Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterization of the solitary pulmonary nodule: 18F-FDG PET versus nodule-enhancement CT.

OBJECTIVE The purpose of this study was to directly compare nodule-enhancement CT and 18F-FDG PET in the characterization of indeterminate solitary pulmonary nodules (SPNs) greater than 7 mm in size. MATERIALS AND METHODS Examinations from patients undergoing both nodule-enhancement CT and 18F-FDG PET to characterize the same indeterminate SPN were reviewed. For nodule-enhancement CT, an SPN was considered malignant when it showed an unenhanced to peak contrast-enhanced increase in attenuation greater than 15 H. Fluorine-18-FDG PET studies were blindly reinterpreted by two qualified nuclear radiologists. SPNs qualitatively showing hypermetabolic activity greater than the mediastinal blood pool were interpreted as malignant. These interpretations were compared with the original prospective clinical readings and to semiquantitative standardized uptake value (SUV) analysis. Results were compared with pathologic and clinical follow-up. RESULTS Forty-two pulmonary nodules were examined. Twenty-five (60%) were malignant, and 17 (40%) were benign. Nodule-enhancement CT was positive in all 25 malignant nodules and in 12 benign nodules, with sensitivity and specificity of 100% and 29%, respectively, and with a positive predictive value (PPV) and negative predictive value (NPV) of 68% and 100%, respectively. Qualitative 18F-FDG PET interpretations were positive in 24 of the 25 malignant nodules and in four benign nodules. Fluorine-18-FDG PET was considered negative in one malignant nodule and in 13 of the 17 benign nodules. This correlates with a sensitivity and specificity of 96% and 76%, respectively, and with a PPV and NPV of 86% and 93%, respectively. Original prospective 18F-FDG PET and semiquantitative SUV analysis showed sensitivity, specificity, PPV, and NPV of 88%, 76%, 85%, and 81% and 84%, 82%, 88%, and 78%, respectively. CONCLUSION Due to its much higher specificity and only slightly reduced sensitivity, 18F-FDG PET is preferable to nodule-enhancement CT in evaluating indeterminate pulmonary nodules. However, nodule-enhancement CT remains useful due to its high NPV, convenience, and lower cost. Qualitative 18F-FDG PET interpretation provided the best balance of sensitivity and specificity when compared with original prospective interpretation or SUV analysis.
Priming of neutrophil [Ca2+]i signaling and oxidative burst by human fracture fluids.

BACKGROUND Patients with major fracture/soft-tissue injuries are at risk for adult respiratory distress syndrome after secondary infection. Fracture fluids (FF) are rich in neutrophil (PMN) -specific chemokines such as interleukin-8. PMN respond to both interleukin-8 and bacterial stimuli with calcium ([Ca2+]i) fluxes, which can initiate respiratory burst (RB). We hypothesize that small amounts of FF entering the circulation could exaggerate PMN [Ca2+]i and RB responses, potentially increasing the risk of adult respiratory distress syndrome. METHODS FF were obtained from 10 patients at open fixation of the femur 2 to 5 days postinjury. Volunteer PMN were isolated and loaded with fura dye. PMN were preincubated either in 30% autologous plasma (AP)/70% buffer, or in 5% FF/25% AP/70% buffer. Cells were resuspended in buffer with 1,2,3-dihydrorhodamine and stimulated with low-dose n-formyl-methionyl-leucyl-phenylalanine (fMLP). [Ca2+]i was assayed by fura fluorescence at 505 nm after excitation at 340/380 nm. RB was assessed by 1,2,3-dihydrorhodamine fluorescence at 530 nm after 488 nm excitation. RESULTS PMN basal [Ca2+]i was higher after FF incubation than AP incubation (94+/-12 vs. 61+/-9 nmol/L, p = 0.0002). Peak [Ca2+]i response to fMLP was 475+/-47 nmol/L after FF but only 356+/-22 nmol/L after AP (p = 0.01). Two hundred seconds after fMLP, [Ca2+]i remained higher after FF (172+/-17 vs. 145+/-9 nmol/L, p = 0.04). Basal RB was slightly higher after FF than AP (13.4+/-0.3 vs. 11.3+/-0.3 units, p = 0.051) as was the maximal rate of extracellular oxidant release (1.10+/-0.17 vs. 0.76+/-0.16 units/s, p = 0.004) and total oxidant production (42.5+/-0.8 vs. 31.7+/-0.8 units, p = 0.006). CONCLUSION Small amounts of FF in plasma can exaggerate PMN [Ca2+]i flux and RB responses to subsequent bacterial stimuli. These findings are consistent with the hypothesis that release of FF into the circulation primes PMN and, thus, may predispose to adult respiratory distress syndrome. Such PMN priming events might have important implications for both the operative and medical management of patients with major fractures.
In Vitro-to-in Vivo Prediction of P-glycoprotein-Based Drug Interactions at the Human and Rodent Blood-Brain Barrier

