Association of Intrinsic Capacity with Frailty, Physical Fitness and Adverse Health Outcomes in Community-Dwelling Older Adults.

BACKGROUND: Intrinsic capacity (IC) and frailty are complementary in advancing disability prevention through maintaining functionality. OBJECTIVES: We examined the relationship between IC and frailty status at baseline and 1-year, and evaluated if IC decline predicts frailty onset among robust older adults. The secondary objectives investigated associations between IC, physical fitness and health-related outcomes. DESIGN: Prospective cohort study. SETTING: Community-based assessments. PARTICIPANTS: Older adults aged>55 years, who were independent in ambulation (walking aids permitted). MEASUREMENTS: 5 domains of IC were assessed at baseline: locomotion (Short Physical Performance Battery, 6-minute walk test), vitality (nutritional status, muscle mass), sensory (self-reported hearing and vision), cognition (self-reported memory, age- and education adjusted cognitive performance), psychological (Geriatric Depression Scale-15, self-reported anxiety/ depression). Composite IC (0-10) was calculated, with higher scores representing greater IC. Frailty status was based on modified Fried criteria, with frailty progression defined as incremental Fried score at 1-year. RESULTS: 809 participants (67.6+6.8 years) had complete data for all 5 IC domains. 489 (60.4%) participants were robust but only 213 (26.3%) had no decline in any IC domain. Pre-frail and frail participants were more likely to exhibit decline in all 5 IC domains (p<0.05), with decremental composite IC [9 (8-9), 8 (6-9), 5.5 (4-7.5), p<0.001] across robust, prefrail and frail. IC was significantly associated with fitness performance, independent of age and gender. Higher composite IC reduced risk for frailty progression (OR=0.62, 95% CI 0.48-0.80), and reduced frailty onset among robust older adults (OR=0.53, 95% CI 0.37-0.77), independent of age, comorbidities and social vulnerability. Participants with higher IC were less likely to experience health deterioration (OR=0.70, 95% CI 0.58-0.83), falls (OR=0.76, 95% CI 0.65-0.90) and functional decline (OR=0.64, 95% CI 0.50-0.83) at 1-year. CONCLUSION: Declining IC may present before frailty becomes clinically manifest, increasing risk for poor outcomes. Monitoring of IC domains potentially facilitates personalized interventions to avoid progressive frailty.

A Non-Controlled Study of a Multi-Factorial Exercise and Nutritional Intervention to Improve Functional Performance and Prevent Frailty Progression in Community-Dwelling Pre-Frail Older Adults.

Background: Preventing frailty is important to avoid adverse health outcomes. Intervention studies have largely focused on frail elderly, although the intermediate pre-frail state may be more amenable to improvement. Objectives: This study aims to assess how physical performance may change among pre-frail elderly enrolled in a pragmatic non-controlled exercise and nutritional intervention programme. Methods: This is a non-controlled study involving a 4-month exercise and nutritional intervention for community dwelling pre-frail older adults. Pre-frailty was defined as the presence of 1 or 2 positive responses on the FRAIL questionnaire, or evidence of weak grip strength (<26kg for males; <18kg for females) or slow gait speed (<0.8m/s) amongst participants who were asymptomatic on FRAIL. Physical performance in flexibility, grip and lower limb strength, endurance, balance, and Short Physical Performance Battery were measured at 3 time-points: baseline, 3-month from recruitment (without intervention), and immediate post-intervention. Repeated measures mixed model analysis was performed to compare physical performance measures across the 3 time-points. Results: 94 pre-frail participants were eligible for intervention, of whom 59 (mean age = 70.9±7.2 years) were ready for the post-intervention review. 21 (35.6%) transitioned to robust phenotype while 32 (54.2%) remained as pre-frail. Significant improvement post-intervention was observed in lower limb strength and power, evident on reduction in time taken for 5 sit-to-stand repetitions (0.46±0.20s, p=0.03). There was no significant change to the other physical performance measures examined. Conclusion: We observed reversibility of pre-frailty, and the benefit of multi-component intervention in improving physical performance of pre-frail older adults. The findings in this non-controlled study will need to be corroborated with future controlled trials.

