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Copyright of Revista de Enfermagem Referência is the property of Escola Superior de Enfermagem de Coimbra and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The objective of this work was to evaluate the rooting of semi-hardwood blueberry minicuttings, from different cultivars and groups, from the Highbush and Rabbiteye groups in the same culture medium. The experiment was carried out in an agricultural greenhouse in a commercial nursery whith semi-hardwood mini-cuttings were used. The work was conducted, with cuttings segmented into mini-cuttings with three gems and an average diameter of 1.5 mm. Subsequently, their bases were immersed, for 10 seconds, in a commercial solution of IBA, in the concentration of 2.000 mg.L-1, with a mixture of coarse-grained sand and commercial substrate in the proportion of 1:1 as a substrate. The Bifactorial experimental design used was in completely randomized blocks, with two groups (highbush and rabbiteye) and six cultivars (Georgiagem, Misty, O'Neal, Bluegem, Powderblue and Woodard), with four replications and ten cuttings per plot. The percentage of rooted cuttings and surviving cuttings, average number of roots and shoots per cuttings, length of the largest root and shoot, were evaluated. It was found that, in general, the rabbiteye group was superior when compared to the highbush group. Blueberry cultivars from the rabbiteye group when propagated by semi-hardwood cuttings, have greater rooting facility than cultivars from the highbush group. The rooting potential between the cultivars in blueberry studied was different, allow the formation of 95% of cuttings rooted in 90 days.

Numerous approaches have been developed to generate optical vortex beams carrying orbital angular momentum (OAM) over the past decades, but the direct intracavity generation of such beams with practical output powers in the femtosecond regime still remains a challenge. Here we propose and experimentally demonstrate the efficient generation of high-peak-power femtosecond optical vortex pulses from a Mamyshev oscillator (MO) based on few-mode polarization-maintaining (PM) ytterbium-doped fibers (YDFs). By employing an appropriate intracavity transverse spatial mode selection technique, ultrafast pulses carrying OAM with selectable topological charge of l = ±1 are successfully generated with an average output power of ∼5.72 W at ∼24.35 MHz repetition rate, corresponding to a single pulse energy of ∼235 nJ. The chirped pulses can be compressed to ∼76 fs outside the cavity, leading to a pulse peak power of ∼2.2 MW. To the best of our knowledge, this is by far the highest pulse energy and peak power for optical vortex pulses ever generated directly from a fiber oscillator. This unprecedented level of performance should be of great interest for a variety of applications including materials processing and imaging.

Copyright of ConScientiae Saúde is the property of Nove de Julho University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BACKGROUND: there is a causal association between carotid sinus hypersensitivity, falls and syncope in elderly subjects. Neurological complications during carotid sinus massage have been reported in case studies and two retrospective series. Our aim was prospectively to ascertain the incidence of complications occurring after carotid sinus massage performed for diagnostic purposes in a consecutive series of patients. METHODS: 1000 consecutive subjects aged 50 years or over who attended the accident and emergency department with syncope or 'unexplained' falls had carotid sinus massage. Carotid sinus massage was performed for 5 s on the right and then left sides both supine and upright (70 degrees head-up tilt) with continuous heart rate and phasic blood pressure recording. Contraindications to carotid sinus massage were the presence of a carotid bruit, recent history of stroke or myocardial infarction or previous ventricular tachyarrhythmia. RESULTS: complications occurred in nine patients immediately after cessation of carotid sinus massage. Eight had transient neurological complications possibly attributable to carotid sinus massage: visual disturbance, 'pins and needles' and sensation of finger numbness in two cases each, leg weakness in one and sensation of 'being drunk' in one. All transient complications resolved within 24 h. In one patient mild weakness of the right hand persisted. CONCLUSIONS: no subjects had cardiac complications and 1% had possible neurological symptoms, which resolved in most cases. Persistent neurological complications are uncommon, occurring in 1:1000 patients (0.1%) or 1: 3805 episodes of carotid sinus massage (0.03%). [ABSTRACT FROM AUTHOR]

