nils-herrmann/clean_scirepeval huggingface dataset:
Oxidative DNA damage in lung tissue from patients with COPD is clustered in functionally significant sequences

Lung tissue from COPD patients displays oxidative DNA damage. The present study determined whether oxidative DNA damage was randomly distributed or whether it was localized in specific sequences in either the nuclear or mitochondrial genomes. The DNA damage-specific histone, gamma-H2AX, was detected immunohistochemically in alveolar wall cells in lung tissue from COPD patients but not control subjects. A PCR-based method was used to search for oxidized purine base products in selected 200 bp sequences in promoters and coding regions of the VEGF, TGF-β1, HO-1, Egr1, and β-actin genes while quantitative Southern blot analysis was used to detect oxidative damage to the mitochondrial genome in lung tissue from control subjects and COPD patients. Among the nuclear genes examined, oxidative damage was detected in only 1 sequence in lung tissue from COPD patients: the hypoxic response element (HRE) of the VEGF promoter. The content of VEGF mRNA also was reduced in COPD lung tissue. Mitochondrial DNA content was unaltered in COPD lung tissue, but there was a substantial increase in mitochondrial DNA strand breaks and/or abasic sites. These findings show that oxidative DNA damage in COPD lungs is prominent in the HRE of the VEGF promoter and in the mitochondrial genome and raise the intriguing possibility that genome and sequence-specific oxidative DNA damage could contribute to transcriptional dysregulation and cell fate decisions in COPD.
The effect of variable cigarette consumption on the interaction with clozapine and olanzapine

Cigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 (CYP1A2) substrates clozapine and olanzapine. The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting. In 73 schizophrenic patients recruited from psychiatric nursing homes, patient characteristics, smoking habits, drug dosing and serum concentrations of clozapine (n=33) and olanzapine (n=40) were registered. Concentration to dose (C/D) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared. Fifty-nine patients (80%) were smokers and these were stratified into the following groups according to smoking habits: 1–6 (n=0), 7–12 (n=13), 13–19 (n=18) and ≥20 (n=28) cigarettes daily. While the mean ratio was twice as high in non-smokers compared to smokers for both drugs (p<0.01), the C/D ratios of clozapine and olanzapine were not significantly different between the subgroups of smokers (p >0.15). Absolute serum concentrations were also higher in non-smokers compared to smokers: 50% for clozapine (p=0.058) and 67% for olanzapine (p<0.01). A daily consumption of 7–12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects.
Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors.

Calcitriol, via its receptor (VDR) is a main regulator of PTH secretion and parathyroid cell proliferation. Recently, marked overrepresentation of the polymorphic VDR alleles b, a, and T was found in patients with primary hyperparathyroidism (pHPT), which suggests pathogenic importance in the disease. Using the ribonuclease protection assay, relative VDR and PTH messenger ribonucleic acid (mRNA) levels of parathyroid adenomas from 42 patients with sporadic pHPT were related to these VDR polymorphisms. The tumors of patients homozygous for the b, a, or T alleles demonstrated significantly lower VDR and higher PTH mRNA levels than those exhibiting the BB, AA, or tt genotypes (P < 0.0001-0.02), whereas heterozygotes had intermediate values. A similar discrepancy was found when comparing the baT and non-baT haplotypes (0.042 +/- 0.005 vs. 0.064 +/- 0.004 for VDR; 34.4 +/- 3.7 vs. 21.6 +/- 2.2 for PTH; both P < 0.005). The lower VDR mRNA levels associated with the b, a, and T alleles may affect the calcitriol-mediated control of parathyroid function and thereby contribute to the development of sporadic pHPT.
Growth after conversion to alternate-day corticosteroids in children with renal transplants: a single-center study

