Miracle-dz/UniFAR-FTUs huggingface dataset:
The Effects of Carbidopa on Uptake of 6-18F-Fluoro-l-DOPA in PET of Pheochromocytoma and Extraadrenal Abdominal Paraganglioma

6-18F-fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA) PET is a useful tool for the detection of certain neuroendocrine tumors, especially with the preadministration of carbidopa, an inhibitor of DOPA decarboxylase. Whether carbidopa also improves 18F-DOPA PET of adrenal pheochromocytomas and extraadrenal paragangliomas is unknown. The aim of this study was to investigate the sensitivity of 18F-DOPA PET in the detection of paraganglioma and its metastatic lesions and to evaluate whether tracer uptake by the tumors is enhanced by carbidopa. Methods: Two patients with nonmetastatic adrenal pheochromocytoma, and 9 patients with extraadrenal abdominal paraganglioma (1 nonmetastatic, 8 metastatic), underwent whole-body CT, MRI, baseline 18F-DOPA PET, and 18F-DOPA PET with oral preadministration of 200 mg of carbidopa. The dynamics of tracer uptake by these lesions and the physiologic distribution of 18F-DOPA in normal tissues were recorded. Results: Seventy-eight lesions were detected by CT or MRI, 54 by baseline 18F-DOPA PET (P = 0.0022 vs. CT/MRI), and 57 by 18F-DOPA PET plus carbidopa (P = 0.0075 vs. CT/MRI, not statistically significant vs. baseline). In reference to findings on CT and MRI, the sensitivities of baseline 18F-DOPA PET were 47.4% for lesions and 55.6% for positive body regions, versus 50.0% (lesions) and 66.7% (regions) for 18F-DOPA PET plus carbidopa (neither is statistically significant vs. baseline). Compared with baseline, carbidopa detected additional lesions in 3 (27%) of 11 patients. Carbidopa increased the mean (±SD) peak standardized uptake value in index tumor lesions from 6.4 ± 3.9 to 9.1 ± 5.6 (P = 0.037). Pancreatic physiologic 18F-DOPA uptake, which may mask adrenal pheochromocytoma, is blocked by carbidopa. Conclusion: Carbidopa enhances the sensitivity of 18F-DOPA PET for adrenal pheochromocytomas and extraadrenal abdominal paragangliomas by increasing the tumor-to-background ratio of tracer uptake. The sensitivity of 18F-DOPA PET for metastases of paraganglioma appears to be limited.
Interferon regulatory factor 3 protects against adverse neo-intima formation.

AIMS Vascular smooth muscle cell (VSMC) proliferation is central to the pathophysiology of neo-intima formation. Interferon regulatory factor 3 (IRF3) inhibits the growth of cancer cells and fibroblasts. However, the role of IRF3 in vascular neo-intima formation is unknown. We evaluated the protective role of IRF3 against neo-intima formation in mice and the underlying mechanisms. METHODS AND RESULTS IRF3 expression was down-regulated in VSMCs after carotid wire injury in vivo, and in SMCs after platelet-derived growth factor (PDGF)-BB challenge in vitro. Global knockout of IRF3 (IRF3-KO) led to accelerated neo-intima formation and proliferation of VSMCs, whereas the opposite was seen in SMC-specific IRF3 transgenic mice. Mechanistically, we identified IRF3 as a novel regulator of peroxisome proliferator-activated receptor γ (PPARγ), a negative regulator of SMC proliferation after vascular injury. Binding of IRF3 to the AB domain of PPARγ in the nucleus of SMCs facilitated PPARγ transactivation, resulting in decreased proliferation cell nuclear antigen expression and suppressed proliferation. Overexpression of wild-type, but not truncated, IRF3 with a mutated IRF association domain (IAD) retained the ability to exert anti-proliferative effect. CONCLUSIONS IRF3 inhibits VSMC proliferation and neo-intima formation after vascular injury through PPARγ activation.
Regulation of Eukaryotic Initiation Factor 4E (eIF4E) Phosphorylation by Mitogen-Activated Protein Kinase Occurs through Modulation of Mnk1-eIF4G Interaction

