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Biomedical subjects

S C Allen

Publications and source records attributed to S C Allen.

At least 19 recordsLinked to original sources
PubMed2006

The tendency to altered perception of airflow resistance in aged subjects might be due mainly to a reduction in diaphragmatic proprioception.

Elderly patients with asthma, particularly those above the age of 80 years, appear less able to detect early worsening of their airflow resistance and hence might not take 'rescue' bronchodilator medication promptly. No consistent explanation for the observation has been posited. We hypothesize that deterioration in the sensitivity and accuracy of inspiratory (mainly diaphragmatic) proprioception is a plausible mechanism. This contention is supported by observations that indicate the central role of afferent phrenic nerve fibres arising from mechanoreceptors in diaphragmatic muscle and entheses in the ability to sense changes in intrathoracic pressure and volume. Other sensory afferent sources appear less important in this context because the ability to detect intrathoracic pressure and volume changes is preserved in patients with heart-lung transplants (parenchymal and airway denervation), topically anaesthetized upper airways and spinal cord transection below C4 (intact phrenic function) but not cord transection above C2 (phrenic function absent) if the airways are simultaneously anaesthetized. Further support for the hypothesis comes from demonstration of reduced integrated proprioceptive function in older subjects, such as increased postural sway, reduced ability to judge changes in joint position and slower recovery from eye and hand perturbation. In the context of asthma, the detection of a change in airflow resistance depends mainly on the subconscious detection of a mismatch between the inspiratory effort and the volume change achieved; the resulting discrepancy between length (volume) and tension (muscular effort) is felt as a sensation of obstructed breathing, resulting in greater effort to breath and conscious actions such as self-medication. Our hypothesis proposes that a reduced ability to detect accurately the volume change during tidal breathing delays the sensing of the obstruction in older subjects.

Aged↗
PubMed2006

A simple drawing test to identify patients who are unlikely to be able to learn to use an inhaler.

Previous research has shown that patients are not able to learn to use self-administered inhaler devices if they have impaired general cognition, executive (frontal lobe) dysfunction or dyspraxia. These impairments are most frequently encountered in frail elderly people. Some of the tests required to detect such impairments are time-consuming and are therefore not easily adopted in routine clinical practice, particularly in an outpatient setting. We performed a study of 50 elderly inhaler-naïve patients to explore the use of a simple quick drawing test (copying overlapping pentagons) to determine whether that test was able to identify patients who were unable to learn to use a Turbohaler. Patients who were not able to perform the pentagon copying test were found to be unable to learn to use a Turbohaler with a specificity of 93% and positive predictive value of 87%. This was at least as discriminating as the Abbreviated Mental Test and the Mini Mental State Examination. The overlapping pentagon drawing test is useful in clinical practice to identify patients who will probably not use a self-administered inhaler correctly, and who will require an alternative approach to the treatment of their airways disease. This finding might have implications for other self-administered treatment, such as insulin pens and complex drug regimens.

Administration, Inhalation↗
PubMed2004

The effects of age, seropositivity and disease duration on autonomic cardiovascular reflexes in patients with rheumatoid arthritis.

Previous studies have shown that autonomic cardiovascular reflexes (ACRs) are impaired in rheumatoid arthritis (RA) and in old age. To investigate the integrity of ACRs in patients with RA, with reference to age, duration of disease and rheumatoid factor (RF) positivity, we conducted a prospective open study of 62 RA outpatients (age 38-84) and 41 healthy controls (age 22-82) using five standard tests of ACR function. Patients of all ages with RA were found to have blunted ACRs when compared with younger controls, though this effect was subclinical. Older RA patients did not have significantly more ACR impairment than older controls. There was a tendency to greater impairment of ACRs in RA patients with a positive RF. The age-associated changes in ACRs in normal subjects are similar to those seen in RA patients of all ages. The effects of RA and age on ACRs do not appear to be additive.

