Upregulation of p53 protein induces either growth arrest or apoptosis in response to cellular injury This is signaled from a highly conserved p53 domain between codons 64 and 92, where a functional ...polymorphism results in either a proline (p53-72P) or an arginine (p53-72R) at codon 72. Preliminary studies suggest that p53-72R may be a risk factor for cervical cancer and, consistent with this, preferential mutation and retention of the p53-72R allele has also been demonstrated in other cancers of squamous cell origin. Here we examine the relationship between allelic forms of p53 and nonmelanoma skin cancer, by determining the correlation with susceptibility to sunburn, which is a known risk factor, and then by p53 sequence analysis of a large series of tumors. We found a significant positive association between p53-72R and susceptibility to sunburn, as assessed by skin phototype and minimal erythemal dose following solar-simulated radiation (p = 0.0001 for trend). We also found a significant association between p53-72R homozygosity and nonmelanoma skin cancer in renal transplant recipients (basal cell carcinoma, p < 0.01; squamous cell carcinoma, p < 0.05) but not in immunocompetent patients compared with skin type matched controls. p53 sequence data revealed mutations in 30 of 70 (42.9%) nonmelanoma skin cancers, 28 (93%) of which were in the p53-72R allele. Loss of heterozygosity occurred more frequently in p53-72RP than in p53-72RR tumors (p = 0.0001) with preferential loss of p53-72P in heterozygotes (p = 0.016), irrespective of the mutant status of the concomitant allele. Together these data infer functional differences between polymorphic forms of p53 that are likely to be relevant to skin carcinogenesis.
Background:
Clozapine is the most effective antipsychotic but requires careful titration to therapeutic blood levels. Methods to predict therapeutic doses are based on population data.
Aims:
We aimed ...to construct a model based on genetic variants which accurately predicted plasma levels for clozapine.
Method:
We measured clozapine plasma levels in patients on a stable dose of clozapine who were known to be fully compliant. Measured plasma levels were adjusted for sampling time and dose. Hepatic enzyme variants were analysed and models were constructed to predict the required dose. These predictions were compared with a standard population-based algorithm.
Results:
We measured plasma clozapine concentrations in 18 adherent patients on stable doses of clozapine and recorded the exact timing of sampling. For the algorithm-predicted dose, the mean difference was −49.9 mg/day ((SD 155.9), r = 0.36) from the actual dose required to give a plasma concentration of 0.35 ng/ml. The gene variant activity score predicted a dose for which the mean difference was −43.5 mg/day ((SD 140.1), r = 0.55). For the gene variant activity score with omeprazole correction predicted dose, the mean difference was −31.0 mg/day ((SD 140.8), r = 0.54), and with the gene variant CYP1A2 inducibility predicted dose the mean difference was 44.9 mg/day ((SD 160.8), r = 0.32).
Conclusion:
Our gene variant activity score with omeprazole correction gave the best estimate of the clozapine dose required to achieve a minimum therapeutic plasma concentration. The use of this model will allow safer titration of clozapine and may reduce the need for plasma-level monitoring during titration.
Background:
Data from case series suggest that clozapine may benefit inpatients with borderline personality disorder (BPD), but randomised trials have not been conducted.
Methods:
Multicentre, ...double-blind, placebo-controlled trial. We aimed to recruit 222 inpatients with severe BPD aged 18 or over, who had failed to respond to other antipsychotic medications. We randomly allocated participants on a 1:1 ratio to receive up to 400 mg of clozapine per day or an inert placebo using a remote web-based randomisation service. The primary outcome was total score on the Zanarini Rating scale for Borderline Personality Disorder (ZAN-BPD) at 6 months. Secondary outcomes included self-harm, aggression, resource use and costs, side effects and adverse events. We used a modified intention to treat analysis (mITT) restricted to those who took one or more dose of trial medication, using a general linear model fitted at 6 months adjusted for baseline score, allocation group and site.
Results:
The study closed early due to poor recruitment and the impact of the COVID-19 pandemic. Of 29 study participants, 24 (83%) were followed up at 6 months, of whom 21 (72%) were included in the mITT analysis. At 6 months, 11 (73%) participants assigned to clozapine and 6 (43%) of those assigned to placebo were still taking trial medication. Adjusted difference in mean total ZAN-BPD score at 6 months was -3.86 (95% Confidence Intervals = -10.04 to 2.32). There were 14 serious adverse events; 6 in the clozapine arm and 8 in the placebo arm of the trial. There was little difference in the cost of care between groups.
