Three-dimensional distribution of bone density in the proximal humerus.

Bone quality of the proximal humerus is important for the surgical treatment of proximal humeral fractures and rotator cuff tears. However, very few studies have evaluated the areal bone mineral density (BMD) of the proximal humerus. The aim of this study was to analyze the volumetric BMD (vBMD) using peripheral-quantitative-computed-tomography. Total, trabecular and cortical vBMD were determined separately for the proximal and distal half of the humeral head, the surgical neck and seven specific regions of interest. The greater tuberosity (GT) was divided into three regions, and the lesser tuberosity (LT) and articular surface (AS) were each divided into two regions. The proximal head showed a significantly higher trabecular (+ 46%) and cortical vBMD (+ 15%) than the distal one. The mean trabecular vBMD of AS was significantly higher (+ 80%), and the cortical vBMD was significantly lower (- 11%) than that of the tuberosities. In the proximal half of GT, trabecular vBMD was higher in the posterior than in the middle and anterior regions. Cortical vBMD was higher in middle region than in the anterior and posterior ones. In the distal half of GT, trabecular vBMD was significantly higher in the posterior than in the middle region, and cortical vBMD was significantly higher in the anterior than in the middle region. In one. These results point to bone sites that may provide stronger fixation for implants, reduce the risk of implant loosening, and therefore improve patient outcome.

The presence of smooth muscle actin in fibroblasts in the torn human rotator cuff.

The rotator cuff frequently sustains athletic and occupational injury, often resulting in chronic pain and disability. However, despite the high incidence of such shoulder problems, the pathophysiology of rotator cuff injury and healing has not yet been fully elucidated. The notable finding of this study was the presence of a contractile actin isoform, alpha-smooth muscle actin (SMA), in nonvascular cells in all of the seven torn human rotator cuff specimens evaluated immunohistochemically. Up to 95% of cells in any one region, and over 95% of elongated cells found in association with crimped collagen, contained SMA. Most of the cells staining positive for SMA in these sections had morphological features of the fibroblast, though a small number were chondrocyte-like. Treatment of cells growing out from human rotator cuff explants with TGF-beta1 significantly increased the amount of SMA evaluated by Western blot analysis. PDGF-BB and IFN-gamma had no effect on the cell content of SMA. This is the first documentation of the presence of SMA-positive cells in the human rotator cuff tendon. SMA has been found in a number of other healing connective tissues including skin, ligament, meniscus, cartilage, and other types of tendon. Of importance are previous findings that SMA-positive cells can contract a collagen-glycosaminoglycan analog of extracellular matrix in vitro. The results of the present study thus suggest that SMA-containing cells could contribute to the retraction of the torn ends of a ruptured rotator cuff and play an important role in healing.

Patient-held shared care records for individuals with mental illness. Randomised controlled evaluation.

BACKGROUND: Few formalized shared care schemes exist within psychiatry and the evidence base for sharing psychiatric care is weak. AIMS: To evaluate the utility of patient-held shared care records for individuals with long-term mental illness. METHOD: Cluster-randomised controlled parallel-group 12-month trial involving 90 patients with long-term mental illness drawn from 28 general practices. RESULTS: Carrying a shared care record had no significant effect on mental state or satisfaction with psychiatric services. Compared with controls, patients in the shared care group were no more likely to be admitted (relative risk 1.2, 95% CI 0.86-1.67) and attend clinic (relative risk 0.96, 95% CI 0.67-1.36) over the study period. Uptake of the shared care scheme was low by patients and professionals alike. Subjects with psychotic illness were significantly less likely to use their records (relative risk 0.51, 95% CI 0.27-0.99). CONCLUSIONS: Patient-held records may not be helpful for patients with long-term mental illness.

Evidence-based psychopharmacology 3. Assessing evidence of harm: what are the teratogenic effects of lithium carbonate?

Critical appraisal techniques are not only useful in evaluating evidence of therapeutic trials. In this final article of the series of evidence-based psychopharmacology, the evidence about the teratogenic effects of lithium carbonate is considered. This exercise highlights the importance of assessing the evidence oneself and not relying on the interpretation others put on it.

Evidence-based psychopharmacology 1. Appraising a single therapeutic trial: what is the evidence for treating early Alzheimer's disease with donepezil?

Expertise in setting appropriate, answerable clinical questions, undertaking an accurate search of databases, and appraising the evidence found are all key elements to practising evidence-based medicine. Using the published evidence of the utility of donepezil in Alzheimer's disease as an example, I have attempted to illustrate the process of critical appraisal of a therapeutic intervention. The study appraised was well conducted and the results indicate that donepezil may benefit some patients with Alzheimer's disease.

Evidence-based psychopharmacology 2. Appraising a systematic review: is risperidone better than conventional antipsychotics in the treatment of schizophrenia?

Systematic reviews are increasingly used to combine the results of several studies in order to define the treatment effect with a high degree of precision. However, reviews of this nature may lead to spurious results and should not be accepted uncritically. This article, the second in a series on evidence-based psychopharmacology, is intended to illustrate the process of critical appraisal of a systematic review. In this example, a systematic review of studies comparing risperidone with conventional antipsychotics is appraised. Interpretation of the results of the systematic review may be hampered by the way in which studies were selected.

