Associations between physical fitness and cardiovascular disease in older adults with intellectual disabilities: Results of the Healthy Ageing and Intellectual Disability study.

BACKGROUND: Reduced physical fitness is a cardiovascular disease (CVD) risk factor in the general population. However, generalising these results to older adults with intellectual disabilities (ID) may be inappropriate given their pre-existing low physical fitness levels and high prevalence of co-morbidities. Therefore, the aim of this study is to investigate the difference in physical fitness between older adults with ID with and without CVD. METHOD: Baseline data of a cohort of older adults with borderline to profound ID (HA-ID study) were used (n = 684; 61.6 ± 8.2 years; 51.3% male). CVD status (coronary artery disease, heart failure, stroke) was obtained from medical files. Cardiorespiratory fitness (10-m incremental shuttle walking test), comfortable and fast gait speed (over 5 m distance) and grip strength (hand dynamometer) were measured. Multivariable linear regression models were used to investigate the association between these physical fitness components and the presence of CVD, adjusted for participant characteristics. RESULTS: Of the 684 participants 78 (11.4%) had CVD. Participants with CVD scored lower on cardiorespiratory fitness (-81.4 m, P = 0.002), comfortable gait speed (-0.3 km/h, P = 0.04) and fast gait speed (-1.1 km/h, P = 0.04). No significant differences were found for grip strength (-0.2 kg, P = 0.89). CONCLUSIONS: Older adults with CVD had significantly lower physical fitness levels than those without CVD, except for grip strength. Longitudinal research is needed to investigate causality.

Development and validation of a shortened and practical frailty index for people with intellectual disabilities.

BACKGROUND: There is no widely used instrument to detect frailty in people with intellectual disabilities (IDs). We aimed to develop and validate a shorter and more practical version of a published frailty index for people with IDs. METHOD: This study was part of the longitudinal 'Healthy Ageing and Intellectual Disability' study. We included 982 people with IDs aged 50 years and over. The previously developed and validated ID-Frailty Index consisting of 51 deficits was used as the basis for the shortened version, the ID-FI Short Form. Content of the ID-FI Short Form was based on statistics and clinical and practical feasibility. We evaluated the precision and validity of the ID-FI Short Form using the internal consistency, the correlation between the ID-FI Short Form and the original ID-Frailty Index, the agreement in dividing participants in the categories non-frail, pre-frail and frail, and the association with survival. RESULTS: Seventeen deficits from the original ID-Frailty Index were selected for inclusion in the ID-FI Short Form. All deficits of the ID-FI Short Form are clinically and practically feasible to assess for caregivers and therapists supporting people with ID. We showed acceptable internal consistency with Cronbach's alpha of 0.75. The Pearson correlation between the ID-Frailty Index and the ID-FI Short Form was excellent (r = 0.94, P < 0.001). We observed a good agreement between the full and short forms in dividing the participants in the frailty categories, with a kappa statistic of 0.63. The ID-FI Short Form was associated with survival; with every 1/100 increase on the ID-FI Short Form, the mortality probability increased by 7% (hazard ratio 1.07, P < 0.001). CONCLUSION: The first validation of the ID-FI Short Form shows it to be a promising, practical tool to assess the frailty status of people with ID.

Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

Meta-analysis shows clinically relevant and long-lasting deterioration in health-related quality of life after esophageal cancer surgery.

PURPOSE: The purpose of the study is to (1) estimate the direction, clinical relevance, and duration of health-related quality of life (HRQL) change in the first year following esophageal cancer surgery and (2) to assess the robustness of the estimates by subgroup and sensitivity analyses, and an exploration of publication bias. METHODS: A systematic literature search in MEDLINE, EMBASE, CINAHL, PsychINFO, and CENTRAL to identify randomized and non-randomized studies was performed. We compared the baseline HRQL data with 3-, 6-, 9-, or 12-month follow-ups to estimate the magnitude and duration of HRQL change. These estimates were then classified as trivial, small, medium, or large. Primary outcomes were role functioning, eating, and fatigue. Secondary outcomes were physical and social functioning, dysphagia, pain, and coughing problems. We conducted subgroup analysis for open surgery, open surgery preceded by neo-adjuvant therapy, and minimally invasive surgery. Sensitivity analyses assessed the influence of study design, transformation/imputation of the data, and HRQL questionnaire used. RESULTS: We included data from 15 studies to estimate the change in 28 HRQL outcomes after esophageal cancer surgery. The main analysis showed that patients' social functioning deteriorated. Symptoms of fatigue, pain, and coughing problems increased. These changes lasted for 9-12 months, although some symptoms persisted beyond the first year after surgery. For many other HRQL outcomes, estimates were only robust after subgroup or sensitivity analyses (e.g., role and physical functioning), or remained too heterogeneous to interpret (e.g., eating and dysphagia). CONCLUSIONS: Patients will experience a clinically relevant and long-lasting deterioration in HRQL after esophageal cancer surgery. However, for many HRQL outcomes, more and better quality evidence is needed.