Since the early conceptual and practical demonstrations in the late 1990s, Hollow-Core Photonic Band Gap Fibres (HC-PBGFs) have attracted huge interest by virtue of their promise to deliver a unique range of optical properties that are simply not possible in conventional fibre types. HC-PBGFs have the potential to overcome some of the fundamental limitations of solid fibres promising, for example, reduced transmission loss, lower nonlinearity, higher damage thresholds and lower latency, amongst others. They also provide a unique medium for a range of light: matter interactions of various forms, particularly for gaseous media. In this paper we review the current status of the field, including the latest developments in the understanding of the basic guidance mechanisms in these fibres and the unique properties they can exhibit. We also review the latest advances in terms of fibre fabrication and characterisation, before describing some of the most important applications of the technology, focusing in particular on their use in gas-based fibre optics and in optical communications.

Abstract Background The objective of this study is to characterize the effect of temperature on emergency department visits for asthma and modification of this association by season. This association is of interest in its own right, and also important to understand because temperature may be an important confounder in analyses of associations between other environmental exposures and asthma. For example, the case-crossover study design is commonly used to investigate associations between air pollution and respiratory outcomes, such as asthma. This approach controls for confounding by month and season by design, and permits adjustment for potential confounding by temperature through regression modeling. However, such models may fail to adequately control for confounding if temperature effects are seasonal, since case-crossover analyses rarely account for interactions between matching factors (such as calendar month) and temperature. Methods We conducted a case-crossover study to determine whether the association between temperature and emergency department visits for asthma varies by season or month. Asthma emergency department visits among North Carolina adults during 2007–2008 were identified using a statewide surveillance system. Marginal as well as season- and month-specific associations between asthma visits and temperature were estimated with conditional logistic regression. Results The association between temperature and adult emergency department visits for asthma is near null when the overall association is examined [odds ratio (OR) per 5 degrees Celsius = 1.01, 95% confidence interval (CI): 1.00, 1.02]. However, significant variation in temperature-asthma associations was observed by season (chi-square = 18.94, 3 degrees of freedom, p Conclusions Our empirical example suggests that there is significant seasonal variation in temperature-asthma associations. Epidemiological studies rarely account for interactions between ambient temperature and temporal matching factors (such as month of year) in the case-crossover design. These findings suggest that greater attention should be given to seasonal modification of associations between temperature and respiratory outcomes in case-crossover analyses of other environmental asthma triggers.

Abstract Background Kinesins, a superfamily of molecular motors, use microtubules as tracks and transport diverse cellular cargoes. All kinesins contain a highly conserved ~350 amino acid motor domain. Previous analysis of the completed genome sequence of one flowering plant (Arabidopsis) has resulted in identification of 61 kinesins. The recent completion of genome sequencing of several photosynthetic and non-photosynthetic eukaryotes that belong to divergent lineages offers a unique opportunity to conduct a comprehensive comparative analysis of kinesins in plant and non-plant systems and infer their evolutionary relationships. Results We used the kinesin motor domain to identify kinesins in the completed genome sequences of 19 species, including 13 newly sequenced genomes. Among the newly analyzed genomes, six represent photosynthetic eukaryotes. A total of 529 kinesins was used to perform comprehensive analysis of kinesins and to construct gene trees using the Bayesian and parsimony approaches. The previously recognized 14 families of kinesins are resolved as distinct lineages in our inferred gene tree. At least three of the 14 kinesin families are not represented in flowering plants. Chlamydomonas, a green alga that is part of the lineage that includes land plants, has at least nine of the 14 known kinesin families. Seven of ten families present in flowering plants are represented in Chlamydomonas, indicating that these families were retained in both the flowering-plant and green algae lineages. Conclusion The increase in the number of kinesins in flowering plants is due to vast expansion of the Kinesin-14 and Kinesin-7 families. The Kinesin-14 family, which typically contains a C-terminal motor, has many plant kinesins that have the motor domain at the N terminus, in the middle, or the C terminus. Several domains in kinesins are present exclusively either in plant or animal lineages. Addition of novel domains to kinesins in lineage-specific groups contributed to the functional diversification of kinesins. Results from our gene-tree analyses indicate that there was tremendous lineage-specific duplication and diversification of kinesins in eukaryotes. Since the functions of only a few plant kinesins are reported in the literature, this comprehensive comparative analysis will be useful in designing functional studies with photosynthetic eukaryotes.

