tbuckley/cabot-search huggingface dataset:
Long-term reduction of jaundice in Gunn rats by nonviral liver-targeted delivery of Sleeping Beauty transposon
Authors: Xia Wang, Debi P. Sarkar, Prashant Mani, Clifford J. Steer, Yong Chen, Chandan Guha, Voshavar Chandrasekhar, Arabinda Chaudhuri, Namita Roy-Chowdhury, Betsy T. Kren, Jayanta Roy-Chowdhury
Journal: Hepatology (2009)

Abstract Asialoglycoprotein receptor (ASGPR)-mediated endocytosis has been used to target genes to hepatocytes in vivo . However, the level and duration of transgene expression have been low because of lysosomal translocation and degradation of the DNA and lack of its integration into the host genome. In this study we packaged the DNA of interest in proteoliposomes containing the fusogenic galactose-terminated F-glycoprotein of the Sendai virus (FPL) for targeted delivery to hepatocytes. After the FPL binds to ASGPR on the hepatocyte surface, fusogenic activity of the F-protein delivers the DNA into the cytosol, bypassing the endosomal pathway. For transgene integration we designed plasmids containing one transcription unit expressing the Sleeping Beauty transposase (SB) and another expressing human uridinediphosphoglucuronate glucuronosyltransferase-1A1 (pSB-hUGT1A1). The latter was flanked by inverted/direct repeats that are substrates of SB . In cell culture, FPL-mediated delivery of the E. coli β-galactosidase gene (LacZ) resulted in transduction of ASGPR-positive cells (rat hepatocytes or Hepa1 cell line), but not of ASGPR-negative 293 cells. Intravenous injection of the FPL-entrapped pSB-hUGT1A1 (4-8 μg/day, 1-4 doses) into UGT1A1-deficient hyperbilirubinemic Gunn rats (model of Crigler-Najjar syndrome type 1) resulted in hUGT1A1 expression in 5%-10% of hepatocytes, but not in other cell types. Serum bilirubin levels declined by 30% ± 4% in 2 weeks and remained at that level throughout the 7-month study duration. With histidine containing FPL, serum bilirubin was reduced by 40% ± 5%, and bilirubin glucuronides were excreted into bile. No antibodies were detectable in the recipient rats against the F-protein or human UGT1A1. Conclusion: FPL is an efficient hepatocyte-targeted gene delivery platform in vivo that warrants further exploration toward clinical application. (Hepatology 2009.)
Surgical treatment of deeply infiltrating endometriosis with colorectal involvement
Authors: C. Meuleman, C. Tomassetti, A. D'Hoore, B. Van Cleynenbreugel, F. Penninckx, I. Vergote, T. D'Hooghe
Journal: Human Reproduction Update (2011)

Treatment of colorectal endometriosis is difficult and challenging. We reviewed the clinical outcome of surgical treatment of deeply infiltrating endometriosis (DIE) with colorectal involvement.Review was based upon a literature search using following search terms: (1) 'surgery' and 'colorectal endometriosis', (2) 'bowel' and 'endometriosis' and 'surgery'.clear explanation of surgical technique and follow-up data on at least one of the following items: complications, pain, quality of life (QOL), fertility and recurrence.Most of the 49 studies included complications (94%) and pain (67%); few studies reported recurrence (41%), fertility (37%) and QOL (10%); only 29% reported (loss of) follow-up. Out of 3894 patients, 71% received bowel resection anastomosis, 10% received full-thickness disc excision and 17% were treated with superficial surgery. Comparison of clinical outcome between different surgical techniques was not possible. Post-operative complications were present in 0-3% of the patients. Although pain improvement was reported in most studies, pain evaluation was patient-based in <50% (Visual Analogue Scale in only 18%). While QOL was improved in most studies, prospective data were only available for 149 patients. Pregnancy rates were 23-57% with a cumulative pregnancy rate of 58-70% within 4 years. The overall endometriosis recurrence rate in studies (>2 years follow-up) was 5-25% with most of the studies reporting 10%. Owing to highly variable study design and data collection, a CONSORT-inspired checklist was developed for future studies.Prospective studies reporting standardized and well-defined clinical outcome after surgical treatment of DIE with colorectal involvement with long-term follow-up are needed.
Respiratory Fluid Mechanics and Transport Processes
Authors: James B. Grotberg
Journal: Annual Review of Biomedical Engineering (2001)

