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Biomedical subjects

A Hall

Publications and source records attributed to A Hall.

At least 109 records · Page 6Linked to original sources
PubMed1999

Cdc42 controls secretory and endocytic transport to the basolateral plasma membrane of MDCK cells.

Cdc42 is a Rho-family GTPase that in yeast is important in establishing polarized bud growth. Here we show that Cdc42 is also essential in establishing and maintaining polarity in epithelial cells. Functional deletion of Cdc42 in Madin-Darby canine kidney (MDCK) cells results in the selective depolarization of basolateral membrane proteins; the polarity of apical proteins remains unaffected. This phenotype does not reflect major alterations in the actin cytoskeleton, but rather results from the selective inhibition of membrane traffic to the basolateral plasma membrane in both the endocytic and the secretory pathways. Thus, Cdc42 plays a critical part in epithelial-cell polarity, by, unexpectedly, regulating the fidelity of membrane transport.

Actins↗
PubMed1999

The prognostic significance of a history of systemic hypertension in patients randomised to either placebo or ramipril following acute myocardial infarction: evidence from the AIRE study. Acute Infarction Ramipril Efficacy.

BACKGROUND: After acute myocardial infarction (AMI), patients with a history of arterial hypertension (AH) have a worse prognosis than normotensives. Whether this adverse risk is beneficially modulated by treatment with angiotensin-converting enzyme (ACE) inhibitors is unknown. We evaluated the prognostic value of antecedent hypertension in post-AMI patients given ACE inhibitor therapy. METHODS: We analysed retrospectively data from the AIRE study (randomised, placebo-controlled trial of ramipril in 2006 post-AMI patients with clinical heart failure). A history of AH was present in 28% of the patients. We examined the prognostic value of antecedent hypertension separately among placebo and ramipril treated patients and also the effect of ramipril on clinical outcomes according to whether or not a history of AH was present. RESULTS: Antecedent hypertension was a significant indicator of adverse prognosis in the placebo (P) treated patients (Hazard Ratio 1.49, 95% Confidence Intervals 1.13 to 1.97, P = 0.005) but not in the ramipril (R) treated patients (1.17, 0.84 to 1.61, P = 0.34). A similar pattern was observed for the risks of sudden death (P: 1.75, 1.21 to 2.54, P = 0.003; R: 1.34, 0.86 to 2.07, P = 0.18) and severe/resistant heart failure (P: 1.48, 1.08 to 2.03, P = 0.014; R: 1.18, 0.83 to 1.68, P = 0.37). Treatment with ramipril reduced the all-cause mortality risk in both hypertensive (0.63, 0.44 to 0.89, P = 0.009) and normotensive patients (0.78, 0.61 to 0.99, P = 0.041). CONCLUSION: Antecedent hypertension is not a significant prognosticator in patients with AMI and clinical heart failure given ACE inhibitor therapy.

Aged↗
PubMed1999

Carbonate induced dissolution of uranium containing precipitates under cement leachate conditions.

The effects of carbonate on uranium (VI) solubility under aerobic and cementitious conditions have been investigated. The information is of relevance to low level nuclear waste disposal. Aqueous NaOH, KOH, Ca(OH)2 and a cement leachate solution were added to uranyl nitrate solution. Afterwards, increasing amounts of ammonium carbonate were added to re-dissolve the precipitates. The precipitates were characterised by means of X-ray powder diffraction (XRPD) measurements and modelling studies. The model calculations were performed using the MINTEQA2 speciation code, with an expanded database incorporating uranium stability constants taken from the HATCHES database. The measured and predicted amounts of CO3(2-) needed to dissolve the precipitates were compared. The knowledge gained from the 'pure' systems was used to rationalise the precipitation and re-dissolution behaviour observed in the leachate system. The lack of uranium solubility at low carbonate levels brought into question literature formation constants for UO2(OH)3- and UO2(OH)4(2-). An approximate log K value of 26.8 for K2U2O7 formation was estimated from the KOH results at pH 12. Generally, uranium solubilities are expected to be insignificant at low level nuclear waste sites because anaerobic conditions should persist. However, this study has demonstrated that solubility in leachate could rise at high pH and high carbonate levels, if aerobic conditions were to develop. Soluble U(VI) species would be formed. The novel part of the study has been to reproduce the effects and to correlate enhanced solubilities with model predictions. Consequently, the study has re-emphasised the need for appropriate environmental monitoring of such sites.

