Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.     

Balance and recovery from a perturbation are impaired in people with functional ankle instability.

OBJECTIVE: To determine if differences in balance and recovery would be found between controls and participants with unilateral or bilateral functional ankle instability (FAI). DESIGN: Cross-Sectional Study. SETTING: University laboratory and Community premises. PARTICIPANTS: Twenty healthy participants(C), 19 participants with unilateral FAI [both the uninjured (UC) and unstable ankle (UI) were included] and 22 participants with bilateral FAI (BI). MAIN OUTCOME MEASURES: Balance was measured in single leg stance as: number of part foot lifts in 30 s; magnitude of medio-lateral ankle movement in two foot positions; and ability to balance on the ball of the foot. Recovery was determined by time to return to baseline medio-lateral ankle movement after a 15 degree inversion perturbation. RESULTS: The controls lifted the foot fewer times than the other three groups [C = 12.7 +/- 1.8 (mean +/- SE) foot lifts, UC = 22.9 +/- 2.5, UI = 25.1 +/- 2.3, and BI = 21.1 +/- 2.2, t-test, P = 0.006] and recovered significantly faster than the unstable ankles [C = 1.53 +/- 0.42 sec (median +/- SE), UI = 2.34 +/- 0.30 sec, BI = 2.15 +/- 0.70 sec, P < 0.02]. With FAI measured by the Cumberland Ankle Instability Tool, the external control group balanced on demi-pointe better than both instability groups (P < 0.05), and recovered quicker than all groups. CONCLUSION: There are differences in balance and recovery between external controls and participants with both unilateral and bilateral FAI but not between the legs of participants with unilateral FAI.     

A Review of Staffing in Childcare Centres in Six Countries

A review of the international literature on staffing in childcare centres in five English language countries and Denmark reveals both remarkable similarities and interesting differences in the childcare workforce. The paper compares characteristics of the workforce; their training and professional membership. It also compares conditions of work in each country, including salaries, staff benefits, and features of the working environment such as job satisfaction and staff turnover. Findings indicate that childcare workers tend to be young and female; that a relatively high proportion of untrained staff work in childcare centres; that, except in Denmark, the level of extrinsic benefits is startlingly low. Workers are paid relatively little compared to the average pay for women in their countries but the workforce does not benefit from enhanced conditions of work to compensate for low pay. However, the level of intrinsic satisfaction with the work is high. Caring for children is a satisfying form of employment, even if it offers a limited career structure.     

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats

Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.     

Structure-activity relationship of macrocyclic and linear gadolinium chelates: Investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme

Transmetallation between commercially available solutions of gadolinium (Gd) chelates and the zinc (Zn)-dependent angiotensin-converting enzyme (ACE) was investigated. In vitro, the strongest inhibitions were observed for the linear Gd complexes, Gd diethylene-triamine pentaacetic acid (DTPA) bis-methylamide (BMA) (IC₅₀ = .016 ± .006 mmol/1) and Gd-DTPA (IC₅₀ = .350 ± .034 mmol/1). The two macrocycles Gd tetraazacyclododecane tetraacetic acid (DOTA) and Gd-HP-DO3A were similar and 400 times less active than Gd-DTPA-BMA. These effects were mainly due to the presence of free ligand for DTPA and calcium (Ca) chelate in the case of DTPA-BMA because the addition of Zn²⁺ in the same quantities suppresses their inhibitory effects. In vivo, these two solutions of linear Gd chelates significantly inhibited ACE activity (Gd-DTPA: 67 ± 9% versus baseline; and Gd-DTPA-BMA: 73 ± 2% versus baseline at the clinical dose of .1 mmol/kg), whereas no significant effect was observed for the two macrocyclic chelates Gd-DOTA and Gd-HP-DO3A. Formulating the Gd chelate solution with either an excess of free ligand or Ca chelate (to decrease Gd³⁺ release) in the case of linear Gd chelate may have deleterious biologic consequences.     

dazed gene is necessary for late cell type development and retinal cell maintenance in the zebrafish retina.

Several molecules, such as growth factors and neurotrophic factors, are required both for the differentiation of specific retinal cell types and the long-term cell survival of all retinal neurons. As diffusible factors, these molecules act non-cell-autonomously. Here, we describe the loss of function phenotype for dazed (dzd), a gene that acts cell-autonomously for retinal cell survival and affects the differentiation of rod photoreceptors and the Muller glia. By 3 days after fertilization, dazed mutant embryos have small eyes and slight heart edema. Acridine orange staining indicated a significant degree of retinal cell death occurring by 48 hr after fertilization, and histological analysis revealed that dying cells were found in the inner and outer nuclear layers and near the marginal zones. Although molecular and morphological differentiation of the inner retina and cone photoreceptors occurred, rod photoreceptors failed to differentiate beyond a small patch in the ventral retina and rod precursors failed to respond to exogenously added retinoic acid, which normally potentiated rod differentiation. Mosaic analysis indicated that the dazed gene acts cell-autonomously for rod production and cell survival, as dazed clones failed to produce rods outside the ventral patch and dazed cells were not maintained in wild-type hosts. Raising mutants under constant light resulted in severe retinal degeneration, whereas raising embryos under constant darkness did not provide any additional protection from cell death. Behavioral analysis showed that a subpopulation of adult fish that were heterozygous for the dazed mutation had elevated visual thresholds and were night blind, suggesting that dazed may also be required for long-term dim-light vision. Taken together, our studies suggest a role for the dazed gene in rod and Muller cell development and overall retinal cell survival and maintenance.     

