Neuropsychiatric correlates and treatment of lenticulostriatal diseases: a review of the literature and overview of research opportunities in Huntington's, Wilson's, and Fahr's diseases. A report of the ANPA Committee on Research. American Neuropsychiatric Association

This report reviews clinical neuropsychiatric findings and opportunities for research in Huntington's, Wilson's, and Fahr's diseases. Consistent, systematic methodology is lacking among neuropsychiatric studies in these lenticulostriatal diseases. Systematic cross-sectional and longitudinal assessments are needed to ascertain the prevalence of psychiatric disorders as a function of disease course. Preliminary synthesis of existing data suggests the following heuristic relationships in these diseases: depression with parkinsonian states; personality changes with caudate or putamen disease; psychosis, impulsivity, and sexual disorders with caudate disease; dementia and mania with caudate and pallidal diseases; and compulsions with pallidal disease. Correlation of neuropsychiatric findings with disease stage, clinical signs, and radiologic, metabolic, physiologic, and pathologic markers of disease will add to our understanding of these conditions.     

Letter recognition reveals pathways of second-order and third-order motion

How are second-order (texture-defined) and third-order (pattern-tracking) motions processed in our brains? As shown here in the context of an ambiguous motion task involving a nominal second-order stimuli first devised by Werkhoven et al., [Werkhoven, P., Sperling, G. & Chubb, C. (1993) Vision Res. 33, 463-485.], the observers fell into two distinct groups based on the direction of perceived motion. The differences were interpreted in terms of the algorithms used to extract motion: one group by using a second-order motion process and the other by using a third-order motion process. This was investigated further using a dual-task paradigm in which the interference between two tasks indicated the nature of processing involved. Observers who used third-order motion processing experienced interference with letter recognition and a more severe interference in dual third-order motion tasks. Observers who used second-order motion processing experienced interference with another second-order motion detection but not with letter recognition. Insofar as task interference implies the need for attention, the complex interference effects and the apparently paradoxical interference effects of second-order motion perception imply that there are multiple forms of attention. Whether two tasks interfere depends on whether they require the same form of attention. Insofar as spatio-temporal processing is assumed to be carried out in the dorsal stream and pattern recognition in the ventral stream, the interference patterns suggest that second-order motion may be computed entirely in the dorsal stream, and third-order motion may involve two computational processes, one of which shares computational resources with the letter recognition task in the ventral stream.     

In vivo anteroposterior femorotibial translation of total knee arthroplasty: a multicenter analysis

A study was conducted to determine in vivo femorotibial contact patterns for subjects having a posterior cruciate retaining or posterior cruciate substituting total knee arthroplasty. Femorotibial contact of 72 subjects implanted with a total knee replacement, performed by five surgeons, was analyzed using video fluoroscopy. Thirty-one subjects were implanted with a posterior cruciate retaining total knee replacement with a flat polyethylene posterior lipped insert, 12 with a posterior cruciate retaining total knee replacement with a curved insert, and 29 with a posterior cruciate substituting total knee replacement. Each subject performed successive deep knee bends to maximum flexion. Video images at 0 degree, 30 degrees, 60 degrees, and 90 degrees flexion were downloaded onto a workstation computer. Femorotibial contact paths were determined for the medial and lateral condyles using an interactive model fitting technique. Femorotibial contact anterior to the tibial midline in the sagittal plane was denoted as positive and contact posterior was denoted as negative. Analysis of average femorotibial contact pathways of both posterior cruciate retaining designs revealed posterior femorotibial contact in full extension with anterior translation of femorotibial contact commonly observed in midflexion and terminal flexion. In posterior cruciate substituting designs, anterior femoral translation was seen medially at 30 degrees to 60 degrees flexion but rarely was observed laterally. Posterior femoral rollback laterally from full extension to 90 degrees flexion was seen in 100% of subjects implanted with a posterior cruciate substituting total knee replacement, versus 51.6% (posterior lipped polyethylene insert) and 58.3% (curved insert) of those with a posterior cruciate retaining total knee replacement. Data from this multicenter study are remarkably similar to previous fluoroscopy data from a single surgeon series, showing a lack of customary posterior femoral rollback in both posterior cruciate retaining designs, and conversely showing an average anterior femoral translation with knee flexion. Posterior femoral rollback, less than in normal knees, routinely was observed in posterior cruciate substituting total knee arthroplasty, attributed to engagement of the femoral component cam with the tibial post. The abnormal anterior femoral translation observed in posterior cruciate retaining total knee arthroplasty may be a factor in premature polyethylene wear observed in retrieval studies.     

