Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 2. The biological variability of the murine Local Lymph Node Assay (LLNA) for skin sensitisation

The Local Lymph Node Assay (LLNA) is the most common in vivo regulatory toxicology test for skin sensitisation, quantifying potency as the EC3, the concentration of chemical giving a threefold increase in thymidine uptake in the local lymph node. Existing LLNA data can, along with clinical data, provide useful comparator information on the potency of sensitisers. Understanding of the biological variability of data from LLNA studies is important for those developing non-animal based risk assessment approaches for skin allergy. Here an existing set of 94 EC3 values for 12 chemicals, all tested at least three times in the same vehicle have been analysed by calculating standard deviations (SD) for logEC3 values. The SDs range from 0.08 to 0.22. The overall SD for the 94 logEC3 values is 0.147. Thus the 95% confidence limits (2xSD) for LLNA EC3 values are within a factor of 2, comparable to those for physico-chemical measurements such as partition coefficients and solubility. The residual SDs of Quantitative Mechanistic Models (QMMs) based on physical organic chemistry parameters are similar to the overall SD of the LLNA, indicating that QMMs of this type are unlikely to be bettered for predictive accuracy.     

Clinical and Actuarial Prediction of Physical Violence in a Forensic Intellectual Disability Hospital: A Longitudinal Study

Background There is a high rate of physical violence in populations with intellectual disabilities, and this has been linked to problems for the victim, the assailant, members of staff and services. Despite the clinical significance of this behaviour, few studies have assessed methods of predicting its occurrence. The present study examined clinical and actuarial methods of predicting violence in a forensic intellectual disability hospital. Methods The sample for the study consisted of people resident in the hospital during a 1‐year period (n = 124). Clinical prediction used a risk rating made by members of the person's clinical team, whereas actuarial prediction used the number of violent incidents in the 6‐months before the date of the clinical risk assessment. Computerized hospital records of violence in the 6 months after the assessment were used to examine the predictive accuracy of the two methods. Results The clinical method produced an area under the curve of 0.74 (95% CI: 0.65–0.83) in a receiver–operating characteristic curve analysis. The value for the actuarial method was 0.77 (95% CI: 0.69–0.86). Both methods performed at levels significantly above chance, but no one method was found to be superior to the other. Conclusions These findings suggest that it is possible to predict who is at risk of violence in forensic populations with intellectual disabilities. Here, the authors discuss the clinical implications of these findings and the clinical application of risk prediction within clinical services.     

Prediction of Remission of Acute Posttraumatic Stress Disorder in Motor Vehicle Accident Victims

One hundred forty five individuals who sought medical attention as a result of a motor vehicle accident (MVA), and who were initially assessed 1 to 4 months post-MVA, were followed up prospectively for 6 months to determine how many of the 55 with posttraumatic stress disorder (PTSD) and the 43 with sub-syndromal PTSD would remit and what variables would predict remission. Thirty (55%) of those with initial PTSD had remitted at least in part by 6 months while 67% of those with sub-syndromal PTSD had remitted (and 5% had worsened). Four variables, including severity of initial symptoms, degree of initial physical injury, relative degree of physical recovery by 4 months and whether a close family member suffered a trauma during the follow-up interval, combined to classify 6-month clinical status of 84% of those with initial PTSD secondary to MVAs.     

Population kinetics of gentamicin in neonates

A population kinetic analysis was carried out on sparse plasma gentamicin (GE) concentration data from 469 neonates obtained as part of a routine therapeutic drug monitoring (TDM) programme in the hospital neonatology unit.The best predictors of the kinetic parameters of the monoexponential model, volume of distribution (Vd) and clearance (CL), were the weight (WT) and gestational age (GA). Vd of the neonates was only related to WT, whereas the half-life was only related to the GA.     

Eighteen-month Coronal Caries Incidence in North Carolina Older Adults

In this longitudinal study of a random sample of North Carolinians over the age of 65 and living in their homes, 325 blacks and 280 whites were examined and interviewed 18 months after baseline examinations. Coronal caries incidence was greater among whites than blacks. The increment due to teeth becoming root fragments were similar for both races; however, there were more newly crowned teeth among whites. Newly crowned surfaces were not used as part of the caries increment in logistic regression models to investigate potential risk predictors. For blacks, caries development over the 18-month period was associated with a higher lactobacillus score and more coronal caries at baseline, more previously filled coronal surfaces, and lack of active membership in clubs or other groups. For whites, having no self-reported tooth sensitivity, having a lower socioeconomic index score, taking antihistamine medications at baseline, and having the perception of more problems after the age of 40 than before were all associated with the development of coronal caries.     