Meta-analysis shows clinically relevant and long-lasting deterioration in health-related quality of life after esophageal cancer surgery.

PURPOSE: The purpose of the study is to (1) estimate the direction, clinical relevance, and duration of health-related quality-of-life (HRQL) change in the first year following esophageal cancer surgery and (2) to assess the robustness of the estimates by subgroup and sensitivity analyses, and an exploration of publication bias. METHODS: A systematic literature search in MEDLINE, EMBASE, CINAHL, PsychINFO, and CENTRAL to identify randomized and non-randomized studies was performed. We compared the baseline HRQL data with 3-, 6-, 9-, or 12-month follow-ups to estimate the magnitude and duration of HRQL change. These estimates were then classified as trivial, small, medium, or large. Primary outcomes were role functioning, eating, and fatigue. Secondary outcomes were physical and social functioning, dysphagia, pain, and coughing problems. We conducted subgroup analysis for open surgery, open surgery preceded by neoadjuvant therapy, and minimally invasive surgery. Sensitivity analyses assessed the influence of study design, transformation/imputation of the data, and HRQL questionnaire used. RESULTS: We included the data from 15 studies to estimate the change in 28 HRQL outcomes after esophageal cancer surgery. The main analysis showed that patients' social functioning deteriorated. Symptoms of fatigue, pain, and coughing problems increased. These changes lasted for 9-12 months, although some symptoms persisted beyond the first year after surgery. For many other HRQL outcomes, estimates were only robust after subgroup or sensitivity analyses (e.g., role and physical functioning), or remained too heterogeneous to interpret (e.g., eating and dysphagia). CONCLUSIONS: Patients will experience a clinically relevant and long-lasting deterioration in HRQL after esophageal cancer surgery. However, for many HRQL outcomes, more and better quality evidence is needed.

Intestinal first pass metabolism of amygdalin in the rat in vitro.

The intestinal first pass metabolism of amygdalin has been investigated in rat small intestine in vitro. The results show that amygdalin is hydrolyzed to prunasin, essentially in the wall of the proximal jejunum. This specific beta(1-6)hydrolytic cleavage of the terminal glucose residue is pH-dependent and can be inhibited by glucono-delta-lactone, a potent inhibitor of the lysosomal beta-glucosidase of the rat intestine. No substrate competition between phloridzin and lactose vs amygdalin was noted. None of the more common soluble beta- or alpha-enzymatic activities of mammalian intestine (alpha-glucosidase, alpha-amylase) or mammalian liver (beta-galactosidase, beta-glucuronidase) were capable of catalyzing the hydrolysis of the terminal glucose from amygdalin at pH's 5.0, 7.0 or 9.0. Furthermore, no metabolic activity of isolated rat livers toward amygdalin and prunasin was observed within two hours of recirculating perfusion. However, cecal contents of conventional rats, exhibited both amygdalin- and prunasin-hydrolyzing activities. The resulting mandelonitrile dissociates spontaneously into cyanide and benzaldehyde. Therefore, our findings indicate that metabolism of amygdalin to prunasin occurring in the proximal part of jejunum is apparently mediated by enzymatic beta(1-6)glucosidase activity of the gut wall. In contrast, the toxicity of amygdalin due to the release of cyanide obviously requires microbiological activities of the gut flora.

Binding of 3H-spiperone to human lymphocytes: a biological marker in schizophrenia?

The specific binding of the dopamine antagonist 3H-spiperone to lymphocytes from a healthy control group (n = 40), a group of acute, unmedicated schizophrenic patients (n = 27), and a psychiatric control group (n = 16) was investigated. There were no differences in binding parameters between the healthy controls (Bmax 2.6 +/- 0.7 fmoles/10(6) cells; Kd 0.17 +/- 0.07 nM) and the psychiatric control group. Binding capacity of 3H-spiperone was significantly increased in lymphocytes from the schizophrenic patients (Bmax 14.4 +/- 9.3 fmoles/10(6) cells). Moreover, a slight decrease in affinity was observed (Kd 0.44 +/- 0.21 nM). Because the increase in binding appeared only in schizophrenic patients, this peripheral model could prove valuable as a diagnostic criterion.

