Prenatal ß-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a ß-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the ß-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.

Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity.

Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.

Xenopus Xenf: an early endodermal nuclear factor that is regulated in a pathway distinct from Sox17 and Mix-related gene pathways.

We report a novel zygotic gene encoding a Xenopus endodermal nuclear factor, Xenf. Expression of Xenf starts at the late blastula stages and is decreased after gastrulation. Xenf shows no structural homology to any known proteins. When GFP-tagged Xenf is overexpressed in Xenopus cells, Xenf protein is localized to the nucleus, associating closely with the chromosomes. In animal cap assays, Xenf expression is strongly activated by mRNA injection of Vg1 and VegT, maternal vegetal genes that can induce endodermal differentiation. In contrast, Xenf is not induced by endoderm-inducing zygotic transcription factors such as Sox17 and Mix-related genes. In turn, Xenf does not activate expression of Sox17, Mixer or Milk. Thus, Xenf is regulated by maternal vegetal positional information in a parallel manner to Sox17 and Mix-related gene pathways.

Clinical experience of intraorbital optic nerve sheath meningioma--report of eight cases.

Eight cases of primary optic nerve sheath meningioma were treated between 1980 and 1988. Five were females aged 37-61 years. The other three were two boys, one with neurofibromatosis, and an old male aged 71 years. They were first seen by the ophthalmologist with complaints of unilateral progressive visual loss or proptosis. Although blindness of the affected eye mainly occurred between 1 month and 3 years after the initial symptoms, the diagnosis tended to be made late in the adult cases. Intracranial extension was demonstrated in four of the six adult cases when contralateral visual loss or disturbance of consciousness presented. Larger intraorbital meningiomas were easily diagnosed by a combination of computed tomographic (CT) scanning, magnetic resonance (MR) imaging, and carotid angiography. MR imaging provided clear delineation of the optic nerve and its course through the tumor, and perioptic meningioma could be diagnosed. However, it was difficult to make a diagnosis without biopsy at the early stage, for example, when just the enlargement of the optic nerve was demonstrated by CT or MR imaging. Tumor removal was performed when blindness developed after definitive diagnosis by biopsy, intracranial extension was demonstrated, and advanced proptosis presented. The transcranial supraorbital approach or transcranial transorbital approach with resection of the supraorbital rim was used for these large intraorbital meningiomas. From our clinical experience, early diagnosis and early treatment should be emphasized.

Clinicoanatomical study of thalamic stimulation for pain relief.

Our small experiences with electrical stimulation in the VPL and VPM for dysesthetic pain show that it provoked only paresthesia and induced some relief of pain. It does not increase the beta-endorphin level in CSF. To clarify the anatomical substrata in VPL stimulation, neuroanatomical studies were done about the inputs to VPL in man, monkey and cat by the Fink-Heimer method. The spinothalamic tract terminates in VPL in a patchy fashion in the monkey. The corticothalamic fibers from SI and SII cortex project to VPL and VPM in somatotopical organization in the cat. SI and SII cortices have reciprocal connections, in addition to projections to area 5 or SIII cortex. The corticofugal fibers to the magnocellular and gigantocellular tegmental fields are suggested in addition to the dorsal column nuclei, spinal trigeminal nuclei and spinal posterior horn in cat. The medial lemniscus input to VPL and the above neural circuits are thought to be associated with VPL stimulation.

Interstitial chemotherapy with biodegradable ACNU pellet for glioblastoma.

For patients with nonresectable glioblastoma (GB) or recurrent GB, we have recently been using an interstitial chemotherapy with biodegradable polylactic acid pellets containing nimustine chloride (ACNU), in combination with superselective arterial ACNU injection, routine irradiation and chemotherapy. The ACNU pellets are prepared by mixing polylactic acid powder and ACNU, and then melting the mixture at low temperature and moulding it into a thin pellet. Pharmacological anticancer activity was experimentally demonstrated by the finding that a region of suppression was present surrounding an ACNU pellet placed in a B6 melanoma cell culture disc, but that no such suppression was present around a control pellet. In order to determine the spatial and temporal distribution of ACNU, a small pellet (ACNU: 0.6 mg) was implanted in the frontal lobe of rats. ACNU concentration determined by HPLC was 61.0 micrograms/g brain tissue on day 1. 22.5 on day 3, and 5.5 on day 7; small amounts of ACNU were in fact released for at least 4 weeks after implantation. This pellet was used for the clinical treatment of 11 GB patients. Four patients had several pieces of pellets implanted immediately after CT-guided stereotactic biopsy, and the other 7 had pellets placed in residual tumor after partial removal at craniotomy. No ACNU was detectable in serum. CT studies obtained at subsequent appropriate intervals disclosed gas formation around the pellets, a slight increase in edema, and necrosis or decrease in CT enhancement of tumor beginning around day 12 after implantation. Bone marrow suppression did not occur, since ACNU was administered interstitially and in the range of 50-200 mg (average: 126 mg) per patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Location of a DBS-electrode in lateral thalamus for deafferentation pain. An autopsy case report.

Pain relief was obtainable when deep brain stimulation was tried in the sensory thalamic nucleus in a patient with deaffereantation pain to cervical myelopathy. The electrode was histologically verified in post-mortem examination after 20 months and the localization of contact points of the implanted electrode was estimated. The cathode appeared to have been placed in the region from Vim to the rostral border of Vci while the anode was in the medical lemniscus region. Stimulation of the Vim nucleus might have had a pain relieving effects because no facial paraesthesiae was evoked by stimulation. The implanted electrode caused only minor histological changes.

Experimental anatomical considerations of the dorsal root entry zone lesions for pain relief.

