Miracle-dz/UniFAR-FTUs huggingface dataset:
Crooke's Cell Adenoma of the Pituitary: An Aggressive Variant of Corticotroph Adenoma

Cushing's disease is caused by functional corticotroph adenomas of the pituitary, mostly noninvasive microadenomas. Classic Crooke's cells are nonneoplastic corticotrophs with cytoplasmic accumulation of cytokeratin filaments in response to glucocorticoid excess. Corticotroph adenomas exhibiting Crooke's change are rare and incompletely understood. We intend to define more clearly the clinicopathological features of Crooke's cell adenomas (CCA). Thirty-six CCAs were retrieved from the files of Mayo Clinic and from our (B.W.S., K.K.) consultation files. The number of informative cases varied for different criteria. Clinical follow-up was obtained in 31 cases. The 27 females and 9 males were 18 to 81 years of age (mean 46 years). At presentation, Cushing's disease was evident in 22/34 (65%); 81% were macroadenomas and 72% were invasive. All were initially treated by transsphenoidal resection. Twenty-five patients were followed for more than 1 year (mean 6.7 years). Of these, 15 (60%) developed recurrent tumor, and 6 (24%) had multiple recurrences. Lastly, 3 of these 25 patients (12%) died of tumor: 1 after multiple local recurrences and 2 from pituitary carcinoma. Compared with typical corticotroph adenomas, CCAs are aggressive. Most are functional adenomas occurring in middle-aged women and are invasive macroadenomas prone to recurrence. Morbidity and mortality rates are substantial. CCAs represent a distinct entity that should be separated from corticotroph adenomas without Crooke's hyaline change.
Local expression of the serum amyloid A and formyl peptide receptor-like 1 genes in synovial tissue is associated with matrix metalloproteinase production in patients with inflammatory arthritis.

OBJECTIVE To evaluate the regulation of acute-phase serum amyloid A (A-SAA) production in inflamed synovial tissue, and to elucidate a possible pathophysiologic role in the induction of matrix metalloproteinase (MMP) release by fibroblast-like synoviocytes (FLS). METHODS Synovial tissue samples were obtained by arthroscopic biopsy from the knee joints of patients with inflammatory arthritis. Primary cultures of FLS from patients with rheumatoid arthritis (RA), psoriatic arthritis, sarcoid arthritis, and undifferentiated arthritis were established. Total RNA was extracted from FLS and analyzed by reverse transcription-polymerase chain reaction (PCR) using specific primers for A-SAA and formyl peptide receptor-like 1 (FPRL1), an A-SAA receptor. Southern blot analysis confirmed the PCR products generated. Immunohistochemical analysis demonstrated the expression of A-SAA protein production by several synovial cell populations, and immunofluorescence analysis confirmed A-SAA colocalization with the macrophage marker CD68. Primary FLS cultures stimulated with recombinant human A-SAA resulted in dose-dependent MMP-1 and MMP-3 production, as measured by an enzyme-linked immunosorbent assay. RESULTS A-SAA messenger RNA (mRNA) and FPRL1 mRNA were present in FLS, macrophages, and endothelial cells isolated from the synovial tissue of patients with RA and other categories of inflammatory arthritis. A-SAA expression was regulated by proinflammatory cytokines and occurred in association with FPRL1 expression in FLS and endothelial cells, which is consistent with a biologic role at the sites of inflammation. Recombinant human A-SAA induced both MMP-1 and MMP-3 secretion by FLS. The mean fold increases in A-SAA-induced MMP-1 and MMP-3 production were 2.6 and 10.6, respectively, compared with 7.6-fold and 41.9-fold increases in interleukin-1 beta-induced MMP-1 and MMP-3 production. CONCLUSION The up-regulation of the A-SAA and FPRL1 genes in inflamed synovial tissue suggests an important role in the pathophysiology of inflammatory arthritis. A-SAA induces the production of MMPs. Therapeutic targeting of A-SAA, or FPRL1, may modulate pathophysiologic pathways that are associated with matrix degradation in patients with RA and other forms of progressive inflammatory arthritis.
Predisposing factors for hypoglycemia in the intensive care unit*

