Palliative care: views of patients and their families.

OBJECTIVE--To investigate the current problems and needs of terminally ill cancer patients and their family members, and to discover their views of hospital, community, and support team services. DESIGN--Prospective study of patients and families by questionnaire interviews in the patients'' homes. SETTING--Inner London and north Kent (London suburbs). SUBJECTS--65 Patients, each with a member of their family or a career. MAIN OUTCOME MEASURES--Ratings of eight current problems and ratings and comments on three services-hospital doctors and nurses, general practitioners and district nurses, and the support team staff-obtained after a minimum of two weeks'' care from palliative care support teams. RESULTS--Effect of anxiety on the patient''s nearest career. and symptom control were rated as the most severe current problems by both patients and families; a few patients and families identified other severe problems. Families'' ratings of pain control, symptom control, and effect of anxiety on the patient were significantly worse than the patients'' ratings (p less than 0.05). Support teams received the most praise, being rated by 58 (89%) patients and 59 (91%) of family members as good as excellent. General practitioners and district nurses were rated good or excellent by 46 (71%) patients and 46 (71%) family members, but six (9%) in each group rated the service as poor or very bad, and ratings in the inner London district were significantly worse than those in the outer London district. Hospital doctors and nurses were rated good or excellent by 22 (34%) patients and 35 (54%) of family members, and 14 (22%) patients and 15 (23%) family members rated this service as poor or very bad. Negative comments referred to communication (especially at diagnosis), coordination of services, the attitude of the doctor, delays in diagnosis, and difficulties in getting doctors to visit at home. Family members were more satisfied with the services than were patients. CONCLUSIONS--Palliative care needs to include both the patient and family because the needs of the family may exceed those of the patient. Support teams and some hospital and community doctors and nurses met the perceived needs of dying patients and families, but better education and organisation of services are needed.     

Phylogenetic distribution in the genus Mus of t-complex-specific DNA and protein markers: inferences on the origin of t-haplotypes

We have examined the phylogenetic distribution of two t-specific markers among representatives of various taxa belonging to the genus Mus. The centromeric TCP-1a marker (a testicular protein variant specific for all t-haplotypes so far studied) has also been apparently detected in several non-t representatives of the Mus IVA, Mus IVB, and probably M. cervicolor species. By contrast, a t-specific restriction- fragment-length polymorphism allele (RFLP) of the telomeric alpha- globin pseudogene DNA marker alpha-psi-4 was found only in animals belonging to the M. musculus-complex species either bearing genuine t- haplotypes or, like the M. m. bactrianus specimen studied here, likely to do so. This t-specific alpha-psi-4 RFLP allele was found to be as divergent from the RFLP alleles of the latter, non-t, taxonomical groups as it is from Mus 4A, Mus 4B, or M. spretus ones. These results suggest the presence of t-haplotypes and of t-specific markers in populations other than those belonging to the M. m. domesticus and M. m. musculus subspecies, implying a possible origin for t-haplotypes prior to the radiation of the most recent offshoot of the Mus genus (i.e., the spretus/domesticus divergence), some 1-3 Myr ago.      

The contractile basis of amoeboid movement: V. The control of gelation, solation, and contraction in extracts from dictyostelium discoideum

