Pre-treatment CD8+ tumour-infiltrating lymphocyte density predicts distant metastasis after definitive treatment in patients with stage III/IV hypopharyngeal squamous cell carcinoma.

OBJECTIVES: Although inflammatory markers, such as the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and local immune markers have been shown to have prognostic utility, limited information is available regarding inflammatory and pre-existing tumour-infiltrating lymphocyte density and their association with prognosis in patients with hypopharyngeal squamous cell carcinoma. We investigated the prognostic ability of inflammatory markers and tumour-infiltrating lymphocyte density in stage III and stage IV hypopharyngeal squamous cell carcinoma patients receiving definitive treatment. DESIGN: Retrospective cohort study. SETTING: Kurume University Hospital. PARTICIPANTS: Ninety-six stage III or stage IV hypopharyngeal squamous cell carcinoma patients treated at the Kurume University Hospital between 2000 and 2014. MAIN OUTCOME MEASURES: Inflammatory markers and pre-treatment tumour-infiltrating lymphocyte density were examined from recorded haematologic data and immunohistochemical analysis. RESULTS: Multivariate analyses showed that the CD8+ tumour-infiltrating lymphocyte density was an independent predictive factor for distant metastasis and overall survival, whereas inflammatory markers, including the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, were not correlated with distant metastasis or overall survival. CONCLUSIONS: Higher pre-treatment CD8+ tumour-infiltrating lymphocyte density is a useful predictive biomarker for reduced distant metastasis and better prognosis.

A c-fos-monomeric red fluorescent protein 1 fusion transgene is differentially expressed in rat forebrain and brainstem after chronic dehydration and rehydration.

We have previously shown that an acute osmotic stimulation induces the expression of a c-fos and monomeric red fluorescent protein 1 (mRFP1) fusion transgene in osmosensitive rat brain areas, including the supraoptic (SON) and paraventricular nuclei (PVN). However, the effects of chronic stimuli, such as dehydration, have not been investigated. In the present study, the expression patterns of the c-fos-mRFP1 fusion gene in the forebrain and the brainstem of male and female transgenic rats were studied in seven experimental groups: ad lib. water (euhydration), water deprivation for 12, 24 or 48 h (dehydration) and water deprivation for 46 h + ad lib. water for 2, 6 or 12 h (rehydration). The number of cells that express nuclear mRFP1 fluorescence was quantified in the hypothalamus, the circumventricular organs and the brainstem. Compared to the euhydrated state, the number of transgene expressing cells significantly increased in all forebrain areas and in the rostral ventrolateral medulla after dehydration and 2 h of rehydration. In the nucleus of the solitary tract and area postrema, the number of mRFP1 fluorescent cells was markedly increased after 2 h of rehydration. Although the number of mRFP1 fluorescent cells in the organum vasculosum laminae terminalis, median preoptic nucleus and subfornical organ remained significantly increased after 6 h of rehydration, reaching control levels after 12 h of rehydration, the number of mRFP1 fluorescent cells in the SON and the PVN reached control levels after 6 h of rehydration. There were no significant differences between male and female rats. These results show that the expression of the c-fos-mRFP1 fusion gene changes in the forebrain and the brainstem not only after acute osmotic stimulation, but also after chronic osmotic stimulation. Interestingly, these studies reveal the differential activation of different neuronal groups over the time course of dehydration and rehydration.

Hypothalamic brain-derived neurotrophic factor regulates glucagon secretion mediated by pancreatic efferent nerves.