In vitro inhibition of P-glycoprotein (P-gp) expressed in cells is routinely used to predict the potential of in vivo P-gp drug interactions at the human blood-brain barrier (BBB). The accuracy of such predictions has not been confirmed because methods to quantify in vivo P-gp drug interactions at the human BBB have not been available. With the development of a noninvasive positron emission topography (PET) imaging method by our laboratory to determine P-gp-based drug interactions at the human BBB, an in vitro-in vivo comparison is now possible. Therefore, we developed a high throughput cell-based assay to determine the potential of putative P-gp inhibitors [including cyclosporine A (CsA)] to inhibit (EC50) the efflux of verapamil-bodipy, a model P-gp substrate. LLCPK1-MDR1 cells, expressing recombinant human P-gp, or control cells lacking P-gp (LLCPK1) were used in our assay. Using this assay, quinine, quinidine, CsA, and amprenavir were predicted to be the most potent P-gp inhibitors in vivo at their respective therapeutic maximal unbound plasma concentrations. The in vitro EC50 of CsA (0.6 μM) for P-gp inhibition was virtually the same as our previously determined in vivo unbound EC50 at the rat BBB (0.5 μM). Moreover, at 2.8 μM CsA (total blood concentration), our in vitro data predicted an increase of 129% in [11C]verapamil distribution into the human brain, a value similar to that observed by us (79%) using PET. These data suggest that our high throughput cell assay has the potential to accurately predict P-gp drug interactions at the human BBB.
N-Acetylcysteine Restores Sevoflurane Postconditioning Cardioprotection against Myocardial Ischemia-Reperfusion Injury in Diabetic Rats

The effect of sevoflurane postconditioning (sevo-postC) cardioprotection is compromised in diabetes which is associated with increased oxidative stress. We hypothesized that antioxidant N-Acetylcysteine may enhance or restore sevo-postC cardioprotection in diabetes. Control or streptozotocin-induced Type 1 diabetic rats were either untreated or treated with N-Acetylcysteine for four weeks starting at five weeks after streptozotocin injection and were subjected to myocardial ischemia-reperfusion injury (IRI), in the absence or presence of sevo-postC. Diabetes showed reduction of cardiac STAT3 activation (p-STAT3) and adiponectin with concomitantly increase of FoxO1 and CD36, which associated with reduced sevo-postC cardioprotection. N-Acetylcysteine and sevo-postC synergistically reduced the infarct size in diabetic groups. N-Acetylcysteine remarkably increased cardiac p-STAT3 which was further enhanced by sevo-postC. N-Acetylcysteine but not sevo-postC decreased myocardial FoxO1 while sevo-postC but not N-Acetylcysteine significantly increased myocardiac adiponectin in diabetic rats. It is concluded that late stage diabetic rats displayed reduction of cardiac p-STAT3, adiponectin deficiency, and increase of FoxO1 and CD36 expression, which may be responsible for the loss of myocardial responsiveness to sevo-postC cardioprotection. N-Acetylcysteine restored Sevo-postC cardioprotection in diabetes possibly through enhancing cardiac p-STAT3 and adiponectin and reducing Fox1 and CD36.
Plasma Glutathione Peroxidase Activity as an Index of Renal Function