Motile extracts have been prepared from Dictyostelium discoideum by homogenization and differential centrifugation at 4 degrees C in a stabilization solution (60). These extracts gelled on warming to 25 degrees Celsius and contracted in response to micromolar Ca++ or a pH in excess of 7.0. Optimal gelation occurred in a solution containing 2.5 mM ethylene glycol-bis (β-aminoethyl ether)N,N,N',N'-tetraacetate (EGTA), 2.5 mM piperazine-N-N'-bis [2-ethane sulfonic acid] (PIPES), 1 mM MgC1(2), 1 mM ATP, and 20 mM KCI at ph 7.0 (relaxation solution), while micromolar levels of Ca++ inhibited gelation. Conditions that solated the gel elicited contraction of extracts containing myosin. This was true regardless of whether chemical (micromolar Ca++, pH >7.0, cytochalasin B, elevated concentrations of KCI, MgC1(2), and sucrose) or physical (pressure, mechanical stress, and cold) means were used to induce solation. Myosin was definitely required for contraction. During Ca++-or pH-elicited contraction: (a) actin, myosin, and a 95,000-dalton polypeptide were concentrated in the contracted extract; (b) the gelation activity was recovered in the material sqeezed out the contracting extract;(c) electron microscopy demonstrated that the number of free, recognizable F-actin filaments increased; (d) the actomyosin MgATPase activity was stimulated by 4- to 10-fold. In the absense of myosin the Dictyostelium extract did not contract, while gelation proceeded normally. During solation of the gel in the absense of myosin: (a) electron microscopy demonstrated that the number of free, recognizable F- actin filaments increased; (b) solation-dependent contraction of the extract and the Ca++-stimulated MgATPase activity were reconstituted by adding puried Dictyostelium myosin. Actin purified from the Dictyostelium extract did not gel (at 2 mg/ml), while low concentrations of actin (0.7-2 mg/ml) that contained several contaminating components underwent rapid Ca++ regulated gelation. These results indicated : (a) gelation in Dictyostelium extracts involves a specific Ca++-sensitive interaction between actin and several other components; (b) myosin is an absolute requirement for contraction of the extract; (c) actin-myosin interactions capable of producing force for movement are prevented in the gel, while solation of the gel by either physical or chemical means results in the release of F-actin capable of interaction with myosin and subsequent contraction. The effectiveness of physical agents in producting contraction suggests that the regulation of contraction by the gel is structural in nature.     

Roles of creatine in the regulation of cardiac protein synthesis

The observation that increased muscular activity leads to muscle hypertrophy is well known, but identification of the biochemical and physiological mechanisms by which this occurs remains an important problem. Experiments have been described (5, 6) which suggest that creatine, an end product of contraction, is involved in the control of contractile protein synthesis in differentiating skeletal muscle cells and may be the chemical signal coupling increased muscular activity and the increased muscular mass. During contraction, the creatine concentration in muscle transiently increases as creatine phosphate is hydrolyzed to regenerate ATP. In isometric contraction in skeletal muscle for example, Edwards and colleagues (3) have found that nearly all of the creatine phosphate is hydrolyzed. In this case, the creatine concentration is increased about twofold, and it is this transient change in creatine concentration which is postulated to lead to increased contractile protein synthesis. If creatine is found in several intracellular compartments, as suggested by Lee and Vissher (7), local changes in concentration may be greater then twofold. A specific effect on contractile protein synthesis seems reasonable in light of the work of Rabinowitz (13) and of Page et al. (11), among others, showing disproportionate accumulation of myofibrillar and mitochondrial proteins in response to work-induced hypertrophy and thyroxin-stimulated growth. Previous experiments (5, 6) have shown that skeletal muscles cells which have differentiated in vitro or in vivo synthesize myosin heavy-chain and actin, the major myofibrillar polypeptides, faster when supplied creatine in vitro. The stimulation is specific for contractile protein synthesis since neither the rate of myosin turnover nor the rates of synthesis of noncontractile protein and DNA are affected by creatine. The experiments reported in this communication were undertaken to test whether creatine selectively stimulates contractile protein synthesis in heart as it does in skeletal muscle.     

Fatness and fitness: exposing the logic of evolutionary explanations for obesity

To explore the logic of evolutionary explanations of obesity we modelled food consumption in an animal that minimizes mortality (starvation plus predation) by switching between activities that differ in energy gain and predation. We show that if switching does not incur extra predation risk, the animal should have a single threshold level of reserves above which it performs the safe activity and below which it performs the dangerous activity. The value of the threshold is determined by the environmental conditions, implying that animals should have variable ‘set points’. Selection pressure to prevent energy stores exceeding the optimal level is usually weak, suggesting that immediate rewards might easily overcome the controls against becoming overweight. The risk of starvation can have a strong influence on the strategy even when starvation is extremely uncommon, so the incidence of mortality during famine in human history may be unimportant for explanations for obesity. If there is an extra risk of switching between activities, the animal should have two distinct thresholds: one to initiate weight gain and one to initiate weight loss. Contrary to the dual intervention point model, these thresholds will be inter-dependent, such that altering the predation risk alters the location of both thresholds; a result that undermines the evolutionary basis of the drifty genes hypothesis. Our work implies that understanding the causes of obesity can benefit from a better understanding of how evolution shapes the mechanisms that control body weight.     

