bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiretroviral effects on HIV‐1 RNA, CD4 cell count and progression to AIDS or death: a meta‐regression analysis
Authors: Mills EJ , Kelly S , Bradley M , Mollon P , Cooper C , Nachega J 
Published: September 2008

ObjectiveGovernments, clinicians and drug‐licensing bodies have adopted changes in CD4 cell counts and HIV‐1 RNA levels as evidence of effectiveness for new therapeutic interventions. We aimed to determine the strength of the association between the magnitude of the effect of changes in CD4 cell count and HIV‐1 RNA and progression to AIDS or death in the highly active antiretroviral therapy (HAART) era.MethodsWe identified all randomized clinical trials (RCTs) evaluating the effect of HAART on both clinical and surrogate endpoints (1994 to September 2006). We performed a meta‐regression and weighted linear regression. We additionally estimated potential RCT sample sizes that would be required to assess the effectiveness of new interventions in terms of clinical endpoints.ResultsWe included data from 178 RCTs. We were unable to demonstrate a strong relationship at any time‐point. Specifically, this was the case when CD4 T‐cell change and clinical outcomes were examined at week 24 [coefficient −0.01, 95% confidence interval (CI) −0.03 to 0.001, P=0.54], week 48 (coefficient −0.01, 95% CI −0.02 to 0.001, P=0.83) and week 96 (coefficient 0.00, 95% CI −0.03 to 0.04, P=0.76). This was also the case when viral load was examined as a surrogate marker. Given the small number of clinical events occurring in new interventional RCTs, any RCT aiming to evaluate clinical endpoints within these time‐points would require an exceptionally large sample size.ConclusionsOur findings indicate that, within short‐term clinical trial settings, it is not possible to estimate the proportion of treatment effect associated with surrogate endpoints.
Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor‐naïve, nonnucleoside reverse transcriptase inhibitor‐experienced patients: study TMC125‐C227*
Authors: Ruxrungtham K , Pedro RJ , Latiff GH , Conradie F , Domingo P , Lupo S , Pumpradit W , Vingerhoets JH , Peeters M , Peeters I , Kakuda TN , De Smedt G , Woodfall B ,   on behalf of the TMC125‐C227 study group
Published: September 2008

ObjectivesTMC125‐C227, an exploratory phase II, randomized, controlled, open‐label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator‐selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)‐resistant, protease inhibitor‐naïve, HIV‐1‐infected patients.MethodsPatients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs).ResultsIn an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first‐line NNRTI‐failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal‐, lipid‐ and liver‐related events.ConclusionsIn a PI‐naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI‐naïve patients with first‐line virological failure on an NNRTI‐based regimen. Baseline two‐class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.
Liver enzyme elevation after lamivudine withdrawal in HIV–hepatitis B virus co‐infected patients: the Swiss HIV Cohort Study
Authors: Bellini C , Keiser O , Chave J‐P , Evison JM , Fehr J , Kaiser L , Weber R , Vernazza P , Bernasconi E , Telenti A , Cavassini M ,   the Swiss HIV Cohort Study
Published: September 2008

BackgroundThe principal causes of liver enzyme elevation among HIV–hepatitis B virus (HBV) co‐infected patients are the hepatotoxic effects of antiretroviral therapy (ART), alcohol abuse, ART‐induced immune reconstitution and the exacerbation of chronic HBV infection.ObjectivesTo investigate the incidence and severity of liver enzyme elevation, liver failure and death following lamivudine (3TC) withdrawal in HIV–HBV co‐infected patients.MethodsRetrospective analysis of the Swiss HIV Cohort Study database to assess the clinical and biological consequences of the discontinuation of 3TC. Variables considered for analysis included liver enzyme, HIV virological and immunological parameters, and medication prescribed during a 6‐month period following 3TC withdrawal.Results3TC was discontinued in 255 patients on 363 occasions. On 147 occasions (109 patients), a follow‐up visit within 6 months following 3TC withdrawal was recorded. Among these patients, liver enzyme elevation occurred on 42 occasions (29%), three of them (2%) with severity grade III and five of them (3.4%) with severity grade IV elevations (as defined by the AIDS Clinical Trials Group). Three patients presented with fulminant hepatitis. One death (0.7%) was recorded.ConclusionsHBV reactivation leading to liver dysfunction may be an under‐reported consequence of 3TC withdrawal in HIV–HBV co‐infected patients. Regular monitoring of HBV markers is warranted if active therapy against HBV is discontinued.
Thermal pain thresholds are decreased in the migraine preattack phase
Authors: Sand T. , Zhitniy N. , Nilsen K. B. , Helde G. , Hagen K. , Stovner L. J. 
Published: September 2008