Frailty Assessment in Community-Dwelling Older Adults: A Comparison of 3 Diagnostic Instruments.

OBJECTIVES: Compare the diagnostic performance of FRAIL against Fried Phenotype and Frailty Index (FI), and identify clinical factors associated with pre-frailty/frailty. DESIGN: Cross-sectional analysis. SETTING: Community-based screenings in Senior Activity Centres, Residents' Corners and Community Centres in northeast Singapore. PARTICIPANTS: 517 community dwelling participants aged >55 years and ambulant independently (with/ without walking aids) were included in this study. Residents of sheltered or nursing homes, and seniors unable to ambulate at least four meters independently were excluded. MEASUREMENTS: The multidomain geriatric screen included assessments for social vulnerability, mood, cognition, sarcopenia and nutrition. Participants completed a battery of physical fitness tests for grip strength, gait speed, lower limb strength and power, flexibility, balance and endurance, with overall physical performance represented by Short Physical Performance Battery (SPPB). Frailty status was assigned on FRAIL, Fried and 35-item FI. RESULTS: Prevalence of frailty was 1.3% (FRAIL) to 3.1% (FI). Pre-frailty prevalence ranged from 17.0% (FRAIL) to 51.2% (FI). FRAIL demonstrated poor agreement with FI (kappa=0.171, p<0.0001), and Fried (kappa=0.194, p<0.0001). A lower FRAIL cut-off ≥1 yielded significantly improved AUC of 0.70 (95%CI 0.55 to 0.86, p=0.009) against Fried, and 0.71 (95%CI 0.55 to 0.86, p=0.008) against FI. All 3 frailty measures were diagnostic of impaired physical performance on SPPB, with AUCs ranging from 0.69 on FRAIL to 0.77 on Fried (all p values <0.01). Prevalence of low socio-economic status, depression, malnutrition and sarcopenia increased significantly, while fitness measures of gait speed, balance, and endurance declined progressively across robust, pre-frail and frail on all 3 frailty instruments (p <0.05). CONCLUSIONS: Our results suggest that different frailty instruments may capture over-lapping albeit distinct constructs, and thus may not be used interchangeably. FRAIL has utility for quick screening, and any positive response should trigger further assessment, including evaluation for depression, social vulnerability and malnutrition.

Epidemiology of Inflammatory Bowel Disease in Southern Peninsular Malaysia.

AIM: To record the incidence and prevalence of inflammatory bowel disease (IBD), its social demographics, clinical characteristics and treatment, in the state of Johor, Malaysia. METHODS: Hospital Sultanah Aminah, Johor Bahru, is the only public hospital in Johor with a Gastroenterology service. Data on all existing and new IBD patients managed by the Gastroenterology Unit in 2016 were collected. Incidence and prevalence of IBD in 2016 were then calculated based on the estimated population of Johor and Johor Bahru. RESULTS: Twenty-five new cases of IBD were diagnosed in 2016. Among the 25 cases, 13 cases were Crohn's disease (CD), 10 were ulcerative colitis (UC) and two were IBD Unclassified (IBDU). The crude incidence of IBD, CD, UC and IBDU were 0.68, 0.36, 0.27, and 0.05 per 100,000 population respectively. Ethnic Indians had the highest incidence of IBD at 4.21 followed by Malays and Chinese at 0.56 and 0.18 per 100,000 population respectively. A total of 156 IBD cases were captured. Amongst them, 85 cases were UC, 68 cases were CD and three cases were IBDU, hence the prevalence of IBD, UC, CD and IBDU were 4.27, 2.33, 1.86 and 0.08 per 100,000 population respectively. Similarly, Indians had the highest prevalence at 16.84, followed by Chinese at 4.06 and Malays at 3.44 per 100,000 population. CONCLUSIONS: The incidence of IBD in Johor is comparable to that of a previous study in northern Peninsular Malaysia. The ethnicity preponderance is similar to the previous studies conducted in Malaysia.

Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism.

