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Biomedical subjects

J A Powell

Publications and source records attributed to J A Powell.

At least 37 records · Page 2Linked to original sources
PubMed1998

First line treatment with omeprazole provides an effective and superior alternative strategy in the management of dyspepsia compared to antacid/alginate liquid: a multicentre study in general practice.

BACKGROUND: Many patients who present with dyspepsia are prescribed antacid/alginates as their first line and often mainstay therapy. This multicentre study was designed to assess whether early introduction of acid inhibition is an effective strategy in dyspepsia management. METHODS: Dyspeptic patients (n = 674) were randomized to receive either omeprazole 10 mg o.m. or antacid/alginate liquid 10 mL q.d.s. for 4 weeks in an open, parallel group study. RESULTS: Complete relief of the most common symptom at entry, heartburn, was greater in the omeprazole-treated group compared with the antacid/alginate-treated group (64 vs. 30%, respectively, at 4 weeks; P < 0.0001). The percentage of patients who met the stringent health target of complete relief of overall symptoms was higher in the omeprazole-treated group (41% at 4 weeks) compared with the antacid/alginate group (16% at 4 weeks; P < 0.0001). Comparisons of quality of life scores between treatments favoured the omeprazole group at 2 and 4 weeks for both the Psychological General Well-Being Index and the Gastrointestinal Symptom Rating Scale (each P < or = 0.0009). In addition, a greater proportion of patients rated omeprazole to be more effective in symptom relief and more convenient to use (each P = 0.0001) than antacid/alginate. CONCLUSION: This study demonstrates that, compared to antacid/alginate liquid 10 mL q.d.s., omeprazole 10 mg o.m. is more effective in the management of dyspepsia symptoms and is the patients' preferred treatment.

Adult↗
PubMed1998

Initial loading (400 micrograms twice daily) versus static (400 micrograms nocte) dose budesonide for asthma management. PLAN Research Group.

This double-blind study aimed to determine whether superior asthma control is achieved with budesonide (Pulmicort Turbohaler) at a loading dose (LD) (400 micrograms b.d.) for 6 weeks, followed by step down to 400 micrograms nocte for 12 weeks, compared with a static dose (SD) (400 micrograms nocte) for 18 weeks. A total of 682 patients (mean peak expiratory flow rate (PEFR) 413 l/min), who demonstrated > or = 15% reversibility in PEFR, were randomised into the study. After 18 weeks, patients experienced improvements in morning PEFR (+45 l/min, both groups), symptom score (LD -0.57, SD -0.49, on a scale of 0-3), sleep disturbance (LD -1.21 nights/week, SD -1.06 nights/week) and beta 2-agonist use (LD -1.36 puffs/day, SD -1.06 puffs/day), within both groups (each p = 0.0001). At 18 weeks, 82% (LD) and 84% (SD) of patients benefited from no nocturnal wakening in the previous 7 days. Overall, at 18 weeks, asthma control was not significantly different between the groups. After 6 weeks, improvements in morning PEFR (LD +36 l/min, SD +26 l/min) and beta 2-agonist use (LD -1.10 puffs/day, SD -0.94 puffs/day) were greater in the loading dose than in the static dose group (each p < 0.05). The greater improvement in morning PEFR in the loading dose group was significant by day 7 (p < 0.05). While both regimens are equally effective in achieving asthma control at 18 weeks, early clinical advantage is gained with initial loading dose budesonide (400 micrograms b.d.).

Adult↗
PubMed1996

Absence of the beta subunit (cchb1) of the skeletal muscle dihydropyridine receptor alters expression of the alpha 1 subunit and eliminates excitation-contraction coupling.

