A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Some characteristics of ?(1)-pyrroline-5-carboxylate dehydrogenase in rat cerebellum.

?(1)-Pyrroline-5-carboxylate dehydrogenase (P5CDH) in rat cerebellum was assayed with a simple spectrophotometric method using high-speed supernatants of whole tissue homogenates. Kinetic analysis showed that the enzyme has K(m) values of 0.83 +/- 0.21 mM for ?(1)-pyrroline-5-carboxylate and 0.47 +/- 0.02 mM for NAD(+). Various cations inhibited P5CDH but only at relatively high concentrations. Several amino acids were strongly inhibitory in the order GABA > glycine > hydroxyproline > cysteine ? proline > glutamine > glutamate > alanine .

The expression of proteins and activities of metabolic enzymes in transplanted brain tissue.

The middle three-fifths of the forebrains of 14-day-old embryos were obtained and transplanted into the cortical cavities of adult rats made 7 days prior to the transplantation. The expression of proteins, as revealed by 2-dimensional gel electrophoresis studies, and the activities of energy metabolizing enzymes in the mature allografts were compared with those in the 14-day-old embryonic forebrains and corresponding areas in the contralateral cerebral hemispheres of the hosts. They were shown to approach adult pattern and adult values after 10-12 weeks of growth. The biochemical findings were discussed and correlated with some of the anatomical observations.

Effects of kainate on glucose metabolising enzymes in the brain.

Hexokinase and glucose-6-phosphate dehydrogenase activities were studied in brain regions after intraventricular injection of kainic acid. Hexokinase activity was decreased by 10-15% in various regions while glucose-6-phosphate dehydrogenase activity remained unaltered. Soluble hexokinase activity, which remained the smaller fraction of total hexokinase activity, showed slightly more dramatic decreases of 15-35% compared to normal activities in brain regions. This decrease of hexokinase activity in the cytosolic compartment could partly account for the kainate-induced decreases seen in glucose metabolism.

Quality of life survey among long-stay mentally ill patients: patient and staff perspectives.

In order to improve the quality of life of the chronically mentally ill patients, their treatment programmes must be individualised to address their multiple disabilities and social impairment. The patient's perception of his quality of life (QoL) can be used as an organising framework for long-term care. Subjects in the study included staff and inpatients from the 10 rehabilitation wards in New Woodbridge Hospital which offers a wide range of rehabilitation activities. Using subjective indices, patient and staff perception of patients' quality of life were compared across several life domains. Significant differences between the 2 groups were noted in areas including living conditions, relationship with others and sense of purpose in life. Most patients found the new hospital a better place in terms of its physical comfort and the medical and psychiatric care received. The implications of these findings for improving existing care for our patients are discussed.

Delta 1-pyrroline-5-carboxylate dehydrogenase, a possible regulatory enzyme in transmitter glutamic acid metabolism--a preliminary report.

At 10 mM (unless stated), GABA (5 mM), glycine and hydroxyproline inhibited delta 1-pyrroline-5-carboxylate dehydrogenase by 84, 85 and 76%, respectively. Glutamate, glutamine, proline, cysteine and alanine inhibited delta 1-pyrroline-5-carboxylate dehydrogenase by 41-59%. Other amino acids studied were either ineffective or marginally effective. It is concluded that delta 1-pyrroline-5-carboxylate dehydrogenase may be a regulatory enzyme in the ornithine-glutamate pathway.

Tear evaluation of subjects wearing rigid gas permeable contact lens for six months: the Asian context.

OBJECTIVE: Asians are known to have different tear characteristics compared to Caucasians that may affect contact lens wear. There are scanty research studies that have evaluated tears during continuous wear contact lens in Asia. The present study aims to evaluate changes in tears in subjects wearing continuous wear rigid gas permeable contact lens (CWRGP) for 6 months. MATERIALS AND METHODS: Thirty five neophyte subjects (21 females, 14 females) were recruited for this study. Subjects were fitted with CWRGP lenses with Dk of 163 on both eyes. Tear was evaluated using Phenol red thread test (PRT), tear break up time (TBUT) test and tear meniscus height (TMH) measurement. Non parametric and parametric analyses were used to compare the parameters. RESULTS: Values at baseline (BL) and six months (6M) were as follow: PRT, BL=19.10 ± 3.86 mm, 6M= 21.02 ± 4.27 mm, TBUT, BL= 8.58 ± 4.90 sec, 6M=8.08 ± 5.32 sec, TMH, BL= 0.38 ± 0.12 mm, 6M= 0.34 ± 0.07 mm. Statistical analysis showed significant difference in tear volume for PRT only at 6 months (p=0.007). CONCLUSION: Our analysis showed minimal change in the tear characteristics after six months of CWRGP lens wear, which indicated low impact of CWRGP contact lens on tears characteristics of Asian eyes. However, careful monitoring is required to prevent development of adverse events during contact lens wear.