▪ Abstract The field of respiratory flow and transport has experienced significant research activity over the past several years. Important contributions to the knowledge base come from pulmonary and critical care medicine, surgery, physiology, environmental health sciences, biophysics, and engineering. Several disciplines within engineering have strong and historical ties to respiration including mechanical, chemical, civil/environmental, aerospace and, of course, biomedical engineering. This review draws from a wide variety of scientific literature that reflects the diverse constituency and audience that respiratory science has developed. The subject areas covered include nasal flow and transport, airway gas flow, alternative modes of ventilation, nonrespiratory gas transport, aerosol transport, airway stability, mucus transport, pulmonary acoustics, surfactant dynamics and delivery, and pleural liquid flow. Within each area are a number of subtopics whose exploration can provide the opportunity of both depth and breadth for the interested reader.
Alveolar macrophages are the main source for tumour necrosis factor‐α in patients with sarcoidosis
Authors: H. Fehrenbach, G. Zissel, T. Goldmann, T. Tschernig, E. Vollmer, R. Pabst, J. Müller-Quernheim
Journal: European Respiratory Journal (2003)

Tumour necrosis factor (TNF)-alpha is known to play a major role in the formation of noncaseating granuloma, a hallmark of sarcoidosis. The main cellular source in situ is still ambiguous. Serial sections of transbronchial biopsies from 14 patients with and 12 without sarcoidosis were studied, using immunohistochemistry (IHC), for TNF-alpha, T-cells (CD3), macrophages (CD68), and epithelial cells (MNF116). TNF-alpha spontaneously released (sr-TNF-alpha) by freshly isolated bronchoalveolar lavage cells, isolated from the same patients and cultured without any stimulus over a 24-h period was measured using an enzyme-linked immunosorbent assay. IHC revealed colocalisation of TNF-alpha with CD68 cells only. Cases with TNF-alpha tissue immunoreactivity exhibited higher sr-TNF-alpha (1,667 +/- 504 pg x mL(-1)) than cases without tissue immunoreactivity (211 +/- 60 pg x mL(-1)). In an explorative approach, a subgroup of patients could be identified and characterised by the presence of alveolar macrophage aggregates. It was found that sr-TNF-alpha was highest in this subgroup (2,700 +/- 769 pg x mL(-1)) compared with patients with normal histology (221 +/- 61 pg x mL(-1)) or with prominent granuloma (460 +/- 137 pg x mL(-1)), whereas in most clinical parameters this subgroup was intermediate. The findings from this study strongly corroborate the view that alveolar macrophages are the main cellular source for tumour necrosis factor-alpha in the initial phase of sarcoidosis. The authors suggest that in these patients, aggregates of alveolar macrophages may represent at least predecessors to granulomas if not granulomas in statu nascendi.
Response to influenza infection in mice with a targeted disruption in the interferon gamma gene.
Authors: M B Graham, D K Dalton, D Giltinan, V L Braciale, T A Stewart, T J Braciale
Journal: The Journal of Experimental Medicine (1993)

Interferon gamma (IFN-gamma) is a pleiotropic cytokine secreted by T lymphocytes and natural killer (NK) cells and has been noted to be a first line of host defense in the control of viral infections. To examine further the role of this cytokine in the control of viral infections, mice with a targeted mutation in the IFN-gamma gene were infected with influenza virus, and the in vivo antibody and cell-mediated immune response to viral infection were examined. In addition, cell lines and clones were derived from the immunized animals and the in vitro cytokine production and cytotoxic T lymphocyte (CTL) response were analyzed. The absence of IFN-gamma led to increased production of influenza-specific IgG1, IL-4, and IL-5 as compared to wild-type littermate control animals. In contrast, there was no difference noted in the development of an effective CTL response between IFN-gamma-deficient and wild-type animals. In this model of experimental influenza infection, IFN-gamma is not necessary for the development of an effective humoral or cellular immune response to challenge with this respiratory virus.
Marker of erosive progression in RA
Authors: O. SLOT
Journal: Annals of the Rheumatic Diseases (2000)

