characterize the antibacterial activity and mode of action of TBHQ and its oxidation product, tert-butylbenzoquinone (TBBQ). METHODS: The stability of TBHQ/TBBQ was studied in buffer. Susceptibility testing was performed by broth microdilution, and killing and lytic activity were evaluated by viable counting and culture turbidity measurements. Mode of action studies included following the incorporation of radiolabelled precursors into macromolecules. The effect of TBHQ/TBBQ upon bacterial and mammalian membranes was assessed using the BacLight(TM) assay and by monitoring the haemolysis of equine erythrocytes. RESULTS: TBHQ underwent oxidation in solution to form TBBQ. When oxidation was prevented, TBHQ lacked useful antibacterial activity, indicating that TBBQ is responsible for the antibacterial activity attributed to TBHQ. TBBQ demonstrated activity against Staphylococcus aureus SH1000 (MIC 8 mg/L) and against a panel of clinical S. aureus isolates (MIC90 16 mg/L). TBBQ at 4× MIC caused a >4 log10 drop in cell viability within 6 h without lysis, and eradicated staphylococcal biofilms at 8× MIC. TBBQ did not display preferential inhibition of any single macromolecular synthetic pathway, but caused loss of staphylococcal membrane integrity without haemolytic activity. CONCLUSIONS: TBBQ is responsible for the antibacterial activity previously ascribed to TBHQ. TBBQ prompts loss of staphylococcal membrane integrity; it is rapidly and extensively bactericidal, but is non-lytic. In view of the potent and selective bactericidal activity of TBBQ, this compound warrants further investigation as a candidate antistaphylococcal agent.

Bisexual people's experiences with mental health services: a qualitative investigation.

Bisexual people experience minority stress and social isolation as a result of their marginalized sexual identities, and likely due to this stigmatization, previous research has identified high rates of psychological distress, anxiety, depression, suicidality, alcohol misuse, and self-harming behaviour among bisexual populations. It is therefore important that mental health service providers are able to provide culturally competent care to bisexual people. This study used focus groups and interviews with 55 bisexual participants across the province of Ontario, Canada, to investigate their experiences with mental health care. Results suggest that bisexual people have both positive and negative experiences with mental health service providers. Specific provider practices which contribute to the perception of positive and negative experiences with mental heath services are described, and the implications for clinical practice discussed.

What is the pathogenesis of acne?

For a long time, the mantra of acne pathogenesis debates has been that acne vulgaris lesions develop when (supposedly largely androgen-mediated) increased sebum production, ductal hypercornification, and propionibacteria come together with local inflammatory process in the unlucky affected individual. And yet, the exact sequence, precise interdependence, and choreography of pathogenic events in acne, especially the 'match that lights the fire' have remained surprisingly unclear, despite the venerable tradition of acne research over the past century. However, exciting recent progress in this--conceptually long somewhat stagnant, yet clinically, psychologically, and socioeconomically highly relevant--everyday battlefield of skin pathology encourages one to critically revisit conventional concepts of acne pathogenesis. Also, this provides a good opportunity for defining more sharply key open questions and intriguing acne characteristics whose underlying biological basis has far too long remained uninvestigated, and to emphasize promising new acne research avenues off-the-beaten-track--in the hope of promoting the corresponding development of innovative strategies for acne management.

Surveillance programs for early stage non-seminomatous testicular cancer: a practice guideline.