Background and purpose:  Migraine patients may have cutaneous allodynia during attacks. In order to investigate if pain physiology changes in the preattack phase we estimated heat pain and cold pain detection threshold (HPT and CPT) on three different days in 41 migraine patients and 28 controls.Methods:  A thermode was applied at four sites bilaterally: forehead, face, neck, and hand. A subgroup of 11 migraine patients had been tested within 24 h before their next attack and in the interictal phase.Results:  In the preattack phase, HPT was lower compared with the paired interictal recording for the hand (44.8°C vs. 45.9°C, P = 0.009), neck (46.8°C vs. 48.2°C, P = 0.02), and forehead (45.1°C vs. 46.3°C, P = 0.02). Neck and hand CPT were higher in the preattack phase than interictally (10°C vs. 7.3°C, P = 0.01 and 11.6°C vs. 9.4°C, P = 0.06, respectively). Preattack forehead changes were most apparent on the headache side of the subsequent attack.Discussion:  Subclinical preattack thermal pain hypersensitivity seems to be a feature of the process that leads to a migraine attack.
Acute headache: a prospective diagnostic work‐up of patients admitted to a general hospital
Authors: Bø S. H. , Davidsen E. M. , Gulbrandsen P. , Dietrichs E. 
Published: September 2008

Background and purpose:  To find a specified diagnosis for every patient investigated in the hospital emergency room for acute headache suspicious of subarachnoid haemorrhage (SAH), and to describe similarities and differences between the diagnostic groups.Methods:  We used a standardized set of questionnaires and supplementary tests, including cerebral computed tomography (CT) and if needed lumbar puncture, in the investigation of the patients. Two neurologists diagnosed the same cases independently.Results:  We found 30 different diagnoses as the cause of acute headache. Sixteen per cent had a SAH, and 57% had a primary headache. Patient characteristics, conditions at headache onset and accompanying symptoms were surprisingly similar in the diagnostic groups. For three SAH patients, it took 30 min to reach maximum pain intensity. In all diagnostic groups, a large proportion of the patients reached maximum pain within 60 s.Conclusions:  To distinguish between benign and malignant causes of acute headache is difficult based on clinical features. The consistent use of CT and lumbar puncture is valuable when investigating sudden onset ‘first or worst headache ever’. This can reduce the risk of missing a SAH diagnosis, and make it possible to give more exact diagnoses to patients suffering from both primary and secondary headaches.
Acute ethanol suppresses glutamatergic neurotransmission through endocannabinoids in hippocampal neurons
Authors: Basavarajappa Balapal S. , Ninan Ipe , Arancio Ottavio 
Published: September 2008