The kidney is a major source of the plasma enzyme glutathione peroxidase. We measured plasma glutathione peroxidase activity in 130 patients affected with different renal diseases at various stages, and compared it with the following indices of kidney function: serum creatinine, creatinine clearance, and urinary excretion of alpha 1-microglobulin, beta 2-microglobulin, albumin and N-acetyl-beta-D-glucosaminidase. Plasma glutathione peroxidase activity appeared significantly reduced in most of the renal diseases considered, and showed a significant correlation with most of the renal function indices. Linear discriminant analysis showed that the set of indices composed of plasma glutathione peroxidase activity, serum creatinine and creatinine clearance allowed the best classification of renal diseases. During treatment with the nephrotoxic aminoglycoside, tobramycin, plasma glutathione peroxidase activity showed an early and progressive decrease. We suggest the measurement of plasma glutathione peroxidase activity as an adjunctive index for the assessment of kidney alterations.
What kinds of things are psychiatric disorders?

This essay explores four answers to the question ‘What kinds of things are psychiatric disorders? ’ Essentialist kinds are classes whose members share an essence from which their defining features arise. Although elegant and appropriate for some physical (e.g. atomic elements) and medical (e.g. Mendelian disorders) phenomena, this model is inappropriate for psychiatric disorders, which are multi-factorial and ‘fuzzy’. Socially constructed kinds are classes whose members are defined by the cultural context in which they arise. This model excludes the importance of shared physiological mechanisms by which the same disorder could be identified across different cultures. Advocates of practical kinds put off metaphysical questions about ‘reality’ and focus on defining classes that are useful. Practical kinds models for psychiatric disorders, implicit in the DSM nosologies, do not require that diagnoses be grounded in shared causal processes. If psychiatry seeks to tie disorders to etiology and underlying mechanisms, a model first proposed for biological species, mechanistic property cluster (MPC) kinds, can provide a useful framework. MPC kinds are defined not in terms of essences but in terms of complex, mutually reinforcing networks of causal mechanisms. We argue that psychiatric disorders are objectively grounded features of the causal structure of the mind/brain. MPC kinds are fuzzy sets defined by mechanisms at multiple levels that act and interact to produce the key features of the kind. Like species, psychiatric disorders are populations with central paradigmatic and more marginal members. The MPC view is the best current answer to ‘What kinds of things are psychiatric disorders? ’
Use of item response theory to understand differential functioning of DSM-IV major depression symptoms by race, ethnicity and gender

Background Psychological literature and clinical lore suggest that there may be systematic differences in how various demographic groups experience depressive symptoms, particularly somatic symptoms. The aim of the current study was to use methods based on item response theory (IRT) to examine whether, when equating for levels of depression symptom severity, there are demographic differences in the likelihood of reporting DSM-IV depression symptoms. Method We conducted a secondary analysis of a subset (n=13 753) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) dataset, which includes a large epidemiological sample of English-speaking Americans. We compared data from women and men, Hispanics and non-Hispanic Whites, African Americans and Whites, Asian Americans and Whites, and American Indians and Whites. Results There were few differences overall, although the differences that we did find were primarily limited to somatic symptoms, and particularly appetite and weight disturbance. Conclusions For the most part, individuals responded similarly to the criteria used to diagnose major depression across gender and across English-speaking racial and ethnic groups in the USA.
Methadone rotation for cancer patients with refractory pain in a palliative care unit: an observational study.

BACKGROUND Methadone has been reported to be as effective as morphine for cancer pain management. It is commonly used as an alternative opioid in case of insufficient relief. OBJECTIVE Our aim was to assess efficacy and tolerance of opioid rotation to methadone for refractory cancer pain management in palliative care unit (PCU) inpatients. METHODS All the patients undergoing opioid rotation to methadone from 2008 to 2011 in two PCUs (Lyon and Nice, France) were included. Pain assessments were undertaken on day 0 (D0), day 3 (D3), day 7 (D7), and day 14 (D14) using a visual analogue scale (VAS; 0-10) and the Douleur Neuropathique 4 (DN4) scale for neuropathic pain. Patients reported pain relief using a 4-point Likert scale (1=no relief; 4=important relief ). RESULTS Nineteen patients (7 females) with a median age of 55 (Q1-Q3; 44-58) underwent methadone rotation. The most common type of cancer was gastrointestinal. Seventeen patients had a diagnosis of mixed pain syndromes. Morphine equivalent daily dose (MEDD) prior to switching was 480 mg (Q1-Q3; 100-1021), and at least two nonmethadone opioid rotations had already been done for 13 patients. Between D0 and D7, the VAS score decreased by 4 points (p<0.001). The DN4 score became negative on D7 for 11 of 17 patients (65%). On D7, 16 of 18 patients (89%) expressed moderate to greater than moderate pain relief. Methadone was discontinued in one patient on D7 because it was deemed ineffective and for 8 patients, who were unable to take oral drugs, it was discontinued after D14. CONCLUSION Our results suggest that methadone is effective and well tolerated for refractory cancer pain.
Individual trabecula segmentation (ITS)‐based morphological analyses and microfinite element analysis of HR‐pQCT images discriminate postmenopausal fragility fractures independent of DXA measurements

