Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency

This is the first neuropathology report of a male patient (born 1960-died 1975) with an extremely rare, atypical variant of CLN2 that has been diagnosed only in five families so far. The clinical history started during his preschool years with relatively mild motor and psychological difficulties, but with normal intellect and vision. Since age six there were progressive cerebellar and extrapyramidal symptomatology, amaurosis, and mental deterioration. Epileptic seizures were absent. The child died aged 15 years in extreme cachexy. Neuropathology revealed neurolysosomal storage of autofluorescent, curvilinear and subunit c of mitochondrial ATP synthase (SCMAS) rich material. The neuronal storage led to laminar neuronal depopulation in the cerebral cortex and to a practically total eradication of the cerebellar cortical neurons. The other areas of the central nervous system including hippocampus, which are usually heavily affected in classical forms of CLN2, displayed either a lesser degree or absence of neuronal storage, or storage without significant neuronal loss. Transformation of the stored material to the spheroid like perikaryal inclusions was rudimentary. The follow-up, after 30 years, showed heterozygous values of TPP1 (tripeptidylpeptidase 1) activity in the white blood cells of both parents and the sister. DNA analysis of CLN2 gene identified a paternal frequent null mutation c.622C > T (p.Arg208 X) in the 6th exon and a maternal novel mutation c.1439 T > G in exon 12 (p.Val480Gly). TPP1 immunohistochemistry using a specific antibody gave negative results in the brain and other organs. Our report supports the notion that the spectrum of CLN2 phenotypes may be surprisingly broad. The study revealed variable sensitivities in neuronal subpopulations to the metabolic defect which may be responsible for the variant's serious course.     

Glycosylation improves the central effects of DAMGO

A series of mu-agonist DAMGO analogs were synthesized and pharmacologically characterized to test the 'biousian' hypothesis of membrane hopping. DAMGO was altered by incorporating moieties of increasing water solubility into the C-terminus via carboxamide and simple glycoside additions. The hydrophilic C-terminal moieties were varied from glycinol in DAMGO (1) to l-serine amide (2), l-serine amide beta-d-xyloside (3), l-serine amide beta-d-glucoside (4), and finally to l-serine amide beta-lactoside (5). Opioid binding and mouse tail-flick studies were performed. Antinociceptive potency (intravenous) increased, passing through a maximum (A(50) approximately 0.2 micromol/kg) for 2 and 3 as membrane affinity versus water solubility became optimal, and dropped off (A(50) approximately 1.0 micromol/kg) for 4 and 5 as water solubility dominated molecular behavior. Intravenous A(50) values were plotted versus hydrodynamic values (glucose units, g.u.) for the glycoside moieties, or the hydrophilic/hydrophobic Connolly surface areas (A(50) versus e(-Awater/Alipid)), and provided either a V-shaped or a U-shaped curve, as predicted by the 'biousian' hypothesis. The mu-selective receptor profile was maintained (K(i)'s = 0.66-1.3 nm) upon modifications at the C-terminus. The optimal 'degree of glycosylation' for the DAMGO peptide message appears to be between 1.25 and 1.75 g.u. (hydrodynamic g.u.), or 0.75 and 0.90 in terms of the surface-derived amphipathicity values.     

Dactylone inhibits epidermal growth factor-induced transformation and phenotype expression of human cancer cells and induces G1-S arrest and apoptosis

The marine natural chamigrane-type sesquiterpenoid, dactylone, is closely related to secondary metabolites of some edible species of red algae. In the present study, the effect of dactylone was tested on the mouse skin epidermal JB6 P+ Cl41 cell line and its stable transfectants as well as on several human tumor cell lines, including lung (H460), colon (HCT-116), and skin melanomas (SK-MEL-5 and SK-MEL-28). This natural product was effective at nontoxic doses as a cancer-preventive agent, which exerted its actions, at least in part, through the inhibition of cyclin D3 and Cdk4 expression and retinoblastoma tumor suppressor protein (Rb) phosphorylation. The inhibition of these cell cycle components was followed by cell cycle arrest at the G1-S transition with subsequent p53-independent apoptosis. Therefore, these data showed that application of dactylone and related compounds may lead to decreased malignant cell transformation and/or decreased tumor cell proliferation.     

Treatment results in wounds of the ENT organs]

ENT injuries totaled up to 1.4% from all other wounds. As for localization of wounds the most frequent were neck injuries (53%). Wounds of nose or accessory sinus of nose comprised 45.6%, and ear wounds--1.4%, 5.8% of wounded needed emergency care, 45.8%--secondary surgical care, and 48.4%--tertiary surgical care. The article analyses the errors of medical care, and gives the classification of ENT injuries.     