Adult↗
PubMed2004

Biochemical recovery time scales in elderly patients with osteomalacia.

Osteomalacia is not rare in the UK and climatically similar countries, particularly in elderly people and those of Asian descent. Overt clinical osteomalacia is usually treated with a loading dose of vitamin D, followed by a regular supplement. However, little is known of the time taken to reach a stable biochemical state after starting treatment. Such information would shed light on the duration of the bone remineralization phase and guide decisions on the length of follow-up. To address this we conducted a 2-year follow-up study of 42 patients (35 female, mean age 80.8 years) with biopsy proven osteomalacia treated with a standard replacement regimen and general nutritional support. Although normocalcaemia was attained within 4 weeks the mean values continued to rise, to a mid-range plateau at 52 weeks. The phosphate and alkaline phosphatase values also took at least a year to reach a stable mean, with a slight further trend towards the mid-range for the entire 104 weeks. The mean serum albumin also rose throughout the first 52 weeks, indicating an effective response to the general nutritional support measures. Our observations suggest that the dynamic relationship between calcium, phosphate and bone requires at least a year, and probably longer, to reach an equilibrium after treatment for osteomalacia in elderly patients. The findings emphasize the need for close medical and social follow-up in this clinical context.

Aged↗
PubMed2003

Predictors of a nursing home placement from a non-acute geriatric hospital.

BACKGROUND: Identifying patients who need Nursing Home (NH) care following a hospital admission is important. OBJECTIVE: To identify the factors that predispose to an NH discharge. DESIGN: Prospective observational study with blinded end-point evaluation. SETTING: A non-acute geriatric hospital. SUBJECTS: Two hundred consecutive elderly patients who were admitted for rehabilitation following treatment for an acute illness. MAIN OUTCOME MEASURES: Discharge to an NH or home. RESULTS: Thirty-five out of the 150 live discharges (23.3%) were to an NH. NH discharges had a longer length of stay (38.5 versus 19.8 days; p < 0001). They were more likely to have visual impairment (p = 0.0009), confusion (p < 0.0001), wandering behaviour (p = 0.003), incontinence (p < 0.0001 or unsafe gait (p = 0.0005), to be on tranquillizers (p = 0.003), to be at risk of falls (p = 0.02) and to have sustained a fall while in hospital (p = 0.001). Multiple logistic regression identified confusion (p = 0.001), incontinence (p = 0.02), falls in hospital (p = 0.01), gait abnormalities (p < 0.001), tranquillizers (p < 0.001), impaired distant vision (p = 0.01) and living alone (p < 0.001) as independently associated with the risk of an NH discharge. This risk proportionately increased with the number of risk factors present: 4.28% for 0-2 factors, 25.8% for 3-4 factors and 81.8% for 5-6 factors (p < 0.0001). CONCLUSION: These factors should be the target of specific rehabilitation in an attempt to reduce the risk of discharge to a nursing home and improve patient outcome.

Accidental Falls↗
PubMed2003

Ligand-protein docking: cancer research at the interface between biology and chemistry.

In recent years there has been a growing interest in computer-based screening. One of the driving forces has been the increased efficiency of protein crystallography leading to the real possibility of using structure-based design as a significant contributor to the discovery of novel ligands. In 1957 after 22 years of work the first protein structure, determined by x-ray crystallography was produced. Now the process has become increasingly automated and nearly 20,000 protein structures are available in the Protein Data Bank (PDB). Equally, progress in genomics will result in a great expansion of validated targets for cancer therapy. The understanding of the relationships between structure and function of gene products will be one of the key routes to new therapeutic advances. The challenge now is to use this data in the discovery of novel therapeutics. One approach is obviously to synthesize molecules and co-crystallize or soak them into the protein crystal and so determine the position and interaction of the molecule with the protein. The structural information obtained (where does the molecule bind; what are the ligand/protein/solvent interactions?) can be invaluable in the generation of novel molecules or in the re-design of existing molecules whose drug properties are not optimal. However, when dealing with large numbers (millions) of molecules, when crystallization is difficult or in testing hypotheses, a significant contribution can be made using computer based screening methods. In order to use the structural information derived from x-ray crystallography (or other sources, for example NMR or homology modelling) when evaluating the utility of a novel ligand, we need to understand where in the protein (or other macromolecule such as RNA) the ligand is likely to bind and also if possible, the strength of the binding interactions. This problem is known as the 'docking problem'. There have been many approaches to the solution of this problem over the last ten years. For example, some methods rely on complex molecular dynamics simulations while others use less costly graph matching approaches. There is generally a compromise between speed and accuracy, with some methods giving much more information and insight into the nature of the protein/ligand interactions and other methods optimised for speed of docking thousands of putative ligands. We will describe some of the more common methods and algorithms used to solve the docking problem and in particular, we will review recent applications in cancer research.