BACKGROUND AND PURPOSE: To identify an appropriate surveillance program for men with clinical stage I non-seminomatous germ cell tumors of the testis (NSGCT). MATERIALS AND METHODS: A systematic review of the published literature was combined with a consensus process, around the interpretation of the evidence in the context of conventional practice, to develop an evidence-based practice guideline. RESULTS: No randomized controlled trials (RCTs) comparing surveillance schedules were found, but data from 12 case series and one RCT which compared radiotherapy with surveillance were reviewed. Variations in the schedules were not associated with observed variations in relapse, salvage, or survival rates. CONCLUSIONS: Men with clinical stage I testicular cancer, as defined by a normal physical examination, normal radiological scans (computed tomography [CT]) and serum markers (alpha-fetoprotein [AFP] and beta-subunit of human chorionic gonadotropin (betaHCG) which are normal or fall within normal limits during their expected half-lives, are eligible for surveillance. A recommended surveillance schedule is as follows: 1) Physical examination, blood serum marker tests (AFP and HCG), and chest x-rays should be conducted every month in the first year, every 2 months in the second year, every 3 months in the third year, and every 6 months in the fourth and fifth years; and 2) CT scans of the abdomen and pelvis should be conducted every 3 months in the first year, every 4 to 6 months in the second year and every 6 months in the third year, and once a year in the fourth and fifth year.

The use of gemcitabine in non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group. Provincial Systemic Treatment Disease Site Group.

GUIDELINE QUESTION: Is there a role for the use of gemcitabine in the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)? OBJECTIVE: To make recommendations about the use of gemcitabine in the management of medically appropriate patients with stage IIIB-IV NSCLC. OUTCOMES: The outcomes of interest were survival, response rate, symptomatic response, response duration and toxicity. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 2 members of the Provincial Lung Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The practice guideline report was reviewed by the Provincial Lung Cancer DSG and by the Systemic Treatment Disease Site Group. These committees comprise medical and radiation oncologists, surgeons, pathologists, nurses, a psychologist, a medical sociologist and administrators. One community representative participated in the development of this practice guideline. QUALITY OF EVIDENCE: Five phase II studies of single-agent gemcitabine in advanced NSCLC were reviewed. Four of these are published as full reports. Two randomized phase II studies comparing single-agent gemcitabine with etoposide plus cisplatin were also reviewed. One of these studies is fully published. Seven phase II studies of gemcitabine in combination with cisplatin and I phase II study of gemcitabine in combination with ifosfamide were reviewed. Three randomized controlled trials (RCTs) and 1 randomized phase II study, published in abstract form, compared gemcitabine combination chemotherapy with cisplatin combination chemotherapy. An additional phase II study, published in abstract form, of gemcitabine as salvage therapy in previously treated patients was also included. BENEFITS: Four phase II studies of single-agent gemcitabine at a dose of 1000 mg/m2 or more showed a combined response rate of 19% (intention-to-treat analysis; 95% confidence interval [CI] 15% to 24%) or 21% (efficacy analysis; 95% CI 17% to 26%) in advanced NSCLC. Median survival ranged from 7 to 9 months. Improvement from baseline in cough, hemoptysis and dyspnea was comparable to what would be expected with radiation therapy and with standard combination chemotherapy regimens. Improvement from baseline in their performance status was reported in 52% of treated patients. The 2 randomized phase II studies reported equivalent response rates for gemcitabine compared with etoposide plus cisplatin; the response data were pooled, which resulted in a nonsignificant benefit for gemcitabine (common odds ratio [OR] 0.90; 95% CI 0.43 to 1.90; p = 0.78). Gemcitabine has most frequently been combined with cisplatin, yielding a combined response rate of 44% (intention-to-treat; 95% CI 36% to 47%) or 45% (efficacy; 95% CI 39% to 51%) from 7 phase II studies. Median survival times ranged from 10 to 14 months. One phase II randomized study compared gemcitabine-cisplatin-vinorelbine vs. cisplatin-epirubicin-vindesine plus lonidamine and demonstrated a higher response rate (62% vs. 35%) in favour of the gemcitabine combination. Three RCTs demonstrated increased response rates for the combination of gemcitabine-cisplatin over either cisplatin alone or other combination regimens [(gemcitabine-cisplatin 35% vs. etoposide-cisplatin 12%; p = 0.001), (gemcitabine-cisplatin 31% vs. cisplatin 9%; p = 0.0001), (gemcitabine-cisplatin 40% vs. mitomycin, ifosfamide, cisplatin 28%; p = 0.03)]. HARMS: The major dose-limiting toxicity is neutropenia. Despite this, infection rates are low. Significant adverse effects that have an impact on the patient's quality of life or require the discontinuance of treatment are reported to be less than with any other single agent or combination of agents. Grade 3 or 4 dyspnea has been reported to occur in fewer than 2% of cases and may be drug related. (ABSTRACT TRUNCATED)

Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small-cell lung cancer after complete resection. Provincial Lung Cancer Disease Site Group.

