A Rapid Review of the Measurement of Intrinsic Capacity in Older Adults.

OBJECTIVES: This study aims to address the knowledge gap and summarise the measurement for intrinsic capacity for the five WHO domains across different populations. It specifically aims to identify measurement tools, methods used for computation of a composite intrinsic capacity index and factors associated with intrinsic capacity among older adults. METHODS: We performed literature review in Medline, including search terms "aged" or "elderly" and "intrinsic capacity" for articles published from 2000 - 2020 in English. Studies which assessed intrinsic capacity in the five WHO domains were included. Information pertaining to study setting, methods used for measuring the domains of intrinsic capacity, computation methods for composite intrinsic capacity index, and details on tool validation were extracted. RESULTS: Seven articles fulfilling the inclusion criteria were included in the review. Of these, the majority were conducted in community settings (n=5) and were retrospective studies (n=6). The most commonly used tools for assessing intrinsic capacity were gait speed test and chair stand test (locomotion); handgrip-strength and mini-nutritional assessment (vitality); Mini-Mental State Examination (cognition); Geriatric Depression Scale (GDS) and Center for Epidemiological Studies Depression Scale (CES-D) (psychological), and self-reported vision and health questionnaires (sensory). Among the tools used to operationalise the domains, we found variations and non-concordance, especially in the vitality and psychological domains, which make inter-study comparison difficult. Validated scales were less commonly used for vitality and sensory domains. Biomarkers were used for locomotion, vitality, and sensory domains. Self-reported measures were mostly used in the psychological and sensory domains. Three studies operationalised a global score for intrinsic capacity, whereby scores from the individual domains were used to create a composite intrinsic capacity index, using two approaches: a) Structural equation modelling, and b) Sub-scores for each domain which were combined either by arithmetic sum or average. CONCLUSION: We identified considerable variations in measurement instruments and processes which are used to assess intrinsic capacity, especially among the vitality and psychological domains. A standardized intrinsic capacity composite score for clinical or community settings has not been operationalised yet. Further validation via prospective studies of the intrinsic capacity concept and computation of composite score using validated scales are needed.

Inhibition of West Nile virus replication in cells stably transfected with vector-based shRNA expression system.

In this study, the efficacies of short hairpin RNAs (shRNAs) targeting different regions of West Nile virus (WNV) strain Sarafend genome were investigated. Short hairpin RNAs targeting Capsid, NS2B and NS4B genes were cloned into pSilencer 3.1-H1 neo and designated as pshCapsid, pshNS2B and pshNS4B, respectively. Vero cells that were positively transfected were selected for creating stable cell lines expressing shRNAs constitutively. These cells were subjected to West Nile virus at multiplicity of infection (M.O.I.) of 10. The cells stably transfected with pshCapsid gave the best silencing effect among the three stable cell lines (transfected with pshCapsid, pshNS2B and pshNS4B) at both 12- and 24 h p.i. When compared to the non-transfected WNV-infected cells, pshCapsid stably transfected cells showed more than 4 log(10) unit reduction in viral transcripts and greater than 3 log(10) unit reduction in virus production. Cells stably transfected with pshNS2B did not exhibit as strong an inhibition when compared to the pshCapsid stably transfected cells having only 2 log(10) unit reduction in virus titre. The pshNS4B-stably transfected cells did not suppress WNV replication. Hence, from this study, pshCapsid has the potential to be developed into effective antiviral strategy for WNV infection.

Expression of vector-based small interfering RNA against West Nile virus effectively inhibits virus replication.

RNA interference is one of the effective emerging anti-viral strategies to inhibit virus infection in cells. In this study, a small interfering RNA expressing vector (pSilencer-NS5) targeting the NS5 gene of West Nile virus (WNV) was employed to target and destroy WNV transcripts. Real-time PCR revealed drastic reduction in WNV RNA transcripts in pSilencer-NS5-transfected Vero cells. The virus infectious titre was also significantly reduced by 90% as determined by plaque assays. The resulting decrease in virus replication was shown to be specific since both scrambled and nucleotide(s) mismatch siRNA against WNV NS5 gene did not have any effect on WNV productive yields. Furthermore, Western immunoblot analysis on the expression of viral NS5 and envelope (E) proteins showed significant down-regulation on the expression of viral NS5 and envelope (E) proteins in virus-infected cells that were pre-transfected with pSilencer-NS5. These data clearly supported the notion that the expression of vector-based siRNA against WNV NS5 gene is able to exert its silencing effect on WNV-infected cells without inducing cytotoxicity, hence holding promise in therapeutic treatment of this important emerging infectious disease.