Animals↗
PubMed2002

Ability to learn inhaler technique in relation to cognitive scores and tests of praxis in old age.

Clinical observations have shown that some older patients are unable to learn to use a metered dose inhaler (MDI) despite having a normal abbreviated mental test (AMT) score, possibly because of dyspraxia or unrecognised cognitive impairment. Thirty inhaler-naive inpatients (age 76-94) with an AMT score of 8-10 (normal) were studied. Standard MDI training was given and the level of competence reached was scored (inhalation score). A separate observer performed the minimental test (MMT), Barthel index, geriatric depression score (GDS), ideational dyspraxia test (IDT), and ideomotor dyspraxia test (IMD). No correlative or threshold relationship was found between inhalation score and Barthel index, GDS, or IDT. However, a significant correlation was found between inhalation score and IMD (r = 0.45, p = 0.039) and MMT (r = 0.48, p = 0.032) and threshold effects emerged in that no subject with a MMT score of less than 23/30 had an inhalation score of 5/10 or more (adequate technique requires 6/10 or more), and all 17/18 with an inhalation score of 6/10 or more had an IMD of 14/20 or more. The three patients with a MMT >22 and inhalation score <6 had abnormal IMD scores. Inability to learn an adequate inhaler technique in subjects with a normal AMT score appears to be due to unrecognised cognitive impairment or dyspraxia. The MMT is probably a more useful screening test than the AMT score in this context.

Aged↗
PubMed2000

Multiple histone acetyltransferases are associated with a chicken erythrocyte chromatin fraction enriched in active genes.

We have examined salt-soluble chromatin released by micrococcal nuclease from a 15-day-old chicken embryo erythrocyte nuclei for histone acetyltransferase (HAT) activities. This chromatin is enriched in transcriptionally active sequences from within the active beta-globin locus and contains elevated levels of acetylated core histones. HAT activities present in this fraction target histones H4, H3, and H2A when the chromatin itself is used as the substrate. In gel HAT activity assay demonstrates that the salt-soluble chromatin fraction contains four acetyltransferase molecules distinguished by their different molecular masses (47, 33, 32, and 28 kDa). Further separation of the chromatin by centrifugation through sucrose gradients shows that the acetyltransferases segregate into chromatin-bound and chromatin-free populations. The 32- and 28-kDa HATs are associated with chromatin, whereas the 47- and 33-kDa HAT molecules are not. The chromatin-bound HAT activities predominantly target H4 to give the diacetyl and triacetyl species; some acetylation of H2A can also be seen. Our results suggest that the chromatin-associated acetyltransferases have a role in gene regulation.

Acetylation↗
PubMed2000

An epidemiological study of falls on integrated general medical wards.

