Relationship between cerebral interstitial levels of amino acids and phosphorylation potential during secondary energy failure in hypoxic-ischemic newborn piglets

The aim of this study was to determine the validity of the hypothesis that excitatory amino acids are related to phosphorylation potential during primary and secondary cerebral energy failure observed in asphyxiated infants. We report here the results of experiments using newborn piglets subjected to severe transient cerebral hypoxia-ischemia followed by resuscitation. We examined cerebral energy metabolism by phosphorus nuclear magnetic resonance spectroscopy and changes in levels of amino acid neurotransmitters in the cortex by microdialysis before, during, and up to 24 h after the hypoxic-ischemic insult. The concentrations of aspartate, glutamate, taurine, and gamma-aminobutyric acid were significantly elevated during the hypoxic-ischemic insult compared with prebaseline values. Shortly after resuscitation, glutamate, taurine, and gamma-aminobutyric acid concentrations decreased but then began to increase again. These secondary elevations were greater than the primary elevations. A negative linear correlation was found between primary interstitial levels of glutamate and taurine and minimum values of phosphocreatine/inorganic phosphate during the secondary energy failure. The cerebral energy state depended on the time course of changes in excitatory amino acids, suggesting that amino acids play distinct roles during the early and delayed phases of injury.     

Quetiapine treatment for behavioral and psychological symptoms in patients with senile dementia of Alzheimer type

The purpose of this study was to assess the effect of quetiapine in the treatment of behavioral and psychological symptoms of dementia (BPSD) in patients with senile dementia of Alzheimer type (SDAT). Sixteen SDAT patients with BPSD were recruited and quetiapine (25- 200 mg/day) was prescribed for 8 weeks. BPSD were evaluated with the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and Cohen-Mansfield Agitation Inventory (CMAI) at week 0 (baseline) and week 8 (endpoint). The severity of the extrapyramidal symptoms was also assessed by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) at baseline and endpoint. Significant improvements were seen in the CMAI total score and in the BEHAVE-AD subscales of delusions, activity disturbances, aggressiveness, diurnal rhythm disturbances and in the BEHAVE-AD overall severity. There was no significant difference between the baseline and endpoint in the DIEPSS score. These data indicate that quetiapine is effective in controlling BPSD with favorable adverse-event profiles.     

Essential role for ERK2 mitogen-activated protein kinase in placental development

BACKGROUND: Extracellular signal-regulated kinase 2 (ERK2) has been implicated in cell proliferation, differentiation, and survival. However, its role in vivo remains to be determined. RESULTS: Here we show that the targeted disruption of the mouse ERK2 gene results in embryonic lethality by E11.5 and severe abnormality of the placenta. In these animals, the labyrinthine layer of the placenta is very thin and few foetal blood vessels are observed. ERK2 mutants can be rescued by the transgenic expression of ERK2, demonstrating that these abnormalities are caused by ERK2-deficiency. Although ERK2-deficient fetuses are much smaller than wild-type littermates, this seems to be secondary to malfunction of the placenta. When the placental defect is rescued by tetraploid-aggregation, ERK2-deficient foetuses grow as well as littermate controls. CONCLUSION: These observations indicate that ERK2 is essential for placental development and suggest that ERK2 in the trophoblast compartment may be indispensable for the vascularization of the labyrinth.     

Clinical study of weekly paclitaxel administration for metastatic breast cancer based on time to progression (TTP) and survival