Understanding the molecular mechanism of the regulation of glucagon secretion is critical for treating the dysfunction of α cells observed in diabetes. Glucagon-like peptide (GLP)-1 analogues reduce plasma glucagon and are assumed to contribute to their action to lower blood glucose. It has previously been demonstrated that the central administration of brain-derived neurotrophic factor (BDNF) improves glucose metabolism by a mechanism independent of feeding behaviour in obese subjects. Using male rats, we examined whether BDNF influences glucagon secretion from α cells via the the central nervous system. We investigate whether: (i) the central infusion of BDNF stimulates glucagon and/or insulin secretion via the pancreatic efferent nerve from the hypothalamus; (ii) the intraportal infusion of GLP-1 regulates glucose metabolism via the central and peripheral nervous system; and (iii) BDNF receptor and/or BDNF-positive fibres are localised near α cells of islets. The portal glucagon level decreased with the central administration of BDNF (n = 6, in each; P < 0.05); in contrast, there was no significant change in portal insulin, peripheral glucagon and insulin levels with the same treatment. This reduction of glucagon secretion was abolished by pancreatic efferent denervation (n = 6, in each; P < 0.05). In an immunohistochemical study, pancreatic α cells were stained specifically with BDNF and tyrosine-related kinase B, a specific receptor for BDNF, and α cells were also co-localised with BDNF. Moreover, intraportal administration of GLP-1 decreased glucagon secretion, as well as blood glucose, whereas it increased the BDNF content in the pancreas; these effects were inhibited with the central infusion of BDNF antibody (n = 6, in each; P < 0.05). BDNF and GLP-1 affect glucose metabolism and modulate glucagon secretion from pancreatic α cells via the central and peripheral nervous systems.

Determinants of outcomes following acute child encephalopathy and encephalitis: pivotal effect of early and delayed cooling.

BACKGROUND: Acute encephalopathy/encephalitis is one of the most important causatives of mortality and neurological deficit during childhood. The aim of this retrospective observational study was to investigate clinical variables and therapeutic options associated with the outcome of children with acute encephalopathy/encephalitis. METHODS: Relationships between the clinical information at admission and the neurological outcome evaluated using Pediatric Cerebral Performance Category Scale (PCPC) at 12 months after admission were assessed in 43 patients who were treated at 10 Japanese paediatric intensive care units. RESULTS: Sixteen patients were cared for at normothermia, whereas mild hypothermia was applied to 27 children. In univariate analysis, ages ≤ 18 months, marked elevation in serum lactate dehydrogenase (LD) and aspartate transaminase, diagnosis of either acute necrotising encephalopathy or haemorrhagic shock and encephalopathy syndrome and longer hypothermic periods were associated with increased risks of death or severe neurological deficit, whereas hypothermia showed pivotal effects: the outcome of children cooled after 12 h of diagnosis was statistically invariant with normothermic children, but was significantly worse compared with children cooled ≤ 12 h. In multivariate analysis, younger ages and elevated serum LD were associated with adverse outcomes, whereas early initiation of cooling was related to favourable outcomes. For normothermic children, PCPC scores were dependent on the computed tomographic findings suggestive of cerebral oedema, serum LD levels and Glasgow Coma Scale at admission. For hypothermic children, PCPC scores depended on longer delays in cooling initiation. CONCLUSION: Without therapeutic hypothermia, the outcome of children was determined by variables suggestive of the severity of encephalopathy/encephalitis at admission. Hypothermia may have pivotal impacts on the outcome of children according to the timing of cooling initiation following acute encephalopathy/encephalitis.

Beneficial effects of leukotriene receptor antagonists in the prevention of cedar pollinosis in a community setting.

BACKGROUND: In recent years, many countries have experienced an increase in the prevalence of allergic rhinitis. No effective approach is currently available to prevent the onset of symptoms in allergic individuals. Pranlukast, a leukotriene receptor antagonist with a good safety and efficacy record for the management of allergic inflammation, may be appropriate for early intervention in the management of pollinosis. OBJECTIVE: To investigate the efficacy of pranlukast as an early intervention in the control of cedar pollinosis. METHODS: In a double-blind comparative study, pranlukast (n = 102) or placebo (n = 91) was administered to cedar pollinosis patients immediately before the start of the dispersion season and continued for 4 weeks. Subsequently, pranlukast was administered to all patients for 2 weeks until the end of the cedar pollen dispersion season (mid-March). All patients were carefully monitored for severity of nasal symptoms, symptom scores, medication scores, symptom-medication scores, and quality of life (QOL). RESULTS: Compared with placebo, therapy with pranlukast before and during the dispersion of cedar pollen in these patients significantly improved nasal symptoms (paroxysmal sneezing, rhinorrhea, and nasal congestion), symptom scores, and symptom-medication scores. The drug also significantly reduced deterioration of QOL, and improved nasal symptoms and QOL throughout the dispersion period. CONCLUSION: Administering pranlukast immediately before the beginning of cedar pollen dispersion is effective in reducing symptoms of allergic rhinitis throughout the dispersion period.

Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma.