Interpretation:
We recruited insufficient participants to test the primary hypothesis. The study findings highlight problems in conducting placebo-controlled trials of clozapine and in using clozapine for people with BPD, outside specialist inpatient mental health units.
Trial registration
ISRCTN18352058. https://doi.org/10.1186/ISRCTN18352058
Early decompression may improve neurological outcome after spinal cord injury (SCI), but is often difficult to achieve because of logistical issues. The aims of this study were to 1) determine the ...time to decompression in cases of isolated cervical SCI in Australia and New Zealand and 2) determine where substantial delays occur as patients move from the accident scene to surgery. Data were extracted from medical records of patients aged 15-70 years with C3-T1 traumatic SCI between 2010 and 2013. A total of 192 patients were included. The median time from accident scene to decompression was 21 h, with the fastest times associated with closed reduction (6 h). A significant decrease in the time to decompression occurred from 2010 (31 h) to 2013 (19 h, p = 0.008). Patients undergoing direct surgical hospital admission had a significantly lower time to decompression, compared with patients undergoing pre-surgical hospital admission (12 h vs. 26 h, p < 0.0001). Medical stabilization and radiological investigation appeared not to influence the timing of surgery. The time taken to organize the operating theater following surgical hospital admission was a further factor delaying decompression (12.5 h). There was a relationship between the timing of decompression and the proportion of patients demonstrating substantial recovery (2-3 American Spinal Injury Association Impairment Scale grades). In conclusion, the time of cervical spine decompression markedly improved over the study period. Neurological recovery appeared to be promoted by rapid decompression. Direct surgical hospital admission, rapid organization of theater, and where possible, use of closed reduction, are likely to be effective strategies to reduce the time to decompression.
Background:
Amprenavir (APV) is a new HIV-1 protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Objective:
The aim of this study was to ...assess the safety profile and tolerability of APV.
Methods:
A review of data from 358 adults enrolled in 2 phase III, randomized, 48-week, controlled studies and from 268 children enrolled in 1 phase II and 1 phase III study was conducted. The adult data were collected between February 25, 1997, and April 1, 1999. Data were collected in children from September 10, 1997, to January 15, 1999; these data were collected before completion of either study. Adults and children who had and had not been treated previously with antiretroviral agents were enrolled. In these studies, APV was used in combination with 2 nucleoside reverse transcriptase inhibitors.
Results:
The most common drug-related adverse events in patients receiving APV were gastrointestinal events and oral/perioral paresthesia. The majority of adverse events were mild or moderate in intensity, early in onset, and transient. Nausea (
27
358
patients, 8%), vomiting (
15
358
, 4%), rash (
11
358
, 3%), and diarrhea/loose stools (
9
358
, 3%) were the most common adverse events associated with treatment discontinuation. Severe laboratory abnormalities possibly related to APV were rare. In children, the nature and frequency of adverse events were similar to those in adults. Metabolic complications were infrequent in APV studies to date; symptoms related to fat redistribution were reported in <3% of patients treated with APV. Lipid or glucose laboratory abnormalities were reported with similar frequency in the APV and control groups in both studies in adults.
Conclusions:
In the clinical trials reviewed, APV was generally well tolerated when administered with other antiretroviral agents in adult and pediatric patients with HIV infection.
This paper reports on an outbreak of viral gastroenteritis in three institutions (two aged care facilities and one hospital) in Canberra during the winter of 2002. Norwalk-like virus genotype II was ...detected in samples from staff and/or residents in all three institutions. A case series investigation was conducted amongst both staff and residents. It is likely that the outbreaks in the three institutions were linked due to transfers of infected residents from one institution to another, early in the outbreak. A total of 281 cases were identified during the outbreak, which lasted 32 days. Attack rates in the three institutions were 46.3 per cent, 52.7 per cent and 55.2 per cent respectively. Person-to-person spread and/or airborne transmission were postulated as modes of transmission in all three institutions. Infection control practices in each of the aged care institutions were of an acceptable standard for accreditation, but were inadequate to control further spread of the outbreak within and between institutions. Outbreak management plans should be a part of the infection control standards for accreditation of aged care facilities.
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