Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning.

Free Water Imaging is a novel diffusion magnetic resonance (MR) imaging method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, its clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MR imaging data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared with healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. We believe this is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.

Hippocampal subregion volume changes associated with antipsychotic treatment in first-episode psychosis.

BACKGROUND: Hippocampal dysfunction is considered central to many neurobiological models of schizophrenia, yet there are few longitudinal in vivo neuroimaging studies that have investigated the relationship between antipsychotic treatment and morphologic changes within specific hippocampal subregions among patients with psychosis. METHOD: A total of 29 patients experiencing a first episode of psychosis with little or no prior antipsychotic exposure received structural neuroimaging examinations at illness onset and then following 12 weeks of treatment with either risperidone or aripiprazole in a double-blind randomized clinical trial. In addition, 29 healthy volunteers received structural neuroimaging examinations at baseline and 12-week time points. We manually delineated six hippocampal subregions [i.e. anterior cornu ammonis (CA) 1-3, posterior CA1-3, subiculum, dentate gyrus/CA4, entorhinal cortex, and fimbria] from 3T magnetic resonance images using an established method with high inter- and intra-rater reliability. RESULTS: Following antipsychotic treatment patients demonstrated significant reductions in dentate gyrus/CA4 volume and increases in subiculum volume. Healthy volunteers demonstrated non-significant volumetric changes in these subregions across the two time points. We observed a significant quadratic (i.e. inverted U) association between changes in dentate gyrus/CA4 volume and cumulative antipsychotic dosage between the scans. CONCLUSIONS: This study provides the first evidence to our knowledge regarding longitudinal in vivo volumetric changes within specific hippocampal subregions in patients with psychosis following antipsychotic treatment. The finding of a non-linear relationship between changes in dentate gyrus/CA4 subregion volume and antipsychotic exposure may provide new avenues into understanding dosing strategies for therapeutic interventions relevant to neurobiological models of hippocampal dysfunction in psychosis.

An improved procedure for low-temperature embedding of high-pressure frozen and freeze-substituted plant tissues resulting in excellent structural preservation and contrast.

Here we describe refinements in the processing of high-pressure frozen samples of delicate plant tissues for immuno-electron microscopy. These involve: shortened freeze-substitution schedules, lower temperatures during processing and polymerisation, the avoidance of temperature fluctuations and the optimisation of heat transfer from the specimens using small disposable aluminium containers. The application of these modifications leads to very good structural preservation and selective membrane contrast. As a result, the versatility of the method is increased since not only immuno-electron microscopical studies can be performed but often the quality is also quite suitable for structural investigations.

ERES (ER exit sites) and the "secretory unit concept".

The higher plant Golgi apparatus consists of hundreds of individual Golgi stacks which move along the cortical ER, propelled by the actomysin system. Anterograde and retrograde transport between the endoplasmic reticulum (ER) and the plant Golgi occurs over a narrow interface (around 500 nm) and is generally considered to be mediated by COP-coated vesicles. Previously, ER exit sites (ERES) have been identified on the basis of to localization of transiently expressed COPII-coat proteins. As a consequence it has been held that ERES in higher plants are intimately associated with Golgi stacks, and that both move together as an integrated structure: the "secretory unit". Using a new COPII marker, as well as YFP-SEC24 (a bona fide COPII coat protein), we have made observations on tobacco leaf epidermis at high resolution in the CLSM. Our data clearly shows that COPII fluorescence is associated with the Golgi stacks rather than the surface of the ER and probably represents the temporary accumulation of COPII vesicles in the Golgi matrix prior to fusion with the cis-Golgi cisternae. We have calculated the numbers of COPII vesicles which would be required to provide a typical Golgi-associated COPII-fluorescent signal as being much less than 20. We have discussed the consequences of this and question the continued usage of the term "secretory unit".

Vacuolar storage proteins are sorted in the cis-cisternae of the pea cotyledon Golgi apparatus.

Developing pea cotyledons contain functionally different vacuoles, a protein storage vacuole and a lytic vacuole. Lumenal as well as membrane proteins of the protein storage vacuole exit the Golgi apparatus in dense vesicles rather than in clathrin-coated vesicles (CCVs). Although the sorting receptor for vacuolar hydrolases BP-80 is present in CCVs, it is not detectable in dense vesicles. To localize these different vacuolar sorting events in the Golgi, we have compared the distribution of vacuolar storage proteins and of alpha-TIP, a membrane protein of the protein storage vacuole, with the distribution of the vacuolar sorting receptor BP-80 across the Golgi stack. Analysis of immunogold labeling from cryosections and from high pressure frozen samples has revealed a steep gradient in the distribution of the storage proteins within the Golgi stack. Intense labeling for storage proteins was registered for the cis-cisternae, contrasting with very low labeling for these antigens in the trans-cisternae. The distribution of BP-80 was the reverse, showing a peak in the trans-Golgi network with very low labeling of the cis-cisternae. These results indicate a spatial separation of different vacuolar sorting events in the Golgi apparatus of developing pea cotyledons.