Carbonates↗
PubMed1999

Evidence for an association between hookworm infection and cognitive function in Indonesian school children.

The association between helminth infection and cognitive and motor function was investigated in school-age children in Java, Indonesia. 432 children from 42 primary schools participated in the study. Children were stratified by age and sex into two age groups, 8-9 years and 11-13 years. Children infected with hookworm performed significantly worse than children without hookworm infection in 6 of the 14 cognitive or motor tests. After controlling for school (as a random effect) plus age, socio-economic status and parental education, sex, stunting (height-for-age < - 2sd), body mass index, haemoglobin concentration and the presence of A. lumbricoides and T. trichiura infections, infection with hookworm explained significantly lower scores on tests of Fluency (P < 0.01), Digit-Span Forwards (P < 0.01), Number Choice (P < 0.01), Picture Search (P < 0.03), Stroop Colour Word (P < 0.02) and Mazes (P < 0.001). In 4 of the 6-tests (Fluency, Number Choice, Picture Search and Mazes), there was a significant interaction between hookworm infection and age (P < 0.03), indicating that the association between hookworm and lower test scores increased with age. No associations were observed between hookworm infection and scores in tests of Digit-Span Backwards, Corsi-Block, Stroop Colour, Stroop Interference, Free Recall, Verbal Analogies, Bead Threading or the Pegboard (P > 0.05). Tests associated with helminths represented various functions of working memory. No significant associations between helminth infection and motor function were observed that could not be explained by chance. The results suggest that hookworm infection can have a significant adverse effect on children's working memory which may have consequences for a child's reasoning ability and reading comprehension. Although the results are only associational, the fact that differences in cognition were observed at baseline imply that preventing infection with helminths in school-age children could be of benefit.

Adolescent↗
PubMed1999

The impact of population level deworming on the haemoglobin levels of schoolchildren in Tanga, Tanzania.

The impact of albendazole (400 mg) and praziquantel (40 mg/kg body weight) treatment of schoolchildren was compared with placebo according to the presence of anaemia (haemoglobin concentration < 11. 0 g/dl) and heavy (> 5000 epg) or light (< 5000 epg) hookworm egg load. The study was conducted in rural Tanga. Medication was administered in September 1994 and children were followed-up in January 1995. Overall, anthelminthic treatment reduced the fall in haemoglobin concentration compared with that observed in the placebo group (- 0.11 g/dl vs. - 0.35 g/dl; P = 0.02). Anthelminthic treatment was of greatest benefit to the 9% of children with both anaemia and heavy hookworm egg load (+ 0.67 g/dl vs. - 0.67 g/dl) and was also of significant benefit to the 38% of children with anaemia and light hookworm egg load (+ 0.07 g/dl vs. - 0.21 g/dl). It was of no significant benefit to children who were not anaemic. This study suggests that single-dose anthelminthic treatment distributed in schools in this area achieves haematological benefits in nearly half of children infected with S. haematobium and geohelminths (37% of total population).

Anemia↗
PubMed1999

Distribution and latency of muscle responses to transcranial magnetic stimulation of motor cortex after spinal cord injury in humans.

