Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: possible roles in motor neuron survival

In amyotrophic lateral sclerosis (ALS) there is a selective degeneration of motor neurons leading to muscle paralysis and death. The mechanism underlying cell demise in ALS is not fully understood, but involves the activation of different proteolytic enzymes, including the caspase family of cysteine proteases. We have here studied whether other proteases, such as the cathepsins, residing in lysosomes, and the cathepsin inhibitors, cystatinB and -C are changed in ALS. The expression and protein levels of the cathepsinB, -L and -D all increased in the spinal cord in ALS mice, carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. At the cellular level, cathepsinB and -L were present in ventral motor neurons in controls, but in the ALS mice cathepsinB was also expressed by glial fibrillary acidic protein (GFAP) positive astrocytes. The distribution of the aspartic protease, cathepsinD also changed in ALS with a loss of the lysosomal staining in motor neurons. Inhibition of caspases by means of X-chromosome-linked inhibitor of apoptosis protein (XIAP) overexpression did not inhibit cleavage of cathepsinD in ALS mice, suggesting a caspase-independent pathway. Expression of cystatinB and -C increased slightly in the ALS spinal cords. Immunostaining showed that in ALS, cystatinC was present in motor neurons and in GFAP positive astrocytes. CystatinB that is a neuroprotective factor decreased in motor neurons in ALS but was expressed by activated microglial cells. The observed changes in the levels and distributions of cathepsinD and cystatinB and-C indicate a role of these proteins in the degeneration of motor neurons in ALS.     

Prediction of inspiratory flow shapes during sleep with a mathematic model of upper airway forces

STUDY OBJECTIVES: To predict the airflow dynamics during sleep using a mathematic model that incorporates a number of static and dynamic upper airway forces, and to compare the numerical results to clinical flow data recorded from patients with sleep-disordered breathing on and off various treatment options. DESIGN: Upper airway performance was modeled in virtual subjects characterized by parameter settings that describe common combinations of risk factors predisposing to upper airway collapse during sleep. The treatments effect were induced by relevant changes of the initial parameter values. SETTING: Computer simulations at our website (http://www.utu.fi/ml/sovmat/bio/). PARTICIPANTS: Risk factors considered in the simulation settings were sex, obesity, pharyngeal collapsibility, and decreased phasic activity of pharyngeal muscles. INTERVENTIONS: The effects of weight loss, pharyngeal surgery, nasal continuous positive airway pressure, and respiratory stimulation on the inspiratory flow characteristics were tested with the model. MEASUREMENTS AND RESULTS: Numerical predictions were investigated by means of 3 measurable inspiratory airflow characteristics: initial slope, total volume, and flow shape. The model was able to reproduce the inspiratory flow shape characteristics that have previously been described in the literature. Simulation results also supported the observations that a multitude of factors underlie the pharyngeal collapse and, therefore, certain medical therapies that are effective in some conditions may prove ineffective in others. CONCLUSIONS: A mathematic model integrating the current knowledge of upper airway physiology is able to predict individual treatment responses. The model provides a framework for designing novel and potentially feasible treatment alternatives for sleep-disordered breathing.     

Fluid pressure driven fibril reinforcement in creep and relaxation tests of articular cartilage

Biological tissues exhibit diverse mechanical behaviors because of complex material properties. As has been shown for ligaments and intervertebral discs, mathematical models often appear to well predict load responses individually by adjusting model parameters, but likely fail to describe several different load responses simultaneously using the same model parameters. In the present study, we attempted to describe and explain both creep and relaxation responses of articular cartilage using a fibril-reinforced model, which has been successfully used to account for the load response of the relaxation tests of articular cartilage. Experiments were performed on bovine articular cartilage disks (n=8) using multi-step loading protocols, involving both creep and relaxation in each protocol. The experimental results indicated that mechanical changes, such as fiber recruitment in collagen network during stretch, recovered fully upon unloading. Creep loading did not affect relaxation properties, and vice versa. Relaxation proceeded much faster than creep, because of different fluid pressure profiles. The load sharing among the proteoglycan matrix, collagen network and fluid pressurization was predicted to differ for the creep and relaxation testing. The experimentally observed strong creep and relaxation responses in unconfined compression could not be predicted if either fibril reinforcement or fluid pressurization were neglected. It was essential to consider the interplay between nonlinear fibril reinforcement and fluid pressurization for the transient response (this interplay may be best termed as fluid pressure driven fibril reinforcement). Fibril reinforcement played a relatively insignificant role in the compressive load response at equilibrium, in agreement with previous findings for cartilage stress relaxation testing.     