Catecholamines and their receptors in blood: evidence for alterations in schizophrenia.

The simultaneous determination of serum catecholamine (CA) and their receptors in blood cells offers the possibility of evaluating disturbances of the dopamine (DA) and noradrenaline (NA) neuronal systems in man. High-affinity binding sites for 3H-yohimbine in platelets, 3H-DHA in granulocytes, and 3H-spiperone in lymphocytes from healthy control persons, unmedicated (n = 28), and medicated (n = 8) schizophrenics, and from an unmedicated psychiatric control group (n = 14) were investigated. Furthermore, the actual concentration of the circulating CA was determined with HPLC-ECD. In unmedicated schizophrenics, as compared with controls, specific binding of 3H-spiperone to lymphocytes was markedly elevated in capacity and less in affinity. For beta 2 receptors a significant decrease was found in capacity with no change in affinity. The changes in alpha 2 receptors, viz. a slight decrease in capacity, were less distinct. The concentrations of circulating CA ranged from normal values to a more than threefold increase in NA and DA, whereas adrenaline (A) concentrations were nearly unchanged. No overall change in these data was found in the medicated schizophrenic patients. 3H-Spiperone binding was characteristically increased only in schizophrenics, but did not rise above control data in the nonschizophrenic psychiatric control group. Preliminary family studies suggest that this model could be valuable as a vulnerability marker.

Effects and metabolic pathway of 4-dimethylaminophenol during kidney perfusion.

1. Isolated rat kidneys were perfused (single pass) with 4 to 40 microM soln. of 4-dimethylamino[14C]phenol (DMAP). 2. Nephrotoxicity was not detected at concn. of 14C-DMAP up to 18 microM; higher conc. resulted in irreversible loss of physiological functions with simultaneous five-fold increase in covalently bound 14C. 3. At all concn., 85% of the post-renal 14C was due to unchanged DMAP, while 15% corresponded to DMAP conjugates. These conjugates were identified as DMAP-glucuronide (90% total), DMAP-sulphate and DMAP-thioethers. 4. All DMAP conjugates were conc. in the urine with urine/perfusate concn. ratios in the range 5-7 for the glucuronide, 50-100 for the sulphate, and 10-20 for the thioethers. 5. Rates of formation fo metabolites vs DMAP concn. followed Michaelis-Menten kinetics for DMAP-sulphate (Km 25 microM, Vmax 2.2 nmol/min per g) and DMAP-thioethers (Km range 10-100 microM, Vmax 4 nmol/min per g). DMAP-glucuronide formation rate increased linearly with DMAP concn. and showed a four-fold increase at toxic DMAP doses. 6. From the data for DMAP conjugation capacity, urine/perfusate concn. ratios of DMAP conjugates and microautoradiography, it is suggested that DMAP conjugation is located mainly in the proximal convoluted tubule, where deterioration of renal functions originates.

Subcellular distribution of di- and tricarboxylates and pH gradients in perfused rat liver.

The subcellular distribution of malate, 2-oxoglutarate, citrate, aspartate and glutamate and the mitochondrial and cytosolic pH values were determined in perfused livers from fed and fasted rats. The method of fractionation of the freeze-dried tissue in non-aqueous solvents was employed. The following results were obtained: 1) Di- and tricarboxylates are not equally distributed between mitochondria and cytosol. Under the two metabolic conditions studied, the concentrations of citrate and 2-oxoglutarate are higher and those of glutamate and aspartate are lower in the mitochondria than in the cytosol. The distribution of malate varies with the metabolic state. 2) From the distribution of 5,5-dimethyl-2,4-oxazolidinedione it was calculated that the mitochondrial matrix has a more alkaline milieu than the cytosol. The cytosol is also more acidic than the perfusate. The pH difference between mitochondria and cytosol is 0.3 in the fed state and 0.6 in the fasted one, whereas the pH difference between perfusate and cytosol is 0.4 in the fed state and 0.2 in the fasted one. 3) In livers from fed rats, citrate, malate and 2-oxoglutarate appear to be distributed according to the pH gradient across the mitochondrial membrane, whereas in the fasted state, the distribution does not correspond to the pH gradient. Glutamate and aspartate do not follow the pH gradient in either metabolic state. 4) The data indicate that the pH gradient across the mitochondrial membrane does not reflect the membrane potential or the energy state of mitochondria in the intact cell.