Noninvasive transcranial magnetic stimulation (TMS) of the motor cortex was used to evoke electromyographic (EMG) responses in persons with spinal cord injury (n = 97) and able-bodied subjects (n = 20, for comparative data). Our goal was to evaluate, for different levels and severity of spinal cord injury, potential differences in the distribution and latency of motor responses in a large sample of muscles affected by the injury. The spinal cord injury (SCI) population was divided into subgroups based upon injury location (cervical, thoracic, and thoracolumbar) and clinical status (motor-complete versus motor-incomplete). Cortical stimuli were delivered while subjects attempted to contract individual muscles, in order to both maximize the probability of a response to TMS and minimize the response latency. Subjects with motor-incomplete injuries to the cervical or thoracic spinal cord were more likely to demonstrate volitional and TMS-evoked contractions in muscles controlling their foot and ankle (i.e., distal lower limb muscles) compared to muscles of the thigh (i.e., proximal lower limb muscles). When TMS did evoke responses in muscles innervated at levels caudal to the spinal cord lesion, response latencies of muscles in the lower limbs were delayed equally for persons with injury to the cervical or thoracic spinal cord, suggesting normal central motor conduction velocity in motor axons caudal to the lesion. In fact, motor response distribution and latencies were essentially indistinguishable for injuries to the cervical or thoracic (at or rostral to T10) levels of the spine. In contrast, motor-incomplete SCI subjects with injuries at the thoracolumbar level showed a higher probability of preserved volitional movements and TMS-evoked contractions in proximal muscles of the lower limb, and absent responses in distal muscles. When responses to TMS were seen in this group, the latencies were not significantly longer than those of able-bodied (AB) subjects, strongly suggestive of "root sparing" as a basis for motor function in subjects with injury at or caudal to the T11 vertebral body. Both the distribution and latency of TMS-evoked responses are consistent with highly focal lesions to the spinal cord in the subjects examined. The pattern of preserved responsiveness predominating in the distal leg muscles is consistent with a greater role of corticospinal tract innervation of these muscles compared to more proximal muscles of the thigh and hip.

Adolescent↗
PubMed1999

Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: induction of neurite retraction.

Neuronal cells undergo rapid growth cone collapse, neurite retraction, and cell rounding in response to certain G protein-coupled receptor agonists such as lysophosphatidic acid (LPA). These shape changes are driven by Rho-mediated contraction of the actomyosin-based cytoskeleton. To date, however, detection of Rho activation has been hampered by the lack of a suitable assay. Furthermore, the nature of the G protein(s) mediating LPA-induced neurite retraction remains unknown. We have developed a Rho activation assay that is based on the specific binding of active RhoA to its downstream effector Rho-kinase (ROK). A fusion protein of GST and the Rho-binding domain of ROK pulls down activated but not inactive RhoA from cell lysates. Using GST-ROK, we show that in N1E-115 neuronal cells LPA activates endogenous RhoA within 30 s, concomitant with growth cone collapse. Maximal activation occurs after 3 min when neurite retraction is complete and the actin cytoskeleton is fully contracted. LPA-induced RhoA activation is completely inhibited by tyrosine kinase inhibitors (tyrphostin 47 and genistein). Activated Galpha12 and Galpha13 subunits mimic LPA both in activating RhoA and in inducing RhoA-mediated cytoskeletal contraction, thereby preventing neurite outgrowth. We conclude that in neuronal cells, LPA activates RhoA to induce growth cone collapse and neurite retraction through a G12/13-initiated pathway that involves protein-tyrosine kinase activity.

Animals↗
PubMed1999

Detective quantum efficiency dependence on x-ray energy weighting in mammography.

An evaluation of the dependence of detective quantum efficiency (DQE) on the incident energy spectrum has been made for mammography. The DQE dependence on the energy spectrum has been evaluated for energy-integrating detectors, photon-counting detectors, and detectors that measure the energy of each photon. To isolate the effect of the x-ray energy spectrum the detector has been assumed to be ideal, i.e., all noise sources are assumed to be zero except for quantum fluctuations. The result shows that the improvement in DQE, if the energy-integrating detector is compared to a single-photon counting detector, is of the order of 10%. Comparing the energy-integrating detector and the detector measuring the energy for each photon the improvement is around 30% using a molybdenum anode spectrum typical in mammography. It is shown that the optimal weight factors to combine the data in the case the energy is measured are very well approximated if the weight factors are proportional to E(-3). Another conclusion is that in calculating the DQE, a detector should be compared to one that uses ideal energy weighting for each photon since this provides the best signal-to-noise ratio. This has generally been neglected in the literature.