During the 1980s all children with growth potential and stable/adequate renal function at 6–9 months after kidney transplantation underwent conversion to alternate-day corticosteroids in an attempt to maximize growth. Conversion was attempted in 79 of 160 children who received allografts during this decade and was considered successful if they remained on alternate-day prednisone for more than 1 year, with a calculated creatinine clearance of at least 75% of the pre-conversion baseline value. Conversion succeeded in 55 children but failed in 24. Growth was markedly improved among those successfully converted when compared with the failure group, as measured by standard deviation score for growth velocity based on chronological age (+0.94±1.58 vs. −0.86±1.53,P<0.001) and bone age (+0.49±0.61 vs. −1.24±1.47,P<0.001). The improved growth among the successfully converted patients is believed to have been related to the combined effects of lower corticosteroid dose (0.36±0.16 vs. 0.48±0.21 mg/kg per day,P<0.02) and better renal function (calculated creatinine clearance 87±32 vs. 47±21 ml/min per 1.73 m2,P<0.001) at 1 year post conversion. Two factors appeared to improve the likelihood of successful conversion: the use of cyclosporine and receiving a live-related rather than cadaver transplant. Cyclosporine was associated with improvement in the overall rate for successful conversion in all recipients, from 59% to 83% (P<0.05). Recipients of allografts from live-related donors underwent successful conversion in 90% of cases compared with 58% receiving cadaver allografts (P<0.05). Successful conversion to alternate-day corticosteroid therapy is of significant benefit for linear growth, but may be associated with a risk of rejection and loss of renal function. The risk is small in live-related recipients and has been made safer for cadaver recipients with the introduction of cyclosporine.
Methodological aspects in the assessment of severity of depression by the Hamilton Depression Scale

Observer-rating scales are used for the evaluation of drug trials in depression. One of the most widely used depression rating scales is still the Hamilton Depression Scale (HAMD), which was developed at the time when the first antidepressants were becoming available. Due to its construction it seems to have a specific focus on drug effects of classical antidepressants. As a result of different methodological analyses such as principal component analysis, the Rasch model and facet analysis, a differentiation between core symptoms reflecting the severity of depression and additional symptoms describing other aspects of the symptomatology of depression seems meaningful. The use of the HAMD 6-item score, described primarily by Bech, as the main efficacy criterion in antidepressant drug trials gives a fair estimation of drug-induced changes of severity of depression and avoids bias such as the well-known bias of the HAMD total score in favour of tricyclic antidepressants. This is demonstrated by the evaluation of two sertraline-amitriptyline comparative studies.
Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy.

Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti-VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS.



Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately.



Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T(1)), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2).



Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients.
Increased levels of multiple forms of dihydrofolate reductase in peripheral blood leucocytes of cancer patients receiving haematopoietic colony-stimulating factors: Interim analysis

The precise mechanism whereby granulocytes proliferate when haematopoietic colony stimulating factors (CSFs) are used in neutropenic cancer patients is poorly understood. The purpose of this study was to investigate whether these cytokines bring about leucocyte proliferation by increasing the levels of multiple forms of dihydrofolate reductase (DHFR). Blood samples were collected from 36 cancer patients (25 males and 11 females) with chemotherapy-induced neutropenia. One sample of blood from each patient was obtained before therapy either with CSF, such as granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) or with placebo, and another one at the time of resolution of neutropenia. Peripheral blood leucocytes in these blood samples were counted, separated and lysed. From lysates, cytoplasmic samples were prepared and analyzed for active DHFR by a methotrexate-binding assay and for total immunoreactive DHFR by an enzyme linked immunosorbent assay. The increase in total leucocyte count (TLC) was most prominent (P < 0.005) in the CSF group and less so (P < 0.05) in the placebo group. The mean ± SD concentration values of active DHFR before and after stimulation with GM-CSF found were to be 0.34 ± 0.4 ng/mg protein and 0.99 ± 0.82 ng/mg protein, respectively, and in the group treated with G-CSF, 0.24 ± 0.32 ng/mg protein and 1.18 ± 2.4 ng/mg protein, respectively. This increase in active DHFR after stimulation with CSF was statistically significant (P <0.05). Similarly, concentration values of immunoreactive but nonfunctional form of DHFR (IRE) were 110 ± 97 ng/mg protein and 605 ± 475 ng/mg protein before and after stimulation with GM-CSF, and 115 ± 165 ng/mg protein and 1,054 ± 1,095 ng/ mg protein before and after stimulation with G-CSF. This increase in concentration of IRE after stimulation with GM-CSF or G-CSF was statistically significant (P < 0.005). In the control group, there was an increase in the concentration of both active DHFR and IRE after treatment with placebo. However, this was not statistically significant. Resolution of neutropenia was quicker in the groups treated with CSF compared to the control group. Results of this study indicate that colony stimulating factors (G-CSF and GM-CSF) induce white cell proliferation by increasing the levels of multiple forms of DHFR.
Effect of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor fluctuations in patients with Parkinson's disease.

Opicapone (OPC) is a novel third generation catechol-O-methyltransferase (COMT) inhibitor that enhances levodopa availability. This study investigated the effects of OPC in comparison with placebo on levodopa pharmacokinetics, tolerability and safety, COMT activity and motor response to levodopa in Parkinson's disease (PD) patients with motor fluctuations.



