Total synthesis of malagashanine: a chloroquine potentiating indole alkaloid with unusual stereochemistry.

The first total synthesis of malagashanine, a chloroquine potentiating indole alkaloid, is presented. A highly stereoselective cascade annulation reaction was developed to generate the tetracyclic core of the Malagasy alkaloids. This chemistry is likely to be broadly applicable to the synthesis of other members of this stereochemically unique family of natural products.

Iridium(iii)-bis(imidazolinyl)phenyl catalysts for enantioselective C-H functionalization with ethyl diazoacetate.

The intermolecular enantioselective C-H functionalization with acceptor-only metallocarbenes is reported using a new family of Ir(iii)-bis(imidazolinyl)phenyl catalysts, developed based on the interplay of experimental and computational insights. The reaction is tolerant of a variety of diazoacetate precursors and is found to be heavily influenced by the steric and electronic properties of the substrate. Phthalan and dihydrofuran derivatives are functionalized in good yields and excellent enantioselectivities.

An audit of parents'/guardians' wishes recorded after coronial autopsies in cases of sudden unexpected death in infancy: issues raised and future directions.

In the U.K., cases of sudden unexpected death in infancy are under the jurisdiction of the Coroner and consent for a post-mortem is not required. Prior to the Human Tissue Act 2006 (HTA) there was also no requirement to request retention of tissue (blocks and slides). The HTA stipulates that parental/ guardian consent is mandatory to retain or dispose of all tissues after the Coroners' purposes have been fulfilled. In 2007, in order to avoid confusion with the consent needed for hospital post-mortems, a new form was introduced by Sheffield Children's Hospital NHS Foundation Trust (SCH) called Record of parents'/guardians'wishes regarding samples taken at a Coroner's post mortem. This version specifically asks if blocks and slides may be retained as part of the medical record, or are to be disposed of, and for parental agreement (or not) for the frozen tissue, blocks and slides to be used for education, audit, quality control and medical research. One hundred and nineteen Coroners' postmortems covering the years 2006-2007 were reviewed. All parents/guardians (P/G) were contacted and the outcomes of P/G wishes recorded by SCH staff, Coroners' Officers (CO) and Police Family Liaison Officers (PFLO) were analysed and compared (44% from CO were outstanding at the time of audit). Any delay in recording P/G wishes by these three groups was also compared. In 2006, parental agreement to the use of blocks and slides for education, audit, quality control and medical research was 94%, 77% and 75% for SCH, CO and PFLO, respectively. In 2007 it was 84%, 37% and 100% for the same groups. Permission for the retention of frozen tissue given to SCH, CO and PFLO was 90%, 62% and 100% in 2006 and 90%, 44% and 100% in 2007, respectively. Cases where parents did not wish for the retention or use of tissue (including blocks and slides) were 3%, 15% and 0% in 2006 for SCH, CO and PFLO respectively, and 0% for all groups in 2007. Training of staff in all aspects of post-mortem and bereavement care is essential for ascertaining parental wishes. Families should be provided with the knowledge that allows them to make informed choices. The analysis of the results of the audit supports this view.

The DNA sequence and analysis of human chromosome 6.

Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome.

Effect of regimen complexity on patient satisfaction and compliance with warfarin therapy.

This study sought to determine patient satisfaction with anticoagulation care in a pharmacist-managed clinic and assess the effect of warfarin regimen complexity on patient satisfaction, compliance, and international normalized ratios (INRs). Retrospective chart reviews of 476 anticoagulation clinic patients were conducted. Patients were divided into groups by complexity of warfarin regimen (whole tablet, split tablet, alternating dose) for comparisons of compliance and INRs. An oral Likert scale satisfaction survey was administered to a convenience sample of 100 patients. Degree of satisfaction was compared based on warfarin regimen. Compliant patients were more likely to have therapeutic INRs (p < 0.01) and to be taking whole tablet dosage regimens (p < 0.01). Patients were generally satisfied with the pharmacist-managed clinic. There was a significantly (p < 0.025) higher score for patients on split tablet regimens, indicating a greater likelihood for agreement that alternating doses made taking their medication more difficult. A relationship exists between patient compliance and prescribed dosage regimen, as well as with therapeutic INR values.

The DNA sequence and comparative analysis of human chromosome 20.

The finished sequence of human chromosome 20 comprises 59,187,298 base pairs (bp) and represents 99.4% of the euchromatic DNA. A single contig of 26 megabases (Mb) spans the entire short arm, and five contigs separated by gaps totalling 320 kb span the long arm of this metacentric chromosome. An additional 234,339 bp of sequence has been determined within the pericentromeric region of the long arm. We annotated 727 genes and 168 pseudogenes in the sequence. About 64% of these genes have a 5' and a 3' untranslated region and a complete open reading frame. Comparative analysis of the sequence of chromosome 20 to whole-genome shotgun-sequence data of two other vertebrates, the mouse Mus musculus and the puffer fish Tetraodon nigroviridis, provides an independent measure of the efficiency of gene annotation, and indicates that this analysis may account for more than 95% of all coding exons and almost all genes.

Clinical and economic effects of pharmacy services in geriatric ambulatory clinic.

Pharmacy services were introduced in an established multidisciplinary geriatric ambulatory clinic. The pharmacist collaborated with primary care providers to optimize patients' drug regimens. Over 8 months there were 250 patient visits to the clinic. Traditional medical care was provided at 144 (57.6%) of these visits and traditional medical care plus pharmacist evaluation was provided at 106 (42.4%). The pharmacist identified 220 potential and actual drug-related problems. Acceptance of pharmacist-recommended changes in drug therapy was 98.6%. A mean reduction of 3.4 agents/patient was achieved in the intervention group (p<0.0001). Clinical outcomes of changes in drug therapy were neutral or positive in 99.5% of cases. Pharmacy services resulted in net savings of $7,788 annually.

Clinical significance of rare and benign side effects: propofol and green urine.

A 55-year-old man requiring airway protection for esophagogastroduodenoscopy was sedated with propofol. On the third day of propofol infusion his urine was dark green. Although he was afebrile and his white blood cell count was within normal limits, the green urine was suspected to be of infectious etiology. Laboratory tests were ordered and broad-spectrum antibiotics were considered. Antibiotics were avoided when propofol was recognized as a rare and benign potential cause of the green urine. Earlier recognition of this side effect may have averted unnecessary laboratory monitoring. Prompt recognition of such side effects is important in limiting medical expenditures, inordinate drug exposure, and distress among patients and clinicians.

The DNA sequence of human chromosome 22.

Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.