The multisubunit (alpha 1s, alpha 2/delta, beta 1, and gamma) skeletal muscle dihydropyridine receptor transduces transverse tubule membrane depolarization into release of Ca2+ from the sarcoplasmic reticulum, and also acts as an L-type Ca2+ channel. The alpha 1s subunit contains the voltage sensor and channel pore, the kinetics of which are modified by the other subunits. To determine the role of the beta 1 subunit in channel activity and excitation-contraction coupling we have used gene targeting to inactivate the beta 1 gene. beta 1-null mice die at birth from asphyxia. Electrical stimulation of beta 1-null muscle fails to induce twitches, however, contractures are induced by caffeine. In isolated beta 1-null myotubes, action potentials are normal, but fail to elicit a Ca2+ transient. L-type Ca2+ current is decreased 10- to 20-fold in the beta 1-null cells compared with littermate controls. Immunohistochemistry of cultured myotubes shows that not only is the beta 1 subunit absent, but the amount of alpha 1s in the membrane also is undetectable. In contrast, the beta 1 subunit is localized appropriately in dysgenic, mdg/mdg, (alpha 1s-null) cells. Therefore, the beta 1 subunit may not only play an important role in the transport/insertion of the alpha 1s subunit into the membrane, but may be vital for the targeting of the muscle dihydropyridine receptor complex to the transverse tubule/sarcoplasmic reticulum junction.

Action Potentials↗
PubMed1996

Formation of triads without the dihydropyridine receptor alpha subunits in cell lines from dysgenic skeletal muscle.

Muscular dysgenesis (mdg/mdg), a mutation of the skeletal muscle dihydropyridine receptor (DHPR) alpha 1 subunit, has served as a model to study the functions of the DHPR in excitation-contraction coupling and its role in triad formation. We have investigated the question of whether the lack of the DHPR in dysgenic skeletal muscle results in a failure of triad formation, using cell lines (GLT and NLT) derived from dysgenic (mdg/mdg) and normal (+/+) muscle, respectively. The lines were generated by transfection of myoblasts with a plasmid encoding a Large T antigen. Both cell lines express muscle-specific proteins and begin organization of sarcomeres as demonstrated by immunocytochemistry. Similar to primary cultures, dysgenic (GLT) myoblasts show a higher incidence of cell fusion than their normal counterparts (NLT). NLT myotubes develop spontaneous contractile activity, and fluorescent Ca2+ recordings show Ca2+ release in response to depolarization. In contrast, GLTs show neither spontaneous nor depolarization-induced Ca2+ transients, but do release Ca2+ from the sarcoplasmic reticulum (SR) in response to caffeine. Despite normal transverse tubule (T-tubule) formation, GLT myotubes lack the alpha 1 subunit of the skeletal muscle DHPR, and the alpha 2 subunit is mistargeted. Nevertheless, the ryanodine receptor (RyR) frequently develops its normal, clustered organization in the absence of both DHPR alpha subunits in the T-tubules. In EM, these RyR clusters correspond to T-tubule/SR junctions with regularly spaced feet. These findings provide conclusive evidence that interactions between the DHPR and RyR are not involved in the formation of triad junctions or in the normal organization of the RyR in the junctional SR.

Animals↗
PubMed1995

Myofibrillogenesis in rodent skeletal muscle in vitro: two pathways involving thick filament aggregates.

Thick filament aggregates play an important role in myofibrillogenesis in rodent skeletal muscle in vitro. This ultrastructural study describes these aggregates, shows their involvement in the process of myofibril formation, and correlates their appearance and function with current models of myofibrillogenesis. Initially, following myoblast fusion in normal mouse skeletal muscle in vitro, abundant stress fiber-like structures (SFLS) are found near the periphery of early myotubes. These undergo internal rearrangements, forming subcortical sarcomeres and early myofibrils. However, additional thick filaments are synthesized, and some join appositionally to the nascent myofibrils, increasing their diameter. More interiorly, this thick filament synthesis accelerates, with filaments aligning into aggregates resembling discrete A-bands, usually with M-lines and M-regions. The ends of these 'A-band' aggregates are infiltrated with ribosomes and capped by flocculent material. Ultimately, aggregates are incorporated into preexisting myofibrils or associate end-to-end to form new, parallel myofibrils, the flocculent material forming putative I-bands with diminished Z-lines and few thin filaments. As differentiation continues, Z-lines and thin filaments appear, forming true myofibrils. Dysgenic mouse skeletal muscle develops similarly, but when this non-contractile cell matures (i.e., generates action potentials), filaments and their organization break down. Cloned myogenic rat L5/A10 cells also follow this developmental pattern, but in mature, contracting myotubes, Z-lines remain irregular and thin filaments are reduced. In all three types of muscle developing in vitro, thick filament aggregates are a common and predominant feature and as such appear to constitute an additional or alternate pathway to previously described models of myofibrillogenesis.