Enquadramento: Diante de múltiplas solicitações e recursos insuficientes, os profissionais de enfermagem podem não executar alguns cuidados requeridos. Objetivos: Identificar os cuidados de enfermagem omissos, as razões atribuídas pelos profissionais de enfermagem e verificar se as razões diferem entre as categorias profissionais Metodologia: Estudo descritivo, transversal, utilizando o instrumento MISSCARE-Brasil numa amostra por conveniência de 115 participantes, distribuídos entre 48 enfermeiros e 67 técnicos em enfermagem. Resultados: Os participantes apresentaram média de idade de 34,9 anos, predominando o sexo feminino, 88,6%. Os cuidados de enfermagem mais omitidos foram a deambulação três vezes por dia ou conforme prescrito, 58,3%; a participação em discussão da equipa interdisciplinar sobre a assistência ao paciente, 55,6%; e a oferta das refeições para os pacientes que se alimentam sozinhos, 53,1%. As principais razões para omissão foram relacionadas os domínios “Recursos Materiais” e “Laborais”. Conclusão: Os recursos materiais e laborais influenciam na frequência de cuidados de enfermagem omissos, apesar das justificações diferenciadas para omissão do cuidado entre enfermeiros e técnicos em enfermagem.

Background: United States healthcare has increasingly transitioned to outpatient care delivery. The degree to which Academic Medical Centers (AMCs) have been able to shift surgical procedures from inpatient to outpatient settings despite higher patient complexity is unknown., Methods: This observational study used a 20% sample of fee-for-service Medicare beneficiaries age 65 and older undergoing eight elective procedures from 2011 to 2018 to model trends in procedure site (hospital outpatient vs. inpatient) and 30-day standardized Medicare costs, overall and by hospital teaching status., Results: Of the 1,222,845 procedures, 15.9% occurred at AMCs. There was a 2.42% per-year adjusted increase (95% CI 2.39%-2.45%; p < .001) in proportion of outpatient hospital procedures, from 68.9% in 2011 to 85.4% in 2018. Adjusted 30-day standardized costs declined from $18,122 to $14,353, (-$560/year, 95% CI -$573 to -$547; p < .001). Patients at AMCs had more chronic conditions and higher predicted annual mortality. AMCs had a lower proportion of outpatient procedures in all years compared to non-AMCs, a difference that was statistically significant but small in magnitude. AMCs had higher costs compared to non-AMCs and a lesser decline over time (p < .001 for the interaction). AMCs and non-AMCs saw a similar decline in 30-day mortality., Conclusions: There has been a substantial shift toward outpatient procedures among Medicare beneficiaries with a decrease in total 30-day Medicare spending as well as 30-day mortality. Despite a higher complexity population, AMCs shifted procedures to the outpatient hospital setting at a similar rate as non-AMCs., Implications: The trend toward outpatient procedural care and lower spending has been observed broadly across AMCs and non-AMCs, suggesting that Medicare beneficiaries have benefited from more efficient delivery of procedural care across academic and community hospitals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The Royal College of Physicians (RCP) FallSafe care bundles are the recommended foundation for inpatient falls prevention in the UK. Yet there is a paucity of data to support its widespread use and the reductions in falls demonstrated in the original pilot and in subsequent small studies have not yet been reproduced in larger patient groups. Northumbria Healthcare NHS Foundation Trust (NHCFT) has seen a significant reduction in falls, falls per 1,000 bed days and harm from falls between 2013-2020 when combining the RCP FallSafe care bundles with a supportive observation policy (SOP) related to falls prevention. Highlighting the potential cost savings (∼£5.3 million over a 3-year period) has supported the growth and development of the NHCFT inpatient falls prevention service and the implementation of the SOP., (© Royal College of Physicians 2020. All rights reserved.)