Eradication of Helicobacter pylori in clinical situations.

Helicobacter pylori is prevalent worldwide, especially in developing countries, and is associated with several upper gastrointestinal diseases. Since it is present in over 90% of duodenal ulcer patients, empirical eradication in these patients is often recommended. In gastric ulcer patients, eradication is indicated only after the infection is confirmed. Testing for H. pylori infection should be carried out in patients with peptic ulcer hemorrhage, because eradication has been shown to reduce recurrent bleeding. Both H. pylori and NSAIDs are risk factors for peptic ulceration, and it is reasonable to screen for and eradicate H. pylori infection in peptic ulcer patients taking NSAIDs. H. pylori is a group I carcinogen for gastric adenocarcinoma, and should be eradicated for the primary prevention of this cancer. Eradication of this organism has been reported to result in regression of early low-grade mucosa-associated lymphoid tissue lymphoma. The role of H. pylori infection in the causation of gastroesophageal reflux and non-ulcer dyspepsia is not clearly established. Several tests are available for the diagnosis of H. pylori infection. These include invasive tests, such as histology, culture and urease test, and non-invasive tests, such as serology, urea breath test and stool antigen test. The choice of test is determined by clinical indication, pretest probability of infection, as well as the availability, cost, sensitivity and specificity of the test. H. pylori eradication therapy using proton pump inhibitor with clarithromycin and amoxycillin for 7 days has a success rate of 85-90%. Improved living standard and sanitation are vital in the control of H. pylori transmission and infection. Future development may include the use of vaccines against H. pylori, and therapies specifically targeting cagA strains of the bacteria.

Mechanism-based inhibition of ribonucleoside diphosphate reductase from Corynebacterium nephridii by 2'-C-methyladenosine diphosphate.

The interaction of the adenosylcobalamin-dependent ribonucleoside diphosphate reductase of Corynebacterium nephridii with 2'-C-methyladenosine diphosphate (2'-C-methylADP) has been investigated in more detail [Ong, S. P., McFarlan, S. C., & Hogenkamp, H. P. C. (1993) Biochemistry 32, 11397-11404]. This nucleotide analog partitioned between normal reduction to 2'-deoxy-2'-C-methyladenosine diphosphate and decomposition to adenine, 2-methylene-3(2H)-4-methylfuranone, and presumably pyrophosphate. Reaction of the reduced enzyme with 2'-C-methylADP caused the development of a chromophore at 318 nm that is characteristic of the modification of the enzyme by the furanone [Harris, G., Ator, M., & Stubbe, J. (1984) Biochemistry 23, 5214-5225]. Incubation of [5'-3H2]-2'-C-methylADP with reduced reductase resulted in the covalent incorporation of the radiolabel into the protein and into aquocobalamin. A similar incubation of the enzyme, the labeled nucleotide analog, and dithiothreitol resulted in the formation of three radioactive hydrophilic compounds. Mass spectroscopic analysis of one of these compounds showed the presence of 2-methylene-3(2H)-4-methylfuranone. 2'-Deoxy-2'-C-methylADP is a very effective promoter of the tritium exchange reaction between [5'-3H2]adenosylcobalamin and the solvent, confirming that the exchange reaction is an integral part of the overall reduction. All these observations are consistent with the proposal that 2'-C-methylADP serves as a substrate and a mechanism-based inhibitor of the ribonucleotide reductase of C. nephridii, indicating that the enzyme is able to catalyze the conversion of the nucleotide analog to a 2'-deoxy-2'-C-methyl-3'-ketonucleotide that can collapse to the reactive 2-methylene-3(2H)-4-methylfuranone. Surprisingly, 2'-C-methylADP did not serve as either a substrate or an inhibitor of the ribonucleoside diphosphate reductase of Escherichia coli.

2'-C-methyladenosine and 2'-C-methyluridine 5'-diphosphates are mechanism-based inhibitors of ribonucleoside diphosphate reductase from Corynebacterium nephridii.