Animals↗
PubMed1995

Symptoms of communication breakdown in dementia: carers' perceptions.

The breakdown of applied communication skills associated with the cognitive-communication deficit of dementia is poorly documented, as is carers' awareness of the nature of the problems. This study considered 32 symptoms which may be associated with breakdown of communication. Perceptions of these symptoms by carers of 79 community-living dementia patients were compared with perceptions of family/close friends of a comparable group of 76 control subjects. Communication skills of dementia patients were perceived to be significantly more impaired than those of control subjects. Areas of greatest discrepancy between performance of dementia and control groups included 'Asking the same question a number of times', 'Difficulty following conversation when a group of people are talking', 'Trouble keeping a conversation going' and 'Struggling to think of the names of people and places'. Eleven of the 32 symptoms were reported as occurring 'fairly often', 'usually' or 'always' in at least 50% of the dementia patients. Identification of specific factors likely to contribute to breakdown of communication in dementia will enable involved professionals to guide carers towards a better understanding of the problems. This should help to alleviate domestic stress thereby enhancing the quality of life of patients and their carers.

Aged↗
PubMed1993

Triad formation: organization and function of the sarcoplasmic reticulum calcium release channel and triadin in normal and dysgenic muscle in vitro.

Excitation-contraction (E-C) coupling is thought to involve close interactions between the calcium release channel (ryanodine receptor; RyR) of the sarcoplasmic reticulum (SR) and the dihydropyridine receptor (DHPR) alpha 1 subunit in the T-tubule membrane. Triadin, a 95-kD protein isolated from heavy SR, binds both the RyR and DHPR and may thus participate in E-C coupling or in interactions responsible for the formation of SR/T-tubule junctions. Immunofluorescence labeling of normal mouse myotubes shows that the RyR and triadin co-aggregate with the DHPR in punctate clusters upon formation of functional junctions. Dysgenic myotubes with a deficiency in the alpha 1 subunit of the DHPR show reduced expression and clustering of RyR and triadin; however, both proteins are still capable of forming clusters and attaining mature cross-striated distributions. Thus, the molecular organization of the RyR and triadin in the terminal cisternae of SR as well as its association with the T-tubules are independent of interactions with the DHPR alpha 1 subunit. Analysis of calcium transients in dysgenic myotubes with fluorescent calcium indicators reveals spontaneous and caffeine-induced calcium release from intracellular stores similar to those of normal muscle; however, depolarization-induced calcium release is absent. Thus, characteristic calcium release properties of the RyR do not require interactions with the DHPR; neither do they require the normal organization of the RyR in the terminal SR cisternae. In hybrids of dysgenic myotubes fused with normal cells, both action potential-induced calcium transients and the normal clustered organization of the RyR are restored in regions expressing the DHPR alpha 1 subunit.

Amino Acid Sequence↗
PubMed1992

A negative transcriptional control region of a developmentally-regulated gene co-localizes with the origin of replication of an endogenous plasmid in Dictyostelium.

The endogenous nuclear plasmid Ddp1 from the wild-type Dictyostelium discoideum strain NC4 has been cloned, its origin of replication has been localized, and plasmid-encoded genes have been mapped that are preferentially expressed during growth or development. Here we present an analysis of the regulation of the Ddp1-encoded gene d5, which, in wild-type cells, is expressed only during the multicellular stages of development. In this study, we show that sequences 3' to the d5 coding region are required to suppress constitutive expression of d5 from aberrant transcriptional start sites and that this regulatory region acts at a distance and in an orientation-independent manner. The cis-acting negative regulatory element(s) necessary for repression of aberrant d5 expression is either very tightly linked or identical to sequences required for extrachromosomal replication, such that all 3' deletions that cause constitutive d5 expression result in the integration of the plasmid into the D. discoideum genome. Placing d5 (without the 3' regions containing the Ddp1 origin) on an extrachromosomal vector based on another endogenous plasmid (Ddp2) did not restore proper transcriptional regulation, suggesting that an extrachromosomal environment alone is not sufficient to confer proper transcriptional regulation to d5.