Background: High glycolytic rate is a hallmark of cancer (Warburg effect). Glycolytic ATP is required for fuelling plasma membrane calcium ATPases (PMCAs), responsible for extrusion of cytosolic calcium, in pancreatic ductal adenocarcinoma (PDAC). Phosphofructokinase-fructose-bisphosphatase-3 (PFKFB3) is a glycolytic driver that activates key rate-limiting enzyme Phosphofructokinase-1; we investigated whether PFKFB3 is required for PMCA function in PDAC cells., Methods: PDAC cell-lines, MIA PaCa-2, BxPC-3, PANC1 and non-cancerous human pancreatic stellate cells (HPSCs) were used. Cell growth, death and metabolism were assessed using sulforhodamine-B/tetrazolium-based assays, poly-ADP-ribose-polymerase (PARP1) cleavage and seahorse XF analysis, respectively. ATP was measured using a luciferase-based assay, membrane proteins were isolated using a kit and intracellular calcium concentration and PMCA activity were measured using Fura-2 fluorescence imaging., Results: PFKFB3 was highly expressed in PDAC cells but not HPSCs. In MIA PaCa-2, a pool of PFKFB3 was identified at the plasma membrane. PFKFB3 inhibitor, PFK15, caused reduced cell growth and PMCA activity, leading to calcium overload and apoptosis in PDAC cells. PFK15 reduced glycolysis but had no effect on steady-state ATP concentration in MIA PaCa-2., Conclusions: PFKFB3 is important for maintaining PMCA function in PDAC, independently of cytosolic ATP levels and may be involved in providing a localised ATP supply at the plasma membrane., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2020.)

Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca 2+ ([Ca 2+ ] i ) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC.

Background: Pancreatic ductal adenocarcinoma (PDAC) has poor survival and treatment options. PDAC cells shift their metabolism towards glycolysis, which fuels the plasma membrane calcium pump (PMCA), thereby preventing Ca 2+ -dependent cell death. The ATP-generating pyruvate kinase-M2 (PKM2) is oncogenic and overexpressed in PDAC. This study investigated the PKM2-derived ATP supply to the PMCA as a potential therapeutic locus., Methods: PDAC cell growth, migration and death were assessed by using sulforhodamine-B/tetrazolium-based assays, gap closure assay and poly-ADP ribose polymerase (PARP1) cleavage, respectively. Cellular ATP and metabolism were assessed using luciferase/fluorescent-based assays and the Seahorse XFe96 analyzer, respectively. Cell surface biotinylation identified membrane-associated proteins. Fura-2 imaging was used to assess cytosolic Ca 2+ overload and in situ Ca 2+ clearance. PKM2 knockdown was achieved using siRNA., Results: The PKM2 inhibitor (shikonin) reduced PDAC cell proliferation, cell migration and induced cell death. This was due to inhibition of glycolysis, ATP depletion, inhibition of PMCA and cytotoxic Ca 2+ overload. PKM2 associates with plasma membrane proteins providing a privileged ATP supply to the PMCA. PKM2 knockdown reduced PMCA activity and reduced the sensitivity of shikonin-induced cell death., Conclusions: Cutting off the PKM2-derived ATP supply to the PMCA represents a novel therapeutic strategy for the treatment of PDAC.

