The New Associationism: A Neural Explanation for the Predictive Powers of Cerebral Cortex

The ability to predict is the most importantability of the brain. Somehow, the cortex isable to extract regularities from theenvironment and use those regularities as abasis for prediction. This is a most remarkableskill, considering that behaviourallysignificant environmental regularities are noteasy to discern: they operate not only betweenpairs of simple environmental conditions, astraditional associationism has assumed, butamong complex functions of conditions that areorders of complexity removed from raw sensoryinputs. We propose that the brain's basicmechanism for discovering such complexregularities is implemented in the dendritictrees of individual pyramidal cells in thecerebral cortex. Pyramidal cells have 5–8principal dendrites, each of which is capableof learning nonlinear input-to-outputtransfer functions. We propose that eachdendrite is trained, in learning its transferfunction, by all the other principal dendritesof the same cell. These dendrites teach eachother to respond to their separate inputs withmatching outputs. Exposed to differentbut related information about the sensoryenvironment, principal dendrites of the samecell tune to functions over environmentalconditions that, while different, arecorrelated. As a result, the cell as awhole tunes to the source of the regularitiesdiscovered by the cooperating dendrites,creating a new representation. When organizedinto feed-forward/feedback layers, pyramidalcells can build their discoveries on thediscoveries of other cells, graduallyuncovering nature's hidden order. Theresulting associative network is powerfulenough to meet a troubling traditionalobjection to associationism: that it is toosimple an architecture to implement rationalprocesses.     

Selective Preparation of trans-Carveol over Ceria Supported Mesoporous Materials MCM-41 and SBA-15

Ce-modified mesoporous silica materials MCM-41 and SBA-15, namely 32 wt % Ce–Si–MCM-41, 16 wt % Ce–H–MCM-41 and 20 wt % Ce–Si–SBA-15, were prepared, characterized and studied in the selective preparation of trans-carveol by α-pinene oxide isomerization. The characterizations of these catalysts were performed using scanning electron microscopy, X-ray photoelectron spectroscopy, nitrogen adsorption and FTIR pyridine adsorption. Selective preparation of trans-carveol was carried out in the liquid phase in a batch reactor. The activity and the selectivity of catalyst were observed to be influenced by their acidity, basicity and morphology of the mesoporous materials. The formation of trans-carveol is moreover strongly influenced by the basicity of the used solvent and in order to achieve high yields of this desired alcohol it is necessary to use polar basic solvent.     

Shortened erythrocyte sedimentation rate evaluation is applicable to hospitalised patients

BackgroundWestergren method, commonly used for erythrocyte sedimentation rate (ESR) determination, is simple and inexpensive. However, the 60 min required for the test are disadvantageous, especially for those departments/facilities where prompt evaluation is necessary. We investigated the possibility that earlier ESR recordings might correlate with standard 60-minute ESR and/or be predictive of the latter.MethodsDemographic and clinical data were collected from 220 randomly chosen adult patients hospitalised for various diseases in a medical department. ESR, determined by slightly modified Westergren method, was recorded at 15, 30 and 60 min. Correlation coefficients (r) between the standard and early ESR measurements were calculated for the entire group and for the separate subgroups divided according to patient age, sex and presence of anaemia or of inflammation.ResultsMean ± SD age of the patients was 61.3 ± 19.6, 55% were males; 45% had some inflammatory condition. Mean ± SD ESR values (mm) at 15, 30 and 60 min were 9.0 ± 12.1, 21.4 ± 21.8 and 35.9 ± 27.5, respectively. A statistically significant correlation was found between ESR measurements at 15 and 60 min (r = 0.833, p < 0.001). However, the strongest correlation was observed between 30 and 60 min measurements (r = 0.926, p < 0.001), irrespective of age, sex and presence of anaemia or of inflammation. Based on the ESR determination at 30 min (X), the predicted ESR value at 60 min (Y) could be calculated by a simple equation: Y = 10.7 + 1.2X.ConclusionSixty-minute ESR values can be predicted by the 30-minute estimation. Shortening the test by half an hour might bear practical importance.     

In Vivo RNAi-Mediated ��-Synuclein Silencing Induces Nigrostriatal Degeneration

Two small-interfering RNAs (siRNAs) targeting α-synuclein (α-syn) and three control siRNAs were cloned in an adeno-associated virus (AAV) vector and unilaterally injected into rat substantia nigra pars compacta (SNc). Reduction of α-syn resulted in a rapid (4 week) reduction in the number of tyrosine hydroxylase (TH) positive cells and striatal dopamine (DA) on the injected side. The level of neurodegeneration induced by the different siRNAs correlated with their ability to downregulate α-syn protein and mRNA in tissue culture and in vivo. Examination of various SNc neuronal markers indicated that neurodegeneration was due to cell loss and not just downregulation of DA synthesis. Reduction of α-syn also resulted in a pronounced amphetamine induced behavioral asymmetry consistent with the level of neurodegeneration. In contrast, none of the three control siRNAs, which targeted genes not normally expressed in SNc, showed evidence of neurodegeneration or behavioral asymmetry, even at longer survival times. Moreover, co-expression of both rat α-syn and α-syn siRNA partially reversed the neurodegenerative and behavioral effects of α-syn siRNA alone. Our data show that α-syn plays an important role in the rat SNc and suggest that both up- and downregulation of wild-type α-syn expression increase the risk of nigrostriatal pathology.     

