Prevalence of and factors associated with frailty and disability in older adults from China, Ghana, India, Mexico, Russia and South Africa.

BACKGROUND: The severe burden imposed by frailty and disability in old age is a major challenge for healthcare systems in low- and middle-income countries alike. The current study aimed to provide estimates of the prevalence of frailty and disability in older adult populations and to examine their relationship with socioeconomic factors in six countries. METHODS: Focusing on adults aged 50+ years, a frailty index was constructed as the proportion of deficits in 40 variables, and disability was assessed using the World Health Organization Disability Assessment Schedule (WHODAS 2.0), as part of the Study on global AGEing and adult health (SAGE) Wave 1 in China, Ghana, India, Mexico, Russia and South Africa. RESULTS: This study included a total of 34,123 respondents. China had the lowest percentages of older adults with frailty (13.1%) and with disability (69.6%), whereas India had the highest percentages (55.5% and 93.3%, respectively). Both frailty and disability increased with age for all countries, and were more frequent in women, although the sex gap varied across countries. Lower levels of both frailty and disability were observed at higher levels of education and wealth. Both education and income were protective factors for frailty and disability in China, India and Russia, whereas only income was protective in Mexico, and only education in South Africa. CONCLUSIONS: Age-related frailty and disability are increasing concerns for older adult populations in low- and middle-income countries. The results indicate that lower levels of frailty and disability can be achieved for older people, and the study highlights the need for targeted preventive approaches and support programs.

Chromosome evolution in bats as revealed by FISH: the ongoing search for the ancestral chiropteran karyotype.

Chiroptera, the second largest order of mammals, comprises more than 1,000 species in 18 highly morphologically diverse families. Chromosome painting with human probes has been applied to 10 bat species from 8 families. Except for the combination 10/12pq/22q, all syntenic segmental associations proposed for the mammalian ancestor have been found in Chiroptera. Bat-specific painting probes, established from 4 species of 3 families, have been used in whole chromosome painting experiments in 29 species from 8 families. The results show that the prevailing mode of chromosomal evolution in bats is Robertsonian translocation with a large number of convergent events. Given our present knowledge of chiropteran karyotypes, only a few elements of the ancestral chiropteran karyotype can be reconstructed with confidence.

Karyotypic differences in two sibling species of Scotophilus from South Africa (Vespertilionidae, Chiroptera, Mammalia).

Karyotype descriptions are given for Scotophilus dinganii (2n = 36, FNa = 50) and a recently discovered sister-species, Scotophilus sp. nov. (2n = 36, FNa = 52). These two sibling species occur sympatrically and are distinguished by body size, echolocation frequency and cytochrome b sequence. Cytogenetically, both species differ from other Scotophilus species in the subtelocentric morphology of chromosome 2 and a terminal heterochromatic segment on the X chromosome. Further, Scotophilus sp. nov. is characterized by a subtelocentric chromosome 4 not found in any other Scotophilus species. Comparing the Scotophilus karyotype with that of the vespertilionid genus Myotis, extensive conservation of whole chromosome arms has been found recently. However, out of 25 chromosomal arms six could not be identified in Scotophilus. Therefore, in the present study fluorescence in situ hybridization with whole chromosome painting probes from Myotis myotis was carried out on metaphase preparations from Scotophilus dinganii and Scotophilus sp. nov. These experiments revealed that three previously unidentified Scotophilus chromosomes (A, B, C) contain homologous sequences to Myotis chromosomes 18 plus 22, 19 plus 25, and 16/17, respectively.

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development.

Mastomys enterochromaffin-like (ECL) cell proliferation is initially gastrin driven, but once neoplasia develops, cells become gastrin autonomous. We hypothesized that CCN2 (CTGF), a mitogenic growth factor, may regulate ECL cell proliferation. A Mastomys GeneChip database was examined (dCHIP) to identify CCN2 expression levels. CCN2 in normal and tumor ECL cell preparations obtained using FACS (100 nM acridine orange) was examined by real-time PCR. CCN2 protein was identified in mucosal and ECL cell preparations by immunohistochemistry. Short-term cultured cells were stimulated with either CCN2 or CCN2 + EGF, and proliferation was measured (MTT assay). The ERK1/2 inhibitor PD-98059 (0.1-100 microM) was assessed in terms of CCN2 (1 ng/ml)-mediated proliferation and ERK1/2 phosphorylation. CCN2 transcript and protein was then examined in clinical gastric carcinoids. The ccn2 transcript was upregulated in tumor samples compared with the normal mucosa (+2.36-fold, P < 0.01). PCR demonstrated that ccn2 was not expressed in FACS-prepared (>98% pure) normal ECL cells but was elevated in tumor ECL cell fractions (41.3 +/- 10.7-fold). Immunostaining of the Mastomys gastric mucosa and FACS preparations confirmed that CCN2 protein was present in ECL tumors but not in normal ECL cells. Neither CCN2 nor CCN2 + EGF stimulated normal ECL cell proliferation. CCN2 stimulated tumor proliferation (EC50 approximately 0.01 ng/ml); EGF significantly augmented (P < 0.01) CCN2-induced tumor cell proliferation (EC50 = 20 pg/ml). PD-98059 inhibited CCN2-induced proliferation (-12 +/- 3%, P < 0.05) and ERK1/2 phosphorylation (-34 +/- 5%, P < 0.05) in tumor cells. In clinical samples, both CCN2 transcript and protein were elevated in gastrin-autonomous carcinoids (P < 0.02) compared with the normal mucosa. In conclusion, CCN2 may be a proliferative regulator of Mastomys ECL neoplastic proliferation once these cells become autonomous of gastrin regulation. Identification of CCN2 in gastric carcinoid tissue may be useful both as an indicator of ECL cell transformation and may define gastrin autonomy, a criteria of gastric carcinoid malignancy.