Humans↗
PubMed1999

Rho family GTPases control entry of Shigella flexneri into epithelial cells but not intracellular motility.

Shigella flexneri, an invasive bacterial pathogen, promotes formation of two cytoskeletal structures: the entry focus that mediates bacterial uptake into epithelial cells and the actin-comet tail that enables the bacteria to spread intracellularly. During the entry step, secretion of bacterial invasins causes a massive burst of subcortical actin polymerization leading the formation of localised membrane projections. Fusion of these membrane ruffles leads to bacterial internalization. Inside the cytoplasm, polar expression of the IcsA protein on the bacterial surface allows polymerization of actin filaments and their organization into an actin-comet tail leading to bacterial spread. The Rho family of small GTPases plays an essential role in the organization and regulation of cellular cytoskeletal structures (i.e. filopodia, lamellipodia, adherence plaques and intercellular junctions). We show here that induction of Shigella entry foci is controlled by the Cdc42, Rac and Rho GTPases, but not by RhoG. In contrast, actin-driven intracellular motility of Shigella does not require Rho GTPases. Therefore, Shigella appears to manipulate the epithelial cell cytoskeleton both by Rho GTPase-dependent and -independent processes.

Actins↗
PubMed1999

Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF(alpha) and IL-1, and by the Epstein-Barr virus transforming protein LMP1.

Cdc42, a Rho-family GTPase, has been implicated in several signal transduction pathways, including organization of the actin cytoskeleton, activation of the c-Jun N-terminal MAP kinase (JNK) and stimulation of the nuclear transcription factor kappa B (NF(kappa)B). We report here that exposure of fibroblasts to the inflammatory cytokines tumor necrosis factor (alpha) (TNF(alpha)) and interleukin-1 (IL-1) triggers the activation of Cdc42 leading first to filopodia formation and subsequently to Rac and Rho activation. Inhibition of Cdc42 completely suppresses cytokine-induced actin polymerization, but not activation of JNK or NF(kappa)B. The latent membrane protein 1 of Epstein-Barr virus, LMP1, is thought to mimic constitutively activated TNF family receptors. When expressed in fibroblasts, LMP1 stimulates Cdc42-dependent filopodia formation as well as JNK and NF(kappa)B activation. Using LMP1 mutants, we show that activation of Cdc42 and JNK/NF(kappa)B occur through distinct pathways and that Cdc42 activation is independent of LMP1's interaction with TRADD and TRAF proteins.

3T3 Cells↗
PubMed1999

Cardiopulmonary exercise testing as a screening test for perioperative management of major surgery in the elderly.

STUDY OBJECTIVE: To develop an integrated strategy for the identification and subsequent management of high-risk patients in order to reduce both morbidity and mortality. DESIGN: Prospective consecutive series in which all patients underwent cardiopulmonary exercise (CPX) testing. SETTING: CPX laboratory and level 3 ICU and high-dependency unit (HDU) of a metropolitan teaching hospital. PATIENTS: Five hundred forty-eight patients >60 years of age (or younger with known cardiopulmonary disease) scheduled for major intra-abdominal surgery. INTERVENTIONS: The patients were assigned to one of three management strategies (ICU, HDU, or ward) based on the anaerobic threshold (deltaT) and ECG evidence of myocardial ischemia as determined by CPX testing that was performed as part of the presurgery evaluation, and by the expected oxygen demand stress of the surgical procedure. RESULTS: Overall mortality was 3.9%. Forty-three percent of deaths were attributed to poor cardiopulmonary function, as detected preoperatively. There were no deaths related to cardiopulmonary complications in any patient deemed fit for major abdominal surgery and ward management, as determined by CPX testing. CONCLUSIONS: In elderly patients undergoing major intra-abdominal surgery, the AT, as determined by CPX testing, is an excellent predictor of mortality from cardiopulmonary causes in the postoperative period. Preoperative screening using CPX testing allowed the identification of high-risk patients and the appropriate selection of perioperative management.