Regional development of glutamate dehydrogenase in the rat brain.

The development of glutamate dehydrogenase enzyme activity in rat brain regions has been followed from the late foetal stage to the adult and through to the aged (greater than 2 years) adult. In the adult brain the enzyme activity was greatest in the medulla oblongata and pons greater than midbrain = hypothalamus greater than cerebellum = striatum = cortex. In the aged adult brain, glutamate dehydrogenase activity was significantly lower in the medulla oblongata and pons when compared to the 90-day-old adult value, but not in other regions. The enzyme-specific activity of nonsynaptic (free) mitochondria purified from the medulla oblongata and pons of 90-day-old animals was about twice that of mitochondria purified from the striatum and the cortex. The specific activity of the enzyme in synaptic mitochondria purified from the above three brain regions, however, remained almost constant.

Diabetes induced by streptozotocin causes reduced Na-K ATPase in the brain.

Na-K ATPase activity in the brain decreased significantly after diabetes was induced with streptozotocin in rats. Largest decreases were observed in the hippocampus (-30%) and the cerebral cortex (-26%). Smaller decreases were observed in the thalamus (-13%), hypothalamus (-11%) and brain stem (-10%). Na-K ATPase activity in the striatum and the cerebellum were not significantly decreased. The varied decreases suggest that the regional variation of the enzyme is enhanced in the diabetic state. The enzymes of glucose metabolic pathway, namely hexokinase, lactate dehydrogenase and citrate synthase in the brain regions largely remained unchanged although increases in lactate dehydrogenase were observed in some regions. Acetylcholinesterase activity, a marker for the cholinergic system, remains unaltered in the brain during diabetes. The results are discussed with respect to the possible metabolic factors which alter the Na-K ATPase in the brain and its comparison with the peripheral nerve.

Regional enzyme development in rat brain. Enzymes associated with glucose utilization.

The development of key enzyme activities concerned with glucose metabolism was studied in six regions of the rat brain in animals from just before birth (-2 days) through the neonatal and suckling period until adulthood (60 days old). The brain regions studied were the cerebellum, medulla oblongata and pons, hypothalamus, striatum, mid-brain and cortex. The enzymes whose developmental patterns were investigated were hexokinase (EC 2.7.1.1), aldolase (EC 4.1.2.13), lactate dehydrogenase (EC 1.1.1.27) and glucose-6-phosphate dehydrogenase (EC 1.1.1.49). Hexokinase, aldolase and lactate dehydrogenase activities develop as a single cluster in all the regions studied, although the timing of this development varies from region to region. Glucose-6-phosphate dehydrogenase activity, however, declines relative to glycolytic enzyme activity as the brain matures. When the different brain regions are compared, it is clear that the medulla develops its glycolytic potential, as indicated by its potential enzyme activity, considerably earlier than the other regions (hypothalamus, striatum and mid-brain), with the cortex and cerebellar activities developing even later. This enzyme developmental sequence correlates well with the neurophylogenetic development of the brain and adds support to the hypothesis that the development of the potential for glycolysis in the brain is a necessary prerequisite for the development of neurological competence.

Regional enzyme development in rat brain. Enzymes of energy metabolism.

The development of several key enzymes of pyruvate and 3-hydroxybutyrate metabolism and of the tricarboxylic acid cycle was studied in six regions (cerebellum, medulla oblongata and pons, hypothalamus, striatum, mid-brain and cortex) of the neonatal, suckling and adult rat brain (2 days before birth to 60 days after birth). The enzymes whose developmental patterns were studied were: pyruvate dehydrogenase (EC 1.2.4.1), 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30), citrate synthase (EC 4.1.3.7), NAD-linked isocitrate dehydrogenase (EC 1.1.1.41) and fumarase (EC 4.2.1.2). Citrate synthase, isocitrate dehydrogenase and pyruvate dehydrogenase develop as a cluster in each region, although the pyruvate dehydrogenase appears to lag slightly behind the others. As with the glycolytic-enzyme cluster [Leong & Clark (1984) Biochem. J. 218, 131-138] the timing of the development of the activity of this group of enzymes varies from region to region; 50% of the adult activity developed first in the medulla oblongata, followed by the hypothalamus, striatum and mid-brain, and then in the cortex and cerebellum respectively. The 3-hydroxybutyrate dehydrogenase activity also develops earlier in the medulla oblongata than in the other regions. The results are discussed with respect to the neurophylogenetic development of the brain regions studied and the importance of the development of the enzymes of aerobic glycolysis in relationship to the development of neurological maturation.