Combined virus-like particle-based polyepitope DNA/protein HIV-1 vaccine design, immunogenicity and toxicity studies

We have previously described designing of polyepitope immunogens TBI and TCI, to stimulate the humoral and cellular immune responses to HIV-1. Here, immunogens TBI and TCI were used to create new vaccine construct named CombiHIVvac (Combined HIV-1 vaccine). CombiHIVvac is a virus-like particles (VLP) containing the DNA vaccine pcDNA-TCI as a core encapsulated within a spermidine-polyglucin-TBI conjugate. The immunogenic and toxic properties of the candidate vaccine CombiHIVvac have been studied. CombiHIVvac induces a strong humoral and CTL responses in mice; the antibodies are highly specific and are able to neutralize HIV-1 in vitro. Preclinical study demonstrated that CombiHIVvac does not cause long-term changes in physiological, biochemical and morphological parameters in immunized animals and thus can be recommended for clinical trials.     

Influence of the restorative procedure factors on stress values in premolar with MOD cavity: a finite element study

In order to investigate the influence of cusp reduction, cavity isthmus width, and restorative material on stress values in premolar with mesio-occlusal-distal (MOD) cavity, numerical simulations were done on three-dimensional (3D) models of a maxillary second premolar designed using computerized tomography (CT) scan images. The use of four restorative materials (direct resin composite, direct resin composite with resin-modified glass-ionomer cement as the base, indirect resin composite, ceramic), three cavity preparation designs (without cusp coverage, 2-mm palatal cusp coverage, 2-mm palatal and buccal cusp coverage), and two cavity isthmus widths (1/2 and 2/3 intercuspal width) were simulated. After applying a static load of 200 N on the occlusal surface of the tooth, von Mises stresses in the enamel, dentin, and restoration were calculated using finite element analysis (FEA). Stress values in the enamel were primarily influenced by cavity preparation design, while restorative material showed higher contribution in dentin. The lowest stress values were obtained in models with cusp coverage and indirect restorations. Cavity isthmus width had minimal influence on stress values in tooth structures. None of the investigated factors determined stress values in the restoration. In conclusion, the use of ceramic restoration covering both palatal and buccal cusp provided the most favourable stress distribution of premolars with MOD cavity.

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Graphical abstract ?

     

Detection of misfolded prion protein in blood with conformationally sensitive peptides

BACKGROUND: The long-standing goal of a preclinical diagnostic test for transmissible spongiform encephalopathy (TSE) has recently become urgent because of the discovery that humans with variant Creutzfeldt-Jakob disease can transmit disease via blood transfusions. STUDY DESIGN AND METHODS: The misfolded protein diagnostic (MPD) assay employs a pyrene-labeled palindromic sequence of prion peptides that undergoes a cascade of coil to beta-sheet conversion in the presence of the misfolded prion protein (PrP(TSE)). The ability of the assay to detect PrP(TSE) in brain, serum, and plasma was tested. The basic protocol involved a several-hour incubation of 200-microL sample volumes with the peptide reagent in 96-well plates, after which fluorescence was monitored by a fluorescence plate reader with an excitation wavelength of 350 nm and emission scanning wavelength range of 365 to 600 nm. RESULTS: Target specificity for PrP(TSE) was documented by correlation of assay signal with Western blot signals in brain tissue from TSE-infected, normal, and knockout mice and negative assay signals by use of reagents with different peptide sequences. When applied to plasma or serum, the assay discriminated between samples from a variety of experimental and natural TSE infections compared to uninfected controls, with a sensitivity threshold of approximately 1 infectious dose per mL in pooled plasma from TSE-infected mice. CONCLUSIONS: The MPD assay is a sensitive and specific test for the detection of PrP(TSE) that may be useful in both preclinical and clinical diagnosis of TSE diseases of animals and humans.     

Limited granulomatosis with polyangiitis in an adolescent with Crohn's disease on infliximab therapy: cause or coincidence?

Pulmonary involvement in Crohn's disease (CD) may precede the development of intestinal inflammation, but in most cases occurs during the course of treatment, either as an extra‐intestinal manifestation, because of secondary infections, or as a side effect of the therapy itself. This case highlights the differential diagnosis and work up for multiple pulmonary nodules that developed in a patient with CD who had been in remission on infliximab therapy. Even though infectious causes, such as Mycobacteria and Fungi, account for majority of these cases, the possibility of non‐infectious conditions such as autoimmune disorders should also be considered.