tbuckley/cabot-search huggingface dataset:
Tribbles Homolog 3 Attenuates Mammalian Target of Rapamycin Complex-2 Signaling and Inflammation in the Diabetic Kidney
Authors: Emily Borsting, Shalin V. Patel, Anne-Emilie Declèves, Sarah J. Lee, Qazi M. Rahman, Shizuo Akira, Joe Satriano, Kumar Sharma, Volker Vallon, Robyn Cunard
Journal: Journal of the American Society of Nephrology (2014)

The endoplasmic reticulum (ER) stress response is activated in the diabetic kidney and functions to reduce ER protein accumulation and improve cellular function. We previously showed that tribbles homolog 3 (TRB3), an ER stress-associated protein, is upregulated in the diabetic kidney. Here, we investigated whether absence of TRB3 alters outcomes in diabetic nephropathy. Type 1 diabetes was induced in TRB3 wild-type and knockout (−/−) mice by low-dose streptozotocin, and the mice were followed for 12 weeks. Diabetic TRB3−/− mice developed higher levels of albuminuria and increased expression of inflammatory cytokine and chemokine mRNA in renal cortices relative to wild-type littermates, despite similar hyperglycemia. Diabetic TRB3−/− mice also expressed higher levels of ER stress-associated molecules in both the renal cortices and glomeruli. This change was associated with higher renal cortical phosphorylation of AKT at serine 473 (Ser473), which is the AKT site phosphorylated by mammalian target of rapamycin complex-2 (mTORC2). We show in renal tubular cells that TRB3 binds to mTOR and the rapamycin-insensitive companion of mTOR (Rictor), a protein specific to mTORC2. Finally, we demonstrate in murine tubular cells that TRB3 can inhibit secretion of IL-6. Thus, TRB3 reduces albuminuria and inflammatory gene expression in diabetic kidney disease by a mechanism that may involve inhibition of the mTORC2/AKT pathway and may prove to be a novel therapeutic target.
Ambulatory pulmonary artery pressure monitoring during sleep and exercise in normal individuals and patients with COPD
Authors: D A Raeside
Journal: Thorax (2002)

<b>Background:</b> Pulmonary hypertension is a common complication of chronic obstructive airways disease (COPD) and its presence implies a poor prognosis. However, it is difficult to measure and its specific contribution to symptoms is difficult to quantify. A micromanometer tipped pulmonary artery catheter was used to measure pulmonary artery pressure (PAP) during sleep and on exercise. <b>Methods:</b> Ten patients (five with COPD receiving long term oxygen therapy and five normal individuals) were studied. Pulmonary artery pressure was recorded continuously during two periods of sleep (breathing oxygen followed by air for the COPD group) and during exercise. <b>Results:</b> In the COPD group PAP during sleep on oxygen was significantly lower than PAP during sleep breathing air (mean (SD) difference 9.6 (5.3) mm Hg, 95% CI 4.9 to 14.3, p= 0.016). PAP during exercise was not significantly different from PAP during sleep breathing air (mean (SD) difference 0.8 (8.9) mm Hg, 95% CI –7.0 to 8.6, p= 0.851). In normal individuals the group mean (SD) PAP was 15 (5.9) mm Hg for the first nocturnal period and 15 (5.7) mm Hg for the second nocturnal period. PAP during exercise was not significantly different from PAP during sleep breathing air (mean (SD) difference 3.3 (2.2) mm Hg, 95% CI 1.1 to 5.5, p= 0.061). <b>Conclusion:</b> In patients with COPD, PAP rose significantly during sleep to levels similar to those measured during exercise, but this could be reversed with oxygen.
Dopamine Synthesis Capacity in Patients With Treatment-Resistant Schizophrenia
Authors: Arsime Demjaha, Robin M. Murray, Philip K. McGuire, Shitij Kapur, Oliver D. Howes
Journal: American Journal of Psychiatry (2012)

