The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice

Parkin suppression induces accumulation of β-amyloid in mutant tau mice. We studied the effect of parkin suppression on behaviour and brain pathology in APP_swe mutant mice. We produced double mutant mice with human mutated APP_swe + partial (hemizygote) or total (homozygote) deletion of Park-2 gene. We studied the development, behaviour, brain histology, and biochemistry of 12- and 16-month-old animals in 6 groups of mice, with identical genetic background: wild-type (WT), APP_swe overexpressing (APP), hemizygote and homozygote deletion of Park-2 (PK^+/− and PK^−/−, respectively), and double mutants (APP/PK^+/− and APP/PK^−/−).APP mice have reduced weight gain, decreased motor activity, and reduced number of entrances and of arm alternation in the Y-maze, abnormalities which were partially or completely normalized in APP/PK^+/− and APP/PK^−/− mice. The double mutants had similar number of mutant human APP transgene copies than the APP and levels of 40 and 80 kDa proteins; but both of them, APP/PK^+/− and APP/PK^−/− mice, had less plaques in cortex and hippocampus than the APP mice. APP mutant mice had increased apoptosis, proapoptotic Bax/Bcl2 ratios, and gliosis, but these death-promoting factors were normalized in APP/PK^+/− and APP/PK^−/− mice. APP mutant mice had an increased number of tau immunoreactive neuritic plaques in the cerebral cortex as well as increased levels of total and phosphorylated tau protein, and these changes were partially normalized in APP/PK^+/− heterozygotic and homozygotic APP/PK^−/− mice. Compensatory protein-degrading systems such as HSP70, CHIP, and macroautophagy were increased in APP/PK^+/− and APP/PK^−/−. Furthermore, the chymotrypsin- and trypsin-like proteasome activities, decreased in APP mice in comparison with WT, were normalized in the APP/PK^−/− mice.We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP_swe mice.     

Heme oxygenase-1-generated biliverdin ameliorates experimental murine colitis

BACKGROUND: Heme oxygenase-1 (HO-1) seems to have an important protective role in acute and chronic inflammation. The products of heme catalysis, biliverdin/bilirubin, carbon monoxide (CO), and iron (that induces apoferritin) mediate the beneficial effects of HO-1. Blockade of HO-1 activity results in exacerbation of experimental colitis. We tested whether HO-1 has protective effects in the development of colitis and determined that specific enzymatic products of HO-1 are responsible for these effects. METHODS: Colitis was induced by oral administration of dextran sodium sulfate (5%) to C57BL/6 mice for 7 days. HO-1 was up-regulated by cobalt-protoporphyrin (5 mg/kg, intraperitoneally). Biliverdin, exogenous CO, or the iron chelator desferrioxamine was administered to other groups. RESULTS: Cobalt-protoporphyrin treatment resulted in significant up-regulation of HO-1 protein in mucosal and submucosal cells. Induction of HO-1 was associated with significantly less loss of body weight in mice with induced colitis (-12% versus -22% in the control animals, P < 0.001). Development of diarrhea and gastrointestinal hemorrhage was substantially delayed in animals in which HO-1 was induced, and mucosal injury was significantly attenuated. Administration of CO or desferrioxamine alone had no significant effects, whereas enhanced protection with lesser evidence of bowel inflammation was observed with systemic biliverdin administration (50 micromol/kg, 3 times per day, intraperitoneally). CONCLUSIONS: We conclude that heightened HO-1 expression or administration of biliverdin ameliorates dextran sodium sulfate-induced experimental colitis. Novel therapeutic strategies based on HO-1 and/or biliverdin administration may have use in inflammatory bowel disease.     

The incidence of respiratory symptoms and diseases among pulp mill workers with peak exposures to ozone and other irritant gases

OBJECTIVES: Pulp mills in Sweden started to use ozone as a bleaching agent in the early 1990s. The goal of this study was to investigate whether the incidence of selected respiratory outcomes was associated with peak exposures to ozone or other irritant gases (ie, chlorine dioxide [ClO2] or sulfur dioxide [SO2]) used in these mills. METHODS: Bleachery workers (n = 245) from three pulp mills where ozone was used participated in surveys in the mid- to late-1990s. Comparison workers (n = 80) were from two adjacent paper mills. The person-time at risk was calculated for each participant, covering the period of employment when ozone was used. Data were collected by questionnaire, and a peak exposure was defined as a self-reported exposure to an irritant gas resulting in acute respiratory symptoms. The outcomes analyzed were self-reports of physician-diagnosed asthma, attacks of wheeze, and chronic bronchitis (ie, chronic cough with phlegm). Participants also reported when the peak exposures and outcomes occurred. RESULTS: Based on proportional hazards regression (controlling for gender, age, cigarette smoking, atopy, and peak irritant exposures that occurred before follow-up), workers who reported both ozone and ClO2/SO2 peak exposures had elevated hazard ratios (HRs) for all three outcomes. Those who reported only ozone peak exposures had elevated HRs of 6.5 (95% confidence interval [CI], 1.2 to 36.3) for asthma and 3.3 (95% CI, 1.1 to 10.2) for attacks of wheeze but no increase in risk for chronic bronchitis. Workers with only ClO2/SO2 peak exposures had elevated HRs for attacks of wheeze (HR, 7.5; 95% CI, 1.9 to 29.3) and chronic bronchitis (HR, 22.9; 95% CI, 4.5 to 118.2) but not for asthma. CONCLUSIONS: These findings suggest the need for additional efforts to prevent peak exposures in pulp-bleaching operations.     