Incidence of RA in people with persistently raised RFA criticism of the study reported in the Annals 1 is that age was not taken into account in the evaluation of the probability of development of rheumatoid arthritis (RA) among symptom free subjects with persistently raised rheumatoid factor (RF).The prevalence of RF can be as high as 14.1% in apparently healthy people aged 67-95 (mean age 81). 2 RF is also 3.5 times more common in healthy elderly subjects (aged >65) than in their younger counterparts. 3All these factors may alter the natural history of arthritis in elderly patients who have RF either in good health or in a non-arthritic presentation of RA.The latter is exemplified by a patient admitted at the age of 76 with symptomatic, as well as echocardiographically validated rheumatoid pericarditis in the absence of arthritis.Rheumatoid arthritis latex fixation test (RA LFT) was positive with a titre of 1/160, antinuclear factor (ANF) titre was 1/250, and signs of active inflammatory disease included a platelet count of 750 × 10 9 /l, and an erythrocyte sedimentation rate (ESR) of 98 mm/1st h (Westergren).Arthralgia of the hands and wrists developed for the first time two years later (when she was no longer taking steroids), with a subsequent RA LFT titre of 1/80 and an ANF titre of 1/320 about four months after the onset of arthralgia.Radiography showed narrowing of the joint spaces of the hands 12 months later, but there were as yet no erosions at this stage.Erosions were seen in March 1992, approximately two and a half years after the onset of arthralgia, when the RA LFT titre was 1/160, ANF titre 1/160, platelet count 421 × 10 9 /l, ESR 18 mm/1st h.At her most recent attendance, on 2 February 2000, she was still very active, having continued to receive prednisolone (maximum dose 5 mg/d) continuously since 1989.Her only complaint was a little pain in the left thenar eminence and painful heels.RF was now 768 IU/ml, ANF titre 1/320, platelet count 340 × 10 9 /l, ESR 42 mm/1st h.Antibodies against double stranded DNA had not been reported at any stage. COMMENTThis case shows a remarkable dissociation between arthritic symptoms and levels of RF, perhaps signifying that when the immune status is altered in old age, 2 the relation between RF and the natural history of RA might be less clear than it is in younger people.
Tubulovascular Cross-Talk by Vascular Endothelial Growth Factor A Maintains Peritubular Microvasculature in Kidney
Authors: Henrik Dimke, Matthew A. Sparks, Benjamin R. Thomson, Sebastian Frische, Thomas M. Coffman, Susan E. Quaggin
Journal: Journal of the American Society of Nephrology (2014)

Vascular endothelial growth factor A (VEGFA) production by podocytes is critical for glomerular endothelial health. VEGFA is also expressed in tubular epithelial cells in kidney; however, its physiologic role in the tubule has not been established. Using targeted transgenic mouse models, we found that Vegfa is expressed by specific epithelial cells along the nephron, whereas expression of its receptor (Kdr/Vegfr2) is largely restricted to adjacent peritubular capillaries. Embryonic deletion of tubular Vegfa did not affect systemic Vegfa levels, whereas renal Vegfa abundance was markedly decreased. Excision of Vegfa from renal tubules resulted in the formation of a smaller kidney, with a striking reduction in the density of peritubular capillaries. Consequently, elimination of tubular Vegfa caused pronounced polycythemia because of increased renal erythropoietin (Epo) production. Reducing hematocrit to normal levels in tubular Vegfa–deficient mice resulted in a markedly augmented renal Epo production, comparable with that observed in anemic wild-type mice. Here, we show that tubulovascular cross-talk by Vegfa is essential for maintenance of peritubular capillary networks in kidney. Disruption of this communication leads to increased renal Epo production and resulting polycythemia, presumably to counterbalance microvascular losses.
A case of concurrent pemphigoid vegetans and pemphigus vegetans resolving without oral corticosteroid
Authors: Y. Hatano, K. Ishikawa, H. Koga, N. Ishii, T. Hashimoto, N. Takeo, H. Shimada, T. Sakai, O. Okamoto, S. Fujiwara
Journal: British Journal of Dermatology (2013)