Objective Elevated presynaptic striatal dopaminergic function is a robust feature of schizophrenia. However, the relationship between this dopamine abnormality and the response to dopamine-blocking antipsychotic treatments is unclear. The authors tested the hypothesis that in patients with schizophrenia the response to antipsychotic treatment would be related to the severity of presynaptic dopamine dysfunction, as indexed using [18F]-DOPA uptake positron emission tomography (PET). Method Twelve patients with treatment-resistant schizophrenia, twelve patients with schizophrenia who had responded to antipsychotics, and twelve healthy volunteers matched for gender, age, ethnicity, weight, and cigarette smoking underwent [18F]-DOPA PET scanning. [18F]-DOPA influx rate constants (Kicer values) were measured in the striatum and its functional subdivisions. Results Patients who had responded to antipsychotic treatment showed significantly higher Kicer striatal values than did patients with treatment-resistant illness (effect size=1.11) and healthy volunteers (effect size=1.12). The elevated [18F]-DOPA uptake was most marked in the associative (effect size=1.31) and the limbic (effect size=1.04) striatal subdivisions. There were no significant differences between patients with treatment-resistant illness and healthy volunteers in the whole striatum or any of its subdivisions. Conclusions In some patients with schizophrenia, antipsychotic treatment may be ineffective because they do not exhibit the elevation in dopamine synthesis capacity that is classically associated with the disorder; this may reflect a different underlying pathophysiology or a differential effect of antipsychotic treatment.
Early Molecular Response of Marrow Disease to Biologic Therapy Is Highly Prognostic in Neuroblastoma
Authors: Irene Y. Cheung, M. Serena Lo Piccolo, Brian H. Kushner, Nai-Kong V. Cheung
Journal: Journal of Clinical Oncology (2003)

A promising treatment strategy for stage 4 neuroblastoma patients is the repeated application of anti-GD2 immunotherapy after activating myeloid effectors with granulocyte-macrophage colony-stimulating factor (GM-CSF). To use early marrow response as a prognostic marker is particularly relevant for patients not likely to benefit from this therapy.Eighty-six stage 4 neuroblastoma patients older than 1 year at diagnosis were classified in four clinical groups on protocol entry: complete remission or very good partial remission (n = 33), primary refractory (n = 33), secondary refractory (n = 10), and progressive disease (n = 10). Bone marrow samples collected before and following treatment were assayed for GD2 synthase mRNA by real-time reverse transcriptase polymerase chain reaction. Response and survival analyses were performed on posttreatment samples before the third cycle at 1.8 months from protocol entry.GD2 synthase mRNA was evident in pretreatment marrow samples of the four clinical groups (42%, 52%, 60%, and 80% of samples, respectively), with median transcript level of 10.0, 16.6, 26.5, and 87.2, respectively. This marker became negative following antibody plus GM-CSF in 77% of complete remission or very good partial remission, 45% of primary refractory, 25% of secondary refractory, and 0% of progressive disease group. Progression-free survival was statistically different between responder and nonresponder groups (P <.0001). Among patients with minimal residual disease, molecular responders had a significantly lower risk of disease progression at a median follow-up of 29.8 months (P =.0001).GD2 synthase mRNA is a sensitive response marker of neuroblastoma in the bone marrow. It is particularly useful for minimal residual disease evaluation and may potentially be useful as an early predictor of resistance to antibody plus GM-CSF immunotherapy.
Role of Repeat Resection in Non–Muscle-Invasive Bladder Cancer
Authors: Harry W. Herr
Journal: Journal of the National Comprehensive Cancer Network (2015)

Repeat transurethral resection (TUR) is indicated for high-grade non–muscle-invasive bladder tumors. Repeat TUR is a diagnostic, therapeutic, prognostic, and predictive procedure. Repeat TUR achieves optimal local control by removing residual tumors after initial TUR, improves staging accuracy, provides additional histologic material favoring accurate diagnosis, allocates appropriate therapy with improved outcomes, facilitates response to intravesical therapy, and provides important prognostic information.
Fragile without fractures
Authors: A. A Deodhar
Journal: Annals of the Rheumatic Diseases (2000)

Despite being the commonest inherited disease of bone, osteogenesis imperfecta (OI) is a rare cause of fractures in daily clinical practice. Its prevalence in the general population is 1 to 5 per 100 000. The clinical spectrum ranges from mild forms with relatively few fractures and normal mobility to the lethal form, with multiple intrauterine fractures and death in perinatal period. The diagnosis of OI is based on fracture rates, family history, and clinical signs. However, the rarity of the condition coupled with the subtle signs of mild OI can lead to cases being missed altogether or misdiagnosed in some as “post-menopausal” osteoporosis. In asymptomatic members of a family with mild OI, it is even harder to decide whether they have the condition or not. It has recently been suggested that consultation by a physician familiar with the variability of OI (such as a medical geneticist) is essential for the early diagnosis.1 Clearly, this is possible only in selected centres of expertise, and in most clinical settings one is forced to tackle the problem with locally available resources.