This was a randomized, multicentre, double-blind and placebo-controlled study in four parallel groups of PD patients treated with standard-release 100/25 mg levodopa/carbidopa or levodopa/benserazide and with motor fluctuations (wearing-OFF phenomenon). Subjects were sequentially assigned to be administered, once-daily, up to 28 days (maintenance phase), placebo (n = 10) or 5 (n = 10), 15 (n = 10) and 30 mg (n = 10) OPC. Two levodopa tests were performed, one at baseline and another following the maintenance phase. Subjects kept a diary to record motor fluctuations (ON/OFF periods) throughout the study.



In relation to placebo, levodopa exposure (AUC0-6) increased 24.7%, 53.9% and 65.6% following 5, 15 and 30 mg OPC, respectively. Maximum COMT inhibition (Emax) ranged from 52% (5 mg OPC) to 80% (30 mg OPC). The study was not designed to detect any significant differences in motor performance, but the exploratory analysis performed shows improvement in various motor outcomes, including a dose-dependent change in absolute OFF time corresponding to a percentage decrease of 4.16% (P > 0.05), 29.55% (P > 0.05) and 32.71% (P < 0.05) with 5, 15 and 30 mg OPC, respectively. Treatments were generally well tolerated and safe.



OPC is a promising new COMT inhibitor that significantly decreased COMT activity, increased systemic exposure to levodopa and improved motor response.
Will elderly rest home residents wear hip protectors?

Hip fracture is a common cause of morbidity and mortality in elderly people, for whom osteoporosis, the risk of falling and direct trauma to the hip during the fall are the major risk factors. External hip protectors have been developed which reduce the risk of hip fracture after a fall. However, compliance with their use is uncertain. We addressed this issue in a sample of elderly Dorset rest home residents over a 3-month period.



31 rest homes agreed to participate. Of the 288 female subjects approached, 141 gave their informed consent and 101 were allocated to the intervention arm of the study. Their ages ranged from 64 to 98 years, and 44% reported a fall during the preceding 12 months. Each subject was fitted with three pairs of protector pads (Sahvatex, Denmark) sewn into specially designed undergarments. Randomly timed fortnightly visits were made to each subject to assess compliance for 12 weeks.



27 subjects were compliant for the whole study period; 54 wore the protector pads for less than a week, largely for reasons of poor fitting or discomfort; the remainder withdrew at varying intervals between 1 and 12 weeks. During the study period, there were nine recorded falls onto the hip, six of which occurred in women wearing protectors. None resulted in hip fracture.



Approximately 50% of elderly rest home residents who are mentally able would wear hip protectors in order to prevent hip fractures. Long-term compliance drops to about 30%. Compliance could be increased substantially if the pads and undergarments were modified to enhance their fit and to reduce the discomfort associated with their use.
A phase I study of concurrent external beam radiotherapy with weekly topotecan for primary treatment of locally advanced lung cancers.

recently described a lung adenocarcinoma patient with an EML4-ALK fusion between exon 6 of echinoderm microtubule associated protein like 4 (EML4) and exon 19 of anaplastic lymphoma kinase (ALK) (E6;A19) as a novel molecular variant. It should be noted that this EML4-ALK (E6;A19) fusion has been previously reported by our group in a 62-year-old woman also with lung adenocarcinoma. The second finding of this atypical EML4-ALK breakpoint (the majority of ALK gene fusions occur at exon 20 of ALK) suggests that it may not be an isolated event, and highlights the great diversity of fusion events involving this gene. Furthermore, an FN1-ALK gene fusion was previously identified in a malignant stromal sarcoma patient, in which the fusion also occurs at exon 19 of ALK. The significance of these ALK exon 19 fusion variants is currently unknown, but is interesting as it expresses the ALK transmembrane domain. The subcellular localization of these exon 19-containing variants should be further investigated to better understand the implications of this finding; prior evidence suggests EML4ALK (E13;A20) is localized within the cytoplasm. Oncogenic fusions involving ROS1 and RET in lung cancer have been shown previously to also include the transmembrane domain in some instances. The patient described by our group demonstrated a partial response to crizotinib and experienced a progression free survival of approximately 6.5-months, supporting the argument that these patients be considered for ALK inhibitor therapy like other patients who are positive for ALK rearrangements.
The surgical stress response and postoperative immune function after laparoscopic or conventional total mesorectal excision in rectal cancer: a randomized trial

This study evaluated differences in stress response and immunological function following laparoscopic and conventional total mesorectal excision (TME) for rectal cancer. Patients with non-metastasized rectal cancer were prospectively randomized to open (n = 18) or laparoscopic (n = 22) TME. Blood samples were taken preoperatively (baseline), 2, 24, and 72 h following surgery. Systemic white blood cell and monocyte count, C-reactive protein, interleukin-6 (IL-6), interleukin-8 (IL-8), HLA-DR expression on monocytes, growth hormone, prolactin, and cortisol were measured. Forty patients with a median age of 66 years (interquartile range, 60–74 years) were included. Eighteen patients (45%) were randomized to open surgery and 22 patients (55%) to laparoscopic surgery. Patient demographics in terms of gender, age, BMI, ASA classification, localization of the tumor, and type of neoadjuvant therapy were comparable for both groups. Laparoscopic surgery resulted in a significantly better short-term preservation of postoperative immune function. HLA-DR expression on monocytes was significantly higher (64% vs 50%, P = 0.014) and IL-6 level increase was significantly lower (4.6 vs 10.8, P = 0.003) 2 h after laparoscopic surgery. No differences between the open and laparoscopic technique were observed in postoperative white blood cell count, monocyte count, C-reactive protein, IL-8, growth hormone, prolactin, and cortisol levels. Short-term postoperative immune and inflammatory functions tended to be better after laparoscopic rectal surgery. However, the differences were not consistent at all time intervals, making a definitive conclusion difficult. Better preserved inflammatory function 2 h after surgery may reflect a reduction in operative trauma when the laparoscopic technique is compared with open rectal procedures.
Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial

A randomised trial was done to evaluate the impact of improved sexually transmitted disease (STD) case management at primary health care level on the incidence of HIV infection in the rural Mwanza region of Tanzania. HIV incidence was compared in six intervention communities and six pair-matched comparison communities. A random cohort of about 1000 adults aged 15-54 years from each community was surveyed at baseline and at follow-up 2 years later. Intervention consisted of establishment of an STD reference clinic, staff training, regular supply of drugs, regular supervisory visits to health facilities, and health education about STDs. 12,537 individuals were recruited. Baseline HIV prevalences were 3.8% and 4.4% in the intervention and comparison communities, respectively. At follow-up, 8845 (71%) of the cohort were seen. Of those initially seronegative, the proportions seroconverting over 2 years were 48 of 4149 (1.2%) in the intervention communities and 82 of 4400 (1.9%) in the comparison communities. HIV incidence was consistently lower in the intervention communities in all six matched pairs. Allowing for the community-randomised design and the effects of confounding factors, the estimated risk ratio was 0.58 (95% CI 0.42-0.79, p = 0.007). No change in reported sexual behaviour was observed in either group. We conclude that improved STD treatment reduced HIV incidence by about 40% in this rural population. This is the first randomised trial to demonstrate an impact of a preventive intervention on HIV incidence in a general population.
Effects of Repeated Intrathecal Triamcinolone-Acetonide Application on Cerebrospinal Fluid Biomarkers of Axonal Damage and Glial Activity in Multiple Sclerosis Patients

Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults. Over time, the disease progresses and, with accumulating disability, symptoms such as spasticity may occur. Although several treatment options are available, some patients may not respond to first-line therapeutics. However, some of these patients may benefit from intrathecally administered triamcinolone-acetonide (TCA), a derivative of glucocorticosteroids (GCS). GCS may have neurotoxic effects, and cell apoptosis may occur. The aim of this study was to investigate the effects of TCA on biomarkers in the cerebrospinal fluid (CSF) suggestive of neurodegeneration. In order to assess neurotoxic effects of TCA, neurofilament heavy-chain (NfH)SMI35, tau protein, and S-100B protein levels were determined before and during treatment with TCA in 54 patients with primary progressive MS, as well as relapsing MS (relapsing–remitting and secondary progressive MS). NfHSMI35 levels in the CSF of patients treated with TCA intrathecally did not increase significantly during the treatment cycle (p = 0.068). After application of TCA, tau protein levels were increased significantly at day 4 (p = 0.03) and at day 8 (p ≤ 0.001). S-100B protein levels decreased significantly (p ≤ 0.05) during treatment with TCA. NfHSMI35 levels did not change significantly; however, tau protein levels did increase significantly within the reference range. Taking these findings together, the long-term effects of TCA on NfHSMI35 and tau protein levels need to be investigated further to understand whether levels of both biomarkers will change over repeated TCA applications. Interestingly, S-100B protein levels decreased significantly during the first applications, which may have represented reduced astrocytic activity during TCA treatment.