nils-herrmann/clean_scirepeval huggingface dataset:
Tetrahydrobiopterin Supplementation Improves Endothelial Function But Does Not Alter Aortic Stiffness in Patients With Rheumatoid Arthritis

Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness.



We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH4 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH4 improved endothelial function, but there was no change with placebo (mean±SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH4 supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, ; short-term 0.03±1.46 m/s, P=0.9).



Both acute and short-term supplementation with oral BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.
Outcome of unilateral pallidotomy in advanced Parkinson's disease: cohort study of 32 patients.

In a randomised trial to study the efficacy of unilateral pallidotomy in patients with advanced Parkinson's disease, patients having pallidotomy within 1 month after randomisation were compared with patients having pallidotomy 6 months after the primary outcome assessment. Of the 37 patients enrolled 32 had a unilateral pallidotomy. The follow up study of these patients is presented to report (1) clinical outcome; (2) adverse effects; (3) cognitive and behavioural effects; (4) relation between lesion location and outcome; and (5) preoperative patient characteristics predictive for good outcome.



Outcome measures were the motor section of the unified Parkinson's disease rating scale (UPDRS), levodopa induced dyskinesias, disability, quality of life, and a comprehensive neuropsychological assessment. Multivariate logistic regression was used to identify preoperative patient characteristics independently associated with good outcome.



Off phase assessment showed a reduction in parkinsonism from 49 to 36.5 points on the UPDRS 6 months after surgery. Improvements were also demonstrated for activities of daily living and quality of life. In the on phase dyskinesias were reduced. All effects lasted up to 12 months after surgery. Three patients had major permanent adverse effects. Besides worsening of verbal fluency after left sided surgery, systematic cognitive deterioration was not detected. Patients taking less than 1000 levodopa equivalent units (LEU)/day were more likely to improve.



The positive effects of unilateral pallidotomy are stable up to 1 year after surgery. Patients taking less than 1000 LEU per day were most likely to improve.
A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor - in patients with advanced haematological malignancies.

Tefinostat (CHR-2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first-in-human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20-640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti-proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte-targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose-limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug-related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte-targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non-targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies.
Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema.

To determine the level of vascular endothelial growth factor (VEGF) in the plasma of patients with diabetic macular edema (DME) and of patients with exudative age-related macular degeneration (ARMD) before and after intravitreal injection of bevacizumab, ranibizumab or pegaptanib.



30 patients with DME and 30 patients with ARMD were included in this randomized controlled study. Patients were randomized to treatment with ranibizumab (0.5 mg), bevacizumab (1.25 mg) or pegaptanib (0.3 mg). 10 patients with DME received bevacizumab, 10 ranibizumab and 10 pegaptanib. The same randomized treatment allocation applied to the 30 patients with ARMD. The concentrations of VEGF were measured by ELISA just before the injection, after 7 days and 1 month.



Plasma VEGF in patients with exudative ARMD before the injection of bevacizumab was 89.7 pg/ml. It was significantly reduced to 25.1 pg/ml after 7 days (p=0.01), and to 22.8 pg/ml after 1 month (p=0.008). In patients with DME the same systemic reduction by bevacizumab was observed with a significant decrease of baseline VEGF level from 72.2 pg/ml to 13.7 pg/ml after 7 days (p=0.008) and 17.1 pg/ml at 4 weeks with (p=0.012). No significant reductions of plasma VEGF levels were observed in patients receiving ranibizumab or pegaptanib during follow-up.



Bevacizumab significantly reduces the level of VEGF in the blood plasma for up to one month in patients with DME as well as in those with ARMD. No significant systemic effects of intravitreal ranibizumab or pegaptanib on plasma VEGF could be observed.
Effects of continuous combined hormone replacement therapy on inflammation in hypertensive and/or overweight postmenopausal women.

We observed that estrogen did not show cardioprotective benefits in type 2 diabetic postmenopausal women. We hypothesized that hypertensive and/or overweight women may be less likely to realize cardiovascular benefits from estrogen.