BACKGROUND: Stat3 is a member of the Janus-activated kinase/STAT signalling pathway. It normally resides in the cytoplasm and can be activated through phosphorylation. Activated Stat3 (p-Stat3) translocates to the nucleus to activate the transcription of several molecules involved in cell survival and proliferation. The constitutive activation of Stat3 has been shown in various types of malignancies, and its expression has been reported to indicate a poor prognosis. However, the correlation between the constitutive activation of Stat3 and the prognosis of cervical cancer patients has not been reported. METHODS: The immunohistochemical analysis of p-Stat3 expression was performed on tissues from 125 cervical squamous-cell carcinoma patients who underwent extended hysterectomy and pelvic lymphadenectomy, and the association of p-Stat3 expression with several clinicopathological factors and survival was investigated. RESULTS: Positive p-Stat3 expression was observed in 71 of 125 (56.8%) cases and was significantly correlated with lymph node metastasis, lymph vascular space invasion, and large tumour diameter (>4 cm) by Fisher's exact test. Kaplan-Meier survival analysis showed that p-Stat3 expression was statistically indicative of a poor prognosis for overall survival (P=0.006) and disease-free survival (P=0.010) by log-rank test. CONCLUSION: These data showed that p-Stat3 expression in cervical cancer acts as a predictor of poor prognosis.

Therapeutic hypothermia can be induced and maintained using either commercial water bottles or a "phase changing material" mattress in a newborn piglet model.

BACKGROUND: Therapeutic hypothermia, a safe and effective treatment for neonatal encephalopathy in an intensive care setting, is not available in low-resource settings. Aims/ METHODS: To assess two low-tech, low-cost cooling devices for use in low-resource settings: (i) commercially available water bottles filled with tepid water (25 degrees C); (ii) a mattress made of phase changing material (PCM) with a melting point of 32 degrees C (PCM works as a heat buffer at this temperature). Eleven anaesthetised newborn piglets were studied following transient hypoxia-ischaemia. The cooling device was applied 2-26 h after hypoxia-ischaemia with a target rectal temperature (T(rectal)) of 33-34 degrees C. T(rectal) undershoot was adjusted using cotton blankets; the cooling device was renewed when T(rectal) rose above 35 degrees C. T(rectal) data during cooling were dichotomised (within or without target) to assess: (a) the total period within the target T(rectal) range; (b) the stability and fluctuation of T(rectal) during cooling. RESULTS: Therapeutic hypothermia was achieved with both water bottles (n = 5) and the PCM mattress (n = 6). The mean (SD) time to reach target T(rectal) was 1.8 (0.5) h with water bottles and 1.9 (0.3) h with PCM. PCM cooling led to a longer period within the target T(rectal) range (p<0.01) and more stable cooling (p<0.05). Water bottle cooling required device renewal (in four out of five piglets). CONCLUSION: Simple, low-tech cooling devices can induce and maintain therapeutic hypothermia effectively in a porcine model of neonatal encephalopathy, although frequent fine tuning by adjusting the number of blankets insulating the piglet was required to maintain a stable temperature. PCM may induce more stable cooling compared with water bottles.

Hyperglycosylated HCG expression in pregnancy: cellular origin and clinical applications.

Employing a monoclonal antibody (B152) specific for a carbohydrate epitope found on a choriocarcinoma derived hCG, it was discovered that a similar hCG isoform is expressed during early pregnancy. This form differs from later pregnancy hCG in carbohydrate moieties. Profiling of these two hCG isoforms throughout pregnancy utilized two IRMA's: B152-B207 ("hyperglycosylated hCG"-specific assay) and B109-B108 (an IRMA for standard intact hCG isoforms in the WHO hCG reference preparation). The WHO hCG standard was used in both assays. Values were presented as a ratio of hCG isoform concentrations (B152/B109 ratio). In early pregnancy urine concentrations of B152 hCG were significantly higher in normal pregnancy (NP) compared to early pregnancy loss (EPL). Matched serum-urine samples from the first and third trimesters revealed that the B152 hCG form is predominant in both serum and urine in the first trimester compared with the third trimester. The proportion of the B152 hCG (HhCG) form is higher in urine than in matched serum. There was a significant difference in the B152/B109 ratio between days 5 and 20 from time of embryo transfer in normally developing pregnancy versus EPL in the urine of IVF patients. In spontaneous abortion (SA) the level of B109 hCG remained higher in NP compared with SA. However, the B152/B109 ratio declined with gestational age faster in SA than in NP suggesting perhaps a different loss mechanism in SA versus EPL. The cellular origin of the different hCG glycoforms was identified by assay of cell media from cytotrophoblasts (CTBs) and syncytiotrophoblasts (STBs). Isolated CTBs expressed predominantly HhCG. The level of expression was the highest in the first trimester. STBs were the source of the less glycosylated B109 hCG isoform. Analysis of hCG glycoforms during early pregnancy can distinguish pregnancies that will fail from those that will proceed normally. Since the B152 assay does not effectively discriminate between intact HhCG and free beta HhCG (HhCGbeta), a new HhCGbeta assay was developed. This assay recognizes the HhCGbeta which is produced by CTBs. We hypothesize that the measurement of HhCGbeta may have a potential use in screening for Down syndrome and perhaps other pregnancy disorders and certain types of cancer.