Predicting the experience of dentinal caries or restorative dental treatment in adolescents using D1 and D3 visual caries assessments

Standardised epidemiological caries assessments used in oral health surveys have been shown to be poor at predicting whether a tooth surface will be treated restoratively when a patient visits a dentist. However, it has been argued that oral health surveys may be more relevant in determining needs at the level of an individual or groups of individuals. The objective of this study was to determine the discriminatory power of visual caries assessments at two thresholds (D₁ & D₃) in adolescents of average age 12.1 years to predict experience of dentinal caries 3 years later or the experience of restorative treatment (not re‐treatment) during the 3‐year period. The data was derived from a prospective 3‐year longitudinal study in which the dental care provided by 41 dentists for 403 adolescents was monitored. Dental caries experience was monitored by annual standardised assessments of caries undertaken by a single trained examiner. ROC analysis showed that caries assessed visually at the D₁ threshold in 12‐year‐olds was a better predictor (P < 0.001) of experiencing some dentinal caries after 3 years (Az = 0.781) than was caries assessed visually at D₃ threshold in 12‐year‐olds (Az = 0.670). Assessing caries visually at either the D₁ or the D₃ threshold had no discriminatory power for predicting whether an individual would experience some restorative treatment during the ensuing 3‐year period (Az for D₁ = 0.507; Az for D₃ = 0.518).     

Acute subdural hematoma: Outcome and outcome prediction

Patients with traumatic acute subdural hematoma were studied to determine the factors influencing outcome.Between January 1986 and August 1995, we collected 113 patients who underwent craniotomy for traumatic acute subdural hematoma. The relationship between initial clinical signs and the outcome 3 months after admission was studied retrospectively.Functional recovery was achieved in 38% of patients and the mortality was 60%. 91% of patients with a high Glasgow Coma Scale (GCS) score (9–15) and 23% of patients with a low GCS score (3–8) achieved functional recovery. All of 14 patients with a GCS score of 3 died. The mortality of patients with GCS scores of 4 and 5 was 95% to 75%, respectively. Patients over 61 years old had a mortality of 73% compared to 64% mortality for those aged 21–40 years. 97% of patients with bilateral unreactive pupil and 81% of patients with unilateral unreactive pupil died. The mortality rates of associated intracranial lesions were 91% in intracerebral hematoma, 87% in subarachnoid hemorrhage, 75% in contusion.Time from injury to surgical evacuation and type of surgical intervention did not affect mortality. Age and associated intracranial lesions were related to outcome. Severity of injury and pupillary response were the most important factors for predicting outcome.     

Prediction of lactose malabsorption in referral patients

Two hundred forty-two patients referred for various gastrointestinal complaints were evaluated for clinical parameters that would predict findings of lactose malabsorption. Breath hydrogen and blood glucose lactose tests were performed after ingestion of 50 g lactose. Presenting complaints, duration of symptoms, and patient demographics such as age, sex, and ethnic heritage were not different between lactose malabsorbers and absorbers as defined by the breath hydrogen lactose test. Foodrelated symptoms in general and after specific foods such as milk, ice cream, cheese, and yogurt were also similar between groups. Prior to testing, 30% of malabsorbers (N=161) and 36% of absorbers (N=81) reported lactoserelated symptoms (P=NS). The blood glucose response to lactose was abnormal in 60% of malabsorbers and 15% of absorbers. This study confirmed our impression that it is difficult to predict lactose absorption status by clinical parameters. The majority of our lactose malabsorber patients were unaware of lactose-associated symptoms. Furthermore, symptom assessment, demographics, food history, and blood glucose testing did not predict abnormal hydrogen responses to lactose.The opinions and assertations expressed herein are those of the authors and are not to be construed as reflecting opinions of the United States Air Force or the Department of Defense.This work has been presented in part at the Annual Scientific Session of the American Gastroenterological Association, San Francisco, California, May 19, 1986, and published as an abstract (Gastroenterology 90:1562, 1986).     

Photodynamic therapy of tumours: value of quantum chemical procedures for characterization of new drugs. Prediction of the electronic structure of zinc(II) phthalocyanine with special emphasis on triplet state excitation energies

Zinc(II) phthalocyanine is the active component of the liposomal formulation CGP 55847 which showed a high activity in photodynamic therapy in a variety of animal tumours. The photophysical properties of zinc(II) phthalocyanine have been studied in detail and compared to those of Photofrin, the only sensitizing agent approved so far for phase III/IV clinical trials. Since the efficacy of photodynamic therapy intrinsically depends on the spectroscopic features of the sensitizer, quantum chemical methods have proven to be an efficient means for optimizing chemical structures. As will be shown, a simple modification of the time-honoured INDO model of Pople allows a prediction of the singlet and triplet state properties of molecules of the size of zinc(II) phthalocyanine with an rms error of ≤ 1000 cm⁻¹.