We administered micronized progesterone (MP) 100 mg or medroxyprogesterone acetate (MPA) 2.5 mg with conjugated equine estrogen (CEE) 0.625 mg daily during 2 months to 35 hypertensive and/or overweight postmenopausal women with a randomized, double-blind, crossover design. With significant changes of lipoproteins, CEE+MP or MPA significantly improved flow-mediated dilation and reduced plasma E-selectin, intercellular adhesion molecule type-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha levels (P<0.001, P<0.001, P=0.021, P<0.001, and P<0.001 by ANOVA, respectively), but not C-reactive protein and fibrinogen levels. Of note, there were no significant differences between each therapy regarding these effects. However, the magnitude of improvement of flow-mediated dilation in these women was less than in healthy postmenopausal women and more than in diabetic postmenopausal women reported by our previous studies. The effects of CEE+MP or MPA on inflammatory markers were comparable to healthy postmenopausal women, but not comparable to diabetic postmenopausal women.



Estrogen combined with synthetic progestin significantly improved flow-mediated brachial artery dilator response and reduced inflammation markers in hypertensive and/or overweight women, comparable to estrogen combined with natural progesterone.
Effects of saxagliptin on early microvascular changes in patients with type 2 diabetes

Patients with diabetes mellitus are at increased risk for microvascular complications. Early changes in microcirculation are characterized by hyperperfusion (e.g. in the retina and kidney) and increased pulse wave reflection leading to increased aortic pressure. We investigated the effects of the DPP-4-inhibitor saxagliptin on early retinal microvascular changes.



In this double-blind, controlled, cross-over trial 50 patients (without clinical signs of microvascular alterations) with type-2 diabetes (mean duration of 4 years) were randomized to receive placebo or 5 mg saxagliptin for 6 weeks. Retinal arteriolar structure and retinal capillary flow (RCF) at baseline and during flicker-light exposure was assessed by scanning laser Doppler flowmetry. Central hemodynamics were assessed by pulse wave analysis.



Postprandial blood glucose (9.27 ± 0.4 versus 10.1 ± 0.4 mmol/L; p = 0.001) and HbA1c (6.84 ± 0.15 (51 ± 1.6) versus 7.10 ± 0.17% (54 ± 1.9 mmol/mol); p < 0.001) were significantly reduced with saxagliptin treatment compared to placebo. RCF was significantly reduced after treatment with saxagliptin (288 ± 13.2 versus 314 ± 14.1 AU; p = 0.033). This was most pronounced in a subgroup of patients (n = 32) with a fall in postprandial blood glucose (280 ± 12.1 versus 314 ± 16.6 AU; p = 0.011). No significant changes in RCF were seen during flicker-light exposure between placebo and saxagliptin, but the vasodilatory capacity increased two-fold with saxagliptin treatment. Central augmentation pressure tended to be lower after treatment with saxagliptin (p = 0.094), and central systolic blood pressure was significantly reduced (119 ± 2.3 versus 124 ± 2.3 mmHg; p = 0.038).



Our data suggest that treatment with saxagliptin for 6 weeks normalizes retinal capillary flow and improves central hemodynamics in type-2 diabetes.
Clinical effectiveness of an ultra-brief intervention for common mental health syndromes in primary care: study protocol for a cluster randomized controlled trial

Although mild to moderate mental health problems are common and often debilitating, treatment options in primary care settings in New Zealand are often severely limited for patients with these conditions. Previously, we developed an ultra-brief intervention (UBI) to address mild to moderate psychological concerns, designed to be delivered by primary care clinicians. Recent feasibility testing, including an adaptation for Māori individuals (the indigenous people of New Zealand), showed that the brief intervention was feasible and acceptable to both clinicians and their patients. This protocol describes a large pragmatic randomized controlled trial of our UBI in primary care settings across the greater Wellington region, compared with practice as usual.



We are using a two-arm cluster randomized controlled trial, with primary care practices randomized to exclusively deliver either the UBI or practice as usual to all their recruited participants. The structured, guided self-help UBI is delivered in three brief general practitioner (GP) appointments over a five week period. Participants are invited into the study based on partner primary health organization access criteria (youth, people with low income, or people with Māori or Pacific Island heritage). Improvements in mental health from baseline to post-treatment will be compared between the intervention and control groups using a mixed-models application of analysis of covariance. Data analysis will be on an intention-to-treat basis, to increase the real-world relevance of UBI and to meet the study's objective of releasing UBI to primary care clinicians nationwide.