Quality of life and social issues in older depressed patients.

Depression is a common disorder in old age, affecting at least 10% of individuals over 65. In older people, the relationship between depression and impaired social functioning and quality of life is complex and ill defined. Despite well-tolerated and effective treatments, many depressed individuals are undiagnosed or under-treated. The impact of depression on the quality of life (QOL) and social functioning of older people can be considerable. Furthermore, impairment of social functioning, consequent on the social isolation and functional disability that goes hand-in-hand with ageing, may be a causative factor in old age depression. Once depression develops, it may result in further narrowing of social repertoire, compounding the problem. Notwithstanding some of the difficulties in measuring social functioning and quality of life, progress has been made in defining the extent of these problems in older depressed individuals. The impact treatment of depression has on these parameters is becoming increasingly recognised and evaluated in clinical trials.

Organization of the human glucokinase regulator gene GCKR.

Glucokinase plays an important role in regulating insulin secretion in response to changes in blood glucose levels. As a result, one form of maturity onset diabetes of the young (MODY) results from haploinsufficiency of glucokinase. In both liver and pancreatic islet, glucokinase is allosterically regulated by an inhibitory protein (glucokinase regulatory protein, GCKR). GCKR has therefore become an important gene for functional analysis in type 2 diabetes. To allow genetic assessment of any such role, we have determined the structure of the human GCKR gene. Characterization of P1 and YAC clones containing GCKR shows it to consist of 19 exons spanning 27 kb. RT-PCR, RACE, and RNase protection experiments defined a transcriptional start site for GCKR 66 bp upstream of the initiation codon, but provided no evidence for islet cell specific alternative splicing in the rat. By SSCP screening, a common polymorphic sequence variant has been defined within exon 15 of human GCKR, at nt 1400 of the cDNA. This alters amino acid residue 446 from proline, conserved in rat and Xenopus, to leucine.

P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population.

Only three mutant cystic fibrosis (CF) alleles have to date been established as conferring a dominant mild effect on affected subjects who are compound heterozygotes. We now add a fourth, P67L, which occurs on about 1.4% of Scottish CF chromosomes. Among 13 patients (12 unrelated) with this allele, the average age at diagnosis was 22.5 +/- 11.3 years. None of the cases had consistently raised sweat chloride concentrations, the average value being 57 +/- 9 mmol/l; 77% of the patients were pancreatic sufficient. When compared to three other established mild CF alleles, R117H, A455E, and 3849 + 10kb C-T, a compound heterozygote for P67L has minimal disease and clinical suspicions are unlikely to be confirmed other than by DNA typing.

Psychiatrists and their patients: views on forms of dress and address.

BACKGROUND: Dress styles and forms of address vary among psychiatrists. METHOD: A semi-structured interview was administered to a sample of psychiatric in-patients, and a questionnaire was sent to junior and consultant psychiatrists, to identify preferences for dress styles and terms of address. RESULTS: Forty-nine (71%) of the in-patient sample participated. A preference was found for smart attire and white coats. Of the 69 (80%) doctors returning questionnaires, the majority supported smart dress as the most appropriate attire. Most patients preferred to be called by their first name while addressing doctors by title and surname. Junior doctors preferred to use first names when talking to patients while almost all consultants used title and surname. Doctors of all grades liked to be called by their title and surname. CONCLUSIONS: Paying more attention to the way we present ourselves and interact at work may help to facilitate the therapeutic alliance.

Strength of fixation with transosseous sutures in rotator cuff repair.

The effect of various configurations of placement of transosseous sutures on the immediate strength of fixation was studied in forty-five fresh-frozen humeri from cadavera of older individuals (mean age at the time of death, sixty-three years). The ultimate strength (the strength to failure) was significantly greater (p < 0.05) when the sutures were placed at sites more distal to the tip of the greater tuberosity or when the sutures were tied over a wider bone bridge. Cortical augmentation with use of a plastic button through which the transosseous sutures were tied increased the ultimate strength approximately 1.9-fold. The increase in the ultimate strength of the transosseous repair corresponded significantly with the increasing mean thickness of the cortical bone as the sutures were placed more distally along the lateral aspect of the humerus. We concluded that the strength of the fixation of a rotator cuff repair can be increased by placing the transosseous sutures at least ten millimeters distal to the tip of the greater tuberosity and by tying them over a bone bridge that is at least ten millimeters wide. When bone is very osteoporotic, cortical augmentation with a readily available plastic button strengthens the repair.

BRCA1 5382insC mutation in sporadic and familial breast and ovarian carcinoma in Scotland.