Funding sources: No external funding. Conflicts of interest: None declared. Dear Editor, Pemphigoid vegetans and pemphigus vegetans are variants of bullous pemphigoid and pemphigus vulgaris, respectively, and both typically show elevated skin lesions on the intertriginous areas.1 2 3 4 5 6 We report a patient with inguinal nodular lesions, diagnosed as concurrent pemphigoid vegetans and pemphigus vegetans. The skin lesions resolved completely with only topical corticosteroid and ketoconazole. An 85‐year‐old Japanese male presented with itchy nodular lesions on the inguinal areas, which had gradually enlarged over 5 months. Antifungal ointments had been prescribed by a local dermatologist because fungal components were identified microscopically. Physical examination revealed lobulated nodules on both inguinal areas (Fig. 1a). The lesions in the right inguinal region were 43 × 24 mm in size and 14 mm high, while those in the left inguinal region were 35 × 77 mm in size and 20 mm high. Erosions and crusts on the surface of the nodules, as well as peripheral erythematous macules, were noted. No vesicles or pustules were observed around the nodular lesions. No mucous membrane lesions were observed. All laboratory data were within normal limits, except for slightly reduced haemoglobin (12·5 gdL−1; normal 13·6–17·3).
Positive inotropic effect of calcitonin gene-related peptide mediated by cyclic AMP in guinea pig heart.
Authors: T Ishikawa, N Okamura, A Saito, T Masaki, K Goto
Journal: Circulation Research (1988)

The mechanism of cardiac actions of rat calcitonin gene-related peptide (CGRP) was analyzed on isolated guinea pig hearts. CGRP exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atria but not on the ventricles. Immunohistochemical studies demonstrated that CGRP-like immunoreactive nerves were distributed densely in the myocardia of the atria but only sparsely in those of the ventricles. The CGRP-induced augmentation of the contraction was accompanied by the shortening of the time to peak force and the increase in the relaxation velocity. The positive inotropic response to CGRP was significantly enhanced by isobutylmethylxanthine and was attenuated by adenosine. CGRP increased the action potential amplitude and prolonged action potential duration at the level of 50% repolarization in the left atria. In the preparations, which were partially depolarized with an increase in extracellular potassium, CGRP induced slow response action potentials. These electrophysiological results indicate that CGRP causes an increase in the slow inward Ca2+ current. The cyclic AMP content in the left atria significantly increased following the addition of CGRP, the time course of which was nearly consistent with that of the augmentation of the contractile force. In the membrane preparation of the atria, the activity of adenylate cyclase was enhanced by CGRP in a dose-dependent manner. These effects of CGRP are qualitatively similar to those of beta-adrenoceptor stimulation. It is concluded that the CGRP-induced response in the guinea pig atria is attributed to the activation of adenylate cyclase via stimulation of its specific receptor and the subsequent increase in the intracellular cyclic AMP level.
Antisaccade Performance in Monozygotic Twins Discordant for Schizophrenia: The Maudsley Twin Study
Authors: Ulrich Ettinger, Marco Picchioni, Mei-Hua Hall, Katja Schulze, Timothea Toulopoulou, Sabine Landau, Trevor J. Crawford, Robin M. Murray
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: Deficiency in antisaccade performance has been proposed as a schizophrenia endophenotype. METHOD: The authors assessed performance on an antisaccade task (and a prosaccade control condition) by 10 monozygotic twin pairs discordant for DSM-IV schizophrenia and 10 monozygotic healthy twin pairs matched for age, sex, and parental socioeconomic status. The authors computed antisaccade gain, latency, and error rate, as well as prosaccade gain and latency. RESULTS: The schizophrenic twins made more antisaccade reflexive errors than the nonschizophrenic co-twins and comparison twins, who did not significantly differ from each other. The nonschizophrenic members of discordant pairs performed worse than the comparison twins on antisaccade gain and latency but did not differ from their schizophrenic co-twins on these variables. There were no differences on prosaccade performance. Antisaccade errors were correlated with negative symptoms in the patients. CONCLUSIONS: Antisaccade spatial accuracy and latency deficits may serve as markers of genetic liability for schizophrenia.
PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment
Authors: Jing Li, Hyun-Bae Jie, Yu Lei, Neil Gildener-Leapman, Sumita Trivedi, Tony Green, Lawrence P. Kane, Robert L. Ferris
Journal: Cancer Research (2014)

