Correlation between magnesium pre-loading and cisplatin-induced nephrotoxicity in 5-fluorouracil/cisplatin combination therapy for esophageal cancer.

The use of cisplatin may cause nephrotoxicity in patients. Hydration solutions supplemented with magnesium could reduce cisplatin-induced nephrotoxicity. In this study, we evaluated the preventive effect of magnesium pre-loading on cisplatin-induced nephrotoxicity in patients with esophageal cancer. We retrospectively evaluated the prevalence of, and risk factors for, nephrotoxicity in 160 patients with esophageal cancer treated with the 5-fluorouracil/cisplatin regimen from 2014 to 2016 with and without magnesium supplementation. Significant differences were observed between the magnesium and non-magnesium groups in terms of frequency of estimated creatinine clearance of grade 2 or higher that was at 4% (n = 3) and 13% (n = 10) (p = 0.027), respectively. The logistic regression analysis revealed that eCcr of grade 2 or higher was significantly associated with the non-magnesium regimen (odds ratio (OR), 4.175; 95% confidence interval (CI) = 1.061-16.430; p = 0.041) and age ≥ 65 years (OR, 13.951; 95% CI = 1.723-112.974; p = 0.014). This study suggests that 20 mEq magnesium pre-loading significantly reduces the prevalence of cisplatin-induced nephrotoxicity. Furthermore, when cisplatin is administered to individuals older than 64 years, a close observation for the onset of cisplatin-induced nephrotoxicity is crucial.

Characterizing learning by simultaneous analysis of continuous and binary measures of performance.

Continuous observations, such as reaction and run times, and binary observations, such as correct/incorrect responses, are recorded routinely in behavioral learning experiments. Although both types of performance measures are often recorded simultaneously, the two have not been used in combination to evaluate learning. We present a state-space model of learning in which the observation process has simultaneously recorded continuous and binary measures of performance. We use these performance measures simultaneously to estimate the model parameters and the unobserved cognitive state process by maximum likelihood using an approximate expectation maximization (EM) algorithm. We introduce the concept of a reaction-time curve and reformulate our previous definitions of the learning curve, the ideal observer curve, the learning trial and between-trial comparisons of performance in terms of the new model. We illustrate the properties of the new model in an analysis of a simulated learning experiment. In the simulated data analysis, simultaneous use of the two measures of performance provided more credible and accurate estimates of the learning than either measure analyzed separately. We also analyze two actual learning experiments in which the performance of rats and of monkeys was tracked across trials by simultaneously recorded reaction and run times and the correct and incorrect responses. In the analysis of the actual experiments, our algorithm gave a straightforward, efficient way to characterize learning by combining continuous and binary measures of performance. This analysis paradigm has implications for characterizing learning and for the more general problem of combining different data types to characterize the properties of a neural system.

A three-dimensional synthetic metallic crystal composed of single-component molecules.

Molecular metals normally require charge transfer between two different chemical species. We prepared crystals of [Ni(tmdt)2] (tmdt, trimethylenetetrathiafulvalenedithiolate) and carried out crystal structure analyses and resistivity measurements. The analyses and measurements revealed that these single-component molecular crystals are metallic from room temperature down to 0.6 kelvin. Ab initio molecular orbital calculations suggested that pi molecular orbitals form conduction bands. The compact molecular arrangement, intermolecular overlap integrals of the highest occupied and lowest unoccupied molecular orbitals, and tight-binding electronic band structure calculation revealed that [Ni(tmdt)2] is a three-dimensional synthetic metal composed of planar molecules.

Altered expression of CYP in TSOD mice: a model of type 2 diabetes and obesity.

To investigate the pharmacokinetic characteristics in TSOD (Tsumura, Suzuki, obese, diabetes) mice, a model of type 2 diabetes and obesity, the expressions of major hepatic CYP enzymes in TSOD and TSNO (Tsumura, Suzuki, non-obesity; control) mice were compared. The 7-month-old TSOD mice, which represented severe obesity/diabetes-related pathophysiology, showed higher expressions of Cyp2c and Cyp3a compared with TSNO mice, while those of Cyp1a and Cyp2e were lower. Cyp3a metabolic activity was also higher in TSOD mice. In the 7-month-old liver, pregnane X receptor (PXR) (nuclear receptor) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) (cofactor) mRNA expression were higher in TSOD mice, possibly playing a role in the altered expression of Cyp3a. This specifically altered CYP expression in TSOD mice suggests that the biotransformation of drugs metabolized by these CYP enzymes differs from that in normal animals. Based on these findings, further investigation on the relationship between altered CYP expression and pathophysiology may be useful in elucidating changes in pharmacokinetics in obese/diabetic patients.