Brefeldin A action and recovery in Chlamydomonas are rapid and involve fusion and fission of Golgi cisternae.

CHLAMYDOMONAS NOCTIGAMA has a non-motile Golgi apparatus consisting of several Golgi stacks adjacent to transitional ER. These domains are characterized by vesicle-budding profiles and the lack of ribosomes on the side of the ER proximal to the Golgi stacks. Immunogold labelling confirms the presence of COPI-proteins at the periphery of the Golgi stacks, and COPII-proteins at the ER-Golgi interface. After addition of BFA (10 microg/ml) a marked increase in the number of vesicular profiles lying between the ER and the Golgi stacks is seen. Serial sections of cells do not provide any evidence for the existence of tubular connections between the ER and the Golgi stacks, supporting the notion that COPI- but not COPII-vesicle production is affected by BFA. The fusion of COPII-vesicles at the CIS-Golgi apparatus apparently requires the presence of retrograde COPI-vesicles. After 15 min the cisternae of neighbouring Golgi stacks begin to fuse forming "mega-Golgis", which gradually curl before fragmenting into clusters of vesicles and tubules. These are surrounded by the transitional ER on which vesicle-budding profiles are still occasionally visible. Golgi remnants continue to survive for several hours and do not completely disappear. Washing out BFA leads to a very rapid reassembly of Golgi cisternae. At first, clusters of vesicles are seen adjacent to transitional ER, then "mini Golgis" are seen whose cisternae grow in length and number to produce "mega Golgis". These structures then divide by vertical fission to produce Golgi stacks of normal size and morphology roughly 60 min after drug wash-out.

PIP1 Aquaporins Are Concentrated in Plasmalemmasomes of Arabidopsis thaliana Mesophyll.

The PIP1 subfamily of water channel proteins (aquaporins) constitute about 1% of the plasma membrane (PM) proteins from Arabidopsis thaliana leaves. Immunogold electron microscopy has confirmed their localization at the PM of mesophyll cells. Very high labeling density at PM invaginations known as plasmalemmasomes was observed. Therefore, we suggest that these subcellular structures are involved in water transport between the apoplast and the vacuole.

Dictyosome-endoplasmic reticulum associations in higher plant cells? A serial-section analysis.

Serial sections through permanganate and glutaraldehyde/osmium fixed dictyosomes from suspension cultured sycamore cells and maize root cap cells have been analyzed. The results may be summarized as follows. For both sycamore and maize dictyosomes are: 1. transition vesicles between ER and dictyosome, and therefore a "forming face" to the dictyosome, not present. 2. direct, tubular ER-cisternal connections doubtful, if at all present; 3. "Maturing faces" to dictyosomes, i.e. a polarity in terms of the pinching-off of secretory vesicles, not a typical feature; 4. two types of vesicle associated with the dictyosome: large and small (in part "coated"); 5. cisternae present as a flattened, continuous central portion at whose periphery an extensive, anastomosing tubule system exists; 6. cisternae in the dictyosome stack not concentrically arranged, but lie somewhat displaced to one another. A characteristic feature of maize dictyosomes, in addition, is a bi- or unilateral distribution of hypertrophied slime vesicles. The kidney-shaped slime vesicles are arranged opposite to one another at the tubular periphery of a cisternae; the region in between is occupied with smaller, occasionally coated, vesicles. It would appear from these results that the endomembrane concept sensu strictu [58] is not applicable to higher plant cells whose main secretory product is polysaccharide rather than protein. Consequences and alternatives in relation to membrane-flow in such cells are discussed.

The ionic sensitivity of secretion-associated organelles in root cap cells of maize.

Ionophores selective for Na+ (monensin, dianemycin), for K+ (valinomycin, nigericin), for Ca2+ (A23 187, X-537A), the calcium deregulatory substances amiprophosmethyl, fluphenazine, caffeine and the chelator EGTA have been applied to intact slime-producing root tips. An accumulation of secretory vesicles within the cells is observed after treatments up to 3 h by all of these agents. Occasionally the vesicles fuse with one another producing an internal "secretion vacuole". Secretory vesicles may or may not remain attached to the dictyosomes but in all cases the cisternae lengthen, ending most often in a cup-shaped form. Application of ionophore plus a 5 mM chloride solution of the corresponding cation had the same effect as treatment with the ionophore alone. These effects are reversible upon withdrawal of the "ion-deregulatory" agents.

Structure, synthesis and orientation of microfibrils. VII. Microtubule reassembly in vivo after cold treatment in Oocystis and its relevance to microfibril orientation.

A large reduction in cortical microtubule number occurs upon maintaining cultures of O. solitaria at 1 degrees C. Returning the cultures to 25 degrees C results in a rapid (15 min) recovery of the microtubule population. This feature is discussed in terms of the structural and synthetic requirements of a microfibril orientation model.

Structure, synthesis, and orientation of microfibrils. IX. A freeze-fracture investigation of the Oocystis plasma membrane after inhibitor treatments.