Genetic analysis and attribution of microbial forensics evidence

Because of the availability of pathogenic microorganisms and the relatively low cost of preparing and disseminating bioweapons, there is a continuing threat of biocrime and bioterrorism. Thus, enhanced capabilities are needed that enable the full and robust forensic exploitation and interpretation of microbial evidence from acts of bioterrorism or biocrimes. To respond to the need, greater resources and efforts are being applied to the burgeoning field of microbial forensics. Microbial forensics focuses on the characterization, analysis and interpretation of evidence for attributional purposes from a bioterrorism act, biocrime, hoax or inadvertent agent release. To enhance attribution capabilities, a major component of microbial forensics is the analysis of nucleic acids to associate or eliminate putative samples. The degree that attribution can be addressed depends on the context of the case, the available knowledge of the genetics, phylogeny, and ecology of the target microorganism, and technologies applied. The types of genetic markers and features that can impact statistical inferences of microbial forensic evidence include: single nucleotide polymorphisms, repetitive sequences, insertions and deletions, mobile elements, pathogenicity islands, virulence and resistance genes, house keeping genes, structural genes, whole genome sequences, asexual and sexual reproduction, horizontal gene transfer, conjugation, transduction, lysogeny, gene conversion, recombination, gene duplication, rearrangements, and mutational hotspots. Nucleic acid based typing technologies include: PCR, real-time PCR, MLST, MLVA, whole genome sequencing, and microarrays.     

Antifungal coating by biofunctionalized polyelectrolyte multilayered films

The surface of medical devices is a common site of bacterial and fungal adhesion, first step to the constitution of a resistant biofilm leading frequently to chronic infections. In order to prevent such complications, several physical and chemical modifications of the device surface have been proposed. Here, we experiment a new type of topical antifungal coating using the layer-by-layer technique. The nanometric multilayer film obtained by this technique is functionalized by the insertion of a chromogranin A-derived antifungal peptide (CGA 47-66, chromofungin). We show that the embedded peptide keeps its antifungal activity by interacting with the fungal membrane and penetrating into the cell. In vitro studies demonstrate that such an antifungal coating is able to inhibit the growth of yeast Candida albicans by 65% and completely stop the proliferation of filamentous fungus Neurospora crassa. The cytotoxicity of such a coating was also assessed by growing human gingival fibroblasts at its surface. Finally, the antifungal coating of poly(methylmethacrylate), a widely used material for biomedical devices, is successfully tested in an in vivo oral candidiasis rat model. Taken together, these results assessed the functionalized multilayer films containing a new potent antifungal non-toxic peptide, as a novel and promising technique for local antifungal protection.     

Fibrolamellar Carcinoma of Liver: A Primary Malignant Oncocytic Carcinoid?

Immunohistochemical and ultrastructural findings in two cases of fibrolamellar carcinoma of the liver and two cases of hepatocellular carcinoma of the common histologic type are described. Ultrastructural examination of both cases of fibrolamellar carcinoma revealed the presence of neurosecretory (NS) granules which were sparse in some cells and abundant in others. Many of the tumor cells had a distinct oncocytic appearance with abundant mitochondria. A portion of the glutaraldehyde-fixed neoplasm was processed for the uranaffin reaction (an ultrastructural cytochemical stain specific for the NS granules of neuroendocrine tissue). Abundant uranaffin-positive granules were found in the neoplastic cells of both cases of fibrolamellar carcinoma, whereas no uranaffin-positive granules were found in hepatocellular carcinoma of the common histologic type. There was no statistical difference in the mean diameter of the uranaffin-positive granules measured from both cases. Immunohisto-chemistry revealed the presence of neuron-specific enolase (NSE) and serotonin in one of the two cases of fibrolamellar carcinoma and no NSE staining in two cases of hepatocellular carcinoma of the common histologic type. These findings suggest that some liver tumors presenting histologically as fibrolamellar carcinoma may be neuroendocrine in nature.     

Three highly polymorphic microsatellites at the human myelin oligodendrocyte glycoprotein locus, 100 kb telomeric to HLA-F : Characterization and relation to HLA haplotypes

The MOG locus, located on chromosomal bands 6p21.3-p22 and mapped about 100 kb telomeric to HLA-F, was isolated from cosmid ICRFcl09A2434 and shown to contain three microsatellites. These CA-repeat polymorphic markers were characterized in a sample of 173 healthy unrelated individuals and 84 DNAs from the HLA Workshop reference panel, by a method combining fluorescence labeling of PCR products and use of an automated DNA sequencer. For the three markers, frequencies of heterozygotes are well predicted from allele frequencies by the Hardy—Weinberg rule, which suggests that problems of allele nonamplification are unlikely. Typing of cell lines homozygous in the HLA region allowed unambiguous definition of 81 HLA-MOG haplotypes and showed that several HLA ancestral haplotypes extended to the MOG region. The high degree of polymorphism (59%, 51%, and 81% at the three loci, respectively, and 87% at the haplotype level) makes these new markers informative for association or linkage studies with diseases such as hemochromatosis or multiple sclerosis, and for studies aimed at precisely delineating the site of crossover in chromosomes in which recombination occurred in the distal part of the HLA class I region.