The anatomy, physiology and functions of the perirhinal cortex.

The perirhinal cortex is a polymodal association area that contributes importantly to normal recognition memory. A convergence of recent findings from lesion and electrophysiological studies has provided new evidence that this area participates in an even broader range of memory functions than previously thought, including associative memory and emotional memory, as well as consolidation functions. These results are consistent with neuroanatomical research showing that this area has strong and reciprocal connections with widespread cortical sensory areas and with other memory-related structures, including the hippocampal formation and amygdala.

The hippocampus and memory: a comparative and ethological perspective.

During the past year, considerable progress has been made in our understanding of the wide-ranging functions of the hippocampus. Highlights include the development of new tasks with which to assess spatial/topographic memory in humans and monkeys, novel tests of relational memory in rats, and episodic-like memory tasks in birds. In addition, novel theories of hippocampal function have been developed that are notable for their applicability to both humans and animal models.

Connections between anterior inferotemporal cortex and superior temporal sulcus regions in the macaque monkey.

We examined the connections between the anterior inferotemporal cortex and the superior temporal sulcus (STS) in the macaque monkey by injecting Phaseolus vulgaris leucoagglutinin (PHA-L) or wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into the dorsoanterior and ventroanterior subdivisions of TE (TEad and TEav, respectively) and observing the labeled terminals and cell bodies in STS. We found a clear dichotomy in the connections of the rostral part of STS: the injections into TEad resulted in a dense distribution of labeled terminals and cell bodies in the upper bank of rostral STS, whereas labeling was confined to the lower bank and fundus of rostral STS after injections into TEav. The distribution of labeling in the rostral STS was discontinuous from the distribution of labeling surrounding the injection sites: the lower bank of the rostral STS was spared from labeling in the TEad injection cases, and TEad had only sparse distribution in the TEav injection cases. These results revise the classical view that the lower bank of rostral STS is connected with TE, whereas the upper bank of rostral STS is connected with the parietal, prefrontal, and superior temporal regions (Seltzer and Pandya, 1978, 1991, 1994). The upper bank of the rostral STS is called the superior temporal polysensory area (STP), because it was previously found that neurons there respond to auditory, somatosensory, and visual stimuli. The present results thus suggest that the polymodal representation in STP interacts more with information processing in TEad than TEav. It is also suggested that the information processing in the ventral bank of the rostral STS is distinct from that in TEad, and the former more directly interacts with TEav than TEad.

Genetic analysis of obese diabetes in the TSOD mouse.

The molecular pathogenesis of diabetes remains poorly understood because of the genetic complexity of the disease. One possibly effective approach to elucidate the pathogenesis is to study an animal model with a similar phenotype. The TSOD (Tsumura, Suzuki, Obese Diabetes) mouse, a newly developed animal model, exhibits both diabetes and obesity with marked hyperinsulinemia and hypertrophy of the pancreatic islets and might represent a common form of obese type 2 diabetes in humans. Phenotypic characterization revealed that the TSOD mouse had both insulin resistance and impaired glucose-stimulated insulin secretion. A comprehensive genetic dissection of diabetes and obesity has been performed using F1 and F2 progeny between the TSOD and control BALB/cA strains. A genome-wide screen for loci linked to glucose homeostasis and body weight allowed us to map three quantitative trait loci (QTLs) involved in this disorder. The major genetic determinant of blood glucose levels was identified on chromosome 11. Furthermore, two independent QTLs involved in controlling body weight were found on chromosomes 1 and 2. The QTL on chromosome 2 also affected insulin levels significantly. Each QTL has distinct effects on different traits and a different mode of inheritance. Our study indicates that hyperglycemia and obesity are clearly controlled by distinct combinations of genetic loci in this mouse model and provides insights into the genetic basis of common forms of human type 2 diabetes with obesity.