A 30 year old lady with known OI presented to the “Bone Clinic” with her two children in February 1992. The diagnosis of OI in the family was established three years before this visit when her 3 year old daughter was brought to the local accident and emergency department for a skull fracture with minor trauma. This child had suffered two long bone fractures previously, also with minor trauma. This led to initial suspicion for “non-accidental injury” or child abuse, though the family history suggested otherwise. The child's 65 year old grandmother had a history of four fractures, fracture of both “legs” (details unclear) at age 6 months, fracture of a bone in left foot age 16 and a fractured right forth …
An Investigation of the Statistical Power of Neutrality Tests Based on Comparative and Population Genetic Data
Authors: W. Zhai, R. Nielsen, M. Slatkin
Journal: Molecular Biology and Evolution (2008)

In this report, we investigate the statistical power of several tests of selective neutrality based on patterns of genetic diversity within and between species. The goal is to compare tests based solely on population genetic data with tests using comparative data or a combination of comparative and population genetic data. We show that in the presence of repeated selective sweeps on relatively neutral background, tests based on the dN/dS ratios in comparative data almost always have more power to detect selection than tests based on population genetic data, even if the overall level of divergence is low. Tests based solely on the distribution of allele frequencies or the site frequency spectrum, such as the Ewens–Watterson test or Tajima's D, have less power in detecting both positive and negative selection because of the transient nature of positive selection and the weak signal left by negative selection. The Hudson–Kreitman–Aguadé test is the most powerful test for detecting positive selection among the population genetic tests investigated, whereas McDonald–Kreitman test typically has more power to detect negative selection. We discuss our findings in the light of the discordant results obtained in several recently published genomic scans.
Unusual findings in the biliary tract
Authors: N Ueno
Journal: Gut (2006)

A 48 year old female patient with intestinal malabsorption and subtotal to total jejunal villous atrophy also had granulomatous inflammation characterised by numerous epitheloid and giant cell granulomas in the stomach, the jejunum, and the liver, On a gluten-free diet a complete remission was achieved that included disappearance of the granulomatous inflammation. It is suggested that the granulomas in this case were manifestations of the gluten intolerance.
Classification of oesophageal motility abnormalities
Authors: S J Spechler, D O Castell
Journal: Gut (2001)

Manometric examination of the oesophagus frequently reveals abnormalities whose cause is unknown and whose physiological importance is not clear. A large body of literature dealing with oesophageal motility abnormalities has evolved over the past few decades but comparisons among studies have been compromised by the lack of a widely accepted system for classifying the abnormal motility patterns, and by the lack of uniform diagnostic criteria for the putative disorders. Based on an extensive review and analysis of the literature, this report suggests an operational scheme to be used for the general classification of oesophageal motility abnormalities, and proposes standardised manometric criteria for the putative oesophageal motility disorders. By applying the guidelines proposed in this report, clinicians and researchers can determine if their patients fulfil the manometric criteria for a putative motility disorder. This should facilitate and improve comparisons among patients and studies. However, it is important to emphasise that fulfilment of the proposed criteria does not establish the clinical importance of the motility abnormalities.
Influence of in vivo prednisolone on increased in vitro O2- generation by neutrophils in emphysema
Authors: TE Renkema, DS Postma, JA Noordhoek, HJ Sluiter, HF Kauffman
Journal: European Respiratory Journal (1993)

Evidence is accumulating that neutrophil-derived oxidants substantially contribute to the development of emphysema, especially in smoking individuals. It is not clear, however, why not all smokers develop emphysema. We tested the hypothesis that an abnormality in the oxidative metabolism of polymorphonuclear leucocytes (PMNs) might contribute to the development of emphysema. We investigated in vitro O2- production by peripheral PMNs in patients with stable emphysema and in healthy controls. In addition, we investigated whether in vivo prednisolone may modulate in vitro O2- production by PMNs in patients with emphysema during a stable phase of the disease. Spontaneous O2- production by PMNs was not significantly different in patients and controls. After stimulation with submaximal concentrations of calcium ionophore A23187 and phorbol myristate acetate, however, PMNs from patients with stable emphysema produced more O2- than those from healthy controls, especially in smoking subjects. Moreover, in vitro O2- generation by PMNs significantly decreased after in vivo prednisolone treatment in patients with emphysema. We suggest that our findings reflect an abnormality of PMNs, acting as one of the factors that contribute to the development of emphysema. This abnormality may, at least partially, be dampened by in vivo prednisolone treatment. These findings may provide new insights into the pathogenesis and treatment of pulmonary emphysema. Further studies on pulmonary PMNs are necessary to extend our findings.
An epidemic of silicosis among former denim sandblasters
Authors: M. Akgun, O. Araz, I. Akkurt, A. Eroglu, F. Alper, L. Saglam, A. Mirici, M. Gorguner, B. Nemery
Journal: European Respiratory Journal (2008)