The Royal College of Physicians' FallSafe care bundles constitute measures of good practice, some of which are recommended for all patients, some are additional measures for older and more vulnerable patients admitted to hospital, and there is another bundle for after an inpatient fall, to reduce the number of inpatient falls. In 2013 a dedicated healthcare assistant, trained by the falls team, started a monthly spot audit looking at preventative measures, on all inpatients on every ward of the trust. Monthly results were fed back to the ward managers, ward falls liaison nurses, doctors, therapists and pharmacy staff on each ward, to discuss at the monthly ward governance meetings. Training and advice on specific aspects of falls prevention were provided by falls nurse practitioners. In total, 9,679 patient episodes were recorded over the year. Compliance with the measures recommended by the FallSafe care bundles has improved following regular spot audit and training. This has led to an overall reduction in the number of inpatient falls. Despite this however, in the real world of changing patient demographics, ward closures and the increasing use of ambulatory care, the number of falls/1,000 bed days has increased., (© Royal College of Physicians 2015. All rights reserved.)

Purpose: Most prostate cancer research is based on relatively homogenous cohorts of men, often with comparatively high socioeconomic status. We describe prostate cancer characteristics in men treated in a public health system and hypothesize a disproportionate burden of high risk disease in this population., Materials and Methods: We created a clinical registry from a review of the medical records of 377 men diagnosed with prostate cancer in the San Francisco General Hospital system, which provides care to underserved, uninsured populations. We compared sociodemographic data and cancer characteristics with those in 2 large prostate cancer databases from a community (CaPSURE™) and an academic (University of California-San Francisco tumor registry) setting to assess differences in risk distribution using the D'Amico and Cancer of the Prostate Risk Assessment scoring systems., Results: Compared to men in CaPSURE or the University of California-San Francisco tumor registry those in the San Francisco General Hospital cohort were nonwhite (76%), insured under Medicaid (31%) or uninsured (8%) and had adverse clinical characteristics, including median prostate specific antigen greater than 10 ng/ml at diagnosis and higher Gleason grade. In addition, the majority of patients (67%) had intermediate or high risk disease based on the D'Amico classification and a higher mean Cancer of the Prostate Risk Assessment score. Using ANOVA for continuous variables and the chi-square test for categorical variables, all comparisons were statistically significant (p <0.001)., Conclusions: Men in the San Francisco General Hospital public health system bear a substantially higher burden of high risk disease that those in an academic or a community setting. Populations such as this would benefit most from targeted efforts for early detection and treatment to decrease prostate cancer morbidity and mortality., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

A 43-year-old man was referred with a history of unexplained falls associated with transient loss of consciousness. He had evidence of cardioinhibitory carotid sinus hypersensitivity (CSH) on carotid sinus massage and subsequently confirmed to have periods of symptomatic asystole on an implantable loop recorder, consistent with a diagnosis of cardioinhibitory CSH.

Morphological hallmarks of apoptosis result from activation of the caspase family of cysteine proteases, which are opposed by a pro-survival family of inhibitors of apoptosis proteins (IAPs). In Drosophila, disruption of IAP function by Reaper, HID, and Grim (RHG) proteins is sufficient to induce cell death. RHG proteins have been reported to localize to mitochondria, which, in the case of both Reaper and Grim proteins, is mediated by an amphipathic helical domain known as the GH3. Through direct binding, Reaper can bring the Drosophila IAP (DIAP1) to mitochondria, concomitantly promoting IAP auto-ubiquitination and destruction. Whether this localization is sufficient to induce DIAP1 auto-ubiquitination has not been reported. In this study we characterize the interaction between Reaper and the mitochondria using both Xenopus and Drosophila systems. We find that Reaper concentrates on the outer surface of mitochondria in a nonperipheral manner largely mediated by GH3-lipid interactions. Importantly, we show that mitochondrial targeting of DIAP1 alone is not sufficient for degradation and requires Reaper binding. Conversely, Reaper able to bind IAPs, but lacking a mitochondrial targeting GH3 domain (DeltaGH3 Reaper), can induce DIAP1 turnover only if DIAP1 is otherwise targeted to membranes. Surprisingly, targeting DIAP1 to the endoplasmic reticulum instead of mitochondria is partially effective in allowing DeltaGH3 Reaper to promote DIAP1 degradation, suggesting that co-localization of DIAP and Reaper at a membrane surface is critical for the induction of DIAP degradation. Collectively, these data provide a specific function for the GH3 domain in conferring protein-lipid interactions, demonstrate that both Reaper binding and mitochondrial localization are required for accelerated IAP degradation, and suggest that membrane localization per se contributes to DIAP1 auto-ubiquitination and degradation.