Perirhinal and parahippocampal cortices of the macaque monkey: cortical afferents.

Neuropsychological studies have recently demonstrated that the macaque monkey perirhinal (areas 35 and 36) and parahippocampal (areas TH and TF) cortices contribute importantly to normal memory function. Unfortunately, neuroanatomical information concerning the cytoarchitectonic organization and extrinsic connectivity of these cortical regions is meager. We investigated the organization of cortical inputs to the macaque monkey perirhinal and parahippocampal cortices by placing discrete injections of the retrograde tracers fast blue, diamidino yellow, and wheat germ agglutinin conjugated to horseradish peroxidase throughout these areas. We found that the macaque monkey perirhinal and parahippocampal cortices receive different complements of cortical inputs. The major cortical inputs to the perirhinal cortex arise from the unimodal visual areas TE and rostral TEO and from area TF of the parahippocampal cortex. The perirhinal cortex also receives projections from the dysgranular and granular subdivisions of the insular cortex and from area 13 of the orbitofrontal cortex. In contrast, area TF of the parahippocampal cortex receives its strongest input from more caudal visual areas V4, TEO, and caudal TE, as well as prominent inputs from polymodal association cortices, including the retrosplenial cortex and the dorsal bank of the superior temporal sulcus. Area TF also receives projections from areas 7a and LIP of the posterior parietal lobe, insular cortex, and areas 46, 13, 45, and 9 of the frontal lobe. As with area TF, area TH receives substantial projections from the retrosplenial cortex as well as moderate projections from the dorsal bank of the superior temporal sulcus; unlike area TF, area TH receives almost no innervation from areas TE and TEO. It does, however, receive relatively strong inputs from auditory association areas on the convexity of the superior temporal gyrus.

Divergent backward projections from the anterior part of the inferotemporal cortex (area TE) in the macaque.

The organization of backward projections from the anterior part of the inferotemporal cortex (area TE) to the posterior part of the inferotemporal cortex (area TEO) was studied in the macaque monkey by using the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). The objectives of the study were to investigate this backward projection and to compare it with 1) the backward projections that have been described previously in the early sensory areas and 2) the forward projection from area TEO to area TE. After a single iontophoretic injection of PHA-L into area TE in three monkeys, a dense distribution of labeled terminals was observed in area TEO and in the ventral bank of the superior temporal sulcus (area PITd) that adjoined area TEO. A less dense distribution was observed in areas V4, V2, and V1. Clusters of labeled terminals in areas TEO and PITd extended more than 4 mm along the cortical surface. The forward projections from area TEO to area TE also were studied for comparison by reanalyzing two previous cases (Saleem et al. ¿1993 Cerebral Cortex 3:454-464). These projections (from area TEO to area TE) were more focal than the terminations that occurred in area TEO after injections into area TE. Nine single axons projecting from area TE to areas TEO/PITd were reconstructed through serial sections. These showed variable, complex branching patterns with multiple arbors (1-12). Arbors were localized in layers 1-3 for four axons, in layer 1 for one axon, layers 5 and 6 for two axons, and in both layers 1-3 and layers 5-6 for two axons. Axons with horizontally elongated arbors confined to layer 1 were not predominant. The size of the individual arbors of these axons along their long axes tended to be larger (1.56 +/- 1.24 mm) than those of TEO-to-TE forward axons (<0.6 mm). Thus, the authors conclude that, like other backward systems described to date, those from area TE to areas TEO/PITd are divergent. However, single axons have more variable laminar patterns of terminal distribution than those in the other backward systems.

Organization of connections between the amygdaloid complex and the perirhinal and parahippocampal cortices in macaque monkeys.