Smoking is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetic patients.

BACKGROUND: Smoking and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. This study tested the hypothesis that smoking is associated with insulin resistance/hyperinsulinaemia and cardiovascular autonomic dysfunction in type 2 diabetic patients who are not treated with insulin. MATERIALS AND METHODS: The study patients were 22 current smokers with type 2 diabetes mellitus (age: 57 +/- 5 years, mean +/- SD) and 30 age-matched never-smoked patients with type 2 diabetes mellitus (control group, 57 +/- 8 years). The quality of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin (F-IRI), homeostasis model assessment (HOMA) index and haemoglobin A1c (HbA1c). The severity of smoking status was expressed by the Brinkman index, which is calculated as number of cigarettes per day multiplied by years of smoking. Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart-rate variability, plasma norepinephrine concentration and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS: Baroreflex sensitivity was lower in the current smokers group than in the never-smoked group (P < 0.05). Early and delayed (123)I-MIBG myocardial uptake values were lower (P < 0.05, and P < 0.01, respectively) and the percentage washout-rate of (123)I-MIBG was higher (P < 0.0001) in the current smokers group than in the never-smoked group. Fasting immunoreactive insulin (F-IRI) concentration (P < 0.0001) and the homeostasis model assessment (HOMA) index (P < 0.0001) were higher in the current smokers group than the never-smoked group. Multiple logistic regression analysis revealed that smoking was independently predicted by F-IRI and the percentage washout-rate of (123)I-MIBG. CONCLUSIONS: The results of the study suggested that smoking was associated with cardiovascular autonomic dysfunction and hyperinsulinaemia and that F-IRI and the percentage washout-rate of (123)I-MIBG were independent predictors of smoking in these Japanese patients with type 2 diabetes mellitus.

Differential expression of human chorionic gonadotropin (hCG) glycosylation isoforms in failing and continuing pregnancies: preliminary characterization of the hyperglycosylated hCG epitope.

Human chorionic gonadotropin (hCG) glycoforms change as pregnancy progresses. We have developed an antibody (B152) which can measure a hyperglycosylated early pregnancy isoform of hCG. This putative hyperglycosylated form of hCG arises very early in pregnancies and is rapidly replaced by an isoform that predominates for the remainder of the pregnancy. The profiles of these hCG glycoforms are measured as a ratio of values of two immunometric assays. The profiles of these ratios differ between pregnancies which persist and those which will experience early failure. In this report, daily urine hCG isoform ratios from donor eggs (no exogenous hCG pretreatment), in vitro fertilization pregnancies were profiled and analyzed from the first day following embryo transfer (ET). Significant differences were found between continuing pregnancy and pregnancy loss throughout days 5-20 post-ET. When hCG isoform ratios were analyzed from the first day of detectable hCG, pregnancy loss could be predicted in the case of a single fetus both during the 5- to 10-day time segment (P=0.018) and the 10- to 15-day time segment (P=0.045). When single and multiple fetus pregnancies were analyzed together significance was approached in the 10- to 15-day time period (P=0.058). In a second population of pregnant women who conceived naturally, in whom urine samples were collected at approximately weekly intervals to either term birth or clinical spontaneous abortion, the ratio could discriminate between miscarriages and normal term pregnancies (P=0.043). In later pregnancy, the ratio of hCG isoforms declined more rapidly in miscarriages than in term pregnancy. Antibody B152 was produced using a choriocarcinoma-derived hCG (C5), which was hyperglycosylated at both N- and O-linked sites and was 100% nicked at position beta(47-48). Western blot analyses supported the assay results showing that early pregnancy urine does not contain nicked C5-like hCG. Also, the early pregnancy hCG appeared to be the same size as later pregnancy hCG as judged by SDS gel electrophoresis. A series of Western blot analyses and immunoassays conducted with the samples either non-reduced or reduced showed that B152 is directed to a linear epitope located in the COOH-terminal peptide region of the beta subunit. This indicated that only the O-glycan groups and not the N-linked glycans are part of the antibody epitope.