Osteoporosis is typically diagnosed by dual‐energy X‐ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD). Emerging technologies, such as high‐resolution peripheral quantitative computed tomography (HR‐pQCT), may increase the diagnostic accuracy of DXA and enhance our mechanistic understanding of decreased bone strength in osteoporosis. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA, trabecular plate and rod microarchitecture measured by HR‐pQCT image‐based individual trabecula segmentation (ITS) analysis, and whole bone and trabecular bone stiffness by microfinite element analysis (µFEA) of HR‐pQCT images at the radius and tibia. DXA T‐scores were similar in women with and without fractures at the spine, hip, and 1/3 radius, but lower in fracture subjects at the ultradistal radius. Trabecular microarchitecture of fracture subjects was characterized by preferential reductions in trabecular plate bone volume, number, and connectivity over rod trabecular parameters, loss of axially aligned trabeculae, and a more rod‐like trabecular network. In addition, decreased thickness and size of trabecular plates were observed at the tibia. The differences between groups were greater at the radius than the tibia for plate number, rod bone volume fraction and number, and plate–rod and rod–rod junction densities. Most differences between groups remained after adjustment for T‐score by DXA. At a fixed bone volume fraction, trabecular plate volume, number, and connectivity were directly associated with bone stiffness. In contrast, rod volume, number, and connectivity were inversely associated with bone stiffness. In summary, HR‐pQCT‐based ITS and µFEA measurements discriminate fracture status in postmenopausal women independent of DXA measurements. Moreover, these results suggest that preferential loss of plate‐like trabeculae contribute to lower trabecular bone and whole bone stiffness in women with fractures. We conclude that HR‐pQCT‐based ITS and µFEA measurements increase our understanding of the microstructural pathogenesis of fragility fracture in postmenopausal women. © 2012 American Society for Bone and Mineral Research
Agoraphobia in adults: Incidence and longitudinal relationship with panic

Background Theories regarding how spontaneous panic and agoraphobia relate are based mostly on cross-sectional and/or clinic data. Aims To determine how spontaneous panic and agoraphobia relate longitudinally, and to estimate the incidence rate of and other possible risk factors for first-onset agoraphobia, using a general population cohort. Method A sample of 1920 adults in east Baltimore were assessed in 1981 -1982 and the mid-1990s with the Diagnostic Interview Schedule (DIS). Psychiatristdiagnoses were made in a subset of the sample at follow-up (n=816). Results Forty-one new cases of DIS/DSM–III–R agoraphobia were identified (about 2 per 1000 person-years at risk). As expected, baseline DIS/DSM-III panic disorder predicted first incidence of agoraphobia (OR=12, 95% CI 3.2-45), as did younger age, female gender and other phobias. Importantly, baseline agoraphobia without spontaneous panic attacks also predicted first incidence of panic disorder (OR=3.9, 95% CI 1.8-8.4). Longitudinal relationships between panic disorder and psychiatrist-confirmed agoraphobia were strong (panic before agoraphobia OR=20, 95% CI 2.3–180; agoraphobia before panic OR=16, 95% CI 3.2–78). Conclusions The implied one-way causal relationship between spontaneous panic attacks and agoraphobia in DSM–IV appears incorrect.
The demethylating agent 5-Aza reduces the growth, invasiveness, and clonogenicity of uveal and cutaneous melanoma.