The authors' objective was to determine circadian blood pressure behavior and the prevalence of orthostatic hypotension in patients with cardioinhibitory carotid sinus syndrome. A prospective consecutive series of 160 patients (mean age, 72 [65-83]) with recurrent syncope attributed to cardioinhibitory carotid sinus syndrome was recruited. Mean maximal slowing of heart rate was 4.5 seconds (3.0-5.5 seconds) during carotid sinus massage. Patients had cardiovascular assessments, including 24-hour ambulatory blood pressure measurements (recordings every half-hour during daytime, hourly at night) and morning orthostatic blood pressures before pacemaker implants. Ambulatory measurements were compared with those of 98 age- and sex-matched controls. Nocturnal systolic blood pressure (130.0+/-21.0 vs. 122.1+/-16.7 mm Hg; p<0.005), diastolic blood pressure (72.8+/-12.5 vs. 68.7+/-9.7 mm Hg; p<0.005), and heart rate (66.5+/-9.4 vs. 65.2+/-9.7 bpm; p<0.005), were significantly higher in patients and independent of cardiovascular medication, cardiovascular diagnoses, and orthostatic hypotension. Almost one half of carotid sinus syndrome patients also had orthostatic hypotension. Blood pressure behavior is abnormal in patients with carotid sinus syndrome as represented by altered nocturnal blood pressures and high prevalence of orthostatic hypotension.

Lavendamycin is a bacterially derived quinolinedione that displays significant antimicrobial and antitumor activities. However, preclinical development of lavendamycin as an anticancer agent was halted due to the poor aqueous solubility and relatively nonspecific cytotoxic activity of this compound. In this report, we have examined the cytotoxic activities of a series of novel lavendamycin analogues. The cytotoxic activities of these compounds were evaluated in clonogenic survival assays with A549 lung carcinoma cells. Compounds bearing an amide or amine substituent at the R(3) position were the most potent inhibitors of colony formation. MB-97, the most active member of this subgroup, decreased clonogenic outgrowth by 70% at a concentration of 10 n. Treatment of A549 cells with MB-97 led to an increase in p53 protein expression and phosphorylation and a concomitant increase in the expression of the p53 target gene, p21. Exposure of p53-positive cells to MB-97 triggered cell cycle arrest in G(1) and G(2) phases but induced a selective G(2)-phase arrest in p53-negative cells. MB-97 treatment also induced a higher level of apoptosis in p53-null cells relative to their p53-positive counterparts. Finally, MB-97 showed significant cytotoxic activity in the National Cancer Institute's panel of 60 cancer cell lines and antitumor activity in vivo in hollow fiber tumorigenesis assays.

Aims: To ascertain the reproducibility of the cardioinhibitory subtype of carotid sinus hypersensitivity (CICSH) in fallers., Methods and Results: One hundred and seventy-five subjects with CICSH and unexplained or recurrent falls were randomized to pacemaker implantation or control. Sixty-four control subjects (61% female, mean age 71.8 years, median 2 falls in the previous year) completed one-year follow-up and had carotid sinus massage (CSM) performed on 4 occasions (twice before randomization, at 6 months and 1 year following randomization). CSM was performed sequentially on the right and then left sides, initially supine and then upright at 70 degrees head-up tilt by the same investigator. On each occasion CSM was discontinued once CICSH was demonstrated. CICSH was demonstrated on 82% of occasions, 75% on right CSM and 77% whilst the subject was supine. Before randomization, and at 6 months and 1 year, 91%, 67%, and 70% of subjects had reproducible CICSH respectively. Half had CICSH on all 4 occasions. Only 17% had a consistent response on the same side in the same position., Conclusions: In the majority of subjects CICSH is reproducible and this is more likely shortly after the initial response. However the cardioinhibitory response to CSM is inconsistent both in side elicited and subject position.