Neuroanatomical studies in macaque monkeys have demonstrated that the perirhinal and parahippocampal (PRPH) cortices are strongly interconnected with the hippocampal formation. Recent behavioral evidence indicates that these cortical regions are importantly involved in normal recognition memory function. The PRPH cortices are also interconnected with the amygdaloid complex, although comparatively little is known about the precise topography of these connections. We investigated the topographic organization of reciprocal connections between the amygdala and the PRPH cortices by placing anterograde and retrograde tracers throughout these three regions. We found that there was an organized arrangement of connections between the amygdala and the PRPH cortices and that the deep (lateral, basal, and accessory basal) nuclei of the amygdaloid complex were the source of most connections between the amygdala and the PRPH cortices. The temporal polar regions of the perirhinal cortex had the strongest and most widespread interconnections with the amygdala. Connections from more caudal levels of the perirhinal cortex had a more discrete pattern of termination. Perirhinal inputs to the amygdala terminated primarily in the lateral nucleus, the magnocellular and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. Return projections originated predominately in the lateral nucleus, the intermediate and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. The interconnections between the amygdala and the parahippocampal cortex were substantially less robust than those with the perirhinal cortex and mainly involved the basal nucleus. Area TF was more strongly interconnected with the amygdala than was area TH. Input from the parahippocampal cortex terminated predominantly in the lateral half of the parvicellular division of the basal nucleus but also to a lesser extent in the magnocellular division of the basal nucleus and the lateral nucleus. Return projections originated predominantly in the magnocellular division of the basal nucleus and were directed almost exclusively to area TF.

Where are the perirhinal and parahippocampal cortices? A historical overview of the nomenclature and boundaries applied to the primate medial temporal lobe.

Strong evidence has emerged over the last 15 years showing that the perirhinal and parahippocampal cortices play an important role in normal memory function. Despite our progress in understanding the mnemonic functions of these areas, controversy still exists concerning the precise location of the boundaries of these areas in the primate brain. To provide a context for understanding the current discrepancies in the literature, we present a historical overview of the different boundary schemes and nomenclatures that have been applied to the medial temporal lobe cortices in both humans and nonhuman primates. We describe how the boundaries and the names applied to these regions have evolved over time, starting with the classic cytoarchitectonisists working in the early 1900s, and ending with the various schemes being used in the contemporary literature. We show that the current controversies concerning the boundaries of the perirhinal and parahippocampal cortices can be traced directly to the classic cytoarchitectonic literature.

Impairment of insulin-stimulated GLUT4 translocation in skeletal muscle and adipose tissue in the Tsumura Suzuki obese diabetic mouse: a new genetic animal model of type 2 diabetes.

BACKGROUND: In skeletal muscle and adipocytes, insulin-stimulated glucose transport has been known to occur through the translocation of glucose transporter (GLUT) 4 from the intracellular pool to the plasma membrane. The Tsumura Suzuki obese diabetic (TSOD) mouse, a new genetic animal model of type 2 diabetes, develops moderate degrees of obesity and diabetes that are especially apparent in animals more than 11 weeks old. A defect in insulin stimulation of GLUT4 translocation also contributes to the characteristics of type 2 diabetes. OBJECTIVE: To characterize this mouse further, we examined the alteration in insulin-stimulated GLUT4 translocation in the skeletal muscle and adipose tissue. METHODS: For glucose and insulin tolerance tests, the mice were given glucose or insulin and blood samples were collected. After isolation of low-density microsomal membrane and plasma membrane from skeletal muscle and adipose tissue, insulin-stimulated translocation of GLUT4 in these TSOD mice was examined by Western blot. RESULTS AND CONCLUSIONS: TSOD mice showed a significant increase in blood glucose after the glucose load, and exhibited a significantly attenuated decrease in blood glucose concentrations after administration of insulin, compared with that in control Tsumura Suzuki non-obese (TSNO) mice. The insulin-stimulated translocation of GLUT4 from low-density microsomal membranes to plasma membrane was significantly reduced in both skeletal muscle and adipose tissue of TSOD mice. These results indicate that the reduced insulin sensitivity in diabetic TSOD mice is presumably due, at least in part, to the impaired GLUT4 translocation by insulin in both skeletal muscle and adipocytes.

The neurophysiology of memory.

How do the structures of the medial temporal lobe contribute to memory? To address this question, we examine the neurophysiological correlates of both recognition and associative memory in the medial temporal lobe of humans, monkeys, and rats. These cross-species comparisons show that the patterns of mnemonic activity observed throughout the medial temporal lobe are largely conserved across species. Moreover, these findings show that neurons in each of the medial temporal lobe areas can perform both similar as well as distinctive mnemonic functions. In some cases, similar patterns of mnemonic activity are observed across all structures of the medial temporal lobe. In the majority of cases, however, the hippocampal formation and surrounding cortex signal mnemonic information in distinct, but complementary ways.