Immune rejection of tumors is mediated by IFNγ production and T-cell cytolytic activity. These processes are impeded by PD-1, a coinhibitory molecule expressed on T cells that is elevated in tumor-infiltrating lymphocytes (TIL). PD-1 elevation may reflect T-cell exhaustion marked by decreased proliferation, production of type I cytokines, and poor cytolytic activity. Although anti-PD-1 antibodies enhance IFNγ secretion after stimulation of the T-cell receptor (TCR), the mechanistic link between PD-1 and its effects on T-cell help (Tc1/Th1 skewing) remains unclear. In prospectively collected cancer tissues, we found that TIL exhibited dampened Tc1/Th1 skewing and activation compared with peripheral blood lymphocytes (PBL). When PD-1 bound its ligand PD-L1, we observed a marked suppression of critical TCR target genes and Th1 cytokines. Conversely, PD-1 blockade reversed these suppressive effects of PD-1:PD-L1 ligation. We also found that the TCR-regulated phosphatase SHP-2 was expressed higher in TIL than in PBL, tightly correlating with PD-1 expression and negative regulation of TCR target genes. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.
Adaptive Randomized Study of Idarubicin and Cytarabine Versus Troxacitabine and Cytarabine Versus Troxacitabine and Idarubicin in Untreated Patients 50 Years or Older With Adverse Karyotype Acute Myeloid Leukemia
Authors: Francis J. Giles, Hagop M. Kantarjian, Jorge E. Cortes, Guillermo Garcia-Manero, Srdan Verstovsek, Stefan Faderl, Deborah A. Thomas, Alessandra Ferrajoli, Susan O’Brien, Jay K. Wathen, Lian-Chun Xiao, Donald A. Berry, Elihu H. Estey
Journal: Journal of Clinical Oncology (2003)

Troxacitabine has activity in refractory myeloid leukemia, either as a single agent or when combined with cytarabine (ara-C) or with idarubicin. A prospective, randomized study was conducted in patients aged 50 years or older with untreated, adverse karyotype, acute myeloid leukemia (AML) to assess troxacitabine-based regimes as induction therapy.Patients were randomized to receive idarubicin and ara-C (IA) versus troxacitabine and ara-C (TA) versus troxacitabine and idarubicin (TI). A Bayesian design was used to adaptively randomly assign patients to treatment. Thus, although there was initially an equal chance for randomization to IA, TA, or TI, treatment arms with a higher success rate progressively received a greater proportion of patients.Thirty-four patients were treated. Randomization to TI stopped after five patients and randomization to TA stopped after 11 patients. Defining success as complete remission (CR) that occurred within 49 days of starting treatment, success rates were 55% (10 of 18 patients) with IA, 27% (three of 11 patients) with TA, and 0% (zero of five patients) with TI. Because three CRs occurred after day 49, final CR rates were 55% (10 of 18 patients) with IA, 45% (five of 11 patients) with TA, and 20% (one of five patients) with TI. The probability that TA was inferior to IA was 70%, with a 5% probability that TA would have a 20% higher CR rate than IA. Survival was equivalent with all three regimens.Neither troxacitabine combination was superior to IA in elderly patients with previously untreated adverse karyotype AML.
Let's Get Serious About Racial and Ethnic Disparities
Authors: Neil R. Powe
Journal: Journal of the American Society of Nephrology (2008)

Racial and ethnic disparities in health and health care have been documented for over two decades in kidney disease, in a variety of other conditions, across settings, and for different medical and surgical interventions. We now have government reports that track progress on reducing racial disparities, but the pace of progress has been disheartening. The reasons for some of these disparities are known and include biologic, socioeconomic, cultural, and environmental factors as well as system, patient, and provider factors that affect access and quality of medical services. For other disparities, they remain an enigma. Solutions have been slow incoming in large part because we have not held ourselves, and others, accountable for better results. It is time to get serious about equitable health care for all of us.
Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations
Authors: Nael H. Alami, Rebecca B. Smith, Monica A. Carrasco, Luis A. Williams, Christina S. Winborn, Steve S.W. Han, Evangelos Kiskinis, Brett Winborn, Brian D. Freibaum, Anderson Kanagaraj, Alison J. Clare, Nisha M. Badders, Bilada Bilican, Edward Chaum, Siddharthan Chandran, Christopher E. Shaw, Kevin C. Eggan, Tom Maniatis, J. Paul Taylor
Journal: Neuron (2014)
PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab
Authors: J.D. Jensen, A. Knoop, A.V. Laenkholm, M. Grauslund, M.B. Jensen, E. Santoni-Rugiu, M. Andersson, M. Ewertz
Journal: Annals of Oncology (2011)
Low-protein diet and chronic renal failure
Authors: Giuliano Barsotti, Sergio Giovannetti, N. Gretz, M. Strauch, Francesco Locatelli, Daniele Alberti, Giorgio Graziani, Gherardo Buccianti, Bruno Redaelli, Alberto Giangrande, T. Hannedouche, G. Albouze, P. Chauveau, P. Jungers
Journal: The Lancet (1991)