A controlled study of brain structure in monozygotic twins concordant and discordant for schizophrenia.

BACKGROUND: We examined monozygotic twins concordant and discordant for schizophrenia to clarify the role of genetic and environmental factors in determining brain abnormalities. METHODS: Magnetic resonance imaging brain scans were obtained from 14 monozygotic twin pairs concordant and 10 monozygotic pairs discordant for schizophrenia, as well as 17 pairs of monozygotic control twins. Twenty-two discordant sibling-pairs and 56 pairs of unrelated control subjects were included to assess the extent of genetic control over these structures. RESULTS: Within-pair similarities for whole brain volume increased as pair members were more closely related genetically (monozygotic twins > siblings > unrelated control subjects). Schizophrenic twins, whether from concordant or discordant pairs, had smaller whole brain volumes than control twins. The probands of discordant pairs showed more abnormalities in hippocampal, third and lateral ventricular volumes than concordant twins. CONCLUSIONS: Whole brain volume is under high genetic control and smaller whole brain volume is a reflection of the genetic liability to develop schizophrenia. The variation in hippocampal and ventricular volumes within discordant monozygotic pairs indicates a role for environmental factors in determining these volume abnormalities in schizophrenia. Such factors may also underlie the more extensive morphometric deviations in patients from monozygotic discordant twins than in their counterparts from concordant twins.     

A New Heterozygous Mutation (R714C) of the Osteopetrosis Gene,Pleckstrin Homolog Domain Containing Family M (With Run Domain) Member 1 (PLEKHM1), Impairs Vesicular Acidification and Increases TRACP Secretion in Osteoclasts

We studied phenotypic and cellular aspects in a patient with a heterozygous mutation of the PLEKHM1 gene and obtained some indications regarding the role of the protein in bone cell function. Plekhm1 is involved in osteoclast endosomal vesicle acidification and TRACP exocytosis, contributing to events involved in osteoclast–osteoblast cross‐talk. Introduction: The gene PLEKHM1 encodes a nonsecretory adaptor protein that localizes to endosomal vesicles. A highly truncated Plekhm1 protein was previously found in a patient with intermediate autosomal recessive osteopetrosis. Materials and Methods: We describe a new heterozygous mutation in the PLEKHM1 gene in a patient presenting with low vertebral and femoral T‐scores and areas of focal sclerosis. Clinical evaluation, mutational analysis, assessment of in vitro osteoclast morphology and activity, transfection studies, and evaluation of osteoclast–osteoblast cross‐talk were carried out. Results: Direct DNA sequencing showed a heterozygous C to T substitution on cDNA position 2140 of the PLEKHM1 gene, predicted to lead to an R714C mutant protein. The mutation was not found in 104 control chromosomes. In vitro, patient's osteoclasts showed normal formation rate, morphology, number of nuclei, and actin rings but lower TRACP activity and higher endosomal pH than control osteoclasts. The patient had high serum PTH and TRACP, despite low TRACP activity in osteoclasts in vitro. HEK293 cells overexpressing either wildtype or Plekhm1‐R714C showed no difference in localization of the variants, and co‐transfection with a TRACP vector confirmed low TRACP activity in cells carrying the R714C mutation. RAW 264.7 osteoclast‐like cells expressing the Plekhm1‐R714C variant also showed low TRACP activity and reduced ability to acidify endosomal compartments compared with cells expressing the wildtype protein. Reduced intracellular TRACP was caused by increased protein secretion rather than reduced expression. TRACP‐containing conditioned medium was able to increase osteoblast alkaline phosphatase, suggesting the focal osteosclerosis is a result of increased osteoclast–osteoblast coupling. Conclusions: We provide further evidence for a role of Plekhm‐1 in osteoclasts by showing that a novel mutation in PLEKHM1 is associated with a complex bone phenotype of generalized osteopenia combined with “focal osteosclerosis.” Our data suggest that the mutation affects endosomal acidification/maturation and TRACP exocytosis, with implications for osteoclast–osteoblast cross‐talk.     

Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity

Administration of sulpiride (2 × 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites (B_max) for [³H]spiperone, [³H]N,n-propylnorapomorphine and [³H]sulpiride. Neither drug altered the dissociation constant (K_D) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.     

Anthracyclic products from Streptomyces erythromogenes nov. sp. Biotransformation of daunomycin (Dn) by an acellular preparation and synergism between Dn and some known antibiotics

The filtrate broth as well as mycelium of the new strain Streptomyces erythrochromogenes nov. sp. isolated from Saudi Arabian soil, produce the antitumor antibiotic daunomycin 1 and two anthracyclic derivatives: 7-deoxy 13-dihydrodaunomycinone 2 and 7-deoxy daunomycinone 4 . The biotransformation of 1 to 2 and 4 by an acellular enzyme preparation from the strain was found to be NADPH and/or NADH dependent. Mixtures of daunomycin 1 with chloramphenicol or penicillin showed superior antimicrobial activities against Bacillus subtilis ICC strain, than the individual antibiotics.     

Integrins and adhesion molecules: Is vitronectin the velcro that binds the gametes together?