Animals↗
PubMed1992

Coordinated development of myofibrils, sarcoplasmic reticulum and transverse tubules in normal and dysgenic mouse skeletal muscle, in vivo and in vitro.

We studied the development of transverse (T)-tubules and sarcoplasmic reticulum (SR) in relationship to myofibrillogenesis in normal and dysgenic (mdg/mdg) mouse skeletal muscle by immunofluorescent labeling of specific membrane and myofibrillar proteins. At E16 the development of the myofibrils and membranes in dysgenic and normal diaphragm was indistinguishable, including well developed myofibrils, a delicate network of T-tubules, and a prominent SR which was not yet cross-striated. In diaphragms of E18 dysgenic mice, both the number and size of muscle fibers and myofibrillar organization were deficient in comparison to normal diaphragms, as previously reported. T-tubule labeling was abnormal, showing only scattered tubules and fragments. However, many muscle fibers displayed cross striation of sarcomeric proteins and SR comparable to normal muscle. In cultured myotubes, cross-striated organization of sarcomeric proteins proceeded essentially in two stages: first around the Z-line and later in the A-band. Sarcomeric organization of the SR coincided with the first stage, while the appearance of T-tubules in the mature transverse orientation occurred infrequently, only after A-band maturation. In culture, myofibrillar and membrane organization was equivalent in normal and dysgenic muscle at the earlier stage of development, but half as many dysgenic myotubes reached the later stage as compared to normal. We conclude that the mdg mutation has little effect on the initial stage of membrane and myofibril development and that the deficiencies often seen at later stages result indirectly from the previously described absence of dihydropyridine receptor function in the mutant.

Animals↗
PubMed1991

Dihydropyridine receptor alpha subunits in normal and dysgenic muscle in vitro: expression of alpha 1 is required for proper targeting and distribution of alpha 2.

We have studied the subcellular distribution of the alpha 1 and alpha 2 subunits of the skeletal muscle dihydropyridine (DHP) receptor with immunofluorescence labeling of normal and dysgenic (mdg) muscle in culture. In normal myotubes both alpha subunits were localized in clusters associated with the T-tubule membranes of longitudinally as well as transversely oriented T-tubules. The DHP receptor-rich domains may represent the sites where triad junctions with the sarcoplasmic reticulum are being formed. In cultures from dysgenic muscle the alpha 1 subunit was undetectable and the distribution patterns of the alpha 2 subunit were abnormal. The alpha subunit did not form clusters nor was it discretely localized in the T-tubule system. Instead, alpha 2 was found diffusely distributed in parts of the T-system, in structures in the perinuclear region and in the plasma membrane. These results suggest that an interaction between the two alpha subunits is required for the normal distribution of the alpha 2 subunit in the T-tubule membranes. Spontaneous fusion of normal non-muscle cells with dysgenic myotubes resulted in a regional expression of the alpha 1 polypeptide near the foreign nuclei, thus defining the nuclear domain of a T-tubule membrane protein in multi-nucleated muscle cells. Furthermore, the normal intracellular distribution of the alpha 2 polypeptide was restored in domains containing a foreign "rescue" nucleus; this supports the idea that direct interactions between the DHP receptor alpha 1 and alpha 2 subunits are involved in the organization of the junctional T-tubule membranes.

Animals↗
PubMed1990

Muscular dysgenesis: a model system for studying skeletal muscle development.