PURPOSE Uveal melanoma is the most common primary intraocular malignancy in adults. Although local disease can be controlled with radiation therapy or enucleation, many cases are complicated by metastases, which account for the significant mortality from this disease. To date, no chemotherapeutic regimens effectively treat local or metastatic disease. Epigenetic silencing of tumor suppressor genes has been shown to be an important factor in the growth and metastasis of many cancers. One form of epigenetic alteration is DNA methylation, which often occurs at promoter elements resulting in the silencing of target gene transcription. METHODS We used 5-aza-2'-deoxycytidine (5-Aza), a well characterized demethylating agent that is US Food and Drug Administration approved to decrease DNA methylation in multiple uveal and cutaneous melanoma cell lines. RESULTS Demethylation of melanoma cell lines using 5-Aza causes significant decreases in growth, invasion, and clonogenicity. Treatment of melanoma cells with combined 5-Aza therapy and irradiation showed an even more pronounced effect on cell viability. In addition, treatment with 5-Aza decreased the number of metastases from the eye to the lung in a murine cutaneous melanoma xenograft model. CONCLUSIONS We demonstrate in vitro and in vivo that demethylating agents such as 5-Aza may be promising chemotherapeutic agents for treating melanoma and decreasing progression to metastatic disease. These results provide proof of concept for an exciting potential therapy to reduce mortality from this disease. Future work will focus on identifying pathways that mediate these changes.
Metagenomic Analysis Reveals Diverse Polyketide Synthase Gene Clusters in Microorganisms Associated with the Marine Sponge Discodermia dissoluta

ABSTRACT Sponge-associated bacteria are thought to produce many novel bioactive compounds, including polyketides. PCR amplification of ketosynthase domains of type I modular polyketide synthases (PKS) from the microbial community of the marine sponge Discodermia dissoluta revealed great diversity and a novel group of sponge-specific PKS ketosynthase domains. Metagenomic libraries totaling more than four gigabases of bacterial genomes associated with this sponge were screened for type I modular PKS gene clusters. More than 90% of the clones in total sponge DNA libraries represented bacterial DNA inserts, and 0.7% harbored PKS genes. The majority of the PKS hybridizing clones carried small PKS clusters of one to three modules, although some clones encoded large multimodular PKSs (more than five modules). The most abundant large modular PKS appeared to be encoded by a bacterial symbiont that made up <1% of the sponge community. Sequencing of this PKS revealed 14 modules that, if expressed and active, is predicted to produce a multimethyl-branched fatty acid reminiscent of mycobacterial lipid components. Metagenomic libraries made from fractions enriched for unicellular or filamentous bacteria differed significantly, with the latter containing numerous nonribosomal peptide synthetase (NRPS) and mixed NRPS-PKS gene clusters. The filamentous bacterial community of D. dissoluta consists mainly of Entotheonella spp. , an unculturable sponge-specific taxon previously implicated in the biosynthesis of bioactive peptides.
The pigmentation locus of Yersinia pestis KIM6+ is flanked by an insertion sequence and includes the structural genes for pesticin sensitivity and HMWP2

The pigmentation (Pgm+) phenotype of Yersinia pestis includes a number of different characteristics which appear to be associated with a 102 kb segment of chromosomal DNA known as the pgm locus. In Y. pestis KIM6+, the pgm locus is flanked by direct copies of a repeated element that probably plays a role in the spontaneous deletion of this region. We have sequenced the ends of these elements and shown that they have features in common with bacterial insertion sequences, in addition we show that a clone, pSDR498, from the pgm locus of KIM6+ restores pesticin sensitivity and the iron‐regulated expression of three polypeptides, 240 kDa, 190 kDa, and 68 kDa in size, to Pgm− cells. In vitro transcription/translation assays and Escherichia coli minicells were used to analyse the products encoded by various subciones of pSDR498. Pesticin sensitivity mapped to a 5.9 kb fragment that encodes a 68 kDa protein derived from a 72 kDa precursor. Synthesis of the 190 kDa protein was restored by a 19.2 kb clone, indicating that the structural gene for this protein also resides within the pgm locus of Y. pestis KIM6+. Finally, a survey of our pgm− strains indicates that 97% have also deleted the sequences encoding the 190 kDa protein and pesticin sensitivity.