Evidence has been presented that the adhesion of human spermatozoato the oolemma is mediated by integrins recognizing the Arg-Gly-Aspsequence (RGD). Fibronectin and vitronectin, glycoproteins thatcontain functional RGD sequences, are both present on humanspermatozoa, and integrins that recognize these ligands havebeen detected on spermatozoa and eggs. In this work, we studiedthe effects of oligopeptides specifically designed to blockfibronectin or vitronectin receptors on the interaction of humanspermatozoa with zona-free hamster oocytes. GRGDdSP, a peptideblocking cell attachment to fibronectin, was without effect,while GdRGDSP, which blocks both fibronectin and vitronectinreceptors, significantly inhibited the binding of human spermatozoato the oolemma of zona-free hamster eggs, in a concentration-dependentmanner, over a range 1–100 µM. As these experimentssuggested that a vitronectin receptor plays a role in sperm-oolemmaladhesion, we performed a series of experiments studying theeffects of exogenous vitronectin, when added to spermatozoaand oocytes, on gamete interactions. Sperm-oolemmal adherence,as well as sperm aggregation, was promoted by vitronectin, overa range of 2.2 nM to 1 µM, but only in the presence ofcalcium ions. We propose that vitronectin released during thesperm acrosome reaction is recognized by both gametes and playsa role in their adhesion. adhesion/gametes/vitronectin     

Purkinje cells in the lateral cerebellum of the cat encode visual events and target motion during visually guided reaching

In this study the receipt of visual information by the lateral cerebellum and its contribution to a motor output was studied using single unit recording of cerebellar cortical neurones in cats trained to perform visually guided reaching. The activity of Purkinje cells and other cortical neurones in the lateral cerebellum was investigated in relation to various aspects of the task, such as visual events, parameters of target movement, and limb and eye movements. Two-thirds (66%) of Purkinje cells tested could signal simple visual events, such as a flash of light. Neurones were also capable of detecting other less potent, but behaviourally important visual events, such as a 'GO' signal (LED brightening). Half of the cells tested were responsive to the on-going motion of the visual target, displaying tonically altered discharge rates for as long as it was moving, and a 'preferred' target velocity. A small proportion of cells showed short latency visual modulation that persisted during the forelimb reach. Anatomical tracing studies confirmed that the recordings were obtained from the D1 zone of crus I. In summary, cells in this region of lateral cerebellar cortex perform simple visual functions, such as event detection, but also more complex visual functions, such as encoding parameters of target motion, and their visual responsiveness is appropriate for a role in accurate visually guided reaching to a moving target.     

The Surface Phenotype of Lymphatic Leukemia, Cells: An Immunoscanning Electron Microscopy Study

Bone-marrow cells from 11 cases of T- and 18 cases of B-lymphatic leukemia, at different maturation stages, were examined by scanning electron microscope (SEMI. All cases were extensively studied for the expression of surface markers by immunofluorescence. In addition six cases of T- and 10 cases of B-cell leukemia were labeled with a panel of monoclon;tl antibodies (including CD3, CD5, CD7, CD10, CD4, CD8, CD19, CD20 and CD22) and, after incubation with a colloidal gold conjugate, observed with SEM in the back-scattered electron imaging mode. Early stages of leukemic lymphoid B- and T-cell differentiation are characterized by prevalently smooth cell surfaces. Short stub-like microvilli constantly appear on more mature T cells, while complex surface features like small ruffles and pleomorphic microvilli are present in well-differentiated B-cell proliferations. Surface microvilli can be interpreted als structural features of lymphoid cells, progressively expressed with maturation and differentiation of leukemic as well as normal cells.     

Increase in the chronically monitored cerebrospinal fluid pressure after experimental brain injury in rats

The early effects of experimental brain injury with diffuse axonal lesions on intracranial pressure (ICP), mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) in rats have been already studied. The aim of this experiment was to examine the effects of brain injury on ICP, MAP and CPP during the first few days post-injury. In order to do that, an accurate technique of ICP measurement had to be developed. In a series of eight rats, a translumbar intrathecal catheter (TIC) was surgically introduced allowing repeated measurements of cerebrospinal fluid pressure (CSFP). Under anaesthesia, a second series of nine rats were equipped simultaneously with TIC and an intracranial fiberoptic device to measure ICP. Simultaneous measurements of CSFP and ICP were recorded for baseline values, than during and after jugular compression which was intended to induce an acute and significant increase in ICP. A third series of 53 rats having TIC received an experimental severe brain injury. MAP was measured non-invasively and CPP was calculated as CPP MAP. CSFP, MAP and CPP were intermittently measured during 5-6 post-traumatic days and compared to the values obtained during ten control rats (SHAM). A clinical score was used to compare clinical condition. The results showed that the translumbar CSFP accurately measured ICP in rats having normal or acutely increased ICP. The experimental brain injury induced increased CSFP lasting up to 5-6 days, with increased MAP during the first 6hours. CPP values were compromised at 24-48hours. The clinical performance was reduced in the brain injured rats. The translumbar technique of CSFP measurement reflected exact ICP in normal and acutely increased ICP in rats. Experimental brain injury with diffuse axonal lesions can increase lumbar CSFP in rats for many days.