Glutamatergic compensatory mechanisms in experimental parkinsonism

Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach. In this regard, N-acetyl-L-cysteine (NAC) and ambroxol have both been frequently investigated. Because of its SH group, NAC scavenges H2O2 (hydrogen peroxide), .OH (hydroxol radical), and HOCl (hypochlorous acid). Furthermore, NAC can easily be deacetylated to cysteine, an important precursor of cellular glutathione synthesis, and thus stimulate the cellular glutathione system. This is most evident in pulmonary diseases characterized by low glutathione levels and high oxidant production by inflammatory cells (e.g. in IPF and ARDS). NAC is an effective drug in the treatment of paracetamol intoxication and may even be protective against side-effects of mutagenic agents. In addition NAC reduces cellular production of pro-inflammatory mediators (e.g. TNF-alpha, IL-1). Also, ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexane hydrochloride] scavenges oxidants (e.g. .OH, HOCl). Moreover, ambroxol reduces bronchial hyperreactivity, and it is known to stimulate cellular surfactant production. In addition, ambroxol has anti-inflammatory properties owing to its inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. For both substances effective anti-oxidant and anti-inflammatory function has been validated when used in micromolar concentrations. These levels are attainable in vivo in humans. This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol.     

Intracranial hypotension presenting with severe encephalopathy. Case report

A patient with severe and protracted symptoms from intracranial hypotension is described. The patient's presentation was marked by diffuse encephalopathy and profound depression of consciousness. This case report expands the presently known clinical spectrum of this uncommon and generally benign illness. The clinical and laboratory findings typically observed in the syndrome of intracranial hypotension are outlined. The pathophysiological mechanisms of the phenomenon are briefly discussed. Intracranial hypotension is a potentially severe illness with specific treatments that are distinct from the treatment of most neurological diseases. Three cardinal features--postural headache, pachymeningitis, and descent of midline cerebral structures--should prompt the diagnosis.     

Consequences of retirement activities for distress and the sense of personal control

Mink were infected with Aleutian Mink Disease Parvovirus (AMDV) and sacrificed at monthly intervals after infection. During this time humoral immune responses and leucocyte numbers in blood, mesenteric lymph node, spleen and thymus were monitored. Serum hypergammaglobulinaemia was observed together with elevated antibody responses to AMDV NS1 and VP1/2 proteins. In blood, a highly significant increase in CD8+ lymphocytes was observed. However, (presumed)CD4+ cells defined as CD3+CD8- cells, and B lymphocytes remained relatively constant throughout the study. The (presumed)CD4+/CD8+ ratio decreased significantly from greater than 2 to less than 0.5 and MHC-II+ blood leucocytes increased significantly during infection, a large proportion of these being CD8+. Similar changes were observed in the mesenteric lymph node and spleen. Immunohistology of lymph nodes showed a massive expansion of the paracortical area due to increased numbers of CD8+ cells. The staining intensity of B lymphocytes in lymph nodes with a CD79a reactive monoclonal antibody was decreased in the late infection, indicating a possible greater number of plasma cells. Thymic involution was observed during the AMDV infection, although relative increases in CD3high (presumed)CD4+ and CD3highCD8+ single positive cells were observed. These increases were countered by a corresponding reduction in the CD3low(presumed)CD4+CD8+ double positive cell population. Immunohistology of the thymus in normal mink showed that most of the matured CD3+ T cells were present in the inner medulla, while only few CD3+ cells could be found in the outer cortex. In severely infected mink the thymic structural organisation vanished, and CD3+ cells were found throughout the organ.     

Development of a capillary electrophoretic separation of an N-(substituted)-glycine-peptoid combinatorial mixture

Conversion of the noninfectious, cellular form of the scrapie prion (PrPC) to the infectious form (PrPSc) is thought to be driven by an alpha-helical to beta-sheet conformational transition. The N-truncated polypeptide PrP27-30, which encompasses residues 90-231 of PrPSc and from which the truncated peptide is derived by limited proteolysis, assembles into amyloid rods that are rich in the beta-sheet conformation. The N-terminal half of PrP27-30, which includes residues 90-145 of PrP (SHa90-145) and contains the two putative alpha-helical domains H1 (PrP109-122) and H2 (PrP129-141), appears to be particularly crucial in the alpha --> beta conversion. To assess their role in this conformational transition, we have analyzed in detail X-ray diffraction patterns from the prion-related peptides A8A (PrP113-120), H1, and SHa90-145. We used iterative Fourier synthesis with beta-silk as an initial model for assigning phases. For H1, the lyophilized and acetonitrile-solubilized/dehydrated specimens gave two different electron density maps. The former showed that the beta-sheets were composed of small side chains as in A8A. The latter showed two types of beta-sheets having smaller and larger side chains, suggesting a turn. Such a turn was not observed in the lyophilized H1, indicating that the internal turn in H1 depends on the physical-chemical environment. In SHa90-145, the beta-chains are assembled in approximately 40 A-wide crystal domains (termed beta-crystallites), and the electron density maps of these crystallites showed evidence for turns within both the H1 and H2 domains. The molecular folding of H1-H2 is compared here with the recent NMR solution structure of recombinant hamster prion, and the effect of pH on the conformational change is discussed. The most compact structure based on the X-ray diffraction analysis showed that the N-terminal, smaller residues of H2 fold back and are hydrogen-bonded with the C-terminal, smaller residues of H1. Similar folding is observed in the NMR solution structure. Comparison of the NMR structures at different pH with the X-ray diffraction results suggests that histidine and lysine residues in the N-terminal sequence of PrP may figure in the alpha --> beta structure transition of PrP.     

Efficacy of a novel infectious bursal disease virus immune complex vaccine in broiler chickens

Two experiments were conducted to test the efficacy of a novel infectious bursal disease virus (IBDV) vaccine in broiler chickens with maternal IBDV immunity. The IBDV vaccine was formulated by mixing IBDV strain 2512 with bursal disease antibodies (BDA) to produce the IBDV-BDA complex vaccine. In Expt. I, 1-day-old Cobb x Cobb broiler chickens were vaccinated subcutaneously with either IBDV-BDA or commercial live intermediate IBDV vaccine (vaccine A) or were left unvaccinated. In Expt. 2, the vaccine A group was not included; instead, IBDV strain 2512 was included. Chickens were maintained in isolation houses. On day 28 (Expt. 1) and day 32 (Expt. 2) of age, chickens from each group were challenged with a standard USDA IBDV (STC strain) challenge. Challenged and unchallenged chickens were evaluated for their bursa/body weight ratios and antibody titers 3 days post-challenge. Bursae collected from Expt. 2 were examined histologically to evaluate bursal lesions and confirm gross examination. None of the unvaccinated chickens was protected against the challenge virus as evidenced by the presence of acute bursal lesions (edema/hemorrhage). All chickens receiving the IBDV-BDA complex or the IBDV strain 2512 (Expt. 2) were protected from the challenge virus as evidenced by no acute bursal lesions. Additionally, chickens receiving the IBDV-BDA complex vaccine or the IBDV strain 2512 had antibody titers to IBDV, indication the presence of an active immune response. In Expt. 1, chickens vaccinated with vaccine A and challenged had bursal lesions similar to those observed in the unvaccinated, challenged chickens. These chickens also showed no indication of active immunity against the virus. These results suggest that the 1-day-of-age-administered IBDV-BDA complex vaccine can induce active immunity and protection against a standard IBDV challenge in the face of variable levels of maternal IBDV immunity.     

The prognostic significance of p34cdc2 and cyclin D1 protein expression in prostate adenocarcinoma

BACKGROUND: Cyclin-dependent kinases (CDK) and cyclins constitute the subunits of the maturation-promoting factor that controls the process of cell division. High levels of these proteins have been reported in human malignancies of the stomach, colon, breast, and lung, and have been implicated in aberrant cell division and dysregulated tumor growth. METHODS: p34cdc2 CDK and cyclin D1 (D1) protein expression were evaluated in 140 radical prostatectomy specimens harboring adenocarcinoma (PAC), using the respective monoclonal antibodies on archival tissue sections. In each case, slides stained with hematoxylin and eosin were examined for evaluation of Gleason's grade and pathologic stage. The DNA content of the tumors was determined by the Feulgen method with the CAS200 Image Analyzer (Cell Analysis Systems, Lombard, IL). Nuclear immunoreactivity for the two proteins was semiquantitatively scored, and results were correlated with Gleason's grade, stage, ploidy, metastatic status, and disease recurrence after radical prostatectomy. RESULTS: p34cdc2 was expressed in 84 of 140 PACs (60%) and correlated with high Gleason's grade (P = 0.0001), advanced pathologic stage (P = 0.01), nondiploid DNA content (P = 0.0001), and metastases (P = 0.04). On multivariate analysis using the Cox proportional hazards model, p34cdc2 immunoreactivity (P = 0.0001) and high Gleason's grade (P = 0.01) each independently predicted disease recurrence. When tumors were of low Gleason's grade and lacked p34cdc2 expression, 4 of 39 PACs (10%) recurred, as compared with 18 of 47 (38%) that recurred when tumors were of high Gleason's grade and expressed p34cdc2 protein. D1 was positive in 31 of 140 PACs (22%) and showed a trend (P = 0.07) of high Gleason's grade, but it did not reach statistical significance with any of the prognostic variables. In the majority of PACs expressing both p34cdc2 and D1 proteins, the adjacent benign prostate acini showed focal, scattered nuclear positivity of the basal and secretory epithelial cells. CONCLUSIONS: p34cdc2 is expressed in a majority of PACs and correlates with high Gleason's grade, advanced pathologic stage, nondiploid DNA content, and metastases. On multivariate analyses high Gleason's grade and p34cdc2 immunoreactivity predict disease recurrence independently of the pathologic stage. Thus, p34cdc2 appears to play a critical role in the evolution, proliferation, and spread of PACs and may be of prognostic value when applied to initial prostate tissue samples taken by needle biopsy.     

Replication and segregation of a miniF plasmid during the division cycle of Escherichia coli

Replication of the miniF plasmid pML31 was examined during the division cycle of Escherichia coli growing with doubling times between 40 and 90 min at 37 degrees C and compared to the replication of plasmid pBR322 and the minichromosome pAL70. The replication pattern of pML31 was indistinguishable from that of pBR322 at all growth rates and very different from the cell-cycle-specific replication of the minichromosome. It is concluded that both pML31 and pBR322 plasmids can replicate at all stages of the division cycle, with a probability of replication that increases gradually, but perhaps not exponentially, during the cycle. In contrast, the modes of segregation of pML31 and pBR322 plasmids into daughter cells at division appeared to differ, raising the possibility that pML31 may segregate in a nonrandom fashion similar to that of chromosomes and minichromosomes.     

Overfeeding macronutrients to critically ill adults: metabolic complications

Metabolic complications from overfeeding critically ill patients are serious and sometimes fatal. Nutrition care is best provided through repeated evaluation of patients' responses to feeding. Nutrition support may need to be modified over time to maintain metabolic stability and promote recovery. This article describes the etiology of 10 metabolic complications of overfeeding. Guidelines for recommending macronutrients are discussed, as are factors that could increase the risk of overfeeding. Patients who are very small, very large, or very old are particularly vulnerable to overfeeding. Overfeeding protein has led to azotemia, hypertonic dehydration, and metabolic acidosis. Excessive carbohydrate infusion has resulted in hyperglycemia, hypertriglyceridemia, and hepatic steatosis. High-fat infusions have caused hypertriglyceridemia and fat-overload syndrome. Hypercapnia and refeeding syndrome have also been caused by aggressive overfeeding. Dietitians can prevent or curtail the metabolic complications of overfeeding by identifying patients at risk, providing adequate assessment, coordinating interdisciplinary care plans, and delivering timely and appropriate monitoring and intervention. Dietitians need to document complications, interventions, and the outcomes of their clinical care to evaluate the appropriateness of existing nutrition guidelines.     

Dissociation of brain ERP topographies for tonal and phonetic oddball tasks

ERP topographies for 30 scalp electrodes were examined in 26 healthy right-handed volunteers during oddball tasks (20% targets) using binaurally presented consonant-vowel syllables or complex tones. Response hand was counterbalanced across participants. Both window averages and a principal components analysis (PCA) with Varimax rotation revealed task-related (tonal/phonetic) hemispheric asymmetries for N2, early P3, and particularly for N2-P3 amplitude. In the tonal task, N2 was maximal over right lateral-temporal regions, and early P3 over right medial-parietal regions. For the phonetic task, N2 was maximal over the left lateral-parietal regions, and late P3/N3 over left medial-parietal regions. A response-related frontal negativity (N3) interacted with task-related asymmetries in an unbalanced fashion. The distinct, asymmetric N2 and P3 topographies for tonal and phonetic tasks presumably reflect differential involvement of cortical structures in pitch (right frontotemporal) and phoneme (left parietotemporal) discrimination.