Sandblasting denim using silica has emerged as a new cause of silicosis in Turkey. Following the discovery of several cases of silicosis in (young) workers who used this process, the frequency and main occupational risk factors of silicosis among former denim sandblasters in the region of Erzurum (Turkey) were evaluated. Demographic characteristics and information on working conditions were obtained by questionnaire and interview. In addition, spirometry testing was performed and chest radiographs were evaluated according to International Labour Office (ILO) classification of pneumoconioses in 157 former denim sandblasters. All subjects were male, with a mean (range) age of 23 (15-44) yrs. They had worked for a mean (range) of 36 (1-120) months, starting employment at a 17 (10-38) yrs of age. Most subjects (83%) had respiratory symptoms, especially dyspnoea (52%) but also chest pain (46%). Radiological evidence of silicosis (ILO score 1/0 or higher) was present in 77 (53%) out of 145 subjects with interpretable chest radiographs. These subjects had lower forced expiratory volume in one second and forced vital capacity. The risk of silicosis correlated with seniority (i.e. working as a foreman), exposure duration and number of places of work. Considering the high prevalence rate of silicosis in such workplaces, further problems are inevitable in the future unless effective measures are taken.
Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (The BeLieVeR-HIFi trial): study design and rationale
Authors: C. Davey, Z. Zoumot, S. Jordan, D. H. Carr, M. I. Polkey, P. L. Shah, N. S. Hopkinson
Journal: Thorax (2014)

Although lung volume reduction surgery improves survival in selected patients with emphysema, there has been ongoing interest in developing and evaluating bronchoscopic approaches to try to reduce lung volumes with less morbidity and mortality. The placement of endobronchial valves is one such technique, and although some patients have had a significant improvement, responses have been inconsistent because collateral ventilation prevents lobar atelectasis. We describe the protocol of a trial (ISRCTN04761234) aimed to show that a responder phenotype, patients with heterogeneous emphysema and intact interlobar fissures on CT scanning, can be identified prospectively, leading to a consistent benefit in clinical practice.
Bacteremia With Streptococcus pneumoniae
Authors: Joseph F. Plouffe
Journal: JAMA (1996)

Objective.  —To determine the incidence and mortality rates of patients with bacteremic infections withStreptococcus pneumoniae, and to determine the serotypes and antimicrobial susceptibilities of the pneumococcal isolates.  Design.  —Prospective case ascertainment and procurement ofS pneumoniaeisolates between January 1991 and April 1994.  Setting.  —Ten adult care hospitals in Franklin County, Ohio.  Patients.  —Patients (N=590) in whomS pneumoniaewas isolated from blood cultures.  Measurements.  —Demographic data from patients with pneumococcal bacteremia were obtained by chart review. Pneumococcal serotyping and antimicrobial susceptibility testing were performed on 499 bacteremic isolates.  Results.  —Among residents of Franklin County, the annual incidence of pneumococcal bacteremia was higher in patients at least 65 years old (83.0 per 100 000 population) compared with younger adults (9.6 per 100 000 population) (odds ratio [OR], 8.74; 95% confidence interval [CI], 7.19 to 10.62) and more common among African Americans than whites (OR, 1.36; 95% CI, 1.06 to 1.75). The relative risk of pneumococcal bacteremia among persons infected with the human immunodeficiency virus was 41.8 times (CI, 19.0 to 92.0) that of county residents 18 to 64 years of age. The overall mortality rate was 19% and was age-dependent, reaching 38% in patients at least 85 years old. The distribution of pneumococcal serotypes causing bacteremia was remarkably consistent over time. The incidence of drugresistant strains increased during the study period; by 1994 14% were resistant to penicillin, 12% to ceftazidime, and 24% to trimethoprim-sulfamethoxazole. The resistant strains included several serotypes ofS pneumoniae. Most serotypes (89.8%) ofS pneumoniaecausing bacteremia are contained in the pneumococcal vaccine.  Conclusions.  —Increased use of pneumococcal vaccine and recognition of antimicrobial resistance patterns may assist physicians in treating patients withS pneumoniaebacteremia. Educational programs to discourage unnecessary antimicrobial drug use should be developed for patients and physicians.  (JAMA. 1996;275:194-198)
Randomized, Controlled Trials
Authors: Marc S. Sabatine
Journal: Circulation (2011)

