The photochemical alkylation and reduction of heteroarenes.

The functionalization of heteroarenes has been integral to the structural diversification of medicinally active molecules such as quinolines, pyridines, and phenanthridines. Electron-deficient heteroarenes are electronically compatible to react with relatively nucleophilic free radicals such as hydroxyalkyl. However, the radical functionalization of such heteroarenes has been marked by the use of transition-metal catalyzed processes that require initiators and stoichiometric oxidants. Herein, we describe the photochemical alkylation of quinolines, pyridines and phenanthridines, where through direct excitation of the protonated heterocycle, alcohols and ethers, such as methanol and THF, can serve as alkylating agents. We also report the discovery of a photochemical reduction of these heteroarenes using only iPrOH and HCl. Mechanistic studies to elucidate the underlying mechanism of these transformations, and preliminary results on catalytic methylations are also reported.

Direct alkylation of heteroarenes with unactivated bromoalkanes using photoredox gold catalysis.

Although visible light photoredox catalysis has emerged as a powerful tool for the construction of C-C bonds, common catalysts and/or their photoexcited states suffer from low redox potentials, limiting their applicability to alkyl radical generation from substrates with activated carbon-halogen bonds. Radicals derived from these activated compounds, being highly electrophilic or stabilized, do not undergo efficient addition to heteroarenes. Herein we describe the photocatalytic generation of nucleophilic alkyl radicals from unactivated bromoalkanes as part of a universal and efficient cross-coupling strategy for the direct alkylation of heteroarenes using a dimeric gold(i) photoredox catalyst, [Au2(bis(diphenylphosphino)methane)2]Cl2. The method proves to be efficient for alkylation of arenes under mild conditions in the absence of directing groups.

Too much of a good thing?: Positive religious coping predicts worse diurnal salivary cortisol patterns for overwhelmed African American female dementia family caregivers.

OBJECTIVES: Religious coping arguably prevents negative health outcomes for stressed persons. This study examined the moderating role of religious coping (positive, negative, and combined) in the connection of care recipient functional status with diurnal salivary cortisol patterns among dementia family caregivers. METHODS: Thirty African American (AA) female dementia caregivers and 48 AA noncaregivers completed the Religious Coping (RCOPE) scale, the Activities of Daily Living scale, and the Revised Memory and Behavior Problem Checklist (RMBPC) and collected five saliva samples daily (at awakening, 9 A.M., 12 P.M., 5 P.M., and 9 P.M.) for 2 straight days. RESULTS: Hierarchical regression tests with mean diurnal cortisol slope as the outcome illustrated surprisingly that higher combined and positive (but not negative) RCOPE scores were associated with increasingly flatter or worse cortisol slope scores for caregivers (but not noncaregivers). Of note, the RCOPE by RMBPC interaction was significant. Among caregivers who reported higher RMBPC scores, higher combined and positive (but not negative) RCOPE scores were unexpectedly associated with increasingly flatter cortisol slopes. CONCLUSIONS: These results extend current findings by showing that being AA, a caregiver, and high in positive religious coping may predict increased daily stress responses, mainly for those with higher patient behavioral problems. Because religious coping is a central coping strategy for AA caregivers, it is vital that epidemiologic assessments of religious coping in health and aging as well as tailored interventions focus on the unique reasons for this disparity.

How much striving is too much? John Henryism active coping predicts worse daily cortisol responses for African American but not white female dementia family caregivers.