��-Synuclein Expression in Rat Substantia Nigra Suppresses Phospholipase D2 Toxicity and Nigral Neurodegeneration

We present genetic evidence that an in vivo role of α-synuclein (α-syn) is to inhibit phospholipase D2 (PLD2), an enzyme that is believed to participate in vesicle trafficking, membrane signaling, and both endo- and exocytosis. Overexpression of PLD2 in rat substantia nigra pars compacta (SNc) caused severe neurodegeneration of dopamine (DA) neurons, loss of striatal DA, and an associated ipsilateral amphetamine-induced rotational asymmetry. Coexpression of human wild type α-syn suppressed PLD2 neurodegeneration, DA loss, and amphetamine-induced rotational asymmetry. However, an α-syn mutant defective for inhibition of PLD2 in vitro also failed to inhibit PLD toxicity in vivo. Further, reduction of PLD2 activity in SNc, either by siRNA knockdown of PLD2 or overexpression of α-syn, both produced an unusual contralateral amphetamine-induced rotational asymmetry, opposite to that seen with overexpression of PLD2, suggesting that PLD2 and α-syn were both involved in DA release or reuptake. Finally, α-syn coimmunoprecipitated with PLD2 from extracts prepared from striatal tissues. Taken together, our data demonstrate that α-syn is an inhibitor of PLD2 in vivo, and confirm earlier reports that α-syn inhibits PLD2 in vitro. Our data also demonstrate that it is possible to use viral-mediated gene transfer to study gene interactions in vivo.     

Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy

Alcohol-related acute pancreatitis can be mediated by a combination of alcohol and fatty acids (fatty acid ethyl esters) and is initiated by a sustained elevation of the Ca²⁺ concentration inside pancreatic acinar cells ([Ca²⁺]_i), due to excessive release of Ca²⁺ stored inside the cells followed by Ca²⁺ entry from the interstitial fluid. The sustained [Ca²⁺]_i elevation activates intracellular digestive proenzymes resulting in necrosis and inflammation. We tested the hypothesis that pharmacological blockade of store-operated or Ca²⁺ release-activated Ca²⁺ channels (CRAC) would prevent sustained elevation of [Ca²⁺]_i and therefore protease activation and necrosis. In isolated mouse pancreatic acinar cells, CRAC channels were activated by blocking Ca²⁺ ATPase pumps in the endoplasmic reticulum with thapsigargin in the absence of external Ca²⁺. Ca²⁺ entry then occurred upon admission of Ca²⁺ to the extracellular solution. The CRAC channel blocker developed by GlaxoSmithKline, GSK-7975A, inhibited store-operated Ca²⁺ entry in a concentration-dependent manner within the range of 1 to 50 μM (IC₅₀ = 3.4 μM), but had little or no effect on the physiological Ca²⁺ spiking evoked by acetylcholine or cholecystokinin. Palmitoleic acid ethyl ester (100 μM), an important mediator of alcohol-related pancreatitis, evoked a sustained elevation of [Ca²⁺]_i, which was markedly reduced by CRAC blockade. Importantly, the palmitoleic acid ethyl ester-induced trypsin and protease activity as well as necrosis were almost abolished by blocking CRAC channels. There is currently no specific treatment of pancreatitis, but our data show that pharmacological CRAC blockade is highly effective against toxic [Ca²⁺]_i elevation, necrosis, and trypsin/protease activity and therefore has potential to effectively treat pancreatitis.     

Distal femoral varus osteotomy for lateral osteoarthritis of the knee: a minimum ten-year follow-up

Distal femoral varus osteotomy (DFVO) may be indicated for symptomatic lateral compartment gonarthrosis associated with valgus deformity in younger, active patients. Thirty-three consecutive DFVOs (31 patients) with a minimum follow-up of ten years (mean 15.1, range 10–25) were reviewed. Fifteen DFVOs were converted to total knee arthroplasty (TKA) and one DFVO was awaiting TKA, reaching an overall failure rate of 48.5% at a mean of 15.6 years (range 6–21.5). Of the remaining 17 DFVOs, ten (58.8%) had good or excellent results, two (11.8%) had fair results and five (29.4%) had poor results. Mean modified Knee Society scores improved significantly (p < 0.01) from 36.8 preoperatively to 77.5 at one year post DFVO. DFVO is a viable treatment alternative for lateral compartment gonarthrosis. Conversion to TKA is expected to be required in approximately half of the patients at a mean of 15.6 years.     

The lower level of natural anti-thomsen-friedenreich antigen (TFA) agglutinins in sera of patients with gastric cancer related to ABO(H) blood-group phenotype

The TFA is a tumorassociated, bloodgrouprelated glycosidic precursor structure [Gal(β^1-3)GalNAc]. Its expression in carcinomas is accompanied by a decrease of natural TFA antibodies in serum. The relationship between the ABO(H)-bloodgroup phenotype and natural anti-TFA immune response in patients with gastric cancer was studied. The level of TFA agglutinins in the sera of patients with gastric cancer and of healthy controls was examined by the hemagglutination of neuraminidasetreated bloodgroup-O donor erythrocytes. Individuals were classified as weak or strong TFA responders. They were also classified by ABO(H)-bloodgroup status, age, cancer stage, tumor morphology and level of isohemagglutinins. The proportion of weak TFA responders (WR) in cancer patients was 33, 50, 50 and 20% (for O, A, B and AB blood groups respectively), as compared with 11.7, 14.5, 13.9 and 26.1% for bloodgrouprelated controls. The difference between cancer patients and controls was significant for all blood groups except group AB. Further analysis showed agedependence in bloodgroup-O and -B controls, with a high level of WR in the older group. Bloodgroup-A cancer patients had the greatest and uniform suppression of the level of TFA agglutinins, irrespective of age, cancer stage or tumor morphology, and lower levels of anti-B isohemagglutinins. © 1995 Wiley-Liss, Inc.