Cortical inputs to the CA1 field of the monkey hippocampus originate from the perirhinal and parahippocampal cortex but not from area TE.

We determined the cortical regions that project directly to the CA1 field of the monkey hippocampus by injecting the retrograde tracers Fast blue, Diamidino yellow or WGA-HRP into CA1 and examining the distribution of labeled cells. In the temporal lobe, large numbers of retrogradely labeled cells were observed in the perirhinal and parahippocampal cortices. Only an occasional labeled cell, however, was observed in the unimodal visual area TE. Additional projections to CA1 arose in the dorsal bank of the superior temporal sulcus, in the rostral and retrosplenial portions of the cingulate cortex, in the agranular insular cortex, and in the caudal orbitofrontal cortex.

Inhibitory activity of camptothecin derivatives against acetylcholinesterase in dogs and their binding activity to acetylcholine receptors in rats.

A camptothecin derivative, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), shows a potent antitumour activity in experimental tumour models and in clinical trials. However, CPT-11 induced early diarrhoea and vomiting at high dose levels in clinical studies and showed an acetylcholine-like action on the guinea-pig ileum and trachea. In the present study, we investigated the activities of camptothecin derivatives in inhibiting acetylcholinesterase (AChE) and in binding to muscarinic acetylcholine receptors (AChR). CPT-11 inhibited AChE and binding of the specific ligand to AChR with respective 50% inhibition concentrations of 0.2 and 5 microM. These inhibitions were induced by camptothecin derivatives having an amino group at the C-10 position (or the C-4 position of hexacyclic derivatives), but were not or were only slightly induced by the others. Early defecation and vomiting in dogs were observed after intravenous injection of DU-6596 and DU-6888, two hexacyclic derivatives having the aminomethyl group at the C-4 position, and of CPT-11. DU-6174, however, which has a hydroxy group at this position, induced no early defecation and little vomiting. Plasma concentrations of CPT-11, DU-6596 and DU-6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or longer at levels sufficient to inhibit AChE. These results suggest that the inhibition of AChE by camptothecin derivatives with an amino group at the C-10 position (or the C-4 position) relates to the early defecation or diarrhoea and vomiting.

A new mouse model of spontaneous diabetes derived from ddY strain.

By the selective breeding of obese male mice of the ddY strain and using indices of the heavy body weight and appearance of urinary glucose, we established two inbred strains in 1992: one with obesity and urinary glucose (Tsumura, Suzuki, Obese Diabetes: TSOD) and the other without them (Tsumura, Suzuki, Non Obesity: TSNO). The male TSOD mice constantly showed signs of obesity and urinary glucose with increases in food and water intake, body weight and some fat weight. The body mass index (BMI) clearly showed moderate obesity. Increases in the levels of diabetic blood parameters (glucose, insulin and lipids) were also found in males, in which the levels of blood glucose and insulin were high to the ages past the growth peak. In the histological studies, pancreatic islets of the TSOD males were found hypertrophic without any signs of insulitis or fibrous formation. Among these diabetic characteristics, some of which were similar to the reported models of non-insulin-dependent diabetes mellitus (NIDDM), the stable appearances of the hyperglycemia, the hyperinsulinemia and the hypertrophy of pancreatic islets to the ages past the growth peak were the prominent features. In these respect the TSOD mouse may be a useful model for researching the mechanisms of human diabetes and its complications.

[Evaluation of lidocaine metabolite (monoethylglycinexylidide) as a liver function test].

In order to determine whether or not the lidocaine metabolism, monoethylglycinexylidide (MEGX) formation, could be used as a liver function test, we measured the serum levels of MEGX in 38 patients. There were significant correlations between values of MEGX (MEGX15, MEGX30, AUC15-30, AUC0-180) and conventional liver function tests (ICG R15, AT III, T. Bil). It appeared that value of MEGX 30 had maximum factor loading on conventional liver function tests by using principal component analysis. The advantage of adapting the MEGX formation as a liver function test of drug metabolism is simplicity of the method. MEGX formation could be useful index of the total liver function.