There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2(Akita) diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels. We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking. Using cholera toxin B-subunit tracer studies, we found a distal reduction in transport in the superior colliculus following VEGF-A neutralization, which occurred prior to net RGC loss. This phenomenon of distal transport loss has been described as a feature of early pathological changes in glaucoma, Alzheimer's and Parkinson's disease models. Furthermore, we observed increased phosphorylation of p38 MAPK and downstream Hsp27 stress pathway signaling in the retinas from these experiments, potentially providing a mechanistic explanation for our findings. These experiments further highlight the possible risks of using VEGF-A antagonists to treat ocular neovascular disease, and suggest that VEGF-A may contribute to the maintenance and function of axonal transport in neurons of the retina.

Atg9 is required for intraluminal vesicles in amphisomes and autolysosomes.

Autophagy is an intracellular recycling and degradation process, which is important for energy metabolism, lipid metabolism, physiological stress response and organism development. During Drosophila development, autophagy is up-regulated in fat body and midgut cells, to control metabolic function and to enable tissue remodelling. Atg9 is the only transmembrane protein involved in the core autophagy machinery and is thought to have a role in autophagosome formation. During Drosophila development, Atg9 co-located with Atg8 autophagosomes, Rab11 endosomes and Lamp1 endosomes-lysosomes. RNAi silencing of Atg9 reduced both the number and the size of autophagosomes during development and caused morphological changes to amphisomes/autolysosomes. In control cells there was compartmentalised acidification corresponding to intraluminal Rab11/Lamp-1 vesicles, but in Atg9 depleted cells there were no intraluminal vesicles and the acidification was not compartmentalised. We concluded that Atg9 is required to form intraluminal vesicles and for localised acidification within amphisomes/autolysosomes, and consequently when depleted, reduced the capacity to degrade and remodel gut tissue during development.

Incidence and predictors of new-onset constipation during acute hospitalisation after stroke.

OBJECTIVES: We investigated new-onset constipation in patients with stroke compared with orthopaedic conditions and explored the predictors associated with constipation during acute hospitalisation. METHODS: This was a prospective matched cohort study of 110 patients comparing stroke patients (n = 55) with orthopaedic patients (n = 55) admitted to a large tertiary acute hospital. Both cohorts were matched by age and sex. The incidence of new-onset constipation which occurred during a patient's acute hospitalisation was determined. Demographics, comorbidity, clinical factors, laboratory parameters and medications were evaluated as possible predictors of constipation. RESULTS: The incidence of new-onset constipation was high for both stroke (33%) and orthopaedic patients (27%; p = 0.66). Seven stroke patients (39%) and four orthopaedic patients (27%) developed their first onset of constipation on day 2 of admission. Mobility gains (RR 0.741, p < 0.001) and the use of prophylactic laxatives (RR 0.331, p < 0.01) had a protective effect against constipation. Bedpan use (RR 2.058, p < 0.05) and longer length of stay (RR 1.032, p < 0.05) increased the risk of developing new-onset constipation. CONCLUSIONS: New-onset constipation is common among patients admitted for stroke and orthopaedic conditions during acute hospitalisation. The early occurrence, on day 2 of admission, calls for prompt preventive intervention for constipation.

A case report on the use of an acetylcholinesterase inhibitor (donepezil) in traumatic brain injury.

Traumatic Brain injury (TBI) is one of the most common causes of death and disability worldwide, with recent interest in the use of cholinomimetics in the treatment of TBI patients for cognitive impairments. Our patient who suffered TBI was started on a trial of an acetylcholinesterase inhibitor (Donepezil) for five weeks. Cognitive and memory testing with the Mini-Mental State Examination (MMSE) and Functional Independence Measurement (FIM) showed some degree of improvement: The three item recall component of MMSE improved and the FIM Memory score increased from 1 (Complete dependence) to 6 (Functional independence). Subjective assessment of his behaviour in the ward also showed improvement. This suggests that donepezil may help improve memory and behaviour of moderately severe traumatic brain injury patients, although more research in this direction should be undertaken.