AbstractEthanol exposure during fetal development is a leading cause of long‐term cognitive impairments. Studies suggest that ethanol exposure have deleterious effects on the hippocampus, a brain region that is important for learning and memory. Ethanol exerts its effects, in part, via alterations in glutamatergic neurotransmission, which is critical for the maturation of neuronal circuits during development. The current literature strongly supports the growing evidence that ethanol inhibits glutamate release in the neonatal CA1 hippocampal region. However, the exact molecular mechanism responsible for this effect is not well understood. In this study, we show that ethanol enhances endocannabinoid (EC) levels in cultured hippocampal neurons, possibly through calcium pathways. Acute ethanol depresses miniature post‐synaptic current (mEPSC) frequencies without affecting their amplitude. This suggests that ethanol inhibits glutamate release. The CB1 receptors (CB1Rs) present on pre‐synaptic neurons are not altered by acute ethanol. The CB1R antagonist SR 141716A reverses ethanol‐induced depression of mEPSC frequency. Drugs that are known to enhance thein vivofunction of ECs occlude ethanol effects on mEPSC frequency. Chelation of post‐synaptic calcium by EGTA antagonizes ethanol‐induced depression of mEPSC frequency. The activation of CB1R with the selective agonist WIN55,212‐2 also suppresses the mEPSC frequency. This WIN55,212‐2 effect is similar to the ethanol effects and is reversed by SR141716A. In addition, tetani‐induced excitatory post‐synaptic currents (EPSCs) are depressed by acute ethanol. SR141716A significantly reverses ethanol effects on evoked EPSC amplitude in a dual recording preparation. These observations, taken together, suggest the participation of ECs as retrograde messengers in the ethanol‐induced depression of synaptic activities.
Tissue‐type plasminogen activator requires a co‐receptor to enhance NMDA receptor function
Authors: Samson Andre L. , Nevin Simon T. , Croucher David , Niego Be’eri , Daniel Philip B. , Weiss Thomas W. , Moreno Eliza , Monard Denis , Lawrence Daniel A. , Medcalf Robert L. 
Published: September 2008

AbstractGlutamate is the main excitatory neurotransmitter of the CNS. Tissue‐type plasminogen activator (tPA) is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate‐binding NMDA receptor (NMDAR). It has been hypothesized that tPA can directly cleave the NR1 subunit of the NMDAR and thereby potentiate NMDA‐induced calcium influx. In contrast, here we show that this increase in NMDAR signaling requires tPA to be proteolytically active, but does not involve cleavage of the NR1 subunit or plasminogen. Rather, we demonstrate that enhancement of NMDAR function by tPA is mediated by a member of the low‐density lipoprotein receptor (LDLR) family. Hence, this study proposes a novel functional relationship between tPA, the NMDAR, a LDLR and an unknown substrate which we suspect to be a serpin. Interestingly, whilst tPA alone failed to cleave NR1, cell‐surface NMDARs did serve as an efficient and discrete proteolytic target for plasmin. Hence, plasmin and tPA can affect the NMDAR via distinct avenues. Altogether, we find that plasmin directly proteolyses the NMDAR whilst tPA functions as an indirect modulator of NMDA‐induced events via LDLR engagement.
ProNGF inhibits NGF‐mediated TrkA activation in PC12 cells
Authors: Sobottka Bettina , Reinhardt Dieter , Brockhaus Manfred , Jacobsen Helmut , Metzger Friedrich 
Published: September 2008

AbstractDegeneration of cholinergic basal forebrain neurons (CBFN) is a hallmark in the pathology of Alzheimer’s disease (AD). Critically depending upon the neurotrophic support through nerve growth factor (NGF), CBFN in the AD brain face elevated concentrations of the pro‐form of NGF (proNGF) and suffer from an imbalance between TrkA and p75NTR expression. Research for the underlying mechanisms of CBFN death suggested a pro‐apoptotic activity of proNGF. However, this finding could not be confirmed by all investigators and other studies even observed a neurotrophic function of proNGF. In the presence of these controversial findings we investigated the activity of proNGF in PC12 cells with specific emphasis on its neurotoxic versus neurotrophic action. In this study, we show that proNGF can mediate TrkA receptor signaling directly, yet in the manner of a partial agonist with a lower maximum activity than NGF. A pro‐apoptotic activity of proNGF could not be confirmed in our cellular system. Interestingly and surprisingly, pre‐incubation with proNGF at low, sub‐active concentrations inhibited TrkA‐mediated neurotrophic NGF signaling in PC12 cells. Our data support a novel hypothesis for the role of elevated proNGF levels in CBFN pathology in AD. Thus, proNGF can indirectly contribute to the slow neurodegeneration in AD by reducing NGF‐mediated trophic support.
Changes in Muscle Mass, Muscle Strength, and Power but Not Physical Function Are Related to Testosterone Dose in Healthy Older Men
Authors: Storer Thomas W. , Woodhouse Linda , Magliano Lynne , Singh Atam B. , Dzekov Connie , Dzekov Jeanne , Bhasin Shalender 
Published: September 2008