Reducing falls in hospital requires an environmental as well as a patient-orientated approach. We studied patient and ward characteristics relating to falls in an acute setting. In a prospective open observational study, we examined fall characteristics in two nuclear designed wards (A and B) and a longitudinal ward (C). We recorded 63 falls among 1609 patients. Ward C had the most falls (31 vs 18/14; p = 0.01), fall positive days (29 vs 15/10; p = 0.002) and fallers (27 vs 13/12; p = 0.001; OR 2.54, CI--1.41-4.57). Ward C had a higher cumulative risk of falls (p = 0.006) and fall positive days (p = 0.003). Choice of ward was a significant independent risk factor for falls (p = 0.01) when controlled for age, sex, and diagnostic variation between the wards. Most falls were intrinsic (A 66.7%, B 64.2%, C 61.3%, p = 0.45). A significantly higher proportion of falls on ward C occurred by the bed (p = 0.04). Significant differences exist between the wards, and fall reduction programmes should identify and compensate for adverse ward-related factors to increase the effectiveness of patient-targeted fall risk assessments.

Accidental Falls↗
PubMed1999

Refined crystal structures of native human angiogenin and two active site variants: implications for the unique functional properties of an enzyme involved in neovascularisation during tumour growth.

Human angiogenin (Ang), an unusual member of the pancreatic RNase superfamily, is a potent inducer of angiogenesis in vivo. Its ribonucleolytic activity is weak (10(4) to 10(6)-fold lower than that of bovine RNase A), but nonetheless seems to be essential for biological function. Ang has been implicated in the establishment of a wide range of human tumours and has therefore emerged as an important target for the design of new anti-cancer compounds. We report high-resolution crystal structures for native Ang in two different forms (Pyr1 at 1.8 A and Met-1 at 2.0 A resolution) and for two active-site variants, K40Q and H13A, at 2.0 A resolution. The native structures, together with earlier mutational and biochemical data, provide a basis for understanding the unique functional properties of this molecule. The major structural features that underlie the weakness of angiogenin's RNase activity include: (i) the obstruction of the pyrimidine-binding site by Gln117; (ii) the existence of a hydrogen bond between Thr44 and Thr80 that further suppresses the effectiveness of the pyrimidine site; (iii) the absence of a counterpart for the His119-Asp121 hydrogen bond that potentiates catalysis in RNase A (the corresponding aspartate in Ang, Asp116, has been recruited to stabilise the blockage of the pyrimidine site); and (iv) the absence of any precise structural counterparts for two important purine-binding residues of RNase A. Analysis of the native structures has revealed details of the cell-binding region and nuclear localisation signal of Ang that are critical for angiogenicity. The cell-binding site differs dramatically from the corresponding regions of RNase A and two other homologues, eosinophil-derived neurotoxin and onconase, all of which lack angiogenic activity. Determination of the structures of the catalytically inactive variants K40Q and H13A has now allowed a rigorous assessment of the relationship between the ribonucleolytic and biological activities of Ang. No significant change outside the enzymatic active site was observed in K40Q, establishing that the loss of angiogenic activity for this derivative is directly attributable to disruption of the catalytic apparatus. The H13A structure shows some changes beyond the ribonucleolytic site, but sites involved in cell-binding and nuclear translocation are essentially unaffected by the amino acid replacement.

Amino Acid Sequence↗
PubMed1999

Crystal structure of a hybrid between ribonuclease A and bovine seminal ribonuclease--the basic surface, at 2.0 A resolution.

A variant of bovine pancreatic ribonuclease A has been prepared with seven amino acid substitutions (Q55K, N62K, A64T, Y76K, S80R, E111G, N113K). These substitutions recreate in RNase A the basic surface found in bovine seminal RNase, a homologue of pancreatic RNase that diverged some 35 million years ago. Substitution of a portion of this basic surface (positions 55, 62, 64, 111 and 113) enhances the immunosuppressive activity of the RNase variant, activity found in native seminal RNase, while substitution of another portion (positions 76 and 80) attenuates the activity. Further, introduction of Gly at position 111 has been shown to increase the catalytic activity of RNase against double-stranded RNA. The variant and the wild-type (recombinant) protein were crystallized and their structures determined to a resolution of 2.0 A. Each of the mutated amino acids is seen in the electron density map. The main change observed in the mutant structure compared with the wild-type is the region encompassing residues 16-22, where the structure is more disordered. This loop is the region where the polypeptide chain of RNase A is cleaved by subtilisin to form RNase S, and undergoes conformational change to allow residues 1-20 of the RNase to swap between subunits in the covalent seminal RNase dimer.