Glucagonoma syndrome. Rapid response following arterial embolization of glucagonoma metastatic to the liver

Transcatheter arterial embolization was used to treat a patient with glucagonoma metastatic to the liver after chemotherapy failed. Rapid amelioration of the syndrome's manifestations followed.     

Clinical, histochemical, and ultrastructural correlation in septal endomyocardial biopsies from chronic chagasic patients: detection of early myocardial damage

In order to recognize early signs of myocardial damage, histologic, histochemical, and ultrastructural studies were performed on septal endomyocardial biopsy tissue obtained from 79 chronic chagasic patients and from 18 patients with atypical chest pain (control group). Abnormal biopsy findings were recognized in 9 of 16 (60%) chagasic patients with no clinical evidence of myocardial damage. In cases of segmental asynergy only, biopsies were abnormal in 18 of 19 patients. When signs of advanced myocardial damage were evidenced by clinical examination or ECGs, all biopsies were abnormal. Mitochondrial, nuclear, and cell membrane irregularities were consistent findings. A peculiar dilatation and filling of the T tubule system with a glycoprotein-like substance and a remarkable increase in monoamine oxidase activity were observed early in the disease and progressed in magnitude and frequency as myocardial damage became more evident by other diagnostic methods. Septal endomyocardial biopsy is a sensitive method for detection of early myocardial damage in chronic chagasic patients. Based on these findings, a modification of the currently used classification is proposed.     

Hiking in Suicidal Patients: Neutral Effects on Markers of Suicidality

Background

Regular physical activity promotes physical and mental health. Psychiatric patients are prone to a sedentary lifestyle, and accumulating evidence has identified physical activity as a supplemental treatment option.

Methods

This prospective, randomized, crossover study evaluated the effects of hiking in high-risk suicidal patients (n = 20) who performed 9 weeks of hiking (2-3 hikes/week, 2-2.5 hours each) and a 9-week control period.

Results

All patients participated in the required 2 hikes per week and thus showed a compliance of 100%. Regular hiking led to significant improvement in maximal exercise capacity (hiking period Δ: +18.82 ± 0.99 watt, P < .001; control period: P = .134) and in aerobic capability at 70% of the individual heart rate reserve (hiking period Δ: +8.47 ± 2.22 watt; P = .010; control period: P = .183). Cytokines, associated previously with suicidality (tumor necrosis factor-α, interleukin-6, S100), remained essentially unchanged.

Conclusions

Hiking is an effective and safe form of exercise training even in high-risk suicidal patients. It leads to a significant improvement in maximal exercise capacity and aerobic capability without concomitant deterioration of markers of suicidality. Offering this popular mode of exercise to these patients might help them to adopt a physically more active lifestyle.     

Necroptotic cell death in failing heart: relevance and proposed mechanisms

As cardiomyocytes have a limited capability for proliferation, renewal, and repair, the loss of heart cells followed by replacement with fibrous tissue is considered to result in the development of ventricular dysfunction and progression to heart failure (HF). The loss of cardiac myocytes in HF has been traditionally believed to occur mainly due to programmed apoptosis or unregulated necrosis. While extensive research work is being carried out to define the exact significance and contribution of both these cell death modalities in the development of HF, recent knowledge has indicated the existence and importance of a different form of cell death called necroptosis in the failing heart. This new cell damaging process, resembling some of the morphological features of passive necrosis as well as maladaptive autophagy, is a programmed process and is orchestrated by a complex set of proteins involving receptor-interacting protein kinase 1 and 3 (RIP1, RIP3) and mixed lineage kinase domain-like protein (MLKL). Activation of the RIP1–RIP3–MLKL signaling pathway leads to disruption of cation homeostasis, plasma membrane rupture, and finally cell death. It seems likely that inhibition of any site in this pathway may prove as an effective pharmacological intervention for preventing the necroptotic cell death in the failing heart. This review is intended to describe general aspects of the signaling pathway associated with necroptosis, to describe its relationship with cardiac dysfunction in some models of cardiac injury and discuss its potential relevance in various types of HF with respect to the underlying pathologic mechanisms.     