OBJECTIVES: To examine the effect of graded doses of testosterone on physical function and muscle performance in healthy, older men.DESIGN: Randomized, double‐blind, placebo‐controlled clinical trial.SETTING: General clinical research center.PARTICIPANTS: Community‐dwelling healthy men aged 60 to 75 (N=44).INTERVENTION: Monthly treatment with a gonadotropin‐releasing hormone agonist plus 25, 50, 125, or 300 mg/wk of intramuscular injections of testosterone enanthate for 20 weeks.MEASUREMENTS: Skeletal muscle mass (SMM) was estimated using dual‐energy X‐ray absorptiometry. Leg press strength was measured by one repetition maximum, leg power by Nottingham Leg Rig, and muscle fatigability by repetitions to failure in the leg press exercise. Stair climbing, 6‐meter and 400‐meter walking speed, and a timed‐up‐and‐go (TUG) test were used to assess physical function.RESULTS: Significant testosterone dose‐ and concentration‐dependent increases were observed in SMM (P<.001) and maximal strength (P=.001) but not muscle fatigability. Leg power also increased dose‐dependently (P=.048). In contrast, changes in self‐selected normal and fast walking speed over 6 or 400 meters, stair climbing power, and time for the TUG were not significantly related to testosterone dose, testosterone concentrations, or changes in muscle strength or power, or SMM.CONCLUSION: Testosterone administration was associated with dose‐dependent increases in SMM, leg strength, and power but did not improve muscle fatigability or physical function. The observation that physical function scores did not improve linearly with strength suggests that these high‐functioning older men were already in the asymptotic region of the curve describing the relationship between physical function and strength.
Defining the Domain of Geriatric Medicine in an Urban Public Health System Affiliated with an Academic Medical Center
Authors: Callahan Christopher M. , Weiner Michael , Counsell Steven R. 
Published: September 2008

The American Geriatrics Society has recommended a reexamination of the roles and deployment of providers with expertise in geriatric medicine. Healthcare systems use a variety of strategies to maximize their geriatric expertise. In general, these health systems tend to focus geriatric medicine resources on a group of older adults that are locally defined as the most in need. This article describes a model of care within an academic urban public health system and describes how local characteristics interact to define the domain of geriatric medicine. This domain is defined using 4 years of data from an electronic medical record combined with data collected from clinical trials.From January 2002 to December 2005, 31,443 adults aged 65 and older were seen at any clinical site within this healthcare system. The mean age was 75 (range 65–105); 61% were women; 35% African American, and 2% Hispanic. The payer mix was 80% Medicare and 17% Medicaid. The local geriatric medicine program includes sites of care in inpatient, ambulatory, nursing home, and home‐based settings.By design, this geriatric medicine clinical practice complements the care provided to older adults by the primary care practice. Primary care physicians tend to cede care to geriatric medicine for older adults with advanced disability or geriatric syndromes. This is most apparent for older adults in nursing facilities or those requiring home‐based care. There is a dynamic interplay between design features, reputation, and capacity that modulates volume, location, and type of patients seen by geriatrics.
Orthostatic Hypotension and Risk of Cardiovascular Disease in Elderly People: The Rotterdam Study
Authors: Verwoert Germaine C. , Mattace‐Raso Francesco U. S. , Hofman Albert , Heeringa Jan , Stricker Bruno H. C. , Breteler Monique M. B. , Witteman Jacqueline C. M. 
Published: September 2008

OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all‐cause mortality in elderly people.DESIGN: Prospective study.SETTING: Community based.PARTICIPANTS: Five thousand sixty‐four subjects from the Rotterdam study aged 55 and older.MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mmHg or more or a decline in diastolic blood pressure of 10 mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing.RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow‐up, 668 subjects had coronary heart disease (CHD) (mean follow‐up 6.0 ± 3.5 years), and 1,835 subjects died (mean follow‐up period 7.8 ± 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR)=1.31, 95% confidence interval (CI)=1.08–1.57) and all‐cause mortality (HR=1.22, 95% CI=1.09–1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all‐cause mortality were 1.80 (95% CI 1.25–2.60), 1.13 (0.89–1.42), and 1.27 (95% CI=1.11–1.44), in the first, second, and third tertile of age, respectively.CONCLUSION: Orthostatic hypotension increases the risk of CHD and all‐cause mortality in elderly people. The risk of CVD and mortality is strongest in younger and very old subjects.
Ventricular Arrhythmias after Left Ventricular Assist Device Implantation
Authors: REFAAT MARWAN , CHEMALY ELIE , LEBECHE DJAMEL , GWATHMEY JUDITH K. , HAJJAR ROGER J. 
Published: September 2008