Cells of Oocystis solitaria after treatment with inhibitors of a) microfibril orientation b) microfibril synthesis, and c) microfibril crystallization have been investigated with the freeze-fracturing technique. Changes in morphology of the E-face of the plasma membrane as a result of these treatments have been recorded. Terminal complexes are removed by cycloheximide, but not by colchicine or congo red treatments. Microfibril imprints are removed by congo red but not by colchicine or cycloheximide treatments. Congo red induces in addition the presence of increased numbers of paired, thickened, terminal complexes. Prolonged (4-6 h) treatment with congo red causes the insertion of a second set (oriented at 90 degrees to the first set) of parallel terminal complexes in the E-face. These results are discussed in relation to plasma membrane turnover.

Structure, synthesis and orientation of microfibrils. VI. The role of ions in microfibril deposition in Oocystis solitaria.

The action of a series of chelators, cryptates and ionophores on microfibril deposition and the presence of cortical microtubules in Oocystis solitaria has been investigated. Having a potent inhibitory effect on cellulose synthesis were the calcium ionophores A 23187 and X-537A, the flourescent calcium chelator chlorotetracycline and the cryptates 211 and 221. Only at unphysiological concentrations, e.g. 100 mM or more, were the chelators EDTA and EGTA effective in completely inhibitory cellulose synthesis. A reduction in the rate of cellulose synthesis was observed with the sodium-selectiv ionophore dianemycin. This partial inhibition was independent of the ionophore concentration. Without effect on microfibril deposition were the potassium-selective ionophore valinomycin and cryptate 222. In all cases, whether cellulose synthesis is blocked or not, none of the above agents prevented the reassembly of cortical microtubules when applied during the recovery from colchicine treatment. Destruction of cortical microtubules through the calcium ionophore may be achieved, but only when additional (2 mM) calcium is added to the culture medium.

Studies on the contractile vacuole of Poterioochromonas malhamensis Peterfi. II. Antimonate stains the contractile vacuole of Poterioochromonas.

Fixation of the chrysophycean flagellate Poterioochromonas malhamensis in the presence of potassium (pyro) antimonate have been carried out. Intense antimonate deposits are characteristic of the various elements of the contractile vacuole as well as a portion of the plasma membrane adjacent to the contractile vacuole. Neither pretreatment of the cells with EGTA or EDTA nor the treatment of sections with these chelators is successful in removing the antimonate precipitates. Despite this, X-ray microanalyses of these deposits indicate the presence of calcium.

Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder.

OBJECTIVE: This study examined the treatment response of patients with first-episode schizophrenia and schizoaffective disorder and potential predictors of response. METHOD: First-episode patients were assessed on measures of psychopathology, cognition, social functioning, and biological parameters and treated according to a standardized algorithm. RESULTS: One hundred eighteen patients (52% male, mean age 25.2 years) entered the study. The cumulative percentage of patients responding by 1 year was 87%; the median time to response was 9 weeks. The following variables were significantly associated with less likelihood of response to treatment: male sex, obstetric complications, more severe hallucinations and delusions, poorer attention at baseline, and the development of parkinsonism during antipsychotic treatment. Variables not significantly related to treatment response were diagnosis (schizophrenia versus schizoaffective disorder), premorbid functioning, duration of psychotic symptoms prior to study entry, baseline disorganization, negative and depressive symptoms, baseline motor function, akathisia and dystonia during treatment, growth hormone and homovanillic acid measures, psychotic symptom activation to methylphenidate, and magnetic resonance measures. CONCLUSIONS: Patients with first-episode schizophrenia and schizoaffective disorder have high rates of response to antipsychotic treatment; there are specific clinical and pathobiologic predictors of response.

Delusional depression. A one year follow-up.

Fifty-two unipolar delusional depressives were matched to 52 unipolar nondelusional depressives on the basis of sex, age at index episode of depression and age at first episode of depression. In a one year follow-up after discharge from inpatient treatment, the delusional depressives had a poorer clinical course than the nondelusional depressives as manifested by significantly higher rates both of major depression or delusions lasting longer than 9 months and of being in a major depressive episode at the end of the follow-up period.

Side effects of antipsychotic drugs. Avoiding and minimizing their impact in elderly patients.

Antipsychotic drugs are very useful in treatment of psychosis and severe agitation in the elderly. Their use for other behavioral problems is contraindicated. Antipsychotics have many potential side effects (e.g., sedation, cardiovascular effects, anticholinergic effects, incontinence, reduced appetite, such motor disturbances as drug-induced parkinsonism, akathisia, dystonia, TD). Prevention, by using the minimum dose and duration of treatment possible, is the key to managing motor side effects. If prevention fails, drug-induced parkinsonism and dystonia may improve with use of anticholinergics, and akathisia may improve with use of benzodiazepines or low-dose propranolol. There is no proven treatment for TD, which is most likely to be observed during dose reduction or after discontinuation of antipsychotic drugs. Compared with older agents, newer antipsychotic drugs are less likely to cause parkinsonism, akathisia, and dystonia and may cause TD less often. More research is needed to clarify use of the new drugs in the elderly.