GUIDELINE QUESTIONS: 1) Does the use of postoperative, adjuvant radiotherapy or chemotherapy, alone or in combination, improve survival rates among patients with completely resected, pathologically confirmed stage II or IIIA non-small-cell lung cancer (NSCLC)? 2) Does the use of radiotherapy reduce the risk of local recurrence among patients with completely resected stage II or IIIA NSCLC? OBJECTIVE: To make recommendations about the use of postoperative adjuvant radiotherapy and chemotherapy in the treatment of patients with completely resected stage II or IIIA NSCLC. OUTCOMES: Overall survival and disease-free survival are the primary outcomes of interest. A secondary outcome of interest is local disease control. PERSPECTIVES (VALUES): Evidence was collected and reviewed by 4 members of the Lung Cancer Disease Site Group (Lung Cancer DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The evidence-based recommendation resulting from this review was approved by the Lung Cancer DSG, which comprises medical oncologists, radiation oncologists, pathologists, surgeons and a medical sociologist. A community representative was present at 1 meeting during which the recommendation was discussed. QUALITY OF EVIDENCE: One meta-analysis and 22 randomized controlled trials (RCTs) were published between 1962 and 1996. The RCTs compared surgery plus radiotherapy with surgery alone; surgery plus adjuvant chemotherapy with surgery alone; surgery plus radiotherapy with surgery plus both chemotherapy and radiotherapy. Many studies included patients with stage IIIB NSCLC; some included patients with incompletely resected stage I NSCLC or with small cell lung cancer (maximum 10%). Older studies used chemotherapy or radiation that would now be considered inferior according to current standards of practice. BENEFITS: There was no survival benefit with adjuvant radiotherapy alone, although 3 RCTs reported a reduction in the rate of local recurrence among patients treated with adjuvant radiotherapy. The meta-analysis showed that postoperative, cisplatin-based chemotherapy alone reduced the relative risk of death by 13% (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.74 to 1.02); in combination with radiotherapy it resulted in a 6% reduction in the relative risk of death (HR 0.94, 95% CI 0.79 to 1.11). HARMS: Postoperative adjuvant chemotherapy with alkylating agents was found in the meta-analysis to increase the relative risk of death by 15%. A study involving prolonged adjuvant chemotherapy (busulfan or cytoxan daily for 2 years) reported that 4 of 726 patients had hematologic malignancies. In 1 study, only 53% of patients received all 4 cycles of chemotherapy with cyclophosphamide-doxorubicin-cisplatin (CAP); in another, 22% of patients refused therapy with CAP because of nausea and vomiting. PRACTICE GUIDELINE: There is evidence from RCTs that postoperative radiotherapy reduces rates of local recurrence by 11% to 18% (or 1.6 to 19-fold) among patients with completely resected, pathologically confirmed stage II or IIIA NSCLC. Therefore, if the outcome of interest is a reduction in the frequency of local tumour recurrence, radiotherapy is recommended. However, there is no evidence of a survival benefit from postoperative radiotherapy alone. In a meta-analysis, postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. The survival benefit was small and achieved only with chemotherapy regimens that produced substantial toxic effects and that are no longer used. Newer chemotherapy regimens are currently being evaluated as adjuvant therapy, but there is insufficient evidence of benefit at this time to recommend them. Therefore, if the outcome of interest is survival, there is insufficient evidence to recommend current chemotherapy regimens with or without radiotherapy as postoperative, adjuvant the