Background:

Left ventricular assist devices (LVADs) have been used as a bridge to cardiac transplantation and as destination therapy in patients with advanced heart failure. The period after LVAD support is associated with ventricular arrhythmias (VAs) despite ventricular unloading and such VAs can have a detrimental effect on survival. Despite the increasing use of LVAD, little is known regarding post‐LVAD VAs at the molecular level and in vivo.
Methods:

Forty‐two patients who received LVAD over a 24‐month period were evaluated and grouped on the basis of the presence or absence of VAs during LVAD support. We completed a comparative microarray analyses between six patients who developed ventricular tachycardia (VT) or ventricular fibrillation (VF) after LVAD support and six patients who did not develop VAs after LVAD.
Results:

VAs occurred in 15 patients (35.7%) during LVAD support at a median post‐LVAD day of 25.2. VAs were strongly associated with nonusage of a β‐blocker post‐LVAD (odds ratio of 7.04, P‐value = 0.001). Analysis of a subset of patients who had VT or VF after LVAD placement showed a decrease in the expression of connexin 43 (0.48 ± 0.07), Na+/K+–ATPase (0.60 ± 0.05), and voltage‐gated K+ channel Kv4.3 (0.42 ± 0.04), and an increase in Na+/Ca2+ exchanger (2.2 ± 0.4) and the structural genes: Titin (2.1 ± 0.2), laminin (1.7 ± 0.4), calsequestrin (1.8 ± 0.5), skeletal muscle isoform of troponin T (5.1 ± 0.9), and skeletal muscle isoform of troponin I (3.9 ± 0.7).
Conclusion:

After LVAD, the increased risk of VAs is strongly associated with nonusage of β‐blocker postoperatively.
Remote Monitoring of CRT‐ICD: The Multicenter Italian CareLink Evaluation—Ease of Use, Acceptance, and Organizational Implications
Authors: MARZEGALLI MAURIZIO , LUNATI MAURIZIO , LANDOLINA MAURIZIO , PEREGO GIOVANNI B. , RICCI RENATO P. , GUENZATI GIUSEPPE , SCHIRRU MILENA , BELVITO CHIARA , BRAMBILLA ROBERTO , MASELLA CRISTINA , DI STASI FRANCESCA , VALSECCHI SERGIO , SANTINI MASSIMO 
Published: September 2008

Purpose:

The Medtronic CareLink allows remote implantable device follow‐up. In this first European experience with CareLink, we assessed the ease of use of the system, the acceptance, and satisfaction of patients and clinicians.
Methods:

Patients implanted with biventricular defibrillators for more than 6 months received the CareLink monitor and were trained to perform home device interrogation and transmission. Patient and clinician experience and preference were evaluated through specific questionnaires.
Results:

Sixty‐seven patients were enrolled and were able to perform data transmissions during the 3‐month study duration. The overall duration of interrogation procedure was 7 ± 5 minutes, and frequently the procedure did not require the assistance of a caregiver. Patients reported a general preference for remote versus in‐clinic follow‐up and described a sense of reassurance created by the remote monitoring capability.
In the centers, the review procedure was successful; its mean duration was 5 ± 2 minutes per transmission and the users indicated that the access and navigation of the review website were easy. At the end of the evaluation, the data available for remote review were judged complete and adequate to provide almost the same standard of care as that offered in traditional in‐clinic visit. In general, the remote monitoring was seen as a potential tool to improve the clinical management of patients with device.
Conclusions:

The ease of use, satisfaction, and acceptance of the CareLink Network in European clinical practice appears elevated both for patients and for clinicians.