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects.     

Progression,Symptoms and Psychosocial Concerns among Those Severely Affected by Multiple Sclerosis: A Mixed-Methods Cross-Sectional Study of Black Caribbean and White British People

Objective

Multiple sclerosis is now more common among minority ethnic groups in the UK but little is known about their experiences, especially in advanced stages. We examine disease progression, symptoms and psychosocial concerns among Black Caribbean (BC) and White British (WB) people severely affected by MS.

Design

Mixed methods study of 43 BC and 43 WB people with MS (PwMS) with an Expanded Disability Status Scale (EDSS) ≥6 involving data from in clinical records, face-to-face structured interviews and a nested-qualitative component. Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) were calculated. To control for selection bias, propensity scores were derived for each patient and adjusted for in the comparative statistical analysis; qualitative data were analysed using the framework approach.

Results

Median EDSS for both groups was (6.5; range: 6.0–9.0). Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) based on neurological assessment of current EDSS scores identified BC PwMS were more likely to have aggressive disease (PI F = 4.04, p = 0.048, MSSS F = 10.30, p<0.001). Patients’ reports of the time required to reach levels of functional decline equivalent to different EDSS levels varied by group; EDSS 4: BC 2.7 years v/s WB 10.2 years (U = 258.50, p = 0.013), EDSS 6∶6.1 years BC v/s WB 12.7 years (U = 535.500, p = 0.011), EDSS 8: BC 8.7 years v/s WB 10.2 years. Both groups reported high symptom burden. BC PwMS were more cognitively impaired than WB PwMS (F = 9.65, p = 0.003). Thematic analysis of qualitative interviews provides correspondence with quantitative findings; more BC than WB PwMS referred to feelings of extreme frustration and unresolved loss/confusion associated with their rapidly advancing disease. The interviews also reveal the centrality, meanings and impact of common MS-related symptoms.

Conclusions

Delays in diagnosis should be avoided and more frequent reviews may be justified by healthcare services. Culturally acceptable interventions to better support people who perceive MS as an assault on identity should be developed to help them achieve normalisation and enhance self-identity.     

Change in knee contact force with simulated change in body weight

The relationship between obesity, weight gain and progression of knee osteoarthritis is well supported, suggesting that excessive joint loading may be a mechanism responsible for cartilage deterioration. Examining the influence of weight gain on joint compressive forces is difficult, as both muscles and ground reaction forces can have a significant impact on the forces experienced during gait. While previous studies have examined the relationship between body weight and knee forces, these studies have used models that were not validated using experimental data. Therefore, the objective of this study was to evaluate the relationship between changes in body weight and changes in knee joint contact forces for an individual's gait pattern using musculoskeletal modeling that is validated against known internal compressive forces. Optimal weighting constants were determined for three subjects to generate valid predictions of knee contact forces (KCFs) using in vivo data collection with instrumented total knee arthroplasty. A total of five simulations per walking trial were generated for each subject, from 80% to 120% body weight in 10% increments, resulting in 50 total simulations. The change in peak KCF with respect to body weight was found to be constant and subject-specific, predominantly determined by the peak force during the baseline condition at 100% body weight. This relationship may be further altered by any change in kinematics or body mass distribution that may occur as a result of a change in body weight or exercise program.     

Paying for nectar with wingbeats: a new model of honeybee foraging

Honeybees acquire wing damage as they age and older foraging honeybees accept lavender inflorescences with fewer flowers. These indicate the operation of some kind of optimal response, but this cannot be based on energy because energy expenditure does not change as the wings get damaged. However, wingbeat frequency increases with wing damage. A deterministic analytical model was constructed, based on the assumptions that bees have a limited total number of wingbeats that the flight motor can perform and that they maximize lifetime energy profit by conserving the number of wingbeats used in foraging. The optimal response to wing damage is to reduce the threshold number of flowers needed to accept an inflorescence. The predicted optimal gradient between wing damage (wingbeat frequency) and acceptance threshold (number of flowers on an inflorescence) was close to the observed gradient from field data. This model demonstrates that wear and tear is a significant factor in optimal foraging strategies.