Prevalent presence of periodic actin–spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species

Actin, spectrin, and associated molecules form a periodic, submembrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal- and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: Spectrin shows a long-range, periodic distribution throughout all axons but appears periodic only in a small fraction of dendrites, typically in the form of isolated patches in subregions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is disrupted in most presynaptic boutons but is present in an appreciable fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus, and Homo sapiens.Actin is critically involved in the regulation of neuronal polarization, differentiation, and growth of neuronal processes, cargo trafficking, and plasticity of synapses (1–3). Spectrin is an actin-binding protein that is important for the development and stabilization of axons and maintenance of neuronal polarization (4–6). In Caenorhabditis elegans, spectrin is important for the stability and integrity of axons under mechanical stress (4, 6) and for mechanosensation (6), and spectrin depletion results in axon breakage during animal locomotion (4). In Drosophila, spectrin has been shown to be involved in axonal path finding (7) and stabilization of presynaptic terminals (8). In mice, spectrin null mutations are embryonically lethal, and neurons with spectrin knockdown display defects in axonal initial segment assembly (5, 9, 10).Actin and spectrin form a 2D polygonal lattice structure underneath the membrane of erythrocytes (11). Recently, a novel form of actin–spectrin-based submembrane skeleton structure was discovered in neuronal axons (12) using superresolution STORM imaging (13, 14). This membrane-associated periodic skeleton (MPS) has been observed in both fixed and live cultured neurons (12, 15, 16) and in brain tissue sections (12). In this structure, short actin filaments are organized into repetitive, ring-like structures that wrap around the circumference of the axon with a periodicity of ∼190 nm; adjacent actin rings are connected by spectrin tetramers, and actin short filaments in the rings are capped by adducin (12). This structure also appears to organize other associated molecules, such as ankyrin and sodium channels, into a periodic distribution in axons (12, 16). During neuronal development, MPS originates from the axonal region proximal to the soma and propagates to distal axonal terminals (16). At a relatively late stage during development, specific isoforms of ankyrin and spectrin molecules, ankyrin-G and βIV spectrin, are recruited to the axon initial segment (AIS) (17, 18), and these molecules are also assembled into the MPS structure, adopting a similar periodic distribution (16, 19). As in the AIS, this periodic structure is also present in the nodes of Ranvier (20). This periodic skeletal structure has been shown to preferentially form in axons compared with dendrites in primary neuronal cultures: actin and spectrin typically form a long-range, periodic lattice structure throughout the entire axonal shaft, except for the very distal region near the growth cone, in essentially all observed axons. In contrast, such a periodic structure was observed in only a small fraction (∼10–30%) of dendrites and typically appeared as short, isolated patches in portions of these dendrites (16, 20). The local concentration of spectrin is a key determinant for the preferential formation of MPS in axons: in wild-type neurons, βII spectrin is enriched in axons, and artificially increasing the concentration of βII spectrin through overexpression is sufficient to induce the formation of MPS in all dendrites (16). Ankyrin-B appears to be an important regulator of this structure: in ankyrin-B knockout mice, βII spectrin becomes evenly distributed between axons and dendrites, leading to the formation of the long-range MPS structure in all dendrites (16) without perturbing the MPS structure in axons (16, 21).The ubiquitous expression of spectrin in the nervous systems of nearly all animal species (22) raises the questions of how widespread the MPS structure is in different nervous system cell types and distinct subcellular compartments and of how conserved this structure is across different animal species. A recent paper reports the presence of periodic actin structures in several nervous system cell types from rodents (23). Here we investigated these questions regarding the prevalence and conservation of the MPS structure by examining the distribution of spectrin in many different types of rodent neurons and glial cells and across a variety of organisms ranging from C. elegans to Homo sapiens. Furthermore, we examined the distribution of spectrin in presynaptic and postsynaptic compartments of axons and dendrites, respectively, to shed light on the relation between the MPS structure and synapses.     

Neutrophils extracellular traps damage Naegleria fowleri trophozoites opsonized with human IgG

Naegleria fowleri infects humans through the nasal mucosa causing a disease in the central nervous system known as primary amoebic meningoencephalitis (PAM). Polymorphonuclear cells (PMNs) play a critical role in the early phase of N. fowleri infection. Recently, a new biological defence mechanism called neutrophil extracellular traps (NETs) has been attracting attention. NETs are composed of nuclear DNA combined with histones and antibacterial proteins, and these structures are released from the cell to direct its antimicrobial attack. In this work, we evaluate the capacity of N. fowleri to induce the liberation of NETs by human PMN cells. Neutrophils were cocultured with unopsonized or IgG‐opsonized N. fowleri trophozoites. DNA, histone, myeloperoxidase (MPO) and neutrophil elastase (NE) were stained, and the formation of NETs was evaluated by confocal microscopy and by quantifying the levels of extracellular DNA. Our results showed N. fowleri induce the liberation of NETs including release of MPO and NE by human PMN cells as exposure interaction time is increased, but N. fowleri trophozoites evaded killing. However, when trophozoites were opsonized, they were susceptible to the neutrophils activity. Therefore, our study suggests that antibody‐mediated PMNs activation through NET formation may be crucial for antimicrobial responses against N. fowleri.