We studied 13 women aged 29-62 years for response to weekly administration of paclitaxel for metastatic breast cancer. Paclitaxel was administered by 1-hour intravenous infusion at a dose of 60-80 mg/m2 once a week. Administration was continued for 3 weeks with a 1-week rest for at least 3 cycles. This was first-line treatment in 1 patient, second-line treatment in 7, and third-line treatment in 5. The overall response rate was 68% among 13 partial responders and there were no complete responders. By recurrence site, the response rate was 71% in the liver, 75% in the lung, 18% in bone, and 67% at local sites. Pain was ameliorated in 4 of 8 patients and local recurrence of tumors decreased in 6 of 8 cases. Tumor markers decreased in 6 of 12 cases. Time to progression reached beyond 6 months in 6 of 13 cases, and was limited to within only 3 months in 6 cases. In terms of survival, 4 of 13 patients who were treated by paclitaxel as a 3rd line treatment for liver or lung metastasis died within 3 months after administration. Weekly administration of paclitaxel appears to be effective against metastatic breast cancer. However, the selection of cases based on the timing of administration is considered to be important to prolong the time to progression and improve survival.     

Two types of VIP neuronal components in rat suprachiasmatic nucleus

Vasoactive intestinal peptide (VIP) neurons constitute a large group in the suprachiasmatic nucleus (SCN) and it is thought that they are involved in the generation and entrainment of circadian rhythm. We have characterized these VIP-expressing neurons in rat SCN by their ability to induce the mammalian Period1 (Per1) gene in response to light exposure, innervation of retinal afferents, day-night variations in VIP mRNA, and coexpression of gastrin releasing peptide (GRP). VIP neurons in the ventrolateral SCN (SCNVL) were subdivided into two groups, light-evoked Per1-inducible main SCNVL (SCNVLmain) and non-Per1-inducible medially located SCNVL (SCNVLmed). Retinal innervation was abundant in the SCNVLmain but nearly absent in the SCNVLmed. Day-night variation in VIP mRNA expression level was observed in the SCNVLmain but not in the SCNVLmed. GRP mRNA was seen in rarely SCNVLmed but abundant in SCNVLmain, where some neurons coexpressed VIP mRNA. These findings indicate that VIP neurons in the SCN can be divided into two topographically and functionally distinct groups.     

Anomalous 235U/238U ratios and metal elements detected in the black rain from the Hiroshima A-bomb

Contents of black rain from the A-bomb are important to clarify the health and environmental hazard caused by nuclear warfare. We analyzed the only existing physical remains of the black rain from Hiroshima A-bomb (Little Boy), a plastered wall with black streaks. Excess 137Cs and anomalous 235U/238U ratios detected in the black residues on the wall confirmed that the black streaks on the wall originated from Little Boy. The results also showed that excess 235U could be used as a fingerprint to clarify the distribution of materials discharged from Little Boy into the environment. High concentrations of lead and zinc, which may have caused a degree of heavy metal pollution in the area where the rain fell, were also detected in the black rain sample.     

Additional heterozygous 2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies

Objectives/Hypothesis:

To describe the audiological profiles in a Japanese family with autosomal dominant hereditary sensorineural hearing loss (SNHL) and to identify the causative gene.

Study Design:

A family study at an academic tertiary referral center.

Methods:

A family with autosomal dominant hereditary SNHL was enrolled. Hearing loss (HL) of affected members showed mid‐frequency SNHL in childhood and progressed at lower frequencies with age, resulting in low‐frequency SNHL. To understand the pathology of HL of this family, we performed a genetic analysis of WFS1, TECTA, and GJB2 by direct sequencing, and further audiovestibular examinations, including speech audiometry, distortion product otoacoustic emissions, electrocochleography, auditory brainstem responses, and electronystagmography for some affected members.

Results:

A heterozygous A‐to‐C nucleotide transversion (c.2507A>C), resulting in a lysine‐to‐threonine substitution at codon 836 (K836T) was identified in exon 8 of WFS1. K836T was segregated with HL in the 15 participants in the genetic study but was not detected in the 212 normal chromosomes. Only polymorphic changes were detected in TECTA and GJB2. Audiovestibular examinations indicated purely cochlear HL and normal vestibular function. The summating potential/action potential ratios in electrocochleography increased in the bilateral ears of the proband.

Conclusions:

The family described with autosomal dominant inheritance of K836T of the WFS1 gene demonstrates a progressive hearing loss in the lower frequencies. Laryngoscope, 2010