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.

Histamine-2 receptor antagonists (H2RA) may negatively impact ADL assessment in patients on a convalescent rehabilitation ward.

Background/aim: In the convalescent rehabilitation ward, many elderly patients undergo rehabilitation. Histamine-2 receptor antagonists (H2RA), which is a one of the acid secretion inhibitors, is frequently prescribed for the patients as a peptic ulcer prevention measure. At present, H2RA are reported as being associated with factors that reduce cognitive function. However, little is known about the relationship H2RA and rehabilitation outcome. Therefore, this study examined the relationship between H2RA use and Functional Independence Measure (FIM) gain, which determines rehabilitation outcomes for patients admitted to the convalescent rehabilitation ward. Patients and methods: We retrospectively investigated FIM gain on discharge by both the administration group (H2RA (+)) (n = 118) and non-administration group (H2RA (-)) (n = 118). Results: The FIM gain scores of Motor FIM total, Cognition FIM total, and Total FIM were significantly lower in H2RA (+) than in H2RA (-) (Motor FIM total: 8.0 [4.0-16.0] [Inter-Quartile Range] vs. 12.0 [5.0-19.2], p =0.0217, Cognition FIM total: 3.0 [1.0-6.0] vs. 5.0 [2.0-7.0], p =0.0120, Total FIM: 11.5 [4.8-20.2] vs. 17.0 [8.0-27.0], p =0.0089). Conclusion: The administration of H2RA to elderly patients undergoing rehabilitation may prevent cognitive function maintenance or recovery by rehabilitation.

Computer-Assisted Detection of Cerebral Aneurysms in MR Angiography in a Routine Image-Reading Environment: Effects on Diagnosis by Radiologists.

BACKGROUND AND PURPOSE: Experiences with computer-assisted detection of cerebral aneurysms in diagnosis by radiologists in real-life clinical environments have not been reported. The purpose of this study was to evaluate the usefulness of computer-assisted detection in a routine reading environment. MATERIALS AND METHODS: During 39 months in a routine clinical practice environment, 2701 MR angiograms were each read by 2 radiologists by using a computer-assisted detection system. Initial interpretation was independently made without using the detection system, followed by a possible alteration of diagnosis after referring to the lesion candidate output from the system. We used the final consensus of the 2 radiologists as the reference standard. The sensitivity and specificity of radiologists before and after seeing the lesion candidates were evaluated by aneurysm- and patient-based analyses. RESULTS: The use of the computer-assisted detection system increased the number of detected aneurysms by 9.3% (from 258 to 282). Aneurysm-based analysis revealed that the apparent sensitivity of the radiologists' diagnoses made without and with the detection system was 64% and 69%, respectively. The detection system presented 82% of the aneurysms. The detection system more frequently benefited radiologists than being detrimental. CONCLUSIONS: Routine integration of computer-assisted detection with MR angiography for cerebral aneurysms is feasible, and radiologists can detect a number of additional cerebral aneurysms by using the detection system without a substantial decrease in their specificity. The low confidence of radiologists in the system may limit its usefulness.

Structural comparison of the PhoB and OmpR DNA-binding/transactivation domains and the arrangement of PhoB molecules on the phosphate box.

PhoB is a transcriptional activator that binds to the phosphate box in the promoters of the phosphate genes of Escherichia coli. PhoB contains two functional domains, an N-terminal phosphorylation domain and a C-terminal DNA-binding/transactivation domain. Here, the three-dimensional structure of the DNA-binding/transactivation domain has been determined by NMR. It consists of an N-terminal four-stranded beta-sheet, a central three helical bundle and a C-terminal beta-hairpin. The second and third helices form a helix-turn-helix (HTH) variant containing a longer turn than the corresponding turn of the classical HTH motif. The overall architecture is very close to that of the OmpR DNA-binding/transactivation domain, however, the conformation of the long turn region of PhoB, a putative interaction site for the RNA polymerase sigma subunit, is entirely different from that of the corresponding turn of OmpR, which interacts with the alpha subunit. In addition, the third helix of PhoB is three amino acid residues longer than the corresponding helix of OmpR. The binding site of PhoB is a TGTCA sequence and the phospahte box contains the two binding sites. NMR studies of the complexes of the PhoB DNA-binding/transactivation domain bound to several different DNA molecules have revealed that two PhoB molecules bind in a tandem array on the phosphate box. In each complex of PhoB the third helix of the DNA-binding/transactivation domain is likely to recognize the TGTCA sequence from the major groove of DNA and the C-terminal beta-hairpin contacts on the minor groove of the 3' site out of the TGTCA sequence in a non-specific manner. The long turn region facing outward is likely to interact with the sigma subunit.

NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains.

Mammalian telomeres are composed of long tandem arrays of double-stranded telomeric TTAGGG repeats associated with the telomeric DNA-binding proteins, TRF1 and TRF2. TRF1 and TRF2 contain a similar C-terminal Myb domain that mediates sequence-specific binding to telomeric DNA. In the budding yeast, telomeric DNA is associated with scRap1p, which has a central DNA-binding domain that contains two structurally related Myb domains connected by a long linker, an N-terminal BRCT domain, and a C-terminal RCT domain. Recently, the human ortholog of scRap1p (hRap1) was identified and shown to contain a BRCT domain and an RCT domain similar to scRap1p. However, hRap1 contained only one recognizable Myb motif in the center of the protein. Furthermore, while scRap1p binds telomeric DNA directly, hRap1 has no DNA-binding ability. Instead, hRap1 is tethered to telomeres by TRF2. Here, we have determined the solution structure of the Myb domain of hRap1 by NMR. It contains three helices maintained by a hydrophobic core. The architecture of the hRap1 Myb domain is very close to that of each of the Myb domains from TRF1, scRap1p and c-Myb. However, the electrostatic potential surface of the hRap1 Myb domain is distinguished from that of the other Myb domains. Each of the minimal DNA-binding domains, containing one Myb domain in TRF1 and two Myb domains in scRap1p and c-Myb, exhibits a positively charged broad surface that contacts closely the negatively charged backbone of DNA. By contrast, the hRap1 Myb domain shows no distinct positive surface, explaining its lack of DNA-binding activity. The hRap1 Myb domain may be a member of a second class of Myb motifs that lacks DNA-binding activity but may interact instead with other proteins. Other possible members of this class are the c-Myb R1 Myb domain and the Myb domains of ADA2 and Adf1. Thus, while the folds of all Myb domains resemble each other closely, the function of each Myb domain depends on the amino acid residues that are located on the surface of each protein.

Comprehensive sequence analysis of translation termination sites in various eukaryotes.

Recent investigations into the translation termination sites of various organisms have revealed that not only stop codons but also sequences around stop codons have an effect on translation termination. To investigate the relationship between these sequence patterns and translation as well as its termination efficiency, we analysed the correlation between strength of consensus and translation efficiency, as predicted according to Codon Adaptation Index (CAI) value. We used RIKEN full-length mouse cDNA sequences and ten other eukaryotic UniGene datasets from NCBI for the analyses. First, we conducted sequence profile analyses following translation termination sites. We found base G and A at position +1 as a strong consensus for mouse cDNA. A similar consensus was found for other mammals, such as Homo sapiens, Rattus norvegicus and Bos taurus. However, some plants had different consensus sequences. We then analysed the correlation between the strength of consensus at each position and the codon biases of whole coding regions, using information content and CAI value. The results showed that in mouse cDNA, CAI value had a positive correlation with information content at positions +1. We also found that, for positions with strong consensus, the strength of the consensus is likely to have a positive correlation with CAI value in some other eukaryotes. Along with these observations, biological insights into the relationship between gene expression level, codon biases and consensus sequence around stop codons will be discussed.

"Chemical preconditioning" by 3-nitropropionate reduces ischemia-reperfusion injury in cardiac-arrested rat lungs.

BACKGROUND: Chemical preconditioning was defined as the induction of resistance to massive disruption of energy metabolism through prior chemical suppression of oxidative phosphorylation, by which phenomena similar to those resulting from increased ischemic tolerance as a result of ischemic preconditioning can be induced. It could be induced by the inhibitor of either mitochondrial complex I or II. We investigated whether or not chemical preconditioning by 3-nitropropionate (an inhibitor of the mitochondrial complex II) can suppress ischemia-reperfusion injury in cardiac-arrested lungs, which will be the major problem in lung transplants donated from non-heart-beating cadavers. METHODS AND RESULTS: In an isolated rat lung perfusion model with fresh rat blood as perfusate, administration of 3-nitropropionate (20 mg/kg) immediately before the induction of cardiac arrest attenuated pulmonary dysfunction during reperfusion after 1 hr postmortem warm ischemia and 1 hr cold preservation. 3-Nitropropionate administration reduced the mitochondrial respiratory functions (state 3 and state 4 respiration, and the respiratory control ratio) before cardiac arrest and kept them at a lower level of activity than when decreased by ischemia alone. 3-Nitropropionate administration also reduced the ATP levels immediately after drug administration. However, 3-nitropropionate did not significantly reduce lipid peroxidation in the lung tissue and mitochondria. CONCLUSIONS: These results demonstrated that chemical preconditioning by 3-nitropropionate administration immediately before cardiac arrest suppressed succinate-related oxidation during postmortem warm ischemia and reduced ischemia-reperfusion injury in cardiac arrested rat lungs.

Paroxysmal discharges on EEG in young autistic patients are frequent in frontal regions.

EEGs were recorded in 86 autistic patients during sleep. Epileptic discharges were observed in 37 cases (43%). Twenty-seven (73%) of these 37 cases had localized spikes, 8 had multiple spike foci, one had generalized spikes, and one had both multiple spike foci and generalized spikes. Forty-seven epileptic discharge foci were registered in 36 cases, the exception being one with generalized spikes. Thirty-six (76.6%) of the registered 47 epileptic discharge foci were in the frontal region, one (2.1%) in the temporal region, 7 (14.1%) in the centro-parietal region, and 3 (6.4%) in the occipital region. Twenty (55.6%) of the 36 frontal spikes were at midline (11 at Fz and 9 at Cz), 8 on the left side, and 8 on the right side. The dipole of midline spikes was in the deep midline frontal region. These results suggest that frontal dysfunctions are important in the mechanism of symptoms in autism.

Partial seizures in two cases of metachromatic leukodystrophy: electrophysiologic and neuroradiologic findings.

This report concerns two cases of metachromatic leukodystrophy presenting partial seizures. One was a 2-year-old boy with a late infantile type and the other a 17-year-old girl with a juvenile type. The former had tonic-clonic seizures on the left with concomitant twitching of the left side of the face and adversive conjugate deviation of the eyes. After a while, his interictal sleep electroencephalogram (EEG) showed spikes in the right central area. The second case had hemiconvulsions on the right side, consisting mainly of tonic flexion of the upper limb followed by clonic flexions, and accompanied by adversive conjugate deviation of the head and eyes. Her ictal EEG showed rhythmic 6- to 7-Hz wave bursts in the left frontal area. To this date, no report has given a detailed discussion of the type of seizures and ictal EEG in metachromatic leukodystrophy. In addition, there have been few detailed reports of magnetic resonance imaging (MRI) in the juvenile type. It is interesting that typical partial seizures were observed in a hereditary metabolic disorder characterized by diffuse demyelination of the white matter, and the pathophysiology is discussed here mainly in relation to MRI findings of the case with the juvenile type.

Somatosensory evoked potentials with a unilateral migration disorder of the cerebrum.

The somatosensory evoked potentials in two children with a unilateral migration disorder (pachygyria) of the cerebrum, which was detected by MRI, were examined in order to evaluate the function of the malformed sensory cortex. A 5-year-old girl had slight left hemiparesis, seizures, and mental retardation, and a 4-month-old boy had left hemiparesis. Neither patient showed distinct sensory disturbance. Short latency somatosensory evoked potentials and somatosensory evoked potentials recordings demonstrated that the early cortical component, N20, was absent and a positive wave appeared on paretic left-hand stimulation. On nonparetic right-hand stimulation, the primary evoked response (N20-P30) of the left hemisphere, which originates in Broadmann area 3b, was almost normal. Multichannel recordings on the scalp of one patient revealed that a positive wave without polarity inversion appeared posterior to the right central sulcus on median nerve stimulation on the paretic side. The radial dipole in the sensory cortex (area 1 or area 3a) or motor cortex (area 4) could have formed the positive/negative biphasic wave in the relatively wide centroparietal area in the present patients. In the case of unilateral cortical dysplasia, the malformed cortex with subnormal function of sensation might induce the change in the early component of somatosensory evoked potentials.

Otoacoustic emission in patients with neurological disorders who have auditory brainstem response abnormality.