The interaction of the adenyosylcobalamin-dependent ribonucleoside diphosphate reductase of Cornyebacterium nephridii with 2'-C-methyladenosine 5'-diphosphate (2'-MeADP) and 2'-C-methyluridine 5'-diphosphate (2'-MeUDP) has been investigated. The nucleotide analogs are converted to adenine and uracil, respectively, suggesting that they may be mechanism-based inhibitors. In addition, both analogs generate nucleotides with properties expected for the 2'-deoxy-2'-C-methylnucleotides. The nucleoside obtained after enzymatic dephosphorylation of the product formed from 2'-MeADP has been identified as 2'-deoxy-2'-C-methyladenosine by 1H NMR and mass spectroscopies. Adenine is the major product derived from 2'-MeADP, indicating that the degradation pathway predominates. During the reaction, the carbon-cobalt bond of the coenzyme is cleaved irreversibly to yield 5'-deoxyadenosine and cob(II)alamin. 2'-MeADP is a potent competitive inhibitor of the reduction of the purine nucleotides ADP and GDP, while 2'-MeUDP competitively inhibits the reduction of the pyrimidine nucleotides UDP and CDP. 2'-MeADP is a very effective promoter of the tritium exchange reaction between [5'-3H2]adenosylcobalamin and the solvent, indicating that the exchange reaction is an integral part of the overall reduction. All these observations are consistent with the reaction mechanism proposed by Stubbe and co-workers [Harris, G., Ashley, G. W., Robins, M. J., Tolman, R. L., & Stubbe, J. (1987) Biochemistry 26, 1895-1902 (1987); Stubbe, J. (1990) J. Biol. Chem. 265, 5329-5332] in which they suggest that the partitioning between reduction and inactivation occurs at the level of the 2'-deoxy-3'-ketoribonucleotide intermediate.

Synthesis of 3'-C-methyladenosine and 3'-C-methyluridine diphosphates and their interaction with the ribonucleoside diphosphate reductase from Corynebacterium nephridii.

Two nucleoside diphosphate analogs, 3'-C-methyl-ADP and 3'-C-methyl-UDP, have been tested as substrate and/or allosteric effectors using the adenosylcobalamin-dependent ribonucleoside diphosphate reductase of Corynebacterium nephridii. Neither analog was a substrate for the reductase. However, they did function as allosteric effectors and as inhibitors of the reduction of ADP and UDP, respectively. The nucleotide analogs did not stimulate the hydrogen exchange reaction between [5'-3H2]adenosylcobalamin and the solvent, indicating that the cleavage of the 3'-carbon-hydrogen bond is a prerequisite for the exchange reaction. A reinvestigation of the requirements for the exchange reaction revealed that the deoxyribonucleoside diphosphate products are very effective promoters of this reaction. Indeed, the deoxyribonucleoside diphosphates were found to be more effective in promoting the exchange reaction than the ribonucleoside diphosphate substrates. In contrast, the deoxyribonucleoside triphosphate effectors, dATP, dUTP, and dTTP, were only marginally effective as promoters of this reaction.

Nutrient intake and associated biochemical status of pregnant Asians in the United Kingdom.

Forty-six women (17 Pakistanis, 19 Indians, ten Bangladeshis) at 8 to 20 weeks of pregnancy were studied during November to January. Dietary intake was assessed by the diet history method. Mean energy intakes (+/- s.d.) for the Pakistanis, Indians and Bangladeshis were 9.80 (1.99), 8.08 (1.59) and 6.95 (1.70) MJ. Intakes of protein, calcium, phosphorus and iron were positively correlated with energy intake. Vitamin D intake was similar in all groups, mean (+/- s.d) = 2.15 (1.39). Mean serum (+/- s.d.) protein, phosphorus and calcium were 70.9 (6.5) g/l; 2.27 (0.12) mmol/l; 1.00 (0.21) mmol/l and fell within the lower normal range. Mean haemoglobin was 12.2 (1.1) g/dl. Mean (+/- s.d.) serum 25-OHD for Pakistanis, Indians and Bangladeshi respectively was 3.80 (2.25), 4.04 (2.64) and 5.22 (2.47) ng/ml. These are within the range found for patients with osteomalacia (less than 10 ng/ml) and substantially lower than values of 14.6 (2.6) ng/l reported by Bashir et al. (1981) for September and October.