[Leptin-induced regulation of fat metabolism and its accumulation].

Recent findings have shown that supplementation of leptin decreases body weight in leptin-deficient ob/ob mice through its suppressive effect on food intake and accelerating effect on energy expenditure, particularly on peripheral fat lipolysis. When endogenously hyperleptinemic obese rats were further induced to be hyperleptinemic exogeously using adenovirus vector, their body fat mass was reduced but not food intake. These findings implicate a direct lipolytic action of leptin on peripheral adipose tissues in obese rats because leptin transport capacity across the blood-brain barrier is almost saturated by the relative hyperleptinemia. Recovery from excessive body fat accumulation after adenovirus-induced hyperleptinemia is much slower than that after caloric restriction because there may be difference between those treatments in decreased lipogenic enzymes activities and/or increased activities of fatty acid oxidative enzymes and thermogenic uncoupling proteins. The fat melting effects of leptin may show its crucial pharmacologic potencies to design therapeutic strategies against morbid obesity. The studies on leptin provide a better understanding for creative approaches to anti-obesity drug that are efficient for reducing body fat mass without harmful side-effects.

Continuation treatment of delusional depression in older adults.

Delusional depression responds poorly to acute antidepressant monotherapy but appears to respond to intensive combination pharmacotherapy, however with poor short-term outcomes after initial improvement, particularly in later life. The authors compared the efficacy and safety of continuation combination therapy to monotherapy among older patients after remission from a delusional depression. Twenty-nine older adults with SCID-diagnosed major depression with delusions received continuation treatment with nortriptyline-plus-perphenazine or nortriptyline-plus-placebo under randomized double-blind conditions after achieving remission after ECT. Of the 28 subjects included in efficacy analyses, 25% suffered relapses. The relapse frequency was nonsignificantly greater in combination therapy than in monotherapy subjects. However, combination subjects had significantly more extrapyramidal symptoms, an increased incidence of tardive dyskinesia, and a greater number of falls. Continuation treatment with a conventional antipsychotic does not decrease relapse rates but is associated with significant untoward adverse events in older persons after recovery from a delusional depression.

Personality disorder symptoms predict declines in global functioning and quality of life in elderly depressed patients.

The authors evaluated personality disorder symptoms as predictors of change in global functioning and quality of life among elderly depressed patients. Treated elderly patients (N=40) who no longer met RDC criteria for major depression were assessed for personality disorders, depression, global functioning, and quality of life after treatment of the acute episode and at 1-year follow-up. In interaction with persisting or recurrent depression, Cluster B personality disorder symptoms contributed to declines in global functioning and quality of life over a 1-year period. Personality disorder symptoms in elderly patients appear to operate as co-factors that amplify or exacerbate the impact of residual depression on long-term functioning and quality of life.

The role of leptin resistance in the lipid abnormalities of aging.

Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. To determine whether development of leptin resistance in advancing age might account for such abnormalities, we compared the effects of hyperleptinemia (>40 ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+) Zucker diabetic fatty rats by adenovirus gene transfer. The decline in food intake, body weight, and body fat in old rats was only 25%, 50%, and 16%, respectively, of the young rats. Whereas in young rats plasma free fatty acids fell 44% and triacylglycerol (TG) 94%, neither changed in the rats. In hyperleptinemic young rats, adipocyte expression of preadipocyte factor 1 increased dramatically and leptin mRNA virtually disappeared; there was increased expression of acyl CoA oxidase, carnitine palmitoyl transferase 1, and their transcription factor peroxisome proliferator-activated receptor alpha, accounting for the reduction in body fat. These hyperleptinemia-induced changes were profoundly reduced in the old rats. On a high-fat diet, old rats consumed 28% more calories than the young and gained 1.5x as much fat, despite greater endogenous hyperleptinemia. Expression of a candidate leptin resistance factor, suppressor of cytokine signaling 3 (SOCS-3), was compared in the hypothalamus and white adipocytes of young and old rats before and after induction of hyperleptinemia; hypothalamic SOCS-3 mRNA was approximately 3x higher in old rats before, whereas it was 3x higher in WAT after, hyperleptinemia. We conclude that the anorexic and antilipopenic actions of leptin decline with age, possibly through increased SOCS-3 expression, and that this could account for the associated abnormalities in lipid metabolism of the elderly.

Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia.

To test the hypothesis that the physiologic liporegulatory role of hyperleptinemia is to prevent steatosis during caloric excess, we induced obesity by feeding normal Harlan Sprague-Dawley rats a 60% fat diet. Hyperleptinemia began within 24 h and increased progressively to 26 ng/ml after 10 weeks, correlating with an approximately 150-fold increase in body fat (r = 0.91, p < 0.0001). During this time, the triacylglycerol (TG) content of nonadipose tissues rose only 1-2.7-fold implying antisteatotic activity. In rodents without leptin action (fa/fa rats and ob/ob and db/db mice) receiving a 6% fat diet, nonadipose tissue TG was 4-100 times normal. In normal rats on a 60% fat diet, peroxisome proliferator-activated receptor alpha protein and liver-carnitine palmitoyltransferase-1 (l-CPT-1) mRNA increased in liver. In their pancreatic islets, fatty-acid oxidation increased 30% without detectable increase in the expression of peroxisome proliferator-activated receptor-alpha or oxidative enzymes, whereas lipogenesis from [14C]glucose was slightly below that of the 4% fat-fed rats (p < 0.05). Tissue-specific overexpression of wild-type leptin receptors in the livers of fa/fa rats, in which marked steatosis is uniformly present, reduced TG accumulation in liver but nowhere else. We conclude that a physiologic role of the hyperleptinemia of caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing the up-regulation of lipogenesis and increasing fatty-acid oxidation.

Intracellular distribution of the antimutagenic enzyme MTH1 in the liver, kidney and testis of F344 rats and its modulation by cadmium.

Cellular distribution of the antimutagenic MTH1protein in the liver, kidney, and testis of Fischer rat was evaluated using the immunohistochemical staining with anti-MTH1 polyclonal antibody. The present investigation revealed a non-uniform distribution of MTH1 among cells and among the cytoplasmic, nuclear, and membranal structures of cells within a given tissue. A particularly strong expression of MTH1 was observed for the first time in the perinuclear acrosomic bodies of spermatocytes and in the acrosomic vesicles of sperm heads. Treatment of rats with a single sc dose of 20 micromol Cd(II)/kg body wt. produced histopathologic changes in these organs accompanied by redistribution of the cellular MTH1 protein between the cytoplasm and nuclei. The acute phase of Cd(II) toxicity, that in the liver and especially in the testes (but not in kidneys) led to cell necrosis, was accompanied by a characteristic decrease in the abundance of MTH1-expressing nuclei. Chronic toxicity without necrosis, persisting in the kidney over the entire 14-day study, as well as the survival and proliferation of cells, observed in the liver and testis after the necrotizing phase, were signified by increased number of nuclei expressing MTH1. Thus, unlike previous biochemical studies, immunohistochemistry managed to reveal alterations in the patterns of inter- and intracellular distribution of MTH1, associated apparently with the conditional changes in the dynamics of synthesis of nucleic acids, assisted by this protein.

Relationship between exploratory eye movements and clinical course in schizophrenic patients.

Exploratory eye movements are psychophysiological indicators of schizophrenia as well as smooth pursuit eye movements. To investigate whether these eye movements change in accordance with the clinical course of the condition in schizophrenia, exploratory eye movements (number of eye fixations, mean eye scanning length, responsive search score, evaluation of reproduced Fig. 1 and 2) of 28 schizophrenic patients were evaluated in repeat test design, conducted an average of 8 months apart. Subjects were first-medicated schizophrenics, half were outpatients and the remaining half were inpatients at the Neuropsychiatry ward of Tokyo Medical and Dental University Hospital. Exploratory eye movement patterns did not improve despite an improvement in clinical symptoms of schizophrenia. This result and those of previous studies of the exploratory eye movements of schizophrenic patients' families suggest that exploratory eye movements reflect a schizophrenic vulnerability marker. Furthermore, decreased mean eye scanning length (MESL) values were observed in subjects who showed unimproved symptoms, particularly negative symptoms over an extended period of time. The result suggests that a decrease in the MESL value may be the most sensitive indicator in the development of chronicity in schizophrenia.

Age and nortriptyline concentrations in plasma ultrafiltrate.

OBJECTIVES: Since plasma protein binding of tricyclic antidepressants may be relevant to treatment effects and can be influenced by age-associated factors, we examined both plasma ultrafiltrate and total concentrations of nortriptyline (NT) in patients and compared these to age. We hypothesized negative associations with age of both ultrafiltrate NT and the ratio of ultrafiltrate NT to total plasma NT. METHODS: Patients with major depression at a psychiatric service treated with a stable dose of NT were studied. Trough plasma ultrafiltrate NT concentrations and total plasma NT concentrations were measured by high performance liquid chromatography. Concentrations were corrected for dose. RESULTS: Eighty-seven patients aged 26 - 88 years were studied. Ultrafiltrate NT concentrations and the ratio of ultrafiltrate NT to total NT concentrations were both significantly negatively associated with age. Total NT concentrations were not significantly associated with age. CONCLUSIONS: Relatively low ultrafiltrate NT concentrations in older patients may reflect lower tissue exposure at a given total plasma NT concentration. This could be relevant to toxic and therapeutic effects. Studies of relationships between non-bound drug concentrations and NT treatment outcomes across the age span are needed.

Role of leptin in peroxisome proliferator-activated receptor gamma coactivator-1 expression.

Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1), a cold-induced protein expressed in brown adipose tissue (BAT), plays a role in adaptive thermogenesis by up-regulating uncoupling proteins (UCP). Here, we explore its relationship to the thermogenic actions of leptin, which also up-regulates UCPs. We find that PGC-1 messenger RNA (mRNA) is markedly reduced in BAT of obese leptin-deficient (ob/ob mice) and leptin-unresponsive (db/db mice and Zucker diabetic fatty fa/fa rats) rodents. Whereas, after cold exposure (6 C for 7 h), PGC-1 mRNA increases 2.6-fold in BAT of lean +/+ rats, it rises only 30% in fa/fa rats. Four days after induction of hyperleptinemia (>30 ng/ml) in Wistar rats, by adenovirus gene transfer, PGC-1 mRNA in BAT was 2.3-fold and UCP-1, 4-fold above controls. In isolated white adipocytes, PGC-1 mRNA increased 4.4-fold within 6 h of incubation with 20 ng/ml of leptin. We conclude that leptin action is required for normal basal and cold-stimulated PGC-1 expression in BAT in rodents and that hyperleptinemia rapidly up-regulates its expression, at least in part, by direct action.

Child-Adolescent Suicidal Potential Index (CASPI): a screen for risk for early onset suicidal behavior.

This study's purpose was to develop a reliable and valid self-report questionnaire, the Child-Adolescent Suicidal Potential Index (CASPI), to screen for risk for suicidal behavior in children and adolescents. Four hundred twenty-five child and adolescent psychiatric patients and nonpatients completed the CASPI and other research instruments to rate suicidal and assaultive behavior and symptoms of depression, anxiety, and hopelessness. The 30-item CASPI involves 3 factors (anxious-impulsive depression, suicidal ideation or acts, family distress) that contributed to a unidimensional 2nd-order factor accounting for 59% of the total variance. Internal consistency (alpha) for the total score was .90, and test-retest reliability (ICC) for the total score was .76. Total score distinguished between children and adolescents with different severity of psychopathology and different levels of suicidal and assaultive behavior. Each of the 3 factors had different contributions to discriminating between levels of suicidal status. CASPI total score of 11 distinguished suicidal ideation or acts from nonsuicidal behavior, with sensitivity 70% and specificity 65%. CASPI total score positively correlated with symptom severity of depression, anxiety, and hopelessness.