Aged↗
PubMed1999

The HIV patient in general dental practice.

General practitioners, especially those working in areas where there is a high incidence of HIV, will inevitably have to face patients who may or may not know that they are HIV antibody positive. This paper gives some guidelines on how to approach the problem, using two case scenarios.

Adult↗
PubMed1998

Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.

The complement and immunoglobulin receptors are the major phagocytic receptors involved during infection. However, only immunoglobulin-dependent uptake results in a respiratory burst and an inflammatory response in macrophages. Rho guanosine triphosphatases (molecular switches that control the organization of the actin cytoskeleton) were found to be essential for both types of phagocytosis. Two distinct mechanisms of phagocytosis were identified: Type I, used by the immunoglobulin receptor, is mediated by Cdc42 and Rac, and type II, used by the complement receptor, is mediated by Rho. These results suggest a molecular basis for the different biological consequences that are associated with phagocytosis.

3T3 Cells↗
PubMed1998

CdGAP, a novel proline-rich GTPase-activating protein for Cdc42 and Rac.

Cdc42 mediates several signaling pathways leading to actin reorganization, transcriptional activation, and cell cycle control. Mutational analysis of Cdc42 has revealed that actin reorganization and transcriptional activation are induced through independent signaling pathways. The Y40C effector mutant of Cdc42 no longer interacts with many of its known target proteins, such as p65(PAK) and WASP, yet this mutant can still induce filopodia formation. To identify Cdc42 targets involved in actin rearrangements, we have screened a yeast two-hybrid cDNA library using the Y40C mutant of Cdc42 as a bait. We report here the identification of a novel serine- and proline-rich GTPase-activating protein, CdGAP, which is active in vitro on both Cdc42 and Rac. Microinjection of CdGAP into serum-starved fibroblasts inhibits both platelet-derived growth factor-induced lamellipodia and bradykinin-induced filopodia mediated by Rac and Cdc42, respectively. CdGAP does not show in vitro activity toward Rho, and it has no effect on lysophosphatidic acid-induced stress fiber formation when microinjected into fibroblasts. The carboxyl terminus of CdGAP reveals potential protein kinase C phosphorylation sites and five SH3 binding motifs. Thus, CdGAP is a novel GAP that is likely to participate in Cdc42- and Rac-induced signaling pathways leading to actin reorganization.

3T3 Cells↗
PubMed1998

Rho GTPases.

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Actins↗
PubMed1998

Different regions of Rho determine Rho-selective binding of different classes of Rho target molecules.

Based on their Rho binding motifs several Rho target molecules can be classified into three groups; class I includes the protein kinase PKN, rhophilin, and rhotekin, class II includes the protein kinases, Rho-associated coiled-coil containing protein kinases, ROCK-I and ROCK-II, and class III includes citron. Taking advantage of the selectivity in recognition by these targets between Rho and Rac, we examined the regions in Rho required for selective binding of each class of Rho target molecules. Yeast two-hybrid assays were performed using Rho/Rac chimeras and either rhophilin, ROCK-I, or citron. This study showed the existence of at least two distinct regions in Rho (amino acids 23-40 and 75-92) that are critical for the selective binding of these targets. The former was required for binding to citron, whereas the latter was necessary for binding to rhophilin. On the other hand, either region showed affinity to ROCK-I. This was further confirmed by ligand overlay assay using both recombinant ROCK-I and ROCK-II proteins. Consistently, Rho/Rac chimeras containing either region can induce stress fibers in transfected HeLa cells, and this induction is suppressed by treatment with Y-27632, a specific inhibitor of ROCK kinases. These results suggest that the selective binding of different classes of Rho targets to Rho is determined by interaction between distinct Rho-binding motifs of the targets and different regions of Rho.

Adaptor Proteins, Signal Transducing↗