tbuckley/cabot-search huggingface dataset:
Heart Rate Variability Predicts ESRD and CKD-Related Hospitalization
Authors: Daniel J. Brotman, Lori D. Bash, Rehan Qayyum, Deidra Crews, Eric A. Whitsel, Brad C. Astor, Josef Coresh
Journal: Journal of the American Society of Nephrology (2010)

Autonomic imbalance, a feature of both diabetes and hypertension, may contribute to adverse cardiovascular outcomes. In animal models, sympathetic nerve activity contributes to renal damage but the extent to which autonomic dysfunction precedes the development of CKD and ESRD in humans is unknown. We measured resting heart rate and heart rate variability in 13,241 adults (45- to 64-years old) followed for a median of 16 years in the Atherosclerosis Risk in Communities (ARIC) Study. We examined heart rate parameters by quartiles, defining those in the lowest quartile (by time and frequency domain measures separately) as the risk group of interest. We identified 199 cases of incident ESRD and 541 patients with CKD-related hospitalizations; higher resting heart rate and lower heart rate variability associated with both outcomes. The fully adjusted hazard ratios for ESRD were 1.98 (95% confidence interval [CI] 1.45 to 2.70) among those in the highest heart rate quartile and 1.56 (95% CI 1.14 to 2.14) for high-frequency power. Other time and frequency domain measures were similarly and significantly associated with ESRD and CKD-related hospitalizations. These results suggest that autonomic dysfunction may be an important risk factor for ESRD and CKD-related hospitalizations and call for further studies to define the mechanisms that underlie these associations.
Competing Roads to Larynx Preservation
Authors: Everett E. Vokes
Journal: Journal of Clinical Oncology (2013)

Combined modality research in laryngeal cancer has focused on the dual goals of increased survival and functional organ preservation. Competing strategies consist of induction chemotherapy as initially established in the Veterans’ Administration Larynx Preservation trial and of concomitant chemoradiotherapy. Randomized trials established the combination of cisplatin and fluorouracil (PF) as induction chemotherapy and of radiotherapy with systemic-dose cisplatin every 3 weeks as feasible and effective. 1-3 More recently, the addition of docetaxel to the PF regimen (TPF) was shown to further increase overall survival when compared with PF in a general population of patients with head and neck cancer and to allow for a higher larynx preservation rate in patients with laryngeal and hypopharyngeal cancer. 4-6 Bioradiotherapy by using concurrent cetuximab was shown to be superior to single-modality radiotherapy but has not been directly compared with either induction or concurrent chemoradiotherapy, tested specifically for laryngeal cancer, or shown to further improve survival when added to cisplatin radiotherapy. 7,8 Viral carcinogenesis of nasopharyngeal cancer (Epstein-Barr virus) and oropharyngeal cancer (human papillomavirus) is well recognized; in particular, the latter is associated with the current rapid increase in the incidence of oropharyngeal cancers. However, for larynx cancer, tobacco and alcohol exposure remain the dominant risk factors that lead to frequent significant comorbidities and competing mortality risks. In addition, laryngeal cancer can predispose patients to swallowing problems with associated malnutrition and aspiration. Similarly, acute and long-term effects of surgery and radiation can contribute to these complications, especially in older patients and patients with advanced stage disease. 9 In the article that accompanies this editorial, Forastiere et al 10 report 5- and 10-year outcomes for Radiation Therapy Oncology
Reduction of Brain Dopamine Concentration With Dietary Tyrosine Plus Phenylalanine Depletion: An [<sup>11</sup>C]Raclopride PET Study
Authors: Andrew J. Montgomery, Sarah F.B. McTavish, Philip J. Cowen, Paul M. Grasby
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Extracellular dopamine concentrations were estimated through measurement of [11C]raclopride binding with positron emission tomography after dietary manipulation of the dopamine precursors tyrosine and phenylalanine. METHOD: Healthy male subjects were scanned on two occasions: once after receiving a balanced amino acid drink and once after receiving a drink mixture from which tyrosine and phenylalanine were omitted. RESULTS: Dietary tyrosine and phenylalanine depletion increased [11C]raclopride binding in the striatum by a mean of 6%. The change in [11C]raclopride binding correlated significantly with the fall in the ratio of tyrosine and phenylalanine to large neutral amino acids. CONCLUSIONS: This is the first demonstration of an effect of a dietary manipulation on brain dopamine release in humans. This result provides support for the further investigation of the role of dietary manipulations in the treatment of neuropsychiatric disorders.
Evidence for Activation of the Unfolded Protein Response in Collagen IV Nephropathies
Authors: Myrtani Pieri, Charalambos Stefanou, Apostolos Zaravinos, Kamil Erguler, Kostas Stylianou, George Lapathitis, Christos Karaiskos, Isavella Savva, Revekka Paraskeva, Harsh Dweep, Carsten Sticht