Caregivers' satisfaction of healthcare delivery at paediatric clinics of Universiti Kebangsaan Malaysia Medical Centre in 2009.

Patient's satisfaction has become increasingly important as patients evaluate healthcare services for both medical cost and quality. The purpose of this study was to measure the prevalence and the factors influencing caregivers' satisfaction. A cross sectional study of 262 respondents using universal sampling method was conducted at the paediatric clinics of Universiti Kebangsaan Malaysia Medical Centre (UKMMC). Overall, 90.5% were satisfied with the services provided. Satisfaction rates based on various healthcare delivery domains were: 95.0% for communication skills, 88.5% for interpersonal aspect, 83.6% for technical quality, 82.1% for financial aspect, 72.9% for time spent with doctors and 64.9% for ease of contact. This study shows that the caregivers (an unpaid person who helps a person cope with disease) were highly satisfied with the communicational aspect delivered by the clinic. However, there is still room for improvement on ease of contact domain and waiting time in order to produce high quality service.

Performance evaluation of organic emulsion liquid membrane on phenol removal.

The percentage removal of phenol from aqueous solution by emulsion liquid membrane and emulsion leakage was investigated experimentally for various parameters such as membrane:internal phase ratio, membrane:external phase ratio, emulsification speed, emulsification time, carrier concentration, surfactant concentration and internal agent concentration. These parameters strongly influence the percentage removal of phenol and emulsion leakage. Under optimum membrane properties, the percentage removal of phenol was as high as 98.33%, with emulsion leakage of 1.25%. It was also found that the necessity of carrier for enhancing phenol removal was strongly dependent on the internal agent concentration.

Eggerthella lenta as a cause of anaerobic spondylodiscitis.

Anaerobic organisms are a rare cause of spondylodiscitis. Eggerthella lenta is an organism that is not commonly associated with spondylodiscitis. We describe a case of spondylodiscitis due to Eggerthella lenta in an 82-year-old Chinese woman presenting with back pain. The organism was isolated from tissue cultures obtained via radiology-guided biopsy.

Bilateral femoral nerve compression and compartment syndrome resulting from influenza A-induced rhabdomyolysis: a case report.

Bilateral femoral nerve compression neuropathy caused by primary iliopsoas muscle pathology is rare. We report a case of extensive compartment syndrome of the right arm and both legs associated with bilateral femoral nerve palsy resulting from severe muscle swelling secondary to influenza A infection. Our objective is to alert physicians to the possible development of compartment syndrome in patients with influenza and severe myalgia. We also reviewed the literature on the pathophysiology and management of femoral nerve compression neuropathy.

Long term outcome of renal allografts in patients with immunoglobulin A nephropathy.

Recurrent glomerular disease is an important cause of late allograft loss in renal transplant recipients. Immunoglobulin A nephropathy (IgAN) is a leading cause of end-stage renal disease (ESRD) worldwide and its recurrence has been reported in allografts. The present study examined outcomes following renal transplantation (RTX) in 101 patients with ESRD due to biopsy-proven IgAN, in comparison to non-IgA patients, and evaluated the incidence of recurrence. The study population (mean age 34.8 +/- 7.7 years; males 62.2%; Chinese 88.3%) underwent RTX under CsA immunosuppression between November 1984 and December 2004; as two patients underwent retransplantation during the study period, 103 allografts (56.3% cadaveric) were included for retrospective analysis. At time of analysis on 1 January 2005, 78 (75.7%) renal allografts (IgAN RTX) were functioning, of which 51 (49.5%) had normal serum creatinine, 27 (26.2%) had chronic allograft dysfunction, while 25 had graft losses, either due to patient death with functioning grafts (5.8%) or withdrawal to dialysis (18.5%). Persistent microscopic haematuria, not attributable to other causes or proteinuria > 1 g/day occurred in 42.7% and 13.6% of allografts respectively. Of 29 allografts biopsied for evaluation of proteinuria and/or renal dysfunction post-RTX, 8 (27.6%) had IgAN (overall histological recurrence, 7.8%). Of these, three had graft loss due to recurrent IgAN, three had elevated serum creatinine, while two had normal serum creatinine. Overall five and ten year patient survivals for IgAN RTX were 95.3% and 82.2%, and five and ten year actuarial graft survivals were 82.3% and 67.8% respectively. Five and ten year patient and graft survivals for IgAN RTX were not significantly different from that for non-IgAN RTX. In summary, RTX patients with IgAN have a low incidence of documented histological recurrence and recurrence contributing to graft loss occurs in only 2.9%. These results suggest that RTX is an excellent modality of renal replacement therapy in this population.