I n medicine, a randomized, controlled trial (RCT) is a form of research designed to provide information regarding the potential benefits and risks of a treatment in individuals (Figure ). 1 Treatments typically are new drugs or medical devices, but could also include new diagnostic tests or therapeutic strategies (ie, an approach to treating a patient).RCTs are invaluable to the medical community to help improve the care of patients.RCTs come in many shapes and sizes, from enrolling a few patients at 1 hospital to enrolling tens of thousands of patients at hundreds of hospitals or clinics across the world.Given the size and complexity of such RCTs, they are typically designed by a panel of experts (eg, physicians experienced in treating a certain disease) and sponsored by a governmental agency (eg, the National Institutes of Health) or a pharmaceutical or biotechnology company.A scientific protocol serves as an operating manual for how the trial is to be conducted, ensuring consistency across all sites.Common elements of the trial protocol that a study team is likely to discuss with a potential research subject are listed in the Table . 2
PTU-011 A new concept to extend resectability of liver tumours: two stage surgical strategy using an in-situ-split procedure
Authors: M Donati, G A Stavrou, K J Oldhafer
Journal: Gut (2012)

<h3>Introduction</h3> Today only 20%–25% of colorectal liver metastasis are resectable at initial presentation, despite the progress made in liver surgery over the last 25 years.<sup>1</sup> The induction of liver hypertrophy by preoperative portal vein occlusion (Embolisation or Ligation) is the most used tool to prevent postoperative liver failure allows a Future Liver Remnant (FLR) growth of up to 20%–35% in 45 days.<sup>2</sup> For 1 year we have engaged a new method of achieving resectability in patients affected by extensive disease involving both lobes with insufficient future remnant liver volume (FRLV).<sup>3</sup> <h3>Methods</h3> Between March and November 2011 six patients affected by liver tumours (4 colorectal liver metastasis (CRLM), 1 GIST-metastasis, 1 gallbladder carcinoma) were judged to be irresectable because of an insufficient RLV (&lt;20%). Therefore all those patients were submitted to a two staged procedure: (1) Right portal vein ligation, in situ split procedure and additionally atypical resection of a metastasis in the FRL if needed. After CT controls with 3D reconstruction and volumetry (2) Extended right hemihepatectomy.<sup>3</sup> <h3>Results</h3> Resectability was achieved in all patients around 2 weeks after step 1 (range 10–21 days). In five patients the FRL gained about 66% in volume (range 45%–95%); the patients were operated and discharged without complications. One Patient (gallbladder carcinoma)—despite good volumetry (42%)—suffered severe cholangitis postoperatively and died of consecutive liver failure 58 days after the second step operation. <h3>Conclusion</h3> This method showed to be effective in patients initially judged to be irresectable. One possible explanation could be that the in-situ liver transection, causing disruption of intrahepatic portal collaterals, increases portal flow deprivation to the excluded segments and redistribution of hepatotrophic factors, accelerating future remnant liver growth. Patients with jaundice from biliary tract tumours seem not to be good candidates for this approach. The proposed new strategy has had value in extending resectability in patients suffering from extensive CRLM,<sup>3</sup> reducing the risk of postoperatory liver failure, in our preliminary experience, more than other established methods. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Capussotti L</b>. Evolution of resectability criteria. In: Surgical treatment of colorectal liver metastases. Milan, Italy: Springer, 2011:27–34. 2. <b>Hemming AW</b>, Reed AI, Howard RJ, <i>et al</i>. Preoperative portal vein embolization for extended hepatectomy. <i>Ann Surg</i> 2003;<b>237</b>:686–91. 3. <b>Oldhafer KJ</b>, Donati M, Maghsoudi T, <i>et al</i>. Integration of 3D Volumetry, Portal Vein Transection and In Situ Split Procedure: A New Surgical Strategy for Inoperable Liver Metastasis. <i>J Gastrointest Surg</i> 2011.