Dorsal root entry zone (DREZ) lesions were made in the cervical dorsal horn in cat and monkey. Terminal degeneration was observed in the lateral cervical nucleus in cat and contralateral VPL in monkey by Fink-Heimer stain. WGA-HRP was injected in the cervical dorsal horn of cat and retrograde labelled cells were observed mainly in the raphe nucleus, parabrachial nucleus, locus coeruleus, Kölliker-Fuse nucleus, Eddinger-Westphal nucleus, and hypothalamic area, indicating that these descending fiber systems are involved by the DREZ lesion. The functional role of these fibers in regard to deafferentation pain relief seems now to be open to discussion.

c-fos expression after formalin injection into the face in the cat.

Expression of the c-fos gene in CNS induced by formalin injection into the face as pain stimulus was examined in cats. Fos-positive neurons were demonstrated in the anterior cingulate, anterior insula and other areas of the cerebral cortex bilaterally, midline thalamic nuclei, hypothalamus, and brainstem in both the formalin-injected and control group (anesthesia only). Most of these labeled regions appeared to correspond to stress- and anesthesia-related sites. The difference from the control was the finding of Fos-positive cells in the SI, possible SII and trigeminal subnucleus caudalis in the experimental group. Almost significant increase in Fos-positive cells was also observed in areas 24, 23 and the anterior agranular insular cortex in experimental cats. Our findings appear to be compatible with recently reported PET findings in man, except laterality. For full appreciation of the complex pain experience, these diverse areas of the brain appear to be activated.

Xenopus kielin: A dorsalizing factor containing multiple chordin-type repeats secreted from the embryonic midline.

The midline tissues are important inductive centers of early vertebrate embryos. By signal peptide selection screening, we isolated a secreted factor, Kielin, which contains multiple cys-rich repeats similar to those in chordin (Chd). Expression of Kielin starts at midgastrula stages in the notochord and is detected in the floor plate of neurula embryos. Kielin is induced in mesoderm and in ectoderm by nodal-related genes. Chd is sufficient to activate Kielin expression in mesoderm whereas Shh or HNF-3beta in addition to Chd is required for induction in ectoderm. Kielin has a distinct biological activity from that of Chd. Injection of Kielin mRNA causes dorsalization of ventral marginal zone explants and expansion of MyoD expression in neurula embryos. Unlike Chd, Kielin does not efficiently induce neural differentiation of animal cap ectoderm, suggesting that the activity of Kielin is not simply caused by BMP4 blockade. Kielin is a signaling molecule that mediates inductive activities of the embryonic midline.

Remote subarachnoid haemorrhage in the posterior fossa following supratentorial surgery. Clinical observation of 6 cases.

Haemorrhage in regions remote from the site of following intracranial operations is rare, but they do occur. We performed supratentorial craniotomy on 639 patients between the time of introduction of computed tomography (CT) for clinical use in 1983 and June 1992; subarachnoid haemorrhage (SAH) in the posterior fossa occurred postoperatively in six of these cases. These included four patients with tumours in the sellar region, one with an arteriovenous malformation (AVM) and one who underwent superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis. The ages of the six patients ranged from 17-72 years. Haemorrhage occurred on the day of operation in one case and was detected on CT examination on the day following surgery in the remaining five cases. Of three patients with disturbance of consciousness, two underwent suboccipital craniectomy for reduction of intracranial pressure, while one received barbiturate therapy and later underwent cerebrospinal fluid (CSF) shunt surgery. No special treatment was necessary for the remaining three patients with less serious lesions. Five of the six patients ultimately recovered their pre-operative neurological status apart from the primary diseases. Factors inducing such haemorrhages seem likely to include displacement of the cerebellum by reduced CSF pressure during and after operations, and stretching and tearing of the veins and venules in the sulci of the tentorial surface of the cerebellum. Consideration should therefore be given to the maintenance of an appropriate CSF pressure during operation; this is particularly important in elderly patients and those with an atrophied cerebral cortex.

[Anatomo-pathological alterations of the lung in hemorrhagic shock studied with lungs fixed by classical method and when expanded (author's transl)]. / Alterações anátomo-patológicas do pulmäo no choque hemorrágico estudadas com o pulmão fixado de maneira clássica e em expansão.

The authors have studied lungs of 14 dogs that have been submitted to hemorrhagic shock. The right lung was fixed in the ordinary way and the left lung in expansion. They examine preparations of a 11 lobes of both lungs. Vacuolar degeneration of the cells of the terminal bronchioles and the respiratory bronchioles, hypertrophy of the cells of the alveolar sac of mild degree were constant findings. Alveolar edema of some intensity was observed in all preparations. Atelectasias of severe degree were only seen in preparations fixed in the ordinary way.

Comparison of spiramycin and clarithromycin for community-acquired lower respiratory tract infections.

This open multicentre study compared the efficacy and tolerability of clarithromycin and spiramycin in the treatment of lower respiratory tract infections in Brazil and Colombia. A total of 125 patients with a clinical and radiological diagnosis of pneumonia, acute bronchitis or exacerbation of chronic bronchitis were randomised to receive oral doses of either clarithromycin (500 mg) or spiramycin (3 MIU) every 12 hours for courses of 5-10 days. Patients were assessed before the start of treatment, and at days 3-4 and days 9-17. Twenty-six (26) patients (16 in the spiramycin group and 10 in the clarithromycin group) reported adverse events, seven of whom withdrew from the trial. Statistical analysis detected no significant differences between efficacy (p = 0.768) or tolerability (p = 0.236) for the two treatment groups. Spiramycin therefore has similar efficacy to clarithromycin in the treatment of community-acquired lower respiratory tract infections.