Background: Carotid sinus hypersensitivity is a common cardiovascular cause of unexplained or recurrent falls in older adults. Effective treatment is available once carotid sinus hypersensitivity is identified. Carotid sinus massage is the only practical method for achieving a diagnosis. Carotid sinus massage is contraindicated if a carotid bruit is present., Objective: To determine the prevalence of carotid sinus hypersensitivity in adults presenting with unexplained or recurrent falls and a carotid bruit., Design: Prospective consecutive cohort study., Setting: Accident and Emergency department and regional syncope and falls facility., Subjects: Accident and Emergency patients aged 50 years or over with unexplained or recurrent falls and a carotid bruit., Intervention: 1) Carotid doppler ultrasound to identify significant stenosis (> or = 50%). 2) Carotid sinus massage (with electrocardiographic and phasic blood pressure monitoring) was performed supine and possibly upright., Methods: Consecutive adults with unexplained or recurrent falls were screened for carotid bruits. Those with a carotid bruit were referred for carotid Doppler ultrasound and stratified for further investigation depending on presence and degree of underlying carotid artery stenosis. Carotid sinus massage was performed at least supine in those with up to moderate stenosis (50-69%) in either internal or common carotid artery., Main Outcome Measure: Diagnosis of carotid sinus hypersensitivity., Results: We identified 1682 subjects with unexplained or recurrent falls of whom 179 (11%) had a carotid bruit, 167 underwent ultrasound, 31% had a stenosis > or = 50% (20% > or = 70%) in either internal or common carotid artery. A bruit was associated with significant ipsilateral stenosis in 25% and contralateral silent stenosis in a further 5%. Carotid sinus massage was performed in 121 subjects who were suitable (15 with moderate carotid artery stenosis). Carotid sinus hypersensitivity was found in 41 (34%) subjects (4 with moderate stenosis). No serious complications occurred following carotid sinus massage., Conclusions: Carotid sinus hypersensitivity is a possible attributable cause of symptoms in a third of subjects with unexplained or recurrent falls and carotid bruits. Only a small number have severe carotid artery stenosis. Ultrasound will identify high-risk subjects and facilitate accurate diagnosis with carotid sinus massage in the majority.

Most human cancer cells are thought to acquire the ability to divide beyond the capacity of normal somatic cells through illegitimately activating the gene hTERT, which encodes the catalytic subunit of telomerase. While telomerase reverse transcriptase (TERT) is conserved in most eukaryotes, mounting evidence suggests that the C terminus of the human protein may have functions unique to higher eukaryotes. To search for domains responsible for such functions, we assayed a panel of tandem substitution mutations encompassing this region of human TERT for in vitro and in vivo functionality. We found four clusters of mutations that inactivated the biochemical and biological functions of telomerase, separated by mutations that had little or no effect on enzyme activity. We also identified a region where mutations generate catalytically active but biologically inert proteins. This C-terminal region that dissociates activities of telomerase (C-DAT) does not appear to be involved in nuclear localization or protein multimerization. Instead, it appears that the C-DAT region is involved in a step of in vivo telomere synthesis after the assembly of a catalytically active enzyme. Intriguingly, all of the described regions reside in a portion of TERT that is dispensable for cellular viability in yeast, arguing for a divergent role of the C terminus in higher eukaryotes.

Aims: To ascertain the proportion of adults with a pacemaker in situ attending the Accident and Emergency Department because of syncope or unexplained falls and the cause of index symptoms in these patients, including the prevalence of hypotensive syndromes., Methods and Results: Patients presenting to the Accident and Emergency Department with unexplained syncope or non-accidental falls, who had a pacemaker in situ, were studied. Eligible patients had cardiovascular assessment (morning orthostatic blood pressure measurement, heart rate and BP measurements during carotid sinus stimulation (supine and upright), head-up tilt at 70 degrees for 40 min), assessment of haemodynamics during fixed mode pacing and gait and balance assessment. Of 5863 patients screened, 13.5% had unexplained syncope or a non-accidental fall; of these only 3% (26 patients) had pacemakers in situ. Of 18 study patients (82 +/- 8 years), 10 were female. Sixteen had a hypotensive diagnosis. Seven had more than one attributable hypotensive diagnosis. Five of 13 with vasodepressor carotid sinus syndrome had no previous diagnosis of carotid sinus hypersensitivity. No patients had vasovagal syncope induced during passive head-up tilt testing., Conclusion: It is rare for patients who attend the Accident and Emergency Department because of syncope or unexplained falls to have a pacemaker in situ. In those who do, hypotensive disorders are a common finding.