Objective:The introduction of strict glycemic control in the intensive care unit has increased the risk for hypoglycemia. In this study we examined the association between predefined circumstances and the occurrence of hypoglycemia in the intensive care unit. Design:Retrospective cohort study. Setting:Academic medical center. Patients:All episodes of hypoglycemia (glucose value <45 mg/dL) in our intensive care unit between September 2002 and September 2004 were identified. Presence of predefined circumstances previously associated with hypoglycemia was scored around the moment of hypoglycemia using a patient data management system and in-hospital charts. Patients with a first hypoglycemic event were contrasted to controls from the same cohort, who were matched for time since admission, to correct for the effect of length of stay. Data were analyzed using conditional logistic regression analysis. Interventions:None. Measurements and Main Results:Of 2,272 patients, 156 (6.9%) experienced at least one episode of hypoglycemia. Continuous venovenous hemofiltration with bicarbonate-based substitution fluid (odds ratio [OR], 14; 95% confidence interval [CI], 1.8–106), a decrease of nutrition without adjustment for insulin infusion (OR, 6.6; 95% CI, 1.9–23), diabetes mellitus (OR, 2.6; 95% CI, 1.5–4.7), insulin use (OR, 5.3; 95% CI, 2.8–11), sepsis (OR, 2.2; 95% CI, 1.2–4.1), and inotropic support (OR, 1.8; 95% CI, 1.1–2.9) were associated with hypoglycemia. Simultaneous octreotide and insulin use (OR, 6.0; 95% CI, 0.72–50) may also be associated with hypoglycemia. Gastric residual during enteral nutrition without adjusting insulin infusion, liver failure, continuous venovenous hemofiltration with lactate-based substitution fluid, diminished glomerular filtration rate, dose diminishment of glucocorticoids or catecholamines, and use of β-blocking agents were not associated with hypoglycemia. Adjusting for age, gender, and Acute Physiology and Chronic Health Evaluation II score at admission did not materially change ORs. Conclusion:Use of bicarbonate-based substitution fluid during continuous venovenous hemofiltration, a decrease of nutrition without adjustment for insulin infusion, a prior diagnosis of diabetes mellitus, sepsis, and need for inotropic support were found to be associated with hypoglycemia. Simultaneous use of insulin and octreotide may be associated with hypoglycemia.
Bunyamwera Bunyavirus RNA Synthesis Requires Cooperation of 3′- and 5′-Terminal Sequences

ABSTRACT Bunyamwera virus (BUNV) is the prototype of both the Orthobunyavirus genus and the Bunyaviridae family of segmented negative-sense RNA viruses. The tripartite BUNV genome consists of small (S), medium (M), and large (L) segments that are each transcribed to yield a single mRNA and are replicated to generate an antigenome that acts as a template for synthesis of further genomic strands. As for all negative-sense RNA viruses, the 3′- and 5′-terminal nontranslated regions (NTRs) of the BUNV S, M, and L segments exhibit nucleotide complementarity and, except for one conserved U-G pairing, this complementarity extends for 15, 18, and 19 nucleotides, respectively. We investigated whether the complementarity of 3′ and 5′ NTRs reflected a functional requirement for terminal cooperation to promote BUNV RNA synthesis or, alternatively, was a consequence of genomic and antigenomic NTRs having similar functions requiring sequence conservation. We show that cooperation between 3′- and 5′-NTR sequences is required for BUNV RNA synthesis, and our results suggest that this cooperation is due to nucleotide complementarity allowing 3′ and 5′ NTRs to associate through base-pairing interactions. To examine the importance of complementarity in promoting BUNV RNA synthesis, we utilized a competitive replication assay able to examine the replication ability of all possible combinations of interacting nucleotides within a defined region of BUNV 3′ and 5′ NTRs. We show here that maximal RNA replication was signaled when sequences exhibiting perfect complementarity within 3′ and 5′ NTRs were selected.
The multidrug resistance pump ABCB1 is a substrate for the ubiquitin ligase NEDD4-1