ABSTRACT The m7G cap binding protein eukaryotic initiation factor 4E (eIF4E) is a rate-limiting determinant of protein synthesis. Elevated eIF4E levels, commonly associated with neoplasia, promote oncogenesis, and phosphorylation of eIF4E at Ser209 is critical for its tumorigenic potential. eIF4E phosphorylation is catalyzed by mitogen-activated protein kinase (MAPK)-interacting serine/threonine kinase (Mnk), a substrate of Erk1/2 and p38 MAPKs. Interaction with the scaffolding protein eIF4G, which also binds eIF4E, brings Mnk and its substrate into physical proximity. Thus, Mnk-eIF4G interaction is important for eIF4E phosphorylation. Through coimmunoprecipitation assays, we showed that MAPK-mediated phosphorylation of the Mnk1 active site controls eIF4G binding. Utilizing a naturally occurring splice variant, we demonstrated that the C-terminal domain of Mnk1 restricts its interaction with eIF4G, preventing eIF4E phosphorylation in the absence of MAPK signaling. Furthermore, using a small-molecule Mnk1 inhibitor and kinase-dead mutant, we established that Mnk1 autoregulates its interaction with eIF4G, releasing itself from the scaffold after phosphorylation of its substrate. Our findings indicate tight control of eIF4E phosphorylation through modulation of Mnk1-eIF4G interaction.
Up‐regulation of ciliary neurotrophic factor receptor expression by GABAA receptors in undifferentiated neural progenitors of fetal mouse brain

In this study, we evaluated the role of the GABAA receptor (GABAAR), expressed by undifferentiated neural progenitors isolated from fetal mouse neocortex, in the mechanisms relevant to self‐replication and differentiation toward neuronal and astroglial lineages. Round spheres were formed with clusters of proliferating cells within 2–4 days during culture with epidermal growth factor (EGF), whereas the size of these clusters was drastically increased in proportion to increasing durations up to 10 days. Sustained exposure to the GABAAR agonist muscimol at 100 μM led to significant increases in the size of neurospheres cultured for 6–10days, with increased proliferative activity and unchanged lactate dehydrogenase release in a manner sensitive to the GABAAR antagonist bicuculline. Muscimol also significantly increased the incorporation of 5‐bromo‐2′‐deoxyuridine in neurospheres in a bicuculline‐sensitive manner, whereas both high potassium and nifedipine significantly decreased the neurosphere area with increased numbers of apoptotic cells. Prior activation of GABAAR significantly promoted the subsequent expression of an astroglial marker protein in cells differentiated by ciliary neurotrophic factor (CNTF) toward an astroglial lineage after the removal of EGF, with a concomitant decrease in neuronal marker protein expression. In neurospheres with GABAAR activation, a significant and predominant increase was seen in mRNA expression of CNTF receptors. These results suggest that prior tonic activation of GABAAR may preferentially promote the differentiation by CNTF of neural progenitor cells toward an astroglial lineage through selective up‐regulation of CNTF receptor expression in the developing mouse brain. © 2008 Wiley‐Liss, Inc.
[Effectiveness of dialectical behavior therapy for patients with borderline personality disorder in the long-term course--a 30-month-follow-up after inpatient treatment].

BACKGROUND The beneficial effects of Dialectical Behavior Therapy (DBT) for patients with borderline personality disorder (BPD) are well established. However, it is not well known whether this type of treatment relieves symptoms and signs of BPD in the long-term course thereafter and whether the results of DBT are transferable for patients with high comorbidity. METHODS We conducted a follow-up examination of 50 consecutive inpatients with BPD as defined by DSM-IV. The patients were examined at admission, at discharge and 15 and 30 months after discharge. For the clinical diagnosis and to survey psychopathology we used the Structured Clinical Interview for DSM-IV (SCID), the Global Assessment of Functioning (GAF) and several self-rating-instruments. RESULTS Compared to admission 30 months after discharge we observed the following results: A significant number of patients did not meet the DSM-IV criteria for BPD anymore, comorbidity (particularly mood disorders, drug or alcohol abuse/dependence and eating disorders) was reduced, psychosocial functioning was improved and general and BPD-typical symptoms were relieved. CONCLUSION Our findings support the efficacy of DBT in an inpatient setting and show that the achieved success of therapy is stable for a prolonged period of time. Patients with high comorbidity seem to profit from DBT as well.
Superficial Inferior Epigastric Vessels in the Massive Weight Loss Population: Implications for Breast Reconstruction

Background: Breast cancer risk and reconstructive options after massive weight loss are undefined. Use of the resulting pannus for autologous reconstruction is possible, with one option being the superficial inferior epigastric artery (SIEA) flap. Large superficial inferior epigastric vessels have been observed in massive weight loss patients during abdominal contouring procedures, but their anatomical features have not been assessed. Methods: Thirty-two consecutive massive weight loss patients undergoing abdominal contouring had their superficial inferior epigastric vessels measured intraoperatively to assess correlation with body mass indices and pannus weight using appropriate statistical analyses. Results: Sixty-four hemiabdomens were assessed. Mean age was 46 ± 9.8 years. Mean maximum body mass index was 49.5 ± 8.3, current body mass index was 29.6 ± 6.0, change in body mass index was 19.9 ± 5.6, and mean pannus weight was 3338.4 g. Mean artery size was 1.7 mm and mean vein size was 2.9 mm. Thirty-two of 62 hemiabdomens (52 percent) had a usable vessel (≥1.5 mm). Maximum body mass index was related to the overall presence of a SIEA (p = 0.009) or usable artery (p = 0.04), whereas both current body mass index and maximum body mass index were related to superficial inferior epigastric vein size (p < 0.001). Pannus weight was correlated to superficial inferior epigastric vein and SIEA size (p < 0.001) and strongly correlated to current body mass index (r = 0.78) and maximum body mass index (r = 0.46). Conclusions: The superficial inferior epigastric vessel system is commonly present in massive weight loss patients. Body mass index before weight loss is the strongest predictor of SIEA presence and usability. When massive weight loss patients present for breast reconstruction, careful patient selection along with weight loss history and assessment of pannus size may aid in determining the likelihood of using the SIEA flap.
Enigmatic GPCR Finds a Stimulating Drug