Genetic characterization of new Dobrava hantavirus isolate from Greece

The first complete genome sequence of Dobrava hantavirus isolated from yellow-necked mouse Apodemus flavicollis trapped in the northeastern Greece is described. The S, M, and L segments of the Greek isolate of Dobrava virus are 1673, 3635, and 6532 nucleotides (nt) long, respectively, and encode the nucleocapsid (N) protein of 429 amino acids (aa), glycoprotein precursor of 1135 aa, and the L protein of 2151 aa. N protein contains three cysteine residues conserved in all known hantaviruses, as well as structural domains responsible for the RNA binding and presumable interaction with the apoptosis enhancer Daxx. All cysteine residues and glycosylation sites that are conserved among G1G2 sequences of all hantaviruses species were also found in the Greek isolate. The L protein contains all the polymerase motifs and structural domains found in other hantavirus polymerases. Comparison of the Greek isolate of Dobrava virus with other hantaviruses showed the highest level of sequence homology with Dobrava virus isolate from Slovenia. Other hantaviruses carried by Murinae rodents (Saaremaa, Hantaan, Seoul, and Thailand viruses) were more divergent and hantaviruses carried by Arvicolinae or Sigmodontinae rodents showed the highest genetic diversity with the Greek isolate of Dobrava. The results of phylogenetic analyses confirmed these observations and showed a monophily of all the Dobrava virus strains that, in turn, shared more ancient ancestors first with Saaremaa virus and then with other Murinae-borne hantaviruses.     

Self-rated Health and Social Capital Among Aging People Across the Urban–Rural Dimension

Background

Previous studies have found self-rated health to be associated with social capital. However, there is lack of studies examining social capital among aging people and its impact on self-rated health in the urban–rural context.

Purpose

The purpose of this study was to investigate associations between self-rated health and indicators of social capital (trust, various social contacts, social participation, and access to help) among aging people living in urban and rural areas in Finland.

Method

A postal survey was conducted in 2002 among men and women born in 1926–1930, 1936–1940, or 1946–1950 and dwelling in 14 municipalities in the Päijät-Häme hospital district in Finland. A total of 2,815 participants represented 66% of the original stratified (by age, gender, and municipality) sample. Logistic regression analyses were used to examine the associations.

Results

Active social participation and easy access to help from others were associated with good self-rated health, especially in the urban and sparsely populated rural areas. Trust was a particularly important correlate of subjective health in the urban area, though its significance diminished after adjusting to all background variables. No overall disparities in self-rated health between the areas emerged. Social participation and access to help as indicators of social capital seem to be important resources when aging men and women assess their subjective health.

Conclusion

Increasing efforts to encourage social participation and facilitate access to help from other persons should be included among the key priorities in community health promotion.     

Serological microarray for detection of HSV-1, HSV-2, VZV, and CMV antibodies

The seroprevalence of human herpesviruses is high and reactivations occur frequently. A microarray was designed and tested for the detection of IgG and IgM antibodies for Puumala hantavirus (PUUV) and IgG antibodies against four herpesviruses. Initially, a microarray platform was set up using an unrelated in-house antigen, PUUV recombinant nucleocapsid protein, to optimize the protocol for the detection of antibodies. Detection of the four herpesviruses was set up in a microarray using the recombinant proteins of herpes simplex virus (HSV) glycoprotein G1 and G2, varicella-zoster virus (VZV) glycoprotein E, and cytomegalovirus (CMV) pp150 phosphoprotein.The results of the PUUV panel were in good agreement with the PUUV IgG immunofluorescent assay and IgM enzyme immunoassay (EIA). Seropositive and negative clinical reference panels were tested for herpesviruses by the serological microarray, and the results were compared to those of individual EIAs used for standard diagnostic purposes.The serologic microarray for HSV, VZV and CMV antibody detection gave good specificities for IgG. However, sensitivities of the assay varied depending on the herpesvirus detected. The serological microarray showed potential for screening purposes. The microarray based analyses were easy to perform, and HSV-1, HSV-2, VZV, and CMV antibodies could be detected on the same microarray.     

