Screening for the metabolic side effects of antipsychotic medication: findings of a 6-year quality improvement programme in the UK.

OBJECTIVES: To increase the frequency and quality of screening for the metabolic syndrome in people prescribed continuing antipsychotic medication. DESIGN: An audit-based, quality improvement programme (QIP) with customised feedback to participating mental health services after each audit, including benchmarked data on their relative and absolute performance against an evidence-based practice standard and the provision of bespoke change interventions. SETTING: Adult, assertive outreach, community psychiatric services in the UK. PARTICIPANTS: 6 audits were conducted between 2006 and 2012. 21 mental health Trusts participated in the baseline audit in 2006, submitting data on screening for 1966 patients, while 32 Trusts participated in the 2012 audit, submitting data on 1591 patients. RESULTS: Over the 6 years of the programme, there was a statistically significant increase in the proportion of patients for whom measures for all 4 aspects of the metabolic syndrome had been documented in the clinical records in the previous year, from just over 1 in 10 patients in 2006 to just over 1 in 3 by 2012. The proportion of patients with no evidence of any screening fell from almost ½ to 1 in 7 patients over the same period. CONCLUSIONS: The findings suggest that audit-based QIPs can help improve clinical practice in relation to physical healthcare screening. Nevertheless, they also reveal that only a minority of community psychiatric patients prescribed antipsychotic medication is screened for the metabolic syndrome in accordance with best practice recommendations, and therefore potentially remediable causes of poor physical health remain undetected and untreated.

[Perioperative mortality: retrospective cross-sectional study of surgical patients who died between 2004 and 2008 in a tertiary care hospital]. / Mortalidad perioperatoria de los pacientes quirúrgicos: estudio transversal retrospectivo de los pacientes fallecidos en el periodo 2004 a 2008 en un hospital terciario.

OBJECTIVE: Retrospective analysis of all surgical, early postoperative, and 1-week to detect risk factors. MATERIAL AND METHODS: A database was established to record clinical, anesthetic, and surgical variables, grouped as preoperative, intraoperative and postoperative factors, and reflecting comorbidities and postoperative complications. Each patient's cause of death was also recorded. Factors influencing mortality during surgery, at 48 hours, and at 1 week were explored by comparing frequencies to detect correlations. RESULTS: From 2004 to 2008, a total of 809 deaths occurred in the 82412 hospitalized surgical patients. Patients who died during surgery or within 48 hours were younger, had a higher ASA physical status classification, had more cardiovascular risk factors, were less likely to have a diagnosis of cancer, and had spent less time in hospital before the operation. Intraoperative complications, particularly bleeding and cardiac events, were more frequent in patients whose condition was more complex and who died during surgery; that pattern was similar but less marked in patients dying within 48 hours. The patients who died within 48 hours had a higher rate of postoperative hemodynamic complications; the patients who died during the week following surgery had higher rates of septic, neurologic, and respiratory complications. CONCLUSIONS: Emergency surgery stands out as an important predictor of death during or after surgery; other significant risk factors are postoperative complications.

Nucleosome positioning in the rat protamine 1 gene in vivo and in vitro.

The positions of the nucleosomes along the rat protamine 1 gene have been determined in vivo through micrococcal nuclease digestion of isolated nuclei followed by Southern analysis and indirect end labeling with a protamine 1 gene probe. Several strong positioning signals are detected in rat liver nuclei where the gene is repressed. In vitro reconstitution of nucleosomes along the cloned rat protamine 1 gene results in a precisely positioned nucleosome with a dyad axis at -109 bp upstream from the transcriptional start site. The position of this nucleosome reconstituted in vitro coincides with the position of one of the nucleosomes present in vivo in rat liver nuclei. Two important regulatory elements of the expression of the protamine 1 gene, the serum response element (CArG box) and the protamine 1 consensus (cAMP response element), are positioned over the -109 nucleosome with potential functional implications for transcriptional activation.

Apolipoprotein E polymorphism in Alzheimer's disease: a comparative study of two research populations from Spain and the United States.

We examined the distribution of the apolipoprotein E (APOE) polymorphism in two Caucasian populations of Alzheimer's disease (AD) patients referred to dementia clinics; one in Gerona, Spain (66 AD patients, 49 controls), and the other in Pittsburgh, Pa., USA (209 AD patients, 58 controls). The presence of the APOE*4 allele was a significant risk for developing AD in both cohorts: Gerona (odds ratio = 2.34, CI: 1.03-5.55) and Pittsburgh (odds ratio = 3.64, CI: 1.78-7.69). The proportion of AD with the APOE*4 allele was greater in the Pittsburgh cohort than in the Gerona cohort (p = 0.02). However, no statistical difference was noted between the two populations in nondemented controls (p = 0.41). These data emphasize the importance of geographical and ethnic variations in the study of APOE genotypes.

Conserved elements in the 5' regulatory region of the amyloid precursor protein gene in primates.

Oligonucleotides corresponding to conserved sites between the human and mouse amyloid precursor protein (APP) genes have been used to polymerase chain reaction (PCR) amplify and sequence the promoter region of the APP gene from chimpanzee, gorilla, orang-utan, papio and African green monkey. Several novel conserved potentially-regulatory sequences of the APP gene have been detected after alignment of the APP promoter sequences: an apolipoprotein E-B1 (APOE-B1) element at position -450, also present in the APOE gene, two activator protein-2 (AP-2) sites at positions -450 and -301 and an intermediate early-1 gene (IE1) site at position -280. These elements are conserved in all mammalian APP promoter sequences studied. Additionally a previously detected heat shock element (HSE) at position -317, and an activator protein-1 (AP-1) site at position -350 are also conserved. Knowledge of the essential regulatory elements at the APP gene constitute the basis for understanding its transcriptional control and subsequent model studies.

Low apolipoprotein E epsilon4 allele frequency in the population of Catalonia (Spain) determined by PCR-RFLP and Laser fluorescent sequencer.

Specific apolipoprotein E alleles have been associated in the last few years with several diseases using appropriate controls. However, these control groups are rarely representative of the general population since they correspond either to aged or healthy control groups (and thus depleted of pathological alleles). For this reason it is difficult at present to compare population allelic frequencies in different countries. In order to provide this essential basic data representative of the general population, in this work we have determined the distribution of apolipoprotein E alleles in 226 individuals from the population of Catalonia (Spain) sampled with the main purpose of paternity testing. The allelic frequencies are: epsilon2 = 0.064, epsilon3 = 0.810 and epsilon4 = 0.126, predicting a lower incidence of Alzheimer disease and possibly also of other pathologies where this allele is a risk factor.

High apolipoprotein E epsilon 4 allele frequency in age-related memory decline.

Many studies have demonstrated a strong association between the presence of one or two epsilon 4 alleles and Alzheimer's disease (AD), although few data are available on the apolipoprotein E (APOE) epsilon 4 frequencies at the preclinical stages of AD. Thus, with a view to determining whether APOE genotyping could be useful in the early detection of AD, we determined the Apoe allele frequencies in patients with memory complaints without dementia (age-related memory decline, ARMD). We found an APOE epsilon 4 allele frequency of 0.315 in the ARMD group, similar to 0.293 in the AD group, in contrast to 0.057 in the control group. Significant differences (t=-2.91, df=25, p=0.008) were found between the Alzheimer's Disease Assessment Scale (ADAS) total scores in the ARMD patients with at least one epsilon 4 allele (mean=24.2) compared with the ARMD patients without the epsilon 4 allele (mean=14.7). Our results suggest that the patients with memory complaints, a high ADAS score, and the presence of one or two APOE-4 alleles could be at high risk for developing AD. Thus, we propose that genotyping in conjunction with the ADAS scale may prove useful as diagnostic markers of AD in the presymptomatic stages.

Evolution of protamine P1 genes in mammals.

Protamine P1 genes have been sequenced following PCR amplification from 11 mammals representing five major mammalian orders: Rodentia (rat and guinea pig), Carnivora (cat and bear), Proboscidea (elephant), Perissodactyla (horse), and Artiodactyla (camel, deer, elk, moose, and gazelle). The predicted amino acid sequence for these genes together with previously reported sequences results in a data set of 25 different P1 genes and 30 different P1 amino acid sequences. The alignment of all these sequences reveals that protamines are amongst the most rapidly diverging proteins studied. In spite of the large number of differences there are conserved motifs that are also common to birds such as the N-terminal ARYR followed by the triple alternating SRSRSR phosphorylation site. The central region contains 3 arginine clusters consisting of 5-6 arginines each. The C-terminus appears to be the most variable region of the protamines. Overall the molecular evolution of P1 genes is in agreement with the expected species evolution supporting that these genes have evolved vertically.

Apolipoprotein E4 allele frequency in Spanish Alzheimer and control cases.

We have found an APOE epsilon 4 allelic frequency of 0.289 (95% CI 0.195-0.383) in Spanish AD patients (n = 88; average age = 71.2 +/- 9.37) and of 0.061 (95% CI 0.023-0.099) in age-matched controls (n = 147; average age = 71.5 +/- 10.29). Remarkably no ApoE 4/4 subjects were observed in any of the age-matched control groups compared to a total of 22 AD patients with the ApoE 4/4 phenotype. The combined odds ratio for subjects with one or two epsilon 4 alleles in the present study is 6.25 (95% CI 3.13-12.60), which is one of the highest so far reported. Altogether our results suggest a trans-European difference in the ApoE epsilon 4 frequency but no differences in the strength of the association between APOE4 and AD.

Direct sequencing of the human protamine P1 gene and application in forensic medicine.

Protamines are among the most variable nuclear proteins known in eukaryotes. In order to learn more about their evolution and function in humans and to explore the possibility of potential applications in forensic medicine we have developed a rapid method to amplify and directly sequence the protamine P1 gene simultaneously in many different samples. The method takes only 3.5 h from genomic DNA to the sequencing reactions. Despite the high variability of these genes only one polymorphic site was detected at the coding region level in different individuals. This polymorphic variation does not create a change in the amino-acid sequence of the protamine. Because all the protamine genes sequenced from different species are markedly different among them as well as to the human sequence, amplification and direct sequencing of this gene can be used to unequivocally identify the human or animal origin of biological specimens. Furthermore, the single polymorphic site detected in the human P1 gene could be useful in conjunction with other markers in identification studies in humans.

Evolution of protamine P1 genes in primates.

Protamine P1 genes have been sequenced by PCR amplification and direct DNA sequencing from 9 primates representing 5 major families, Cebidae (new world monkeys), Cercopithecidae (old world monkeys), Hylobatidae (gibbons), Pongidae (gorilla, orangutan, and chimpanzee), and Hominidae (human). In this recently diverged group of primates these genes are clearly orthologous but very variable, both at the DNA level and in their expressed amino acid sequences. The rate of variation amongst the protamine P1s indicates that they are amongst the most rapidly diverging polypeptides studied. However, some regions are conserved both in primates and generally in other placental mammals. These are the 13 N-terminal residues (including a region of alternating serine and arginine residues (the motif SRSR, res. 10-13) susceptible to Ser phosphorylation), a tract of six Arg residues (res. 24-29) in the center of the molecule, and a six-residue region (RCCRRR, res. 39-44), consisting of a pair of cysteines flanked by arginines. Detailed consideration of nearest-neighbor matrices and trees based on maximum parsimony indicates that P1 genes from humans, gorillas, and chimpanzees are very similar. The amino acid and nucleotide differences between humans and gorillas are fewer than those between humans and chimpanzees. This finding is at variance with data from DNA-DNA hybridization and extensive globin and mitochondrial DNA sequences which place human and chimpanzee as closest relatives in the super family, Hominoidea. This may be related to the fact that protamine P1s are expressed in germ line rather than somatic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel silent variant at codon 711 and a variant at codon 708 of the APP sequence detected in Spanish Alzheimer and control cases.

Pathogenic mutations have been identified in exons 16 and 17 of the beta-amyloid precursor protein (APP) gene in some cases of early onset Alzheimer's disease. Screening of these exons in a number of familial and sporadic cases of Alzheimer's disease in Spain, resulted in the identification of a novel silent variant at codon 711 whose relevance to the AD pathogenesis remains unclear. The 708 variant was also detected in one of normal controls.

Improved direct sequencing of Alzheimer's amyloid precursor protein (APP) exons 16 and 17.

Direct sequencing of exon 17 of the amyloid precursor protein (APP) gene led to the identification of 3 different types of APP717 pathogenic mutations associated with familial Alzheimer's disease (FAD). The low frequency of these mutations results in having to screen many samples in order to identify new families affected by them, which is laborious and time consuming. Thus, in order to help the identification of these mutations in additional countries and to search for new mutations in APP, perhaps in other exons also causing FAD, we have optimized the procedure and reduced the time necessary for sample preparation from 11 h to 3 1/2 h.