A small-molecule agonist provides insight into the function and therapeutic potential of the receptor GPR17. GPR17 is an orphan G protein–coupled receptor involved in orchestration of oligodendrocyte differentiation and myelination in the central nervous system. In this issue of Science Signaling, Hennen et al. used a signaling pathway-unbiased screen to identify two small molecule activators of this receptor. One of these, MDL29951, was carried forward to illustrate GPR17-dependent activation of Gαi- and Gαq-promoted signaling pathways in cell lines expressing recombinant GPR17, whereas no effect was observed with previously proposed but dubitable agonists (uracil nucleotides and cysteinyl leukotrienes) of this receptor. Conversely, MDL29951 did not activate any of the known uracil or adenine nucleotide-activated P2Y receptors or cysteinyl leukotriene receptors. Gαi- and Gαq-dependent signaling responses also were observed in primary rat oligodendrocytes in the presence of MDL29951. Moreover, MDL29951 diminished myelination in primary oligodendrocytes isolated from heterozygous mice but had no effect on myelination in oligodendrocytes from GPR17 knockout mice. Effects of a small-molecule GPR17 agonist observed during oligodendrocyte differentiation support the idea that development of antagonists of GPR17 is a rational goal for elaboration of pharmacotherapies in demyelinating diseases.
Functional interactions of varenicline and nicotine with nAChR subtypes implicated in cardiovascular control.

INTRODUCTION It has been suggested that varenicline-induced activation of nicotinic acetylcholine receptors (nAChRs) could play a role in the cardiovascular (CV) safety of varenicline. However, since preclinical studies showed that therapeutic varenicline concentrations have no effect in models of CV function, this study examined in vitro profiles of varenicline and nicotine at nAChR subtypes possibly involved in CV control. METHODS Concentration-dependent functional effects of varenicline and nicotine at human α3β4, α3α5β4, α7, and α4β2 nAChRs expressed in oocytes were determined by electrophysiology. The proportion of nAChRs predicted to be activated and inhibited by concentrations of varenicline (1mg b.i.d.) and of nicotine in smokers was derived from activation-inhibition curves for each nAChR subtype. RESULTS Human varenicline and nicotine concentrations can desensitize and inhibit nAChRs but cause only low-level activation of α3β4, α4β2 (<2%), α7 (<0.05%), and α3α5β4 (<0.01%) nAChRs, which is consistent with literature data. Nicotine concentrations in smokers are predicted to inhibit larger fractions of α3β4 (48%) and α3α5β4 (10%) nAChRs than therapeutic varenicline concentrations (11% and 0.6%, respectively) and to inhibit comparable fractions of α4β2 nAChRs (42%-56%) and α7 nAChRs (16%) as varenicline. CONCLUSIONS Nicotine and varenicline concentrations in patients and smokers are predicted to cause minimal activation of ganglionic α3β4* nAChRs, while their functional profiles at α3β4, α3α5β4, α7, and α4β2 nAChRs cannot explain that substituting nicotine from tobacco with varenicline would cause CV adverse events in smokers who try to quit. Other pharmacological properties that could mediate varenicline-induced CV effects have not been identified.
Greater frequency of distraction accelerates bone formation in open-wedge proximal tibial osteotomy with hemicallotasis

Background In chickens, increased distraction frequency stimulates bone formation in distraction osteogenesis.Patients and methods We investigated the effect of two different distraction frequencies on bone formation in the distracted portion, and on the time of removal of the fixator, in open-wedge osteotomies of the proximal tibia with hemicallotasis (HCO). The study included 20 consecutive patients (20 knees) who underwent HCO for medial osteoarthrosis of the knee. 10 knees were distracted at a rate of 0.25 mm four times a day (the 4-step group); and the other 10 knees were distracted at a rate of 0.125 mm eight times a day (the 8-step group). Results There were no significant differences in the preoperative FTAs or the correction angles between the two groups. At all intervals until 6 weeks after the completion of distraction, bone mineral density in the distraction gap was significantly higher in the 8-step group than in the 4-step group. The average time in external fixation was 78 (SD 5) days in the 8-step group as compared to 89 (SD 6) days in the 4-step group, a significantly shorter time.Interpretation Our findings indicate that an increase in the distraction frequency in HCO provides better bone formation, resulting in a shorter external fixation period.
Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study.