Chemokine receptor (CXCR4) mRNA-expressing leukocytes are increased in human renal allograft rejection

BACKGROUND: Mononuclear cell infiltration is a common feature of cell-mediated renal transplant rejection. Chemokines and their corresponding receptors likely play a central role in directing specific classes of leukocytes to graft sites during rejection. Localization of chemokine receptors may help us understand how specificity in leukocyte trafficking is achieved in renal inflammatory processes. The localization of the chemokine receptor CXCR4 in human kidney and in renal transplant rejection is unknown. METHODS: We generated a riboprobe specific for the detection of CXCR4 mRNA by in situ hybridization to evaluate cellular sites of synthesis of this receptor in native human kidneys (n=11) and in human allograft nephrectomies with features of severe rejection (n=14). RESULTS: By in situ hybridization, CXCR4 mRNA expression is undetectable in intrinsic glomerular, tubular, and renovascular cells in native kidneys. When renal interstitial inflammation is present, CXCR4 mRNA expression is localized to a large fraction of infiltrating leukocytes. Large numbers of CXCR4-expressing cells are detected in cell-mediated renal allograft rejection. Double immunolabeling for CD3 antigen identified a large fraction of infiltrating CXCR4 mRNA-expressing cells as T lymphocytes. CXCR4 mRNA-expressing cells were frequently seen in neointimal lesions of vascular rejection in allograft nephrectomies. CXCR4 mRNA expression was identified in infiltrating neointimal T lymphocytes, but not smooth muscle cells by immunolabeling. CONCLUSIONS: We demonstrate the involvement of CXCR4 mRNA-expressing infiltrating cells in human renal interstitial and vascular allograft rejection. Signaling via the CXCR4 receptor may be one mechanism by which chemokines mediate leukocyte trafficking in renal allograft rejection.     

A role for the Ras signalling pathway in synaptic transmission and long-term memory

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.     

The conservative treatment of major kidney injuries

The choice of treatment (surgical or conservative) for major renal trauma still remains controversial. The objective of this study was to compare the results of patients with major renal trauma (grade III and IV) primarily treated by surgical intervention (1980-1992) with those in patients mainly treated conservatively (1992-1995). Between 1980 and 1995, 83 patients with major renal trauma were hospitalized at our institution. Our results show a higher nephrectomy rate of 44% in the case of primary surgical intervention compared to conservative management (27%). The outcome of twenty-two patients treated conservatively was analyzed prospectively with repeated radiological imaging, blood pressure profiles, and renal function assessment by means of MAG 3 renal scintigraphy. No patient developed renovascular hypertension and the relative function of the traumatized kidney was greater than 40% in 95% of patients. In conclusion, our results confirm a lower nephrectomy rate in the case of conservative management without any increase of the immediate or long-term morbidity. Major renal trauma (grade III, IV) can therefore be effectively treated by conservative management and primary surgical repair is only indicated in patients with hemodynamic instability, persistent hematuria and associated visceral injuries.     

Utilization of a recombinant substrate rAgg1 to study the biochemical properties of aggrecanase in cell culture systems

This paper describes the first report of the production and use of an artificial recombinant protein substrate to study "aggrecanase" activity. The substrate (rAgg1) is composed of the complete interglobular domain (IGD) of human aggrecan flanked by the "marker" sequences FLAGTM at the amino terminus and the human immunoglobulin G1 constant region at the carboxyl terminus. The expressed protein occurs as large multimolecular aggregates (>120 kDa) that, upon reduction, consist of a major isoform of 72 kDa (containing the IGD) and a minor 39-kDa species that through alternative splicing has had the IGD deleted. Using this recombinant substrate we developed a novel agarose cell culture system containing either rat chondrosarcoma or bovine chondrocytes that could be used in studies of the biochemical characterization of aggrecanase activities. These studies showed the following. (i) rAgg1 is a suitable substrate for aggrecanase proteolysis. (ii) Aggrecanase activity was specifically induced by exposing chondrocytes to retinoic acid. (iii) A considerable time period was required to synthesize and/or activate aggrecanase, with considerable differences in that found in rat chondrosarcoma versus bovine chondrocyte culture systems. (iv) Aggrecanase cleavage of the aggrecan IGD does not require the presence of the G1 or G2 globular domains or keratan sulfate post-translational modification in the IGD. (v) Aggrecanase is a diffusible activity that does not require association with the chondrocyte plasma membrane or immediate pericellular matrix for its action.     

Intake, digestion, and nitrogen utilization by sheep fed tropical legumes with contrasting tannin concentration and astringency

We conducted an experiment to determine the effects of concentration and astringency of extractable and bound condensed tannins (CT) in tropical legumes on intake, digestibility, and nitrogen (N) utilization by sheep. The test legumes (Desmodium ovalifolium and Flemingia macrophylla) had similar concentrations of extractable CT (90 g/kg DM) but different concentrations of bound CT and astringency of tannins. Chopped, sun-dried forage of each legume was sprayed with either water (control) or polyethylene glycol (PEG, 35 g/kg of DM) to bind extractable CT and fed daily (26 g/kg BW) to eight sheep with ruminal and duodenal cannulas. The sheep also received starch-extracted cassava meal intraruminally (4 g/kg BW) as a constant source of readily fermentable carbohydrates. Intake of the two legumes was not different (P > .05), but it increased an average of 10% (P < .01) when extractable CT were reduced from 90 to 50 g/kg of DM with PEG. Ruminal and total tract digestibilities of OM, NDF, and ADF were greater (P < .01) with D. ovalifolium than with F. macrophylla and increased for both legumes with the addition of PEG. Greater (P < .01) N flow to the duodenum, N absorbed from the intestine, and fecal N were observed with F. macrophylla than with D. ovalifolium. Extraction of CT with PEG resulted in less (P < .05) ruminal escape protein and less (P < .01) fecal N with both legumes, but apparent postruminal N digestion was not affected. Changes in the concentration of extractable CT in tropical legumes can significantly affect forage intake, digestion, and N utilization by sheep.