The adapter protein Crk contains an SH2 domain and two SH3 domains. Through binding of particular ligands to the SH2 domain and the N-terminal SH3 domain, Crk has been implicated in a number of signaling processes, including regulation of cell growth, cell motility, and apoptosis. We report here that the C-terminal SH3 domain, never shown to bind any specific signaling molecules, contains a binding site for the nuclear export factor Crm1. We find that a mutant Crk protein, deficient in Crm1 binding, promotes apoptosis. Moreover, this nuclear export sequence mutant [NES(-) Crk] interacts strongly, through its SH2 domain, with the nuclear tyrosine kinase, Wee1. Collectively, these data suggest that a nuclear population of Crk bound to Wee1 promotes apoptotic death of mammalian cells.

Objectives: The aim of the study was to determine whether cardiac pacing reduces falls in older adults with cardioinhibitory carotid sinus hypersensitivity (CSH)., Background: Cardioinhibitory carotid sinus syndrome causes syncope, and symptoms respond to cardiac pacing. There is circumstantial evidence for an association between falls and the syndrome., Methods: A randomized controlled trial was done of consecutive older patients (>50 years) attending an accident and emergency facility because of a non-accidental fall. Patients were randomized to dual-chamber pacemaker implant (paced patients) or standard treatment (controls). The primary outcome was the number of falls during one year of follow-up., Results: One hundred seventy-five eligible patients (mean age 73 +/- 10 years; 60% women) were randomized to the trial: pacemaker 87; controls 88. Falls (without loss of consciousness) were reduced by two-thirds: controls reported 669 falls (mean 9.3; range 0 to 89), and paced patients 216 falls (mean 4.1; range 0 to 29). Thus, paced patients were significantly less likely to fall (odds ratio 0.42; 95% confidence interval: 0.23, 0.75) than were controls. Syncopal events were also reduced during the follow-up period, but there were much fewer syncopal events than falls-28 episodes in paced patients and 47 in controls. Injurious events were reduced by 70% (202 in controls compared to 61 in paced patients)., Conclusions: There is a strong association between non-accidental falls and cardioinhibitory CSH. These patients would not usually be referred for cardiovascular assessment. Carotid sinus hypersensitivity should be considered in all older adults who have non-accidental falls.

Genotoxic stress triggers the activation of checkpoints that delay cell-cycle progression to allow for DNA repair. Studies in fission yeast implicate members of the Rad family of checkpoint proteins, which includes Rad17, Rad1, Rad9 and Hus1, as key early-response elements during the activation of both the DNA damage and replication checkpoints. Here we demonstrate a direct regulatory linkage between the human Rad17 homologue (hRad17) and the checkpoint kinases, ATM and ATR. Treatment of human cells with genotoxic agents induced ATM/ATR-dependent phosphorylation of hRad17 at Ser 635 and Ser 645. Overexpression of a hRad17 mutant (hRad17AA) bearing Ala substitutions at both phosphorylation sites abrogated the DNA-damage-induced G2 checkpoint, and sensitized human fibroblasts to genotoxic stress. In contrast to wild-type hRad17, the hRad17AA mutant showed no ionizing-radiation-inducible association with hRad1, a component of the hRad1-hRad9-hHus1 checkpoint complex. These findings demonstrate that ATR/ATM-dependent phosphorylation of hRad17 is a critical early event during checkpoint signalling in DNA-damaged cells.