Endoribonucleases↗
PubMed1997

Competence thresholds for the use of inhalers in people with dementia.

METHODS: the ability to learn three inhaler techniques of increasing levels of complexity was studied in 50 normal and demented inhaler-naive elderly people (mean age 81 years) with stable 10-point mini-mental test scores (MTS). There were 10 subjects in each of the following groups: MTS 8-10 (non-demented), MTS 7 (borderline), MTS 6 (mild dementia), MTS 5 and MTS 4 (2 moderate dementia groups). The techniques were taught on one day and reassessed on the following day on consecutive days in ascending order of complexity. RESULTS: those with an MTS of 4 were unable to learn any of the techniques, while all the non-demented people could learn all three techniques. For the five-stage technique (standard metered dose inhaler) the 0% threshold (i.e. when none of the subjects was able to learn) was MTS 6, the 50% threshold (at least half but not all could learn) MTS 7 and the 100% threshold (all could learn) MTS 8. For the four-stage technique (inhaler with large spacer) the 0% threshold was MTS 5, the 50% threshold MTS 6 and the 100% threshold MTS 8. For the three-stage technique (inspiration-triggered inhaler) the 0% threshold was MTS 4, the 50% threshold MTS 5 and the 100% threshold MTS 7. CONCLUSIONS: MTS can be used to determine the likelihood of a mild or moderately demented patient being able to learn a multiple-stage inhaler technique.

Aged↗
PubMed1997

A study of autonomic cardiovascular reflexes in elderly patients with pneumonia.

People recovering from pneumonia are often weak for no apparent reason. Clinical features such as postural hypotension, arrhythmia and syndrome of inappropriate ADH have, in other circumstances, been attributed to impaired autonomic function. The aim of this study was to see whether elderly patients with pneumonia had impaired autonomic cardiovascular reflexes and, if so, how long this persisted. We compared healthy elderly controls, elderly controls with trauma (fractured femoral neck) and elderly patients with pneumonia. Thirty-eight subjects were studied in a series of cardiovascular autonomic function tests. Results suggest that elderly people have a high prevalence of impaired cardiovascular autonomic reflexes in the immediate post-pneumonic phase, and that this improves significantly after six weeks, with a further improvement by six months. Elderly patients recovering from pneumonia are predisposed to the adverse effects of drugs and other factors which can further impair autonomic cardiovascular reflexes.

Aged↗
PubMed1996

Refined three-dimensional structure of cat-muscle (M1) pyruvate kinase at a resolution of 2.6 A.

The three-dimensional structure of cat-muscle pyoruvate kinase has been refined at a resolution of 2.6 A. The details of the structure permit interpretation of the original heavy-atom studies and give insight into the importance of conserved residues in pyruvate kinases and the allosteric behaviour of the enzyme. There are a small number of essential residues which determine the relative orientations of domains and the precise nature of intersubunit contacts. Arginine residues are particularly important.

Journal Article↗
PubMed1994

Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease.

Angiogenin, a potent inducer of neovascularization, is the only angiogenic molecule known to exhibit ribonucleolytic activity. Its overall structure, as determined at 2.4 A, is similar to that of pancreatic ribonuclease A, but it differs markedly in several distinct areas, particularly the ribonucleolytic active center and the putative receptor binding site, both of which are critically involved in biological function. Most strikingly, the site that is spatially analogous to that for pyrimidine binding in ribonuclease A differs significantly in conformation and is "obstructed" by glutamine-117. Movement of this and adjacent residues may be required for substrate binding to angiogenin and, hence, constitute a key part of its mechanism of action.

Amino Acid Sequence↗