The UBI is a first-line intervention tool for GPs that models the stepped care approach advocated in New Zealand, against a background of limited access to treatments for often-overlooked patient groups. It is proposed to be accessible to clinicians and patients alike, with the potential to be relevant to primary care clinicians across New Zealand.
Phase II study of the combination carboplatin and paclitaxel in patients with ovarian cancer.

Recently the feasibility of combining carboplatin with paclitaxel has been demonstrated in dose-finding studies. Maximum tolerated doses were 550 mg/m2 and 200 mg/m2 (three hours), respectively. We report now a phase II study in ovarian cancer patients.



Twenty-one chemo-naïve patients with optimally (n = 6) or suboptimally (n = 15) debulked stage III or IV ovarian cancer were treated every three weeks for six courses with paclitaxel (200 mg/m2) as a three-hour infusion, immediately followed by carboplatin (550 mg/m2) as a 30-minute infusion.



Uncomplicated neutropenia was the principal toxicity, with mild anemia occurring regularly. As observed in the preceding phase I study, a relative lack of thrombocytopenia, generally grade III was found. Other toxicities consisted of mild neurotoxicity, nausea and vomiting, alopecia, myalgia, and bone pain. All suboptimally debulked patients responded to therapy. Overall, 12 patients underwent second-look laparoscopy, which revealed a pathologically confirmed complete remission in six. The median follow-up interval at the time of analysis was 14 months. Twelve patients are currently free of progression, at 8+ to 19 +/- months after the start of therapy.



The carboplatin/paclitaxel combination appears to be a well-tolerated regimen, yielding high response rates. This combination has now gone forward to be evaluated in prospective randomized trials versus the cisplatin/paclitaxel combination.
Neuropsychological consequences of endarterectomy and endovascular angioplasty with stent placement for treatment of symptomatic carotid stenosis

Previous studies compared carotid endarterectomy (CEA) and carotid artery stent placement (CAS) for treatment of symptomatic carotid artery stenosis. Whereas most previous studies showed both treatment modalities to be associated with a comparable risk of periprocedural cerebrovascular complications, these previous studies have shown significantly more microemboli and significantly more lesions in diffusion-weighted MR imaging after CAS compared to CEA. The clinical relevance of these differences remains unknown.We therefore compared the neuropsychological consequences of CAS and CEA and additionally measured the S100β protein, a marker of cerebral damage. A total of 48 patients with symptomatic carotid artery stenosis greater than 70 % (according to ECST criteria) were enrolled and 45 patients participated in the follow-up. The patients were randomly assigned for CEA (24 patients) or CAS (21 patients). S100β protein values were evaluated 2 hours before the procedure, as well as one and two hours thereafter. Patients were assessed before treatment, and again 6 and 30 days after treatment using a comprehensive neuropsychological test battery. Patients of the CAS and the CEA groups did not significantly differ in terms of age, gender, education, degree of carotid artery stenosis, cerebrovascular symptoms and vascular risk factors. Following previously used criteria, a cognitive change in patients was assumed to have occurred when there was a decline of more than one standard deviation in two or more tests assessing various cognitive domains. Six days and 30 days after the treatment both groups showed a comparable number of patients with cognitive changes compared to baseline. There were no significant differences in S100β protein values. These results provide some reassurance that CAS is not associated with greater cognitive deterioration than CEA is.
Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial.

Lymphocyte-predominant Hodgkin disease (LPHD) is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy. In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease. All 22 patients responded to rituximab (overall response rate, 100%) with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in our trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD. Further clinical trials are warranted to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.
Effect of nifedipine on bronchomotor tone and histamine reactivity in asthma.