Characteristics and acute rehabilitation of Guillain-Barré syndrome in Singapore.

INTRODUCTION: The objectives of this study are to describe the demographics, clinical characteristics, complications and functional outcomes in patients with Guillain-Barr é syndrome (GBS) or the Miller-Fisher syndrome (MFS) variant admitted to our institution. We also aim to identify prognostic outcome indicators. MATERIALS AND METHODS: A retrospective review of the case records of all patients discharged from our hospital with a diagnosis of GBS or MFS over a 2- year period was performed. The clinical characteristics charted included the time of symptom onset to nadir. The Modified Barthel Index (MBI) and Expanded Grading Scale (EGS) for GBS were the functional outcome measures used. RESULTS: Thirty-one cases were reviewed and 8 (25.8 %) had the MFS variant. Twenty-two (71 %) patients were male, with a mean age of 42.3 years. Weakness and numbness (74 %) were the most common initial symptoms; 9 (29 %) patients were paraparetic and 7 (22.6 %) were tetraparetic. Ten (32.3 %) patients had respiratory involvement and 8 (25.8 %) had urinary retention. Intravenous immunoglobulin (IVIG) was prescribed in 13 (41.9 %) patients. The mean duration to disease nadir was 8.1 days. The mean MBI scores at nadir and discharge were 54.7 and 77.3, respectively, and this gain was highly significant (P <0.01). The majority (84 %) of patients were employed at admission and although most returned to work, 63 % (17/27) of the patients had residual symptoms or signs 3 months after discharge. CONCLUSION: The clinical characteristics and complication frequency closely follows that previously described in Western populations, although our cohort was younger and had a higher proportion of the MFS variant. Predictors of a poorer functional outcome include a high EGS score at nadir, tetraparesis, respiratory involvement, urinary retention and the need for nasogastric enteral feeding. Patients who had MFS or received IVIG had greater functional gains. Good functional outcomes occurred in a large majority of patients.

Immunologically induced histamine release from rat peritoneal mast cells is enhanced by low levels of substance P.

Although direct activation of mast cells by high concentrations (>10(-6) M) of substance P is well established, the effect of sub-micromolar concentrations of the neuropeptide on mast cell activation has not been reported. We hence investigated if substance P would modulate immunologic activation of mast cells by studying the effect of the neuropeptide on anti-rat immunologlobulin E antibody (anti-IgE)-induced histamine release from purified rat peritoneal mast cells. We observed that substance P could dose-dependently potentiate anti-IgE-induced histamine release from rat peritoneal mast cells at concentrations (3x10(-9) M to 3x10(-7) M) which alone induced insignificant or low level of histamine release. While the potentiating effect of substance P was not suppressed by any of the non-peptide tachykinin receptor antagonists CP99994 ((2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), SR48968 ((S)-N-methyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl-benzamide) and SR142801 ((S)-(N)-(1-[3-(1-benzoyl-3(3,4-dichlorophenyl)piperidine-3-yl)propyl]-4-phenylpiperidin-4-yl)-N-methyl-acetamide), it was mimicked by compound 48/80 and suppressed by benzalkonium chloride. Hence, substance P enhanced anti-IgE-induced histamine release through a similar receptor-independent mechanism as the direct mast cell activating action of polybasic compounds. Since high concentrations of substance P required for directly activating mast cells may not be achievable physiologically, the enhancing actions of the neuropeptide on the immunologic activation of mast cells may be more clinically relevant in the pathogenesis of various inflammatory conditions.