Muscular dysgenesis, caused by an autosomal recessive lethal mutation (mdg) in mice, is characterized by an absence of contraction of skeletal muscle. A historical review of the investigation of this disorder is presented. The early studies of the morphological and physiological aspects of the disorder in vivo and in vitro presented evidence for dysfunction in the skeletal muscle excitation-contraction (E-C) system, and thus suggested that skeletal muscle was the primary target of dysfunction in dysgenesis. Subsequent evidence, including the phenomenon of rescue (restoration of contraction) of dysgenic muscle in culture by spinal cord cells, argued for involvement of the nervous system in the disorder. Experiments demonstrating that dysgenic muscle lacks the slow calcium current associated with E-C coupling, and the protein (the dihydropyridine receptor) also associated with such coupling, led to the discovery of the probable site of the mutation: the gene for the alpha 1 subunit of the dihydropyridine receptor. The neuronal involvement hypothesis was further countered by several lines of evidence, including the phenomenon of fusion of nonmyogenic normal cells with dysgenic myotubes in cocultures of normal cells and dysgenic muscle. The use of the mutant as a model for studying the development of normal skeletal muscle is discussed and future avenues of research are explored.

Aging↗
PubMed1990

Reversal of intracellular toxicity of the trichothecene mycotoxin T-2 with monoclonal antibody.

The trichothecene mycotoxin T-2 is a potent inhibitor of intracellular protein synthesis. We have previously shown that a mouse immunoglobulin G1 monoclonal antibody (15H6) specific for T-2 toxin can neutralize the in vitro protein synthesis inhibitory effect of the toxin in human B-lymphoblastoid cultures, and protect rats from lethal toxemia. We now report that these monoclonal antibodies can induce the net efflux of [3H]-T-2 toxin from poisoned human B-lymphoblastoid cells in vitro, and restore protein synthesis. Administration of the monoclonal antibodies (250 mg/kg) 30 min before infusion of a lethal dose (1 mg/kg) of T-2 toxin causes the sequestration of the toxin in the plasma compartment. When administered 35 min after T-2 toxin, a time when the bulk of toxin is in the tissues, the monoclonal antibodies facilitate the migration of toxin back into the plasma compartment. These data demonstrate that monoclonal antibodies can be of therapeutic value against an intracellular toxin.

Animals↗
PubMed1989

Specific absence of the alpha 1 subunit of the dihydropyridine receptor in mice with muscular dysgenesis.

Muscular dysgenesis is a lethal mutation in mice that results in a complete absence of skeletal muscle contraction due to the failure of depolarization of the transverse tubular membrane to trigger calcium release from the sarcoplasmic reticulum. In order to determine whether the defect in muscular dysgenesis leads to a specific loss of one of the components of excitation-contraction coupling or to a generalized loss of all components of excitation-contraction coupling, we have analyzed skeletal muscle from control and dysgenic mice for the sarcoplasmic reticulum and transverse tubular proteins which are believe to function in excitation-contraction coupling. We report that the proteins involved in sarcoplasmic reticulum calcium transport, storage, and release [Ca2+ + Mg2+)-ATPase, calsequestrin, and calcium release channel) are present in dysgenic muscle. Also present in dysgenic muscle is the 175/150-kDa glycoprotein subunit (alpha 2) of the dihydropyridine receptor. However, the 170-kDa dihydropyridine binding subunit (alpha 1) of the dihydropyridine receptor is absent in dysgenic muscle. These results suggest that the specific absence of the alpha 1 subunit of the dihydropyridine receptor is responsible for the defects in muscular dysgenesis and that the alpha 1 subunit of the dihydropyridine receptor is essential for excitation-contraction coupling in skeletal muscle.

Animals↗
PubMed1989

Rescue of excitation-contraction coupling in dysgenic muscle by addition of fibroblasts in vitro.

Muscular dysgenesis (mdg) in mice causes the failure of excitation-contraction (E-C) coupling in skeletal muscle. Cultured dysgenic muscle fails to contract upon depolarization, lacks typical muscle ultrastructure, including normal triads, and lacks functional voltage-dependent slow calcium channels. We show that normal rodent fibroblasts and 3T3 fibroblasts "rescue" dysgenic myotubes, reestablishing contractions (i.e., E-C coupling), normal ultrastructure, and functional slow calcium channels. These results support the finding that the expression of the slow calcium channel is affected in the mdg mutation and that this protein is essential for E-C coupling. Additionally, fibroblast rescue provides a system for examining the mechanisms of heterotypic cellular influence on cell function.

Action Potentials↗