Abstract The ATP Binding Cassette transporter ABCB1 can export the neurotoxic peptide β-amyloid from endothelial cells that line the blood-brain barrier (BBB). This has the potential to lower cerebral levels of β-amyloid, but ABCB1 expression in the BBB appears to be progressively reduced in patients with Alzheimer’s disease. The surface density of many membrane proteins is regulated by ubiquitination catalyzed by ubiquitin E3 ligases. In brain capillaries of mice challenged with β-amyloid ex vivo, we show that the level of the ubiquitin ligase Nedd4 increases concomitant with reduction in Abcb1. In vitro we show that human ABCB1 is a substrate for human NEDD4-1 ligase. Recombinant ABCB1 was purified from Sf21 insect cells and incubated with recombinant NEDD4-1 purified from Escherichia coli. The treated ABCB1 had reduced mobility on SDS-PAGE, and mass spectrometry identified eight lysine residues, K271, K272, K575, K685, K877, K885, K887 and K1062 that were ubiquitinated by NEDD4-1. Molecular modelling showed that all of the residues are exposed on the surface of the intracellular domains of ABCB1. K877, K885 and K887 in particular, are located in the intracellular loop of transmembrane helix 10 (TMH10) in close proximity, in the tertiary fold, to a putative NEDD4-1 binding site in the intracellular helix extending from TMH12 (PxY motif, residues 996–998). Transient expression of NEDD4-1 in HEK293 Flp-In cells stably expressing ABCB1 was shown to reduce the surface density of the transporter. Together, the data identify this ubiquitin ligase as a potential target for intervention in the pathophysiology of Alzheimer’s disease.
Immune checkpoint inhibitors in challenging populations

Immune checkpoint inhibitors, including those targeting the programmed cell death 1/programmed cell death ligand 1 and cytotoxic T lymphocyte antigen 4 pathways, are revolutionizing cancer therapeutics. Both activity and toxicities largely stem from unleashing tumor‐ or host‐specific cytotoxic T cells. Many patients seen in routine clinical practice have not qualified for or have been seriously underrepresented in immune checkpoint inhibitor clinical trials. Thus, a major gap in knowledge regarding the safety and efficacy of these agents persists in many populations, even after regulatory approval. To address this challenge, this review aggregates and synthesizes the available preclinical and clinical data surrounding immune checkpoint inhibitor therapy in challenging clinical populations to assist both academic and community oncologists in treatment decision making. Specifically, this review focuses on the safety and activity of immune checkpoint inhibitors in patients with autoimmune disorders, organ transplant patients, patients with chronic viral infections, patients with ongoing immunosuppressant use, patients with organ dysfunction, pregnant patients, patients with brain metastases, patients at extremes of age, and patients with an impaired functional status. Cancer 2017;123:1904–1911. © 2017 American Cancer Society.
A meta-analysis of the literature on climate change and migration

Abstract Recent surveys of the literature on climate change and migration emphasize the important diversity of outcomes and approaches of the empirical studies. In this paper, we conduct a meta-analysis in order to investigate the role of the methodological choices of these empirical studies in finding some particular results concerning the role of climatic factors as drivers of human mobility. We code 51 papers representative of the literature in terms of methodological approaches. This results in the coding of more than 85 variables capturing the methodology of the main dimensions of the analysis at the regression level. These dimensions include authors' reputation, type of mobility, measures of mobility, type of data, context of the study, econometric methods, and last but not least measures of the climatic factors. We look at the influence of these characteristics on the probability of finding any effect of climate change, a displacement effect, an increase in immobility, and evidence in favor of a direct vs. an indirect effect. Our results highlight the role of some important methodological choices, such as the frequency of the data on mobility, the level of development, the measures of human mobility and of the climatic factors as well as the econometric methodology.
Exploring the benefits of international government bond portfolio diversification strategies

ABSTRACT We use the Bayesian approach of Wang (1998) to examine the diversification benefits of investing in international government bonds. We find that no short-selling constraints substantially reduce but do not eliminate the diversification benefits when only investing in G7 government bonds with different maturities. There are significant diversification benefits when using the G7 bonds, an inflation-linked bond index, and emerging market bonds even in the presence of no short-selling constraints. The superior performance is driven by the emerging markets bonds. We also find that the diversification benefits vary across different economic states.
Ultrastructure of the oviductal mucosa of Leptodactylus chaquensis. Analysis of the preovulatory and postovulatory periods