Differential expression of VEGF isoforms in mouse during development and in the adult.

Vascular endothelial growth factor (VEGF), a factor that is critical for development of the vascular system in mouse embryos, exists as at least three isoforms, VEGF120, VEGF164, and VEGF188. The isoforms have different affinities for heparan sulfate as well as for the three known VEGF receptors, VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), and neuropilin-1, suggesting that different VEGF isoforms may play distinct roles in vascular development. To determine whether there are differences in the organ-specific expression patterns that would support this concept, we used a quantitative RNase protection assay (RPA) to determine the distribution of different VEGF isoform mRNA in developing and adult mouse organs. Results revealed that the ratios of the three VEGF isoforms changed during organ development and that adult organs expressed different levels of the three VEGF isoforms. Because the lung expressed the highest levels of VEGF188 isoform, we used VEGF isoform-specific in situ hybridization in the developing lung and determined that type II alveolar epithelial cells were expressing high levels of VEGF188 mRNA. Finally, targeted exon deletion of the VEGF gene revealed that mice that developed in the absence of the heparan sulfate binding isoforms VEGF164 and VEGF188, displayed a variety of vascular defects, including abnormal pulmonary vascular development. Our results support the concept that different VEGF isoforms have distinct functions in vascular development.

The mouse gene for vascular endothelial growth factor. Genomic structure, definition of the transcriptional unit, and characterization of transcriptional and post-transcriptional regulatory sequences.

We describe the genomic organization and functional characterization of the mouse gene encoding vascular endothelial growth factor (VEGF), a polypeptide implicated in embryonic vascular development and postnatal angiogenesis. The coding region for mouse VEGF is interrupted by seven introns and encompasses approximately 14 kilobases. Organization of exons suggests that, similar to the human VEGF gene, alternative splicing generates the 120-, 164-, and 188-amino acid isoforms, but does not predict a fourth VEGF isoform corresponding to human VEGF206. Approximately 1. 2 kilobases of 5'-flanking region have been sequenced, and primer extension analysis identified a single major transcription initiation site, notably lacking TATA or CCAT consensus sequences. The 5'-flanking region is sufficient to promote a 7-fold induction of basal transcription. The genomic region encoding the 3'-untranslated region was determined by Northern and nuclease mapping analysis. Investigation of mRNA sequences responsible for the rapid turnover of VEGF mRNA (mRNA half-life, <1 h) (Shima, D. T. , Deutsch, U., and D'Amore, P. A. (1995) FEBS Lett. 370, 203-208) revealed that the 3'-untranslated region was sufficient to trigger the rapid turnover of a normally long-lived reporter mRNA in vitro. These data and reagents will allow the molecular and genetic analysis of mechanisms that control the developmental and pathological expression of VEGF.

Equal transcription of wild-type and mutant p53 using bicistronic vectors results in the wild-type phenotype.

Somatic and germ-line mutations of p53 alleles inactivate the function of the protein. It has been suggested that mutant p53 can inactivate the wild-type protein and therefore have a trans-dominant negative effect. To investigate the interaction between wild-type and mutant proteins when both alleles are equally transcribed, we designed bicistronic vectors containing the internal ribosome entry site of the encephalomyocarditis virus and expressing wild-type and mutant p53. Analysis of the transcriptional activity and of the effect on cell growth of these plasmids indicates that the mutant protein is unable to completely suppress wild-type function. These results could explain why the inactivation of both p53 alleles is required in cancer development.

A functional screen for germ line p53 mutations based on transcriptional activation.

Germ line p53 mutations represent a genetic predisposition for cancer development. At the present time, their detection requires extensive work and their functional significance must be documented. Therefore, we have designed a simple biological assay which detects functionally significant germ line p53 mutations. This assay is based on the cloning of the patient's p53 complementary DNA into a eukaryotic expression vector followed by the cotransfection into human cells of the recombinant vector with a reporter plasmid for the transcriptional activity of p53. This assay potentially offers a powerful method to screen fibroblasts or lymphocytes from patients for germ line mutations which inactivate the p53 tumor suppressor gene.