A restriction site-generating polymerase chain reaction (RG-PCR) assay was developed to detect the BRCA1 5382insC mutation that has been reported in multiple, apparently unrelated breast/ovarian carcinoma families. The assay has been used to screen tumour DNA from 250 breast cancer patients (aged 19-86 years) and from 80 ovarian cancer patients (aged 25-90 years) in a local population of patients with no known family history. Altogether, 0/80 (0%) ovarian and 1/250 (0.4%) breast tumour DNAs were found to have the 5382insC mutation. The sole positive case was a 26-year-old woman (BC185) with no known family history. One of the reasons for carrying out this analysis was that the 5382insC mutation had previously been shown to segregate with the disease in a very large Scottish 'West Lothian' kindred having breast/ovarian carcinoma. To investigate whether this apparently isolated case and the known family might be related, haplotypes for the markers D17S855, D17S1322, D17S1323 and D17S1327 were analysed. The mutant haplotype in the large kindred was identical to that reported in all other 5382insC mutation families for all markers with the exception of D17S1327. This implies that there has been a recombination event at the telomeric end of common ancestral haplotype in this family. Since the isolated case we identified carries the 'complete' common haplotype, it is unlikely that she is closely related to the West Lothian family.

A general method for the detection of large CAG repeat expansions by fluorescent PCR.

The expansion of a tandemly repeated trinucleotide sequence, CAG, is the mutational mechanism for several human genetic diseases. We present a generally applicable PCR amplification method using a fluorescently labelled locus specific primer flanking the CAG repeat together with paired primers amplifying from multiple priming sites within the CAG repeat. Triplet repeat primed PCR (TP PCR) gives a characteristic ladder on the fluorescence trace enabling the rapid identification of large pathogenetic CAG repeats that cannot be amplified using flanking primers. We used our method to test a cohort of 183 people from myotonic dystrophy families including unaffected subjects and spouses. Eighty five clinically affected subjects with expanded alleles on Southern blot analysis were all correctly identified by TP PCR. This method is applicable for any human diseases involving CAG repeat expansions.

Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of chromosome 2p23.

The glucokinase regulator (GCKR) is a 65-kDa protein that inhibits glucokinase (hexokinase IV) in liver and pancreatic islet. The role of glucokinase (GCK) as pancreatic beta cell glucose sensor and the finding of GCK mutations in maturity onset diabetes of the young (MODY) suggest GCKR as a further candidate gene for type 2 diabetes. The inhibition of GCK by GCKR is relieved by the binding of fructose-1-phosphate (F-1-P) to GCKR. F-1-P is the end product of ketohexokinase (KHK, fructokinase), which, like GCK and GCKR, is present in both liver and pancreatic islet. KHK is the first enzyme of the specialized pathway that catabolizes dietary fructose. We have isolated genomic clones containing the human GCKR and KHK genes. By fluorescent in situ hybridization (FISH), KHK maps to Chromosome (Chr) 2p23.2-23.3, a new assignment corroborated by somatic cell hybrid analysis. The localization of GCKR, originally reported by others as 2p22.3, has been reassessed by high-resolution FISH, indicating that, like KHK, GCKR maps to 2p23.2-23.3. The proximity of GCKR and KHK was further demonstrated both by two-color interphase FISH, which suggests that the two genes lie within 500 kb of each other, and by analysis of overlapping YAC and P1 clones spanning the interval between GCKR and KHK. A new microsatellite polymorphism was used to place the GCKR-KHK locus between D2S305 and D2S165 on the genetic map. The colocalization of these two metabolically connected genes has implications for the interpretation of linkage or allele association studies in type 2 diabetes. It also raises the possibility of coordinate regulation of GCKR and KHK by common cis-acting regulatory elements.

Electrocardiographic changes in patients receiving neuroleptic medication.

The precise aetiology of sudden death in patients receiving neuroleptic medication is uncertain, but cardiac arrhythmias are a possible cause. We investigated the link between neuroleptic medication and electrocardiographic changes predictive of malignant cardiac arrhythmias. Electrocardiographs were performed on 111 patients receiving neuroleptic medication and on 42 unmedicated controls. Prolonged QTc intervals were more common in the patient sample, but QTc dispersion was not significantly increased. QTc interval prolongation was more likely in patients on doses above 2000 mg chlorpromazine equivalents daily (odds ratio 4.28, P < 0.02). Neuroleptic medication, especially at high doses, is associated with ECG changes that may herald more serious cardiac problems.

The use of risperidone in treatment-resistant schizophrenia: two case reports.

The role of risperidone in the management of treatment-resistant schizophrenia remains unclear. We describe two patients with treatment-resistant schizophrenia characterized by unremitting delusions, thought disorder and self-neglect who had a sustained improvement in their symptoms soon after starting risperidone. Risperidone may be a suitable alternative to clozapine in some patients unresponsive to conventional antipsychotics.

A human parthenogenetic chimaera.

In mice, parthenogenetic embryos die at the early postimplantation stage as a result of developmental requirements for paternally imprinted genes, particularly for formation of extraembryonic tissues. Chimaeric parthenogenetic<==>normal mice are viable, however, due to non-random differences in distribution of their two cell types. Species differences in imprinting patterns in embryo and extra-embryonic tissues mean that there are uncertainties in extrapolating these experimental studies to humans. Here, however, we demonstrate that parthenogenetic chimaerism can indeed result in viable human offspring, and suggest possible mechanisms of origin for this presumably rare event.