Otoacoustic emissions (OAEs) were evaluated in 51 ears of 30 patients with a severe auditory brainstem response (ABR) waveform abnormality. Thirteen ears showed no ABR to click sound of higher intensity than 100 dBSPL (group 1). Fourteen ears exhibited only wave V or a decreased amplitude pattern of ABR (group 2). Twenty-four ears showed a predominant wave I or no wave III pattern (group 3). Almost all the ears with absent ABR showed no OAE, which strongly suggested hearing loss of cochlear origin, although one patient with alternating hemiplegia of childhood exhibited definite OAEs and auditory reactions without ABR. One patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) and her mother in group 2 had OAE abnormalities, which also suggested mild to severe hearing impairment. When OAEs are present, an accompanying ABR abnormality may be produced by brainstem dysfunction of the underlying disorder such as Pelizaeus-Merzbacher disease. There was a significant relationship (chi-square test P<0.001) between the positivity of the distortion product OAE response and the clinical auditory reactions in 24 patients, although their ABR abnormalities did not reflect hearing impairment directly. Careful examination of both audiometry and OAEs might be necessary for further assessment of the hearing function in pediatric patients with neurological disorders and specific auditory nerve disease.

Neuropathology of early-infantile epileptic encephalopathy with suppression-bursts; comparison with those of early myoclonic encephalopathy and West syndrome.

For the critical lesions and pathomechanism of early-infantile epileptic encephalopathy (EIEE) with suppression-bursts, we investigated the brains of EIEE, early myoclonic encephalopathy (EME), and West syndrome (WS) patients using immunohistochemical technique and neuropathological examination. We could compare with the results of these diseases. The EIEE patients had the most severe lesions, which were in the putamen, thalamus, hippocampus as well as the tegmentum of the brainstem. Among the syndromes, EIEE brains showed the most expanded lesions. Tyrosine hydroxylase-immunopositive cells and fibers were not demonstrated in EIEE, but were detected in WS. Reduced tyrosine hydroxylase immunoexpression in the EIEE brains was in the putamen, globus pallidus, and substantia nigra. Tryptophan hydroxylase immunoreactivity was reduced in the three epileptic syndromes, but especially in EIEE. Reduced expression of tyrosine hydroxylase and tryptophan hydroxylase may demonstrate dysfunction of the catecholaminergic and serotonergic neurons. From this study, the lesions in EIEE were widespread, including in the lower brainstem and cerebellum, compared with in EME and WS. Dysfunction of the catecholaminergic and serotonergic systems could be suggested. These characteristic changes may lead to the pathophysiology of EIEE.

Mechanical ventilation care in severe childhood neurological disorders.

Forty-five patients underwent long-term life-sustaining mechanical ventilation care in the Child Neurology Ward, National Center Hospital for Mental, Nervous and Muscular Disorders from 1990 to 2000. Twenty patients had chronic respiratory insufficiency due to neuromuscular disorders, nine of whom underwent home mechanical ventilation care. Nineteen of the 45 patients had chronic respiratory insufficiency due to progressive central nervous system disorders, three of whom underwent home mechanical ventilation care. Six patients with chronic respiratory insufficiency due to the sequelae of transient events were on ventilation, two of whom underwent home mechanical ventilation care. In some patients, especially ones with neuromuscular disorders, mechanical ventilation care is very useful for improving their daily activity and quality of life. In other patients, however, mechanical ventilation care is merely a means of prolonging life without visible improvement of their quality of life. As medical resources are limited, home mechanical ventilation care is a recommended method for patients who need life-sustaining mechanical ventilation care. Considering an individual or social consensus, the indication of long-term life-sustaining mechanical ventilation care for chronic respiratory insufficiency due to severe childhood neurological disorders should be further discussed.

Idiopathic lactic acidemia with developmental delay and type 1 muscle fiber atrophy: report of two patients.

Two infants with generalized muscle hypotonia with mild muscle weakness and markedly delayed developmental milestones, had high lactate levels in serum and cerebrospinal fluid from early infancy. Biochemical and morphologic studies of biopsied muscles disclosed no abnormality except for type 1 fiber atrophy, which was quite different from patients with central nervous involvement with type 2 fiber atrophy. In both patients, the disease was not progressive and lactate levels gradually decreased. Although no metabolic defect was found, these patients probably shared common pathogenetic mechanism.

Siblings of Schwartz-Jampel syndrome with abnormal muscle computed tomographic findings.

Schwartz-Jampel syndrome (SJS) is a disorder characterized by myotonia, joint contractures, skeletal abnormalities, facial dysmorphism and growth retardation. We present two boys of ages 4 and 8 years with SJS. Their clinical, electromyographic and histopathological findings were similar to those described, except for computed tomography (CT) images that revealed diffuse high attenuation in sternocleidomastoid muscles and low attenuation in the paraspinal, quadriceps, sartorius, soleus and gastrocnemius muscles. This is the first report describing abnormal muscle CT findings associated with SJS. Additional studies of muscle CT might help to improve understanding of the pathogenesis of SJS.

Polysomnographic studies of Lesch-Nyhan syndrome.

Three cases of Lesch-Nyhan syndrome (LNS) were examined by polysomnography to assess the brainstem function, and to determine the causes of the neurological manifestations and sudden death in this syndrome. In the two older cases, the amount of slow wave and rapid eye movement (REM) sleep, the REM density and the frequency of REM bursts were decreased. In the youngest case, symmetrical phasic movements of all four limbs were observed at all sleep stages other than REM sleep. Although movements other than these symmetrical body movements appeared to be normal in this case, the frequency of twitch movements showed an abnormal pattern in each sleep stage in the two older cases. These findings suggest that in the brainstems of younger cases with LNS the REM-non REM generator as well as multiple neurotransmitter systems influencing body movements during sleep remain relatively normal, but become progressively impaired in adult cases. Severe obstructive apnea was observed in one case with hypothyroidism, but there were no respiratory abnormalities in other two cases.

Study of the maturation of the child's brain using 31P-MRS.

The maturation of human cerebrum and cerebellum in 37 normal children aged 4 months to 13 years 8 months was evaluated by 31P-magnetic resonance spectroscopy using two different conditions of repetition time (TR) (TR = 3 seconds and 15 seconds) in each region. The results were as follows. First, the PME/PDE, PCr/gamma-ATP and Pi/PCr ratios differed between the cerebrum and the cerebellum. The PME/PDE and PCr/gamma-ATP ratios were greater in the cerebellum than in the cerebrum. However, the Pi/PCr ratio was smaller in the cerebellum than in the cerebrum. At TR = 3 seconds, the ratio of (PME/PDE ratio in the cerebellum)/(PME/PDE ratio in the cerebrum) and the ratio of (PCr/gamma-ATP ratio in the cerebellum)/(PCr/gamma-ATP ratio in the cerebrum) manifested a nearly constant value independent of age. Second, the phosphomonoester peak in the cerebrum contained a substance with a longer relaxation time than 3 seconds; this substance was present in large amounts in the early period, then gradually decreased during maturation.

Pentobarbital therapy for status epilepticus in children: timing of tapering.

Three children with refractory status epilepticus, unresponsive to intravenous administration of diazepam, phenytoin, and lidocaine, received pentobarbital therapy and were monitored by electroencephalography (EEG). They required mechanical ventilation and vasopressor therapy. Intravenous pentobarbital therapy was successful and without distinct sequelae in all 3 patients, and could be incrementally discontinued without breakthrough seizures after 12-65 hours of a burst-suppression or complete suppression pattern on EEG. Obtaining a suppression pattern was important for controlling status epilepticus in children as well as adults. We suggest that 12 hours after a burst-suppression pattern is obtained, tapering of pentobarbital should be attempted to avoid serious complications of extended pentobarbital anesthesia (e.g., respiratory depression, hypotension, pneumonia).

MRI and CT findings in Krabbe disease.

The progression and characteristics of magnetic resonance imaging (MRI) and computed tomographic (CT) findings in 3 patients with infantile Krabbe disease (i.e., globoid cell leukodystrophy or galactocerebroside beta-galactosidase deficiency) are reported. We obtained initial CT and MRI studies when patients demonstrated hyperirritability and hypertonicity. The following results facilitated early diagnoses: increased density in the thalami, corona radiata, and cerebellar cortex on CT and plaque-like, high signal intensity in the periventricular region and cerebellar white matter on MRI T2-weighted images. After severe motor and mental deterioration and spasticity had developed, progressive brain atrophy, low density in the white matter, and calcification-like, symmetric, punctate high-density areas in the corona radiata were evident on CT and high signal intensity in T2-weighted images and low signal intensity in T1-weighted images in the white matter were present on MRI. In particular, linear patterns were observed in the centrum semiovale on MRI.

A case of Noonan syndrome with cortical dysplasia.

We report the case of a 20-year-old woman with Noonan syndrome. She had severe mental retardation and intractable epilepsy. Magnetic resonance imaging revealed dilated perivascular spaces and a dysplastic lesion in the left temporal lobe, which is thought to have caused her neurologic symptoms. These findings suggest that neuronal in addition to somatic migration can be impaired in Noonan syndrome.