Summary In the present study we analysed the ultrastructural characteristics of the oviductal mucosa of Leptodactylus chaquensis during the preovulatory period and immediately after ovulation. Epithelial secretory cells, ciliated cells, basal cells and glandular secretory cells are described. During the preovulatory period, the oviduct exhibits its maximum degree of development at both the epithelial and the glandular levels, with numerous secretory cells that contain a large number of secretory granules whose contents are released into the oviductal lumen by apocrine and exocytotic secretory processes. The secretory cells present throughout the oviduct display considerable variability in the characteristics of their secretory granules, which show different shapes, sizes, organization of the material contained and electron density. The different cell types are distributed following a characteristic pattern for each oviductal zone, thus creating an ultrastructural mosaic along the oviduct. During the postovulatory period, the number of secretory cells decreases and the remaining ones exhibit a marked reduction in secretory granules. Ciliated cells show a typical ultrastructural organization that is not modified throughout the reproductive cycle. Basal cells, located at the basal region of the epithelium, are characterized by their heterochromatic nuclei and electron-lucent cytoplasm, while glandular secretory cells exhibit oval, round or polyhedric granules, most of them with a prominent core. Our results, which indicate a high heterogeneity of secretory cell contents, allow us to suggest differential synthesis and secretion of specific products in each oviductal zone.
Decentralization Reform in Ukraine: Assessment of the Chosen Transformation Model

Abstract Ukraine has to reform the spatial organization of power, which involves alteration of the administrative-territorial division in very difficult socio-economic and political conditions. Despite a great interest in the Ukrainian decentralization reform in scientific publications and media, the influence of chosen voluntary consolidation mode on the newly formed territorial communities, including their spatial configuration, economic potential and institutional capability, remains uncovered. Trying to shed some light on the issue, the authors made an attempt to reveal advantages and disadvantages of the selected model of reform on the example of the Perspective Plan of Territorial Communities Formation in Kyiv Region.
articles: Trade policy and regional inequalities

This article aims to analyze the effects of trade policies on the pattern of regional inequalities within a country. It is inspired, firstly, by the debate concerning the role of protectionist policies in the development of a pattern of striking regional inequalities during the Spanish industrialization process and, secondly, by current evidence of an increase in these inequalities following Spain's entry in the EU, in 1986. We employ an economic geography model comprising three regions: two domestic and one external. Labor mobility is permitted between the domestic regions but not with the external region. The model shows that trade liberalization increases regional inequalities.
Blockage of N-Methyl-D-Aspartate Receptors Decreases Testosterone Levels and Enhances Postnatal Neuronal Apoptosis in the Preoptic Area of Male Rats

Sexual dimorphism has been found in the preoptic area of the hypothalamus (POA), a major site of glutamate actions via N-methyl-D-aspartate (NMDA) receptors. The sexually dimorphic nucleus of the preoptic area (SDN-POA) of male rats exhibits about seven-fold greater nuclear volume than that of females. A naturally occurring neonatal neuronal apoptosis, that can be prevented by testosterone, may contribute to this sexual difference in SDN-POA nuclear volume. Since activation of NMDA receptors in the POA induces GnRH secretion, it may be involved in both elevation of serum testosterone and prevention of neuronal death in the SDN-POA. In the present study, protein expression of NMDA receptors in the POA of male and female fetuses was quantified on the day preceding the fetal testosterone peak (embryonic day 16; ED 16). Rats were then distributed in four groups: (1) untreated males, (2) untreated females, (3) males pretreated with MK-801 (a noncompetitive NMDA receptor antagonist), and (4) females pretreated with MK-801. Serum levels of testosterone were estimated on the afternoon of ED 18. Expression of Bcl-2 and Bax, as well as neuronal apoptosis in SDN-POA, were observed on postnatal day 8. The results showed that (1) expression of NMDA receptors in the POA of male fetuses was higher than that of females on ED 16; (2) levels of testosterone were lower in MK-801 pretreated male fetuses than in intact males on ED 18; (3) expression of Bcl-2 in the POA of MK-801 pretreated male rats was significantly less than that of control males; (4) the apoptotic incidence in the SDN-POA of MK-801 pretreated male rats was significantly greater than in control males, while there was no significant difference in apoptotic incidence in the SDN-POA between MK-801 pretreated and intact females. These results suggest that the NMDA receptor is highly expressed in prenatal male fetuses, and that it might play an important role in the elevation of testosterone levels. Moreover, activation of NMDA receptors may protect SDN-POA neurons from naturally occurring neuronal death, by modulating testosterone and/or Bcl-2 expression.
Improved Management of Multiple Brain Abscesses: A Combined Surgical and Medical Approach: 76