Noncorrelation of choline kinase or ATP citrate lyase with cholinergic activity in rat brain.

The activity of choline acetyltransferase was used as an index of cholinergic structures in regions of rat brain. The activities of ATP citrate lyase and choline kinase correlated poorly with cholinergic activity in whole tissue fractions, contrasting with the good correlation between acetylcholinesterase and choline acetyltransferase. Choline acetyltransferase was preferentially localised in synaptosomes prepared from regions of high (striatum) or intermediate (cortex, medulla oblongata/pons) cholinergic activity. In general, this was not true for either choline kinase or ATP citrate lyase.

Regional distribution in rat brain of 1-pyrroline-5-carboxylate dehydrogenase and its localization to specific glial cells.

A possible alternative route for production of a small glutamate pool in brain is from proline or ornithine to 1-pyrroline-5-carboxylate (P5C) and thence to glutamate. The conversion from ornithine to P5C is catalyzed by ornithine delta-aminotransferase (OrnT) whereas that from proline is catalyzed by proline oxidase (PrO). The conversion of P5C to glutamate is catalyzed by 1-pyrroline-5-carboxylate dehydrogenase (PDH). Biochemical assays of PDH and PrO in various rat brain regions indicate no positive correlation between the two enzymes nor between either activity and high-affinity glutamate uptake or the regional distribution of OrnT. We have localized PDH and PrO histochemically by modifications of the Van Gelder [J. Neurochem. 12, 231-237, (1965)] method for gamma-aminobutyric acid (GABA) transaminase. The enzymes were found only in certain types of glial cells; the best stained were the Bergmann glial cells of the cerebellum but, for PDH, there was also good staining of astrocytes in the dentate area of the hippocampus. Since both these areas are believed to have heavy glutamate innervation and numerous GABA interneurons, these findings may reflect an alternative route of glutamate production in glial cells near some glutamate and/or GABA tracts but they do not support this as a possible route for glutamate formation in most brain regions. The findings do, however, provide further evidence for chemical specialization of glial cells.

Energy-metabolizing enzymes in brain regions of adult and aging rats.

The regional enzyme activities of glucose metabolism in the rat brain were investigated. Hexokinase (EC 2.7.1.1) and pyruvate dehydrogenase (EC 1.2.4.1), key enzymes for glucose metabolism, showed no changes in activity in all the regions studied of the aging brain as compared with the adult brain. However, the activity of D-3-hydroxybutyrate dehydrogenase (EC 1.1.1.30) is low throughout the adult brain and, in contrast with hexokinase and pyruvate dehydrogenase, its activity decreases significantly during aging. Other enzymes that showed significant decreases during aging are aldolase (EC 4.1.2.13), lactate dehydrogenase (EC 1.1.1.27), citrate synthase (EC 4.1.3.7), and NAD+-linked isocitrate dehydrogenase (EC 1.1.1.41). The catabolic enzyme in cholinergic metabolism, acetylcholinesterase (EC 3.1.1.7), selected as an example of a non-energy-metabolising enzyme, also showed significant decreases in all regions of the brain in aging, although its highest activity remained in the striatum. These results are discussed with respect to the energy metabolism in various brain regions and their status with aging.

The activities of some energy-metabolising enzymes in nonsynaptic (free) and synaptic mitochondria derived from selected brain regions.

The enzyme complement of two different mitochondrial preparations from adult rat brain has been studied. One population of mitochondria (synaptic) is prepared by the lysis of synaptosomes, the other (non-synaptic or free) by separation from homogenates. These populations have been prepared from distinct regions of the brain: cortex, striatum, and pons and medulla oblongata. The following enzymes have been measured: pyruvate dehydrogenase (EC 1.2.4.1), citrate synthase (EC 4.1.3.7), NAD-linked isocitrate dehydrogenase (EC 1.1.1.41), NADP-linked isocitrate dehydrogenase (EC 1.1.1.42), fumarase (EC 4.2.1.2), NAD-linked malate dehydrogenase (EC 1.1.1.37), D-3-hydroxybutyrate dehydrogenase (EC 1.1.1.30), and mitochondrially bound hexokinase (EC 2.7.1.1) and creatine kinase (EC 2.7.3.2). The nonsynaptic (free) mitochondria show higher enzyme specific activities in the regions studied than the corresponding values recorded for the synaptic mitochondria. The significance of these observations is discussed in the light of the different metabolic activities of the two populations of mitochondria and the compartmentation of the metabolic activities of the brain.