Screening for cardiovascular risk factors and self-rated health in a community setting: a cross-sectional study in Finland

Background

Self-rated health is an independent predictor of mortality. However, general health checks in populations unselected for disease or risk factors have not been shown to reduce mortality or morbidity.

Aim

To describe new comorbidities and cardiovascular risk factors in apparently healthy people and to relate this to their self-rated health.

Design and setting

A targeted screening programme identified 462 middle-aged people with cardiovascular risk factors without previously diagnosed chronic disease in a Finnish community in 2005–2006.

Method

Home blood pressure monitoring, oral glucose tolerance test, estimated glomerular filtration rate, and ankle brachial index were used to detect previously undiagnosed conditions. The Short-Form Health Survey and Beck’s Depression Inventory were completed by participants before the diagnostic tests were performed.

Results

The prevalence of previously undiagnosed disease was: hypertension 113/462 (24% [95% confidence interval {CI} = 21% to 29%]), diabetes 19/462 (4% [95% CI = 2% to 6%]), renal insufficiency 23/462 (5% [95% CI = 3% to 7%]), and peripheral arterial disease 17/462 (4% [95% CI = 2% to 5%]). Of the 139 participants who regarded their health as ‘fair–poor’, 60 (43%) had a previously undetected condition affecting their vasculature.

Conclusion

Out of the screen-detected apparently healthy cardiovascular risk subjects, one in three had undiagnosed hypertension, diabetes, peripheral arterial disease, or renal insufficiency. Those individuals experiencing ill health tended to be at high risk of cardiovascular problems.     

Tracking and determinants of LDL particle size in healthy children from 7 to 11 years of age: the STRIP Study

Serum low-density lipoprotein (LDL) particle composition varies according to lifestyle and age. To analyze its long-term tracking, we studied LDL particle size consecutively in 100 children at the ages of 7, 9 and 11 years using a high-resolution 3% polyacrylamide gel tube, electrophoresis method, searching also for long-term determinants of the particle size. The mean LDL particle sizes at 7 and 9 years, and at 7 and 11 years correlated directly (r = 0.72 and 0.39, respectively). The probability that children would remain in the same LDL particle size tertile between 7 and 11 years of age was 48% (p = 0.008). Longitudinally, total, high-density lipoprotein (HDL) and LDL cholesterol concentrations and body mass index (BMI) associated directly with mean LDL particle size, and triglyceride concentration and triglyceride/HDL cholesterol ratio correlated inversely. A shift from pre-puberty to puberty was associated with an increase in LDL particle size. Sex, serum insulin concentration, or energy nutrient intakes did not associate with LDL particle size. In conclusion, although mean LDL particle size tracks in 7- to 11-year-old healthy children, changes in serum triglycerides, HDL, LDL, and total cholesterol concentration, BMI, and pubertal status all modify LDL particle size.     

A randomized intervention since infancy to reduce intake of saturated fat: calorie (energy) and nutrient intakes up to the age of 10 years in the Special Turku Coronary Risk Factor Intervention Project

OBJECTIVE: To evaluate the longitudinal impact of dietary counseling on children's nutrient intake. DESIGN: A prospective, randomized, clinical trial. PARTICIPANTS: Children were recruited to the study between December 1, 1989, and May 30, 1992. At the age of 7 months, children were randomized to the intervention group (n = 540) or the control group (n = 522) and were followed up until the age of 10 years.Intervention Families in the intervention group have, since randomization, received regularly individualized counseling about how to modify the quality and quantity of fat in the child's diet, the goal being an unsaturated-saturated fat ratio of 2:1. MAIN OUTCOME MEASURES: Nutrient intakes between the ages of 4 and 10 years based on annual 4-day food records. RESULTS: The fat intake of the intervention children was constantly around 30% of the calorie (energy) intake, while that of the control children was 2 to 3 calorie percentage units higher (P<.001). The intervention children received 2 to 3 calorie percentage units less saturated fats and 0.5 to 1.0 calorie percentage unit more polyunsaturated fats than the control children (P<.001 for both). However, neither group reached the 2:1 goal set for the unsaturated-saturated fatty acid ratio. The vitamin and mineral intakes of the intervention and control children closely resembled each other despite the marked differences in fat intake. CONCLUSION: Individualized, biannually given, fat intake-focused dietary counseling that began at the child's age of 8 months continued to influence favorably the diet of 4- to 10-year-old intervention children without disadvantageous dietary effects, but the 2:1 goal for unsaturated-saturated fat ratio was not reached.