ABSTRACT: BACTERIAL BRAIN ABSCESSES occur in approximately 1500 to 2500 patients each year in the United States. Multiple abscesses have been noted in 10 to 50% of these patients. The goal of this study was to better define the roles of surgery and medical management in patients harboring multiple brain abscesses and to develop an algorithmic approach to the treatment of these complex patients. Between 1976 and 1992, 16 patients with multiple brain abscesses were treated by a single physician (M.L.R.). The ages of the patients ranged from 1.5 to 73 years (median, 47 yr). In all patients, a diagnosis of multiple abscesses was made by computed tomography (15 patients) or magnetic resonance imaging (1 patient) brain scans. The number of abscesses per patient ranged from 2 to 30, and the abscesses were located in all regions of the brain. Thirteen received a combination of antibiotics and surgical drainage, and three received antibiotics only. Surgery was performed on abscesses larger than 2.5 cm or on those situated in critical areas of the brain or causing significant mass effect. Excision and open aspiration via craniotomy and stereotactic aspiration were analyzed on the basis of the location of the lesion and infecting organism. Any abscess that enlarged after 2 weeks of antibiotics or that failed to shrink after 3 to 4 weeks of antibiotics was again aspirated or excised. Forty‐three surgical procedures were performed in 13 patients, and 8 (62%) of the patients operated on required more than one surgical procedure. No significant morbidity was observed in any of the surgical procedures. Antibiotics were administered intravenously for an average of 6 to 8 weeks and were adjusted according to organism type and sensitivity to antibiotics. One patient (6%) died, and the remaining 15 patients had resolution of all abscesses and good neurological recovery within 6 months. On the basis of these results, we propose a combined surgical and medical approach to the treatment of patients with multiple brain abscesses. We recommend the aggressive surgical drainage of all abscesses larger than 2.5 cm in diameter, combined with 6 to 8 weeks of intravenous antibiotics. Biweekly computed tomography or magnetic resonance imaging is necessary to closely monitor patients for evidence of abscess growth or failure to resolve despite antibiotics, prompting another operation. The application of this combined approach should yield cure rates of more than 90% in patients with multiple brain abscesses, a result similar to that expected when treating patients with solitary lesions.
Efficacy of Therapeutic Ultrasound and Transcutaneous Electrical Nerve Stimulation Compared With Botulinum Toxin Type A in the Treatment of Spastic Equinus in Adults With Chronic Stroke: A Pilot Randomized Controlled Trial

Abstract Background: Therapeutic ultrasound and transcutaneous electrical nerve stimulation (TENS) have been described as being effective in the treatment of spasticity. No previous study compared these physical modalities with a first-line treatment for spasticity, such as botulinum toxin type A. Objective: To compare the effects of therapeutic ultrasound and TENS with botulinum toxin type A on spasticity after stroke. Methods: Thirty patients with chronic stroke and spastic equinus were randomly assigned to 3 groups: 1 group received therapeutic ultrasound to the affected leg calf muscles, 1 group underwent TENS to the tibial nerve of the affected leg, and 1 group was injected with onabotulinum toxin A in the spastic gastrocnemius. All patients were evaluated immediately before treatment and 15, 30, and 90 days after the first clinical evaluation. The following outcome measures were considered: ankle passive dorsiflexion range of motion and the modified Ashworth scale. Results: Patients injected with botulinum toxin type A had significantly better ankle passive range of motion than those treated with physical modalities at all posttreatment evaluations. At second and third posttreatment evaluations, the modified Ashworth scale indicated significantly greater improvement in patients injected with botulinum toxin type A than in those treated with physical modalities. No difference was found between groups treated with physical modalities. Conclusions: Our findings support the hypothesis that botulinum toxin type A is more effective than therapeutic ultrasound and TENS for treating focal spasticity in patients with chronic stroke.