it is difficult to explain how successful resuscitation is possible after 40 minutes' submersion.2 The reduced oxygen requirement in profound hypothermia has been suggested by some authors as the mechanism by which tissue viability is maintained in these circumstances ,2 but this alone is an incomplete explanation, as for the submerged body to cool to a degree at which oxygen requirements are sufficiently reduced, heat transfer by mass flow-that is, circulation-must be present (a dead body cools relatively slowly). The degree of cooling encountered in our cases can be explained only by the fact that circulation was maintained for some or all of the period of submersion. The persistence of cardiac activity during such a prolonged period of apnoea supports the hypothesis that some protective mechanism may be present. We do not know whether ventricular fibrillation was present before resuscitative efforts were started and must concede that these efforts alone may have initiated the arrhythmia. Our cases show yet again that successful resuscitation is possible after long periods of immersion and emphasise the importance of performing electrocardiography early in the immersion incident, preferably at the accident site, before death is pronounced. 'Modell JH. The pathophysiology and treatment of drowning and near-Survival after 40 minutes sub-mersion without cerebral sequelae. Effect of nifedipine on bronchomotor tone and histamine reactivity in asthma Secretion of chenmical mediators from mast cells and contraction of bronchial smooth muscle are two major components in the patho-genesis of asthma. Both processes depend on the transmembrane passage of calcium ions, and drugs that inhibit this might therefore be expected to be of value in asthma. Cinnarizine, an antagonist to calcium transport, has been shown to exert a beneficial effect in patients with chronic asthma,' and verapamil, another calcium antagonist, prevents potassium-and serotonin-induced contraction of canine trachealis muscle.2 Nifedipine is a potent inhibitor of trans-membrane calcium ion flux, and results of a recent study suggest that .~~~~~~~~~~~~~~~~ it prevents exercise-induced asthma.3 We therefore investigated the effect of nifedipine on resting bronchomotor tone and on histamine reactivity in patients with asthma. We studied 10 patients, aged 25-60 years, with chronic stable asthma. The protocol was approved by the hospital research ethics committee, and all subjects gave informed consent. Each subject received either nifedipine 20 mg or placebo in a randomised double-blind fashion on separate days and was instructed to bite the capsules and keep the fluid in the mouth as long …
SYNTAX score and Clinical SYNTAX score as predictors of very long-term clinical outcomes in patients undergoing percutaneous coronary interventions: a substudy of SIRolimus-eluting stent compared with pacliTAXel-eluting stent for coronary revascularization (SIRTAX) trial.

To investigate the ability of SYNTAX score and Clinical SYNTAX score (CSS) to predict very long-term outcomes in an all-comers population receiving drug-eluting stents.



The SYNTAX score was retrospectively calculated in 848 patients enrolled in the SIRolimus-eluting stent compared with pacliTAXel-Eluting Stent for coronary revascularization (SIRTAX) trial. The CSS was calculated using age, and baseline left ventricular ejection fraction and creatinine clearance. A stratified post hoc comparison was performed for all-cause mortality, cardiac death, myocardial infarction (MI), ischaemia-driven target lesion revascularization (TLR), definite stent thrombosis, and major adverse cardiac events (MACE) at 1- and 5-year follow-up. Tertiles for SYNTAX score and CSS were defined as SS(LOW) ≤ 7, 7< SS(MID) ≤ 14, SS(HIGH) >14 and CSS(LOW) ≤ 8.0, 8.0 17.0, respectively. Major adverse cardiac events rates were significantly higher in SS(HIGH) compared with SS(LOW) at 1- and 5-year follow-up, which was also seen at 5 years for all-cause mortality, cardiac death, MI, and TLR. Stratifying outcomes across CSS tertiles confirmed and augmented these results. Within CSS(HIGH), 5-year MACE increased with use of paclitaxel- compared with sirolimus-eluting stents (34.7 vs. 21.3%, P = 0.008). SYNTAX score and CSS were independent predictors of 5-year MACE; CSS was an independent predictor for 5-year mortality. Areas-under-the-curve for SYNTAX score and CSS for 5-year MACE were 0.61 (0.56-0.65) and 0.62 (0.57-0.67), for 5-year all-cause mortality 0.58 (0.51-0.65) and 0.66 (0.59-0.73) and for 5-year cardiac death 0.63 (0.54-0.72) and 0.72 (0.63-0.81), respectively.



SYNTAX score and to a greater extent CSS were able to stratify risk for very long-term adverse clinical outcomes in an all-comers population receiving drug-eluting stents. Predictive accuracy for 5-year all-cause mortality was improved using CSS.