Isolation, functional characterization, and transcriptome of Mastomys ileal enterochromaffin cells.

Although the enterochromaffin (EC) cell is one of the primary neuroendocrine regulatory cells of the small intestine, the lack of a purified cell system has precluded characterization of the cell and limited precise physiological evaluation. We developed methodology to obtain a pure population of Mastomys ileal EC cells, evaluated their functional regulation, and defined the transcriptome. Mastomys ilea were everted, end ligated, pronase-collagenase digested, and Nycodenz gradient centrifuged, and EC cells were collected by fluorescence-activated cell sorting (FACS) of acridine orange-labeled cells. Enrichment was confirmed by immunostaining of tryptophan hydroxylase and chromogranin A, specific EC cell markers, serotonin content, EC cell marker gene expression, and electron microscopy. Pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin, and gastrin receptor expression was determined by real-time RT-PCR. Live post-FACS-sorted cells were cultured, and the effects of forskolin, isoproterenol, acetylcholine, GABAA, PACAP-38, and gastrin on serotonin secretion were measured by ELISA. GeneChip Affymetrix profiling of FACS-sorted cells was undertaken to obtain the EC cell transcriptome. FACS produced a >70-fold enrichment of EC cells with a serotonin content of 240 +/- 22 ng/mg protein. Preparations were 99 +/- 0.7% pure by immunostaining for tryptophan hydroxylase. Vasoactive intestinal peptide/PACAP receptor 1 (VPAC1) and somatostatin receptor 2 were present, whereas PACAP receptor 1 (PAC1) and CCK2 receptors were undetectable. Forskolin, isoproterenol, and PACAP-38 stimulated serotonin secretion at EC50 values of 5 x 10(-10), 4.5 x 10(-10), and 1.2 x 10(-9) M, respectively. Isoproterenol stimulated cAMP levels by approximately 3.5 +/- 0.62-fold vs. unstimulated cells (EC50 of approximately 10(-9) M). Octreotide, acetylcholine, and GABAA inhibited serotonin secretion with IC50 values of 3 x 10(-11), 3 x 10(-10), and 2.9 x 10(-10) M, respectively. Gastrin had no effect on serotonin secretion. The naive EC cell transcriptome revealed highly expressed EC cell marker genes, the absence of marker genes for other small intestinal cell types, and a receptor profile that included cholinergic, adrenergic, dopaminergic, serotoninergic, GABAergic, and prostaglandin receptors. We were able to isolate homogeneous preparations (>99%) of live ileal EC cells and demonstrated regulation of serotonin secretion as well as established the normal EC cell transcriptome. Application of this methodology to normal and diseased human ileum will facilitate the elucidation of the pathophysiology of EC cells.

Global expression analysis of ECL cells in Mastomys natalensis gastric mucosa identifies alterations in the AP-1 pathway induced by gastrin-mediated transformation.

Enterochromaffin-like (ECL) cell hyperplasia and then irreversible neoplasia can be generated in the African rodent Mastomys natalensis using the H2 receptor blocker, loxtidine, for 8-16 wk. We used a GeneChip approach complemented by standard technologies to identify gene expression alterations in the gastric mucosa during gastrin-mediated ECL cell transformation. Gastric mucosa (mucosal scrapping) and ECL cell-enriched fractions were obtained from untreated Mastomys (controls) and from animals treated with loxtidine for 8 wk (hyperplasia). Tumor ECL cells were obtained by hand-dissection of gastric ECL cell nodules from animals treated with loxtidine for >16 wk and from a spontaneously developed ECL cell tumor. RNA was isolated, examined on rat U34A GeneChips, and comparison analysis was performed to identify altered gene expression. Alterations in gene expressions were examined further by immunohistochemistry, quantitative RT-PCR (Q-RT-PCR), sequencing and Western blot. GeneSpring analysis demonstrated alterations in few genes (<20) in hyperplastic and tumor mucosa. The histamine H1 receptor was consistently increased in proliferating mucosa. This gene change was confirmed by Q-RT-PCR. Other genes showing alterations included neural-(chromogranin A and somatostatin), cell-cycle-, and AP-1-associated genes. Immunostaining confirmed alterations in neural markers. Cluster analysis of ECL cell-enriched samples demonstrated that c-fos and junD were differently regulated. Q-RT-PCR and Western blot in prospectively collected gastric mucosal samples confirmed the differential expression of Fos and Jun. The negative regulators of AP-1, JunD, and Menin were decreased in tumor mucosa. A missense of unknown function was noted in the menin gene. Hypergastrinemia in an animal model of gastric carcinoids differentially altered the histamine type 1 receptor and gene expression and protein composition of AP-1. These results suggest that expression of this receptor and an altered composition of AP-1 with a loss of inhibition play a role in ECL cell transformation.