INTRODUCTION: The John Henryism active coping (JHAC) hypothesis suggests that striving with life challenges predicts increased risk for cardiovascular disease for those with scarce coping resources. This study examined the moderating role of JHAC in the associations of 1) caregiver status and 2) care recipient functional status with diurnal salivary cortisol patterns among 30 African Americans (AAs) and 24 white female dementia caregivers and 63 noncaregivers (48 AAs). METHODS: Caregiver participants completed the JHAC-12 scale, Activities of Daily Living (ADL) scale, and Revised Memory and Behavior Problem checklist (RMBPC) and collected five saliva samples daily (at awakening, 9 A.M., 12 P.M., 5 P.M., and 9 P.M.) for 2 successive days. RESULTS: Univariate analysis of variance tests with mean diurnal cortisol slope as the outcome illustrated that among AA caregivers, higher JHAC scores were related to flatter (or more dysregulated) cortisol slopes. The JHAC by ADL and JHAC by RMBPC interactions were each significant for AA caregivers. Among AA caregivers who reported higher ADL and RMBPC scores, higher JHAC scores were associated with flatter cortisol slopes. CONCLUSIONS: These findings extend recent studies by showing that being AA, a caregiver, and high in JHAC may elevate the risk for chronic disease, especially for those with higher patient ADL and behavioral problems. Thus, it is imperative that interventions appreciate the pernicious role of high-effort coping style, especially for AA caregivers, to minimize the stressful side effects of patient ADL and memory and behavioral problems for the caregiver.

Lost in summation: depression among African American female caregivers and noncaregivers.

Ethnic differences in mental health have been established using large between-group research designs. Across ethnicity, studies have found that caregivers are at increased risk for depression, but little is known about within-group variability in depressive symptomatology. African American caregivers and noncaregivers were compared on different factors of depressive symptoms as measured by the Center for Epidemiologic Studies Depression subscales. Caregivers reported significantly less positive affect than noncaregivers. Rates were similar for negative affect, somatic complaints, and interpersonal relations. Depression may present itself in different ways among African Americans in the caregiving context, and results suggest information may be lost when global measures of depression are used.

Does depression prior to caregiving increase vulnerability to depressive symptoms among caregivers of persons with Alzheimer's disease?

Based on the vulnerability model of depression, this study tested the hypothesis that caregivers with prior depression are more likely to be depressed during caregiving than caregivers without prior depression. We further hypothesized an interaction effect in which caregivers with prior depression would be affected more by care-recipient dependency in activities of daily living and care-recipient depressive symptoms than those without prior depression. In a sample of 111 caregivers of persons with Alzheimer's disease, in an additive regression model, neither 'prior depressive symptoms' nor the clinically more serious 'prior depressive syndrome' was related to depressive symptoms during caregiving. In an interaction model, for caregivers with either 'no prior depression' or 'prior depressive symptoms,' the greater the care-recipient dependencies in instrumental activities of daily living (IADL), the greater were the depressive symptoms during caregiving. For caregivers with a 'prior depressive syndrome', however, the greater the IADL dependency, the fewer were the depressive symptoms during caregiving. This unexpected finding suggests that caregivers with a history of clinically significant depression are not necessarily more prone to depressive symptoms when caregiving responsibilities, at least for instrumental activities, are high. This result questions the vulnerability model of depression when applied to older caregivers.

Mental health and diurnal salivary cortisol patterns among African American and European American female dementia family caregivers.

Using a sociocultural stress and coping model, this pilot study examines the influence of depressive symptoms and stress on diurnal salivary cortisol patterns among African American (N=30) and European American (N=24) female dementia caregivers and noncaregivers (African American, N=48; European American, N=15). Caregiving participants completed the Center for Epidemiological Studies Depression Scale (CES-D), Perceived Stress Scale (PSS), and Stress-Related Growth Scale (SRGS) as respective measures of depressive symptoms, stress, and stress resilience. Participants also collected five saliva samples daily for two consecutive days. African American caregivers scored significantly higher than European American caregivers on the SRGS, but they did not differ on the PSS and CES-D scales. Regression analyses with age, ethnicity, caregiving status, and depressive symptoms as predictors, and cortisol slope as criterion, showed that only age and ethnicity predicted cortisol slope. African Americans had flatter slopes than the European Americans sampled, regardless of caregiving status. Findings highlight the role of cultural beliefs and of ethnicity in explaining cortisol function.

Enhancing the matching model of recruitment through focus groups.

The present paper discusses recruitment of older African-Americans for a psycho-physiological study using the matching model of recruitment proposed by Levkoff, Levy, and Weitzman (2000). The hallmark of the model by Levkoff et al. is that there must be a match between research and minority communities' perspectives in order for successful recruitment and retention of minority participants. The model by Levkoff et al. of recruitment differs from other recruitment strategies as it incorporates perspectives from both researchers and research institutions, as well as potential minority participants. The importance of holding pre-recruitment community focus groups based upon the tenets of the matching model of recruitment are discussed in this paper, and a community-based partnership research model is presented.

Preferences of older African-Americans for long-term tube feeding at the end of life.

The purpose of this study was to elicit preferences and reasons behind preferences for percutaneous endoscopic gastrostomy (PEG) tube placement in an older African-American sample. Five focus groups were conducted with subjects invited from the Geriatric Clinic of an urban tertiary care hospital. Thematic and latent content analyses were used. Five broad themes emerged as reasons behind the acceptance or rejection of a PEG tube, namely: the nature of the illness; the quality of life at the time of the decision; the concern about dependency; experiences; and religion (including issues of death). The issue of proxy also arose and contained three themes: fear of loss of decision-making ability; trust in family or caregivers as proxy even when the proxy choices differed from their own choices; and trust in the doctor and family to respect personal decisions. Use of a qualitative approach enabled potentially sensitive issues to be discussed. Preferences and the reasons behind these preferences may not always be anticipated by clinicians.

Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: phenotypic findings and genetic considerations.

An association between congenital bilateral absence of the vas deferens (CBAVD), normal renal anatomy and cystic fibrosis (CF) gene mutations is well established (CF/CBAVD). We postulate that unilateral renal agenesis (URA) and CBAVD (URA/CBAVD) may have a non-CF mutation-mediated genetic basis that leads to abnormal development of the entire mesonephric duct at a very early stage in embryo development (< or =7 weeks). The physical, laboratory and radiographic findings of men with URA/CBAVD (n = 17) and CF/CBAVD (n = 97) were compared; the fertilization and pregnancy rates in the URA/CBAVD population calculated, and the incidence of renal agenesis in immediate family members and offspring of men with URA/CBAVD analysed. No statistical differences could be identified within any of the above comparisons. The fertilization rate for the URA/CBAVD group was 58.2 +/- 26.3%. Eight infants and two fetuses had normal renal anatomy, while one terminated male fetus had bilateral renal and vasal agenesis. Thirty first-order relatives had normal renal units. Anatomical expression of the reproductive ductal derivatives in men with URA/CBAVD and CF/CBAVD was similar, but the phenotypic outcome of the renal portion of the mesonephric duct was different. The potential for transmission of this fatal anomaly reinforces the need for prenatal ultrasounds with all pregnancies involving URA/CBAVD men.

Urinary incontinence after radical prostatectomy: implications and urodynamics.

OBJECTIVES: The purpose of this study was to evaluate urine loss, quality of life, and urodynamics in men who had urinary incontinence after radical prostatectomy and who were at least 12 months post surgery. SUBJECTS AND METHODS: Men from a previous study (N = 180) regarding quality of life and treatment of incontinence post prostatectomy were solicited. Twenty-one men were still incontinent 2 or more years post surgery; 16 agreed to further evaluation. The latter patients completed a 24-hour pad test, frequency/volume chart, quality-of-life questionnaire, and underwent video urodynamics. RESULTS: Median time from surgery was 22 months (14 to 33 months) and the mean urine loss over 24 hours was 164 g. Incontinence had an impact on quality of life, but men adjusted their lives and most would undergo radical prostatectomy again. Half of the subjects experiencing stress urinary incontinence on urodynamics also had a component of detrusor dysfunction (urge incontinence/decreased compliance). CONCLUSIONS: Quality of life was significantly affected by urinary incontinence, but most subjects would undergo radical prostatectomy again. Symptoms of stress urinary incontinence alone may not reflect the urodynamic diagnosis. Detrusor dysfunction should be considered in the etiology of incontinence after radical prostatectomy.

Introducing annamarie jagose.

SUMMARY Annamarie Jagose's fiction can be loosely divided into the early short stories and the later novels. The stories are generally feminist and lesbian in content and characters, and contain many traditional story elements. The novels, In Translation and Lulu,are more complex works. In these texts, Jagose is interested in "queering" identity, both heterosexual and homosexual, and in questioning the effectiveness of these traditional taxonomies. Both the stories and novels feature an exquisite control of language, a wry humour, and a deft understanding of human relationships.

Fertility in men with cystic fibrosis: an update on current surgical practices and outcomes.

BACKGROUND: Men with cystic fibrosis (CF) have bilateral absence of the vas deferens causing an obstructive azoospermia that is not amenable to surgical correction. Advances in the field of reproductive medicine allow for the procurement of viable sperm and facilitate fertilization and pregnancy in couples where the man has CF. OBJECTIVES: To describe patient anatomy and semen characteristics and to determine the pregnancy rates of couples in whom the male partner has CF and who have undergone microsurgical epididymal sperm aspiration coupled with in vitro technology, specifically intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective analysis. SETTING: Clinical department of urology and two reproductive medicine units. PATIENTS: Thirteen married men with CF who were referred for infertility. INTERVENTIONS: History, physical examination, semen analysis, transrectal and renal ultrasonography, CF mutation analysis, and microsurgical sperm aspiration coupled with ICSI. RESULTS: All 13 men had low-volume azoospermia, absent vasa, and aplasia/hypoplasia of the seminal vesicles. CF mutation analysis was carried out in 11 of 13 men, and 9 of 11 were DeltaF508 homozygous. Eight men underwent microsurgical sperm aspiration, and their partners underwent one or more cycles of ICSI. Five couples (62.5%) achieved a pregnancy, with four couples delivering (three sets of twins and one singleton). CONCLUSIONS: CF in men is accompanied by bilateral vasal aplasia. The resultant obstructive azoospermia can be treated quite successfully with a combination of sperm aspiration and ICSI. It is important for physicians involved in the care of men with CF to convey the message that prospects for fatherhood are excellent with current technology.

A sociocultural stress and coping model for mental health outcomes among African American caregivers in Southern California.

A sociocultural stress and coping model to explain emotional distress among caregivers of family members who have dementia across ethnic and cultural groups is presented and explored in a sample of 41 African American and 128 non-African American caregivers. In this sample, African American caregivers reported lower levels of burden but equal levels of depression and anxiety. In the structural equation model, previous reports that African Americans' lower appraisal of caregiving as burdensome resulted in lower levels of emotional distress were confirmed. However, in this model, this pathway was counterbalanced by a tendency of African American caregivers to use emotion-focused coping and, therefore, increase emotional distress. African American caregivers were also younger and in poorer health, factors which tend to increase both burden and emotional distress outcomes. As suggested by the sociocultural stress and coping model, the influences of ethnic group variables on stress and coping processes are complex and multidirectional.

Characterization of a novel transplantable orthotopic rat bladder transitional cell tumour model.

An animal tumour model that mimics the human counterpart is essential for preclinical evaluation of new treatment modalities. The objective of this study was to develop and characterize such a model. To accomplish this, the established AY-27 rat bladder transitional cell carcinoma (TCC) cell line was transplanted orthotopically into Fischer CDF344 female rats. AY-27 TCC cells were grown in monolayer cell culture and instilled intravesically as single cell suspensions into bladders that had been conditioned with mild acid washing. Tumour growth was assessed weekly by subjecting the rats to magnetic resonance imaging (MRI). At intervals following implantation and MRI tumour detection, the animals were sacrificed for necropsy, histological examination and immunocytochemical studies. Flow cytometry was also performed for detection of Fas or Fas-ligand expression on AY-27 cells. The overall tumour establishment was 95% (97/102 rats) at 12-50 days, while in a subgroup of animals sacrificed at 16 days, 80 out of 82 animals (97%) developed TCC, the majority of which was superficial. Tumour stage was assessed by gross pathology and light microscopy. Histological examination of the tumour specimens confirmed the presence of grade II-III TCC. Immunocytochemistry confirmed that the tumour model maintained the features of TCC. The changes seen on MRI correlated well with the extent of tumour invasion identified histologically. Patchy carcinoma in situ could be detected histologically 12-13 days post-inoculation, and progressed to papillary tumour or invasive disease thereafter. Neither Fas nor Fas-ligand was expressed on AY-27 cells. The orthotopic AY-27 TCC model is highly reproducible and is ideal for preclinical studies on experimental intravesical therapies.

Biodistribution of Photofrin II and 5-aminolevulinic acid-induced protoporphyrin IX in normal rat bladder and bladder tumor models: implications for photodynamic therapy.

Photodynamic therapy (PDT) has been considered as a potential therapy for superficial bladder carcinomas. Cutaneous photosensitivity and reduction of bladder capacity are the two well-known complications following systemic administration of the commonly used photosensitizer, Photofrin II (PII). The objective of the present study was to evaluate whether intravesical (i.b.) instillation of photosensitizers for PDT of bladder cancer might be a more suitable treatment method. Female Fischer rats were utilized to develop orthotopic and heterotopic bladder tumor models. Rats bearing orthotopic bladder tumors were treated either intravesically or intravenously with graded doses of 5-aminolevulinic acid (ALA) or PII. Normal rats received the same doses of ALA or PII. As well, rats bearing heterotopic tumor were studied for comparison. The biodistribution times (times allowed for tissue uptake and bioconversion following drug administration) were 2, 4 or 6 h. Porphyrin fluorescence intensities within tumor, urothelium, submucosa, bladder muscularis and abdominal muscle were quantitated by confocal laser scanning microscopy. Following intravenous (i.v.) injection of ALA, tumor protoporphyrin IX (PpIX) levels peaked at 4 h and diminished by 6 h. The PpIX ratios of tumor-to-bladder mucosa, submucosa and muscle layers were 3:1, 5:1 and 8:1, respectively, 4 h following 1000 mg/kg ALA injection. After ALA instillation, the optimal biodistribution time appeared to be 4 h. Bladder instillation provided comparable tumor labeling with the i.v. route, but lost selectivity of PpIX accumulation between tumor and normal urothelium. The PpIX ratio of tumor-to-bladder muscularis was 5:1. After i.b. instillation of PII, porphyrin fluorescence was detected only within tumor and urothelium, while porphyrin fluorescence was mainly located in bladder submucosa following i.v. injection. Intravesical administration of ALA or PII might be feasible for PDT of superficial bladder cancers.

Furazolidone-induced injury in the isolated perfused chicken heart.

The Langendorff isolated heart preparation was adapted to determine the effect of furazolidone (0.5 and 2 micrograms/ml of perfusate) on hearts of 3-week-old broiler chickens. Following 115 minutes of perfusion, both concentrations of furazolidone caused approximately a two-fold increase in myocardial vascular resistance and a six-fold increase in lactate dehydrogenase release into the effluent fluid, compared with a control perfused group of isolated hearts (P less than 0.01). Ultrastructural alteration differences were not found between the drug-treated and control groups. It was concluded that: (i) furazolidone, at concentrations only moderately above therapeutic plasma concentrations, caused detrimental changes in myocardial vascular resistance and lactate dehydrogenase release and (ii) the isolated chicken heart preparation is an example of a cost-effective, reliable laboratory tool for screening potential cardiotoxins.