BACKGROUND Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome. We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate. This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial. METHODS Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days. Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points. All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products. RESULTS Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered. Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs. APC normalized significantly faster with increasing dosages of protein C concentrate. No adverse reactions related to protein C concentrate were observed. Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups. Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes. CONCLUSIONS Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.
Community management or coproduction? The role of state and citizens in rural water service delivery in India

This paper makes the case for a realignment in the discourse and conceptualisation of community management of rural water supply. It draws on data from 20 case studies of reportedly successful community management programmes from India to argue that current discourse is remiss not to describe the substantial role of the state and other supporting agencies in financing and supporting service provision. In the context of such substantial levels of support, conceptually, it is argued that the tendency to treat the challenge of rural water supply as one of either a community participation or collective action problem that only the community can address further limits current thinking in this area. Recasting the primary challenge of rural water service delivery as improved cooperation and coordination between state and citizen, the paper proposes a more substantial focus on coproduction as a route to overcome sustainability problems in rural water supply. The paper ends by reflecting on the generalisability of this thinking noting the specific context of the Indian empirical data. It concludes by arguing that, although certain aspects of the study are specific to that empirical domain, the normative and conceptual reasons for shifting the discourse remain applicable in broader contexts.
Persistent asthma due to isocyanates. A follow-up study of subjects with occupational asthma due to toluene diisocyanate (TDI).

Thirty-five subjects with occupational asthma due to toluene diisocyanate (TDI) exposure were examined. All the subjects were studied with inhalation challenges with TDI and with methacholine. TDI asthma was documented by a positive inhalation challenge to low levels of TDI. Airway responsiveness to methacholine was in the range of asthmatic patients at the time of diagnosis. After an average follow-up interval of 10 months, all the subjects were re-examined. Of the 35 subjects examined, 30 subjects (85.7%) left the workplace, and 5 remained in the same job. Twenty-seven subjects (77.1%) continued to have asthmatic attacks requiring medication for relief of symptoms. At follow-up examination, TDI asthma was documented by a positive inhalation challenge to TDI in 27 subjects. Of these 27 TDI reactors, 22 subjects were removed from occupational exposure to TDI. The TDI reactors had persistent respiratory symptoms and airway hyperresponsiveness to methacholine. At follow-up visit, 8 subjects (22.9%) lost sensitization to TDI; 5 subjects (62.5%) in this group had also normal airway responsiveness to methacholine after removal from exposure. Only 1 subject among the TDI nonreactors complained of mild respiratory symptoms. At diagnosis, there were no significant differences between subjects who recovered and those who did not with regard to age, smoking habits, atopy, duration of exposure to isocyanates, duration of symptoms, baseline FEV1 (% pred), and baseline airway responsiveness to methacholine. (ABSTRACT TRUNCATED AT 250 WORDS)
Protective effects of blackberry and quercetin on sodium fluoride-induced oxidative stress and histological changes in the hepatic, renal, testis and brain tissue of male rat

Abstract Background: Sodium fluoride (NaF) intoxication is associated with oxidative stress and altered antioxidant defense mechanism. The present study was carried out to evaluate the potential protective role of blackberry and quercetin (Q) against NaF-induced oxidative stress and histological changes in liver, kidney, testis and brain tissues of rats. Methods: The rats were allocated evenly to seven groups. The first group was maintained as the control, whereas groups 2, 3, 4, 5, 6 and 7 were administered blackberry juice (BBJ), Q, NaF, BBJ+NaF, Q+NaF and BBJ+Q+NaF, respectively, for a period of 30 days. Results and conclusions: NaF caused an elevation in lipid peroxidation level paralleled with significant decline in glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase and catalase activities as well as the total antioxidant activity in liver, kidney, testes and brain. Some histopathological changes were detected in all tested tissues of the NaF treated group. Q and BBJ had successfully maintained normal histological architecture and mitigated the induction of oxidative stress caused by NaF. Q effectively reduced the elevation in thiobarbituric acid reactive substances level and restored the activities of antioxidant enzymes in liver, kidney, testis and brain. Less histopathological changes were observed in Q+NaF and BBJ+NaF treated groups. As a result, BBJ and Q significantly reduced NaF-induced oxidative and histological changes in rats. In the combination of BBJ and Q against NaF toxicity, the effects were more severe than from separate exposure, thus indicating that these flavonoids exhibited synergistic effects on all antioxidant and histological parameters.