Mortality trends for accidental falls in older people in Spain, 2000-2015.

BACKGROUND: Accidental falls in older people are a major public health problem but a relatively limited number of studies have analyzed the mortality trends from this cause. Effective public health interventions have been found to prevent the incidence of falls and their complications. Therefore, characterizing the mortality trends of falls for different subpopulations can help to identify their needs and contribute to develop more appropriate prevention programs for specific target groups. METHODS: This study was based on a longitudinal analysis of death rates from accidental falls (2000-2015) stratified by sex for the population ≥ 65 years and by age groups (65-74, 75-84, ≥85). A joinpoint regression model was used to identify trend inflection points. The Annual Percent Change (APC) was estimated for each trend. RESULTS: Mortality rates per 100,000 person-years increased from 20.6 to 30.1 for men and 13.8 to 20.8 for women between 2000 and 2015. Men presented a relevant trend increase between 2008 and 2015 (APC [95% CI] 7.2% [5.3;9.2]) and women between 2008 and 2013 (7.9% [4.1;11.8]) There were no trend differences between sexes. For 65-74 years old men we found a relevant increase in the last period (2011-2015) (7.8% [1.0;15.1]). Those aged 75-84 years showed a trend increase between 2007 and 2015 (6.4% [4.4;8.4]) and men ≥85 years presented a remarkably high trend between 2008 and 2015 (9.0% [5.2;13]). There were no relevant differences between age groups. Women aged 65-74 had no relevant trend through the period. Those aged 75-84 presented an uniform trend increase for the whole period, 2000-2015, (3.4% [2.3;4.4]) and women ≥85 had and important trend increase between 2008 and 2013 (11.1% [5.3;17.2]), that has reached an stable level in the last 2 years. There were no relevant differences between the 75-84 and ≥85 age groups. CONCLUSIONS: Recent mortality trends from accidental falls increased in men ≥65 years and women ≥75 years. These results recommend the implementation of specific preventive programs.

Correction of murine galactosialidosis by bone marrow-derived macrophages overexpressing human protective protein/cathepsin A under control of the colony-stimulating factor-1 receptor promoter.

Galactosialidosis (GS) is a human neurodegenerative disease caused by a deficiency of lysosomal protective protein/cathepsin A (PPCA). The GS mouse model resembles the severe human condition, resulting in nephropathy, ataxia, and premature death. To rescue the disease phenotype, GS mice were transplanted with bone marrow from transgenic mice overexpressing human PPCA specifically in monocytes/macrophages under the control of the colony stimulating factor-1 receptor promoter. Transgenic macrophages infiltrated and resided in all organs and expressed PPCA at high levels. Correction occurred in hematopoietic tissues and nonhematopoietic organs, including the central nervous system. PPCA-expressing perivascular and leptomeningeal macrophages were detected throughout the brain of recipient mice, although some neuronal cells, such as Purkinje cells, continued to show storage and died. GS mice crossed into the transgenic background reflected the outcome of bone marrow-transplanted mice, but the course of neuronal degeneration was delayed in this model. These studies present definite evidence that macrophages alone can provide a source of corrective enzyme for visceral organs and may be beneficial for neuronal correction if expression levels are sufficient.

Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase.

Human GM1-gangliosidosis is caused by a genetic deficiency of lysosomal acid beta-galactosidase (beta-gal). The disease manifests itself either as an infantile, juvenile or adult form and is primarily a neurological disorder with progressive brain dysfunction. A mouse model lacking a functional beta-gal gene has been generated by homologous recombination and embryonic stem cell technology. Tissues from affected mice are devoid of beta-gal mRNA and totally deficient in GM1-ganglioside-hydrolyzing capacity. Storage material was already conspicuous in the brain at 3 weeks. By 5 weeks, extensive storage of periodic acid Schiff-positive material was observed in neurons throughout the brain and spinal cord. Consistent with the neuropathology, abnormal accumulation of GM1-ganglioside in the brain progressed from twice to almost five times the normal amount during the period from 3 weeks to 3.5 months. Despite the accumulation of brain GM1-ganglioside at the level equal to or exceeding that seen in gravely ill human patients, these mice show no overt clinical phenotype up to 4-5 months. However, tremor, ataxia and abnormal gait become apparent in older mice. Thus, the beta-gal-deficient mice appear to mimic closely the pathological, biochemical and clinical abnormalities of the human disease.

Lack of PPCA expression only partially coincides with lysosomal storage in galactosialidosis mice: indirect evidence for spatial requirement of the catalytic rather than the protective function of PPCA.

Protective protein/cathepsin A (PPCA) is a pleiotropic lysosomal enzyme that complexes with beta-galactosidase and neuraminidase, and possesses serine carboxypeptidase activity. Its deficiency in man results in the neurodegenerative lysosomal storage disorder galactosialidosis (GS). The mouse model of this disease resembles the human early onset phenotype and results in severe nephropathy and ataxia. To understand better the pathophysiology of the disease, we compared the occurrence of lysosomal PPCA mRNA and protein in normal adult mouse tissues with the incidence of lysosomal storage in PPCA(-/-) mice. PPCA expression was markedly variable among different tissues. Most sites that produced both mRNA and protein at high levels in normal mice showed extensive and overt storage in the knockout mice. However, this correlation was not consistent as some cells that normally expressed high levels of PPCA were unaffected in their storage capability in the PPCA(-/-) mice. In addition, some normally low expressing cells accumulated large amounts of undegraded products in the GS mouse. This apparent discrepancy may reflect a requirement for the catalytic rather than the protective function of PPCA and/or the presence of cell-specific substrates in certain cell types. A detailed map showing the cellular distribution of PPCA in nomal mouse tissues as well as the sites of lysosomal storage in deficient mice is critical for accurate assessment of the effects of therapeutic interventions.