The total synthesis of K-252c (staurosporinone) via a sequential C-H functionalisation strategy.

A synthesis of the bioactive indolocarbazole alkaloid K-252c (staurosporinone) via a sequential C-H functionalisation strategy is reported. The route exploits direct functionalisation reactions around a simple arene core and comprises of two highly-selective copper-catalysed C-H arylations, a copper-catalysed C-H amination and a palladium-catalysed C-H carbonylation, which build up the structural complexity of the natural product framework.

Novel hMLH1 and hMSH2 germline mutations in African Americans with colorectal cancer.

CONTEXT: Germline mutations of the DNA mismatch repair (MMR) genes hMLH1 and hMSH2 have been shown to cosegregate with the colorectal cancer phenotype in multiple hereditary nonpolyposis colorectal cancer (HNPCC) pedigrees. However, the frequency of these mutations among African American patients with colorectal cancer is unknown. OBJECTIVE: To investigate the frequency of germline alterations of the DNA MMR genes hMLH1 and hMSH2 among African Americans affected by HNPCC and early-age onset colorectal cancer. DESIGN, SETTING, AND PATIENTS: Forty unrelated African American HNPCC and early-age onset colorectal cancer patients (8 women, 3 men) were identified from the cancer registry at a National Cancer Institute-designated referral center, 11 of whom were available for and agreed to study participation from January 1997 to February 1998. The mean age of the subjects was 44 years. An additional 50 age- and sex-matched African Americans without personal or family history of colorectal, endometrial, ovarian, urinary tract, or upper gastrointestinal tract malignancy were also studied as a polymorphism control population. In all subjects, genomic DNA was amplified by polymerase chain reaction for all hMLH1 and hMSH2 exons and screened using single-strand conformation polymorphism (SSCP) analysis. Samples demonstrating significant SSCP shifts underwent automated nucleotide sequencing analysis. MAIN OUTCOME MEASURE: Frequency of hMLH1 and hMSH2 germline alterations in the affected and control subjects. RESULTS: Germline hMLH1 and hMSH2 mutations were detected in 3 (27%) of the African American colorectal cancer probands studied. Each mutation was novel. Two hMLH1 (an A-->T transversion at codon 26 and a GG-->AT substitution across codons 177 and 178) mutations and 1 hMSH2 mutation (a C-->T transition at codon 389) were identified in 3 female study subjects. Six other hMLH1 and hMSH2 alterations were detected but were presumed to be polymorphisms. Neither missense mutation (at codons 26 and 389) was detected in the control population. CONCLUSIONS: The results of our analysis support an association between the 3 mutations reported and predisposition to colorectal cancer. Further studies are needed to define DNA MMR gene-associated colorectal cancer in African Americans, an understudied population at increased risk of fatal colorectal cancer.

The foster carer experience in Ireland: findings from a postal survey.

Findings from a postal survey of foster carers in a region of Ireland are reported. While a majority of the respondents seem broadly contented in their role, it is clear that some are experiencing difficulties of different kinds. Problems experienced by different minorities of these foster carers included concerns with the level of administrative and professional support, worries about being parted from the child, and problems in the relationship with the child's biological parents. Responses on motivations to foster suggest a high level of altruistic motivation. The possible implication of these and other findings are discussed.

Comparison of three cognitive strategies in altering pain behaviors on a cold pressor task.

The efficacy of three cognitive strategies for coping with pain was examined in a cold-water pressor task in a sample of college students. Subjects were pretested and then randomly assigned to one of three treatment conditions (Paradoxical Intention, Rational Self-statement, or Self-observation) or to an expectancy control group. Following training in the respective cognitive strategies, all groups were given a posttest in the cold-water pressor to determine the effectiveness of the treatment. Pain thresholds, tolerances, and discomfort ratings were recorded for subjects in each condition. No differences were found between the Paradoxical Intention or Rational Self-statement groups and the Expectancy Control on any of the pain measures. The Self-observation treatment condition, however, had significantly higher pain tolerance scores than the Expectancy Control group. The findings were attributed to the subjects' dissociating the sensory aspects of the pain experience from the anxiety when focusing upon the coldness and wetness of the cold water.