Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

[Is bovine leishmaniasis spreading in Switzerland?]. / Breitet sich die bovine kutane Leishmaniose in der Schweiz aus?

The purpose of the present study was based upon the first diagnosed bovine cutaneous leishmaniasis in a cow in Switzerland in April 2009. We continued descriptively the search for other bovine cases in Switzerland. We carried out similar investigations in the original farm where the case had occurred, and in parallel also in the neighboring farm. Additionally, veterinary practitioners sent us an overall of 12 suspected cases of bovine leishmaniasis. Following diagnostic investigations, all cases were negative for Leishmania. The occurrence of this infection appears therefore to be a very rare event. Finally some differential diagnoses are discussed.

Transient immunosuppression: a bridge between infection and the atypical autoimmunity of Guillain-Barré syndrome?

Guillain-Barré syndrome (GBS) is an acute, usually monophasic, disorder of the peripheral nervous system that is assumed to be of immune-mediated pathogenesis. However, several clinical features and experimental findings of GBS are uncharacteristic for an immune-mediated disorder and set this condition apart from other disorders with a putative immune-mediated pathogenesis. These features include, among others, the monophasic nature of GBS, the lack of response to immunosuppressive (unlike immunomodulatory) therapy, the absence of a typical association with immunogenetic background and the inability to establish a valid and relevant animal model. We suggest a comprehensive hypothesis for the pathogenesis of GBS that is based on the assumption that the condition is due to a transient (or occasionally chronic) immune deficiency, as in most cases GBS follows an infection with pathogens known to induce immunosuppression. Such infections may be followed by breakdown of immune tolerance and induction of an immune attack on peripheral nerves. Mounting of the immune-mediated assault might be triggered either by the same infective pathogen or by secondary infection. Clearance of the infection and resumption of a normal immune response and tolerance eventually terminate the immune-mediated damage to the peripheral nerves and enable recovery. This hypothesis assumes that the entire sequence of events that culminates in GBS is due to transient exogenous factors and excludes a significant role for inherent host susceptibility, which explains the monophasic nature of the disorder.

Topological Anderson insulator in three dimensions.

We show that disorder, when sufficiently strong, can transform an ordinary metal with strong spin-orbit coupling into a strong topological "Anderson" insulator, a new topological phase of quantum matter in three dimensions characterized by disordered insulating bulk and topologically protected conducting surface states.

[A survey on intestinal parasites of livestock guardian dogs and herding dogs in Switzerland]. / Überblick über intestinale Parasiten bei Herdenschutzhunden und Hütehunden in der Schweiz.

The present study describes the occurrence of intestinal parasite infections in livestock guardian dogs and herding dogs. A total of 71 guardian dogs (more than half of the total number of guardian dogs in Switzerland) and 21 herding dogs were coprologically examined, using a combined sedimentation-flotation method. In 21 (23 %) of the dogs intestinal parasites were detected, and 8 (8.7 %) of these dogs shed either sporocysts of Sarcocystis sp. (n = 6) or taeniid eggs (n = 2). The evaluation of questionnaires providing data on age, origin and deworming schemes of the dogs completed the study.

Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia.

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a natural inhibitor of metalloproteinases involved in matrix degradation and ectodomain shedding of many cell-surface proteins, including death receptors and/or their ligands. In the present study, we examined the role of TIMP-3 in Fas-mediated neuronal cell death following cerebral ischemia, using both gene deletion and pharmacological approaches. In culture, exposure of primary cortical neurons to 2 h of oxygen-glucose deprivation (OGD) resulted in delayed neuronal cell death that was dependent on activation of the death receptor, Fas. Cortical cultures derived from timp-3(-/-) mice displayed partial resistance against OGD-induced neuronal cell death and also displayed increased shedding of Fas ligand (FasL) into the culture media, compared to wild-type control cultures. Both the increased neuroprotection and increased FasL shedding in timp-3(-/-) cultures were reversed by addition of exogenous metalloproteinase inhibitors, recombinant TIMP-3 or GM6001. In vivo, timp-3(-/-) mice showed marked resistance to a brief (30 min) middle cerebral artery occlusion (MCAO), but were not protected against more severe lesions induced by 90 min of MCAO. These studies demonstrate that TIMP-3 facilitates Fas-mediated neuronal cell death following OGD and plays a pro-apoptotic role in mild cerebral ischemia.

Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia.

Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. Normally, the highly integrated action of these enzyme families remodels all of the components of the matrix and performs essential functions at the cell surface involved in signaling, cell survival, and cell death. During the inflammatory response induced in infection, autoimmune reactions and hypoxia/ischemia, abnormal expression and activation of these proteases lead to breakdown of the extracellular matrix, resulting in the opening of the blood-brain barrier (BBB), preventing normal cell signaling, and eventually leading to cell death. There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.

Diversity of atlantic coastal plain mollusks since the pliocene.

About 70 percent of tropical western Atlantic mollusk species have become extinct since the Pliocene, which has led to perceptions of a corresponding decline in diversity. However, a compilation of gastropod species from Plio-Pleistocene faunas of the United States Atlantic coastal plain and from Recent western Atlantic faunas indicates that regional diversity has not changed since the Pliocene. Gastropod diversity in the Pliocene Pinecrest Beds in Florida approximates that seen today on either coast of Florida. Gastropod diversity is not demonstrably different in the Recent tropical western Atlantic than in the Recent tropical eastern Pacific. High extinction rates must have been balanced by high origination rates.

Calcification inside artificial hearts: inhibition by warfarin-sodium.

Intracavitary calcium phosphate deposits were observed in smooth, elastomeric blood pump sacs implanted in male calves for periods of 115 to 166 days. These deposits occurred predominantly on the flexing surface of the sacs. In contrast, similar pump sacs remained generally free of mineral deposits for up to 150 days in calves treated with the anticoagulant warfarin-sodium. These results implicate a vitamin K-dependent process in calcium phosphate deposition on elastomeric sacs.

Expression cloning and signaling properties of the rat glucagon receptor.

Glucagon and the glucagon receptor are a primary source of control over blood glucose concentrations and are especially important to studies of diabetes in which the loss of control over blood glucose concentrations clinically defines the disease. A complementary DNA clone for the glucagon receptor was isolated by an expression cloning strategy, and the receptor protein was expressed in several kidney cell lines. The cloned receptor bound glucagon and caused an increase in the intracellular concentration of adenosine 3', 5'-monophosphate (cAMP). The cloned glucagon receptor also transduced a signal that led to an increased concentration of intracellular calcium. The glucagon receptor is similar to the calcitonin and parathyroid hormone receptors. It can transduce signals leading to the accumulation of two different second messengers, cAMP and calcium.

A Variable Neighbourhood Descent Heuristic for Conformational Search Using a Quantum Annealer.

Discovering the low-energy conformations of a molecule is of great interest to computational chemists, with applications in in silico materials design and drug discovery. In this paper, we propose a variable neighbourhood search heuristic for the conformational search problem. Using the structure of a molecule, neighbourhoods are chosen to allow for the efficient use of a binary quadratic optimizer for conformational search. The method is flexible with respect to the choice of molecular force field and the number of discretization levels in the search space, and can be further generalized to take advantage of higher-order binary polynomial optimizers. It is well-suited for the use of devices such as quantum annealers. After carefully defining neighbourhoods, the method easily adapts to the size and topology of these devices, allowing for seamless scaling alongside their future improvements.

Tissue inhibitor of matrix metalloproteinases-3 (TIMP-3) lacks involvement in bacterial collagenase-induced intracerebral hemorrhage in mouse.

Intracerebral hemorrhage (ICH) leads to delayed cell death in the regions around the hemorrhagic mass. Apoptosis has been identified in the dying cells, but the mechanism involved is unclear. Others and us have shown that matrix metalloproteinases (MMPs) are increased in ICH and could directly contribute to cell death. Tissue inhibitor to metalloproteinases-3 (TIMP-3) facilitates apoptosis in cancer cells and neurons by inhibiting the shedding of tumor necrosis factor-alpha (TNF-alpha) death receptors, Fas and p55TNF receptor 1, by MMP-3 and TNF-alpha converting enzyme (TACE), respectively. Therefore, TIMP-3 may contribute to cell death in ICH. We adapted the bacterial collagenase-induced hemorrhage (CIH) model to the mouse. Adult C57Bl/6 and Timp-3 knockout mice had CIH. Expression of mRNA for TIMP-3 was determined by real-time PCR. Hemorrhage volume and numbers of apoptotic cells were measured by unbiased stereology. Timp-3 mRNA was similar in the knockout and wild-type mice prior to injury and induction of CIH failed to cause an increase in Timp-3 mRNA in the wild-type. Furthermore, there were no differences found in the hemorrhage size or in the numbers of apoptotic cells between the Timp-3 knockout or wild-type. We were unable to prove the hypothesis that TIMP-3 is involved cell death in CIH in the mouse.

Analysis of transcripts from intracellular stages of Eimeria acervulina using expressed sequence tags.

Coccidiosis in chickens is caused by 7 species of Eimeria. Even though coccidiosis is a complex disease that can be caused by any combination of these species, most of the molecular research concerning chicken coccidiosis has been limited to Eimeria tenella. The present study describes the first large-scale analysis of expressed sequence tags (ESTs) generated primarily from second-stage merozoites (and schizonts) of E. acervulina. In total, 1,847 ESTs were sequenced; these represent 1,026 unique sequences. Approximately half of the ESTs encode proteins of unknown function, or hypothetical proteins. Twenty-nine percent of the E. acervulina ESTs share significant sequence identity with sequences in the E. tenella genome. Additionally, EST hits seem to be much different compared with those of E. tenella. One of the differences is the very low number of ESTs that encode putative microneme proteins. This study underlines the potential differences in the molecular aspects of 2 Eimeria species that in the past were thought to be highly similar in nature.

HBeAg levels at week 24 predict response to 8 years of tenofovir in HBeAg-positive chronic hepatitis B patients.

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion is a treatment endpoint for HBeAg-positive CHB, and a necessary precursor to HBsAg loss. Biomarkers that predict serological outcomes would be useful. AIM: To evaluate the utility of measuring HBeAg levels for predicting HBeAg seroconversion and HBsAg loss under long-term tenofovir (TDF) therapy. METHODS: A total of 266 patients were enrolled into a phase III study of TDF vs adefovir (ADV) for 48 weeks in HBeAg-positive patients, followed by open-label TDF up to 384 weeks. Serum HBeAg levels were measured for subjects with samples available at both baseline and week 24 of treatment (n = 200). Analysis compared subjects who achieved HBeAg seroconversion by week 384 vs no HBeAg seroconversion. RESULTS: HBeAg seroconversion rate was 52% by week 384. Time to HBeAg seroconversion was 80 weeks (IQR: 36-162). HBeAg decline at week 24 was associated with HBeAg seroconversion (1.63 vs 0.90 log10 PEIU/mL, P = .002). The optimal threshold for identifying HBeAg seroconversion was HBeAg decline ≥2.2 log10 PEIU/mL at week 24, with HBeAg seroconversion achieved by 76% of patients, compared to 44% if HBeAg decline <2.2 log10 (P < .0001). HBeAg decline ≥2.2 log10 PEIU/mL at week 24 was associated with HBsAg loss in genotype A or D patients (38% vs 15%, P = .03). Precore/basal core promotor variants were associated with lower baseline HBeAg levels, but not HBeAg seroconversion. CONCLUSION: Decline in HBeAg levels by week 24 was associated with HBeAg seroconversion and HBsAg loss in HBeAg-positive chronic hepatitis B patients treated with long-term TDF.

Correlation between G2m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria.

To determine whether genetic factors influence the human antibody response to polysaccharides, we correlated Ig allotypes with the concentrations of antibody to 14 bacterial capsular antigens in 130 actively immunized Caucasian adults. The 88 individuals possessing G2m(n), an allotype antigen of IgG2 subclass heavy chains, had significantly higher postimmunization antibody levels to Haemophilus influenzae type b (Hib) and 8 of 11 pneumococcal types (P less than 0.05) than the 42 lacking this antigen. For Hib, pneumococcus type 14, and meningococcus group C, an increased response was observed in IgG class but not in IgM or IgA classes of antibody. The G2m(n) positive individuals also had higher preimmunization antibody levels to most polysaccharide antigens. Total IgG2 concentrations were correlated with the mean postimmunization antibody concentrations to pneumococci (P = 0.005), but this correlation was independent of G2m(n) by multiple regression analysis. To determine if the lack of G2m(n) was associated with increased susceptibility to infection, we compared the frequencies of various Ig allotypes in 98 children infected with Hib and 98 matched controls. Caucasian children with Hib infections other than epiglottitis were significantly more likely to lack the G2m(n) allotype than controls (P less than 0.05). G2m(n) negative Caucasian children less than or equal to 18 mo old have a 5.1-fold higher risk of nonepiglottitic Hib infections than G2m(n) positive children (P less than 0.01). We conclude that allotypic variants of the gamma-2 heavy chain genes, or genes in linkage equilibrium with them, exert a regulatory influence on the caucasian antibody response to a variety of immunologically distinct bacterial polysaccharide antigens. Young Caucasian children of the low responder phenotype, i.e., those lacking the G2m(n) allotype, are genetically predisposed to Hib and perhaps other bacterial infections.

Introduction of functional artificial introns into the naturally intronless ura4 gene of Schizosaccharomyces pombe.

Insertion of a 36-base-pair (bp) synthetic oligonucleotide comprising the sequence 5'-GTAGGT(19N)CTAAT (4N)AG-3' into several different positions within the coding region of the naturally intronless ura4 gene of Schizosaccharomyces pombe leads to an efficiently spliced gene producing a functional product. This suggests that the proper signals within an intron are sufficient to initiate and complete a splicing event independent of the location of the intron in the gene. Point mutations in the 5' junction (5'-GTAGGT-3') and in the putative branch sequence (5'-CTAAT-3') affect splicing efficiency significantly. A G-to-A transition at the first nucleotide at the 5' splice junction (5'-ATAGGT-3') abolishes the use of the authentic splice junction and leads to the increased use of an alternative splice site. No functional product is produced from this transcript. An A-to-G transition of the second A in the putative branch sequence (5'-CTAGT-3') lowers the splicing efficiency drastically, but still results in a functional gene product. Furthermore, extension of the 36-bp intron to introns more than 180 bp in size abolishes splicing, suggesting that the splicing apparatus might be restricted to very short introns. We discuss the possibility that S. pombe introns represent a simple type of eucaryotic intron.

Attitudinal changes of involuntarily committed patients following treatment.

Thirty-five involuntarily hospitalized psychiatric patients were interviewed immediately following admission and again prior to discharge to assess attitudinal changes and their relationship to patient characteristics and treatment outcome. The results indicate significant changes toward recognition of the original need for involuntary treatment. Those patients achieving remission of symptoms were most likely to have positive attitudes. Follow-up data indicate that the majority continued to receive outpatient treatment after the index episode, and among those readmissions that occurred, 92% were voluntary.

Reduced creatinine clearance in primary osteoporosis in women.

We determined the relationship between bone mass and age, anthropometric variables, and serum and urine biochemical variables in 77 normal white women and 37 women with primary osteoporosis, 25 of whom had one or more vertebral compression fractures. Skeletal status was assessed by radiography of the hands with measurement of combined cortical thickness of the second metacarpal bones (CCT) or measurement of radial and lumbar bone density, or by both methods. Radial bone mineral content (RBMC) was measured by single-photon absorptiometry (SPA) and lumbar bone mineral density by dual-photon absorptiometry (DPA). Serum and urine biochemical variables were measured on days 6 and 7 of a controlled diet. In this mixed population of normal and osteoporotic women, we confirmed the strong positive correlation between creatinine clearance (Ccr) and bone mass that we previously reported in normal women. Multiple regression analysis showed that the relationship between Ccr and bone mass of the radius and lumbar spine was independent of age and body stature. Ccr was significantly lower in the 25 osteoporotic women with vertebral crush fractures than in age-matched normal women, and Ccr had predictive value for bone mass in individual subjects. The basis for the relationship between Ccr and bone mass has not been established. We excluded diminished production of 1,25-dihydroxyvitamin D as a result of declining renal function as a possible mechanism.

Bone mass is related to creatinine clearance in normal elderly women.

We determined the relationship between bone mass and age, anthropometric variables, creatinine clearance (Ccr), and serum and urine biochemical variables in 77 normal white women (aged 41-86, mean = 67) living in their own homes. A total of 74 women were postmenopausal. Skeletal status was assessed in all subjects by x-rays of the hand with measurement of the mean combined cortical thickness (CCT) of the second metacarpal bones. In 53 women, bone mineral content of the radial shaft (RMBC) was also measured by single-photon absorptiometry (SPA) and lumbar bone mineral density (LBMD) was measured by dual-photon absorptiometry (DPA). Serum and urine biochemical variables were measured under standardized conditions on the sixth and seventh days of a controlled diet. There was a strong positive correlation between Ccr and bone mass. Although our subjects showed the expected linear decline in Ccr with age, we found that the relationship between Ccr and bone mass in the radius and lumbar spine was independent of age. On the other hand, the relationship between Ccr and CCT was not independent of age. We concluded that the relationship between Ccr and lumbar and radial bone mass is probably indicative of a relationship between glomerular filtration rate and bone mass, although this requires validation with a noncreatinine method for measurement of glomerular filtration rate. Age per se does not appear to be a cause of declining lumbar bone mass after the menopause.

White matter damage is associated with matrix metalloproteinases in vascular dementia.

BACKGROUND AND PURPOSE: Vascular disease causes multi-infarct dementia (MID) or Binswanger's disease (BD), the latter of which is a progressive form of vascular dementia (VaD) associated pathologically with fibrinoid and hyaline changes in brain arterioles with injury to the white matter. Clinically, BD patients have long-standing hypertension with disturbances of gait and intellect. Because matrix metalloproteinases (MMPs) are important in cerebral infarction, we hypothesized that disturbances in the MMPs may be involved in VAD: METHODS: Brain tissues from 5 patients with VaD of the BD or multi-infarct type (MID) were immunostained with antibodies to glial fibrillary acidic protein (GFAP), a microglial/macrophage cell marker (PG-M1), gelatinase A (MMP-2), stromelysin-1 (MMP-3), and gelatinase B (MMP-9). Control tissues were from 8 elderly patients: 4 with strokes without dementia and 4 without neurological diseases. RESULTS: PG-M1+ cells appeared around infarcts in patients with strokes without dementia and in patients with VAD: In 2 of the 3 BD patients, PG-M1 cells were prominent near damaged arterioles and scattered diffusely in white matter. MMP-2 was seen normally in perivascular macrophages and in astrocytic processes near blood vessels and was present in patients with strokes in reactive astrocytes. MMP-9 was rarely seen. MMP-3 was seen in PG-M1+ microglial/macrophage cells around the acute infarctions. In BD, MMP-3 persisted in tissue macrophages and disappeared in long-standing white matter gliosis. CONCLUSIONS: These observations suggest that MMPs may participate in the damage to the white matter associated with VAD: Microglia/macrophage-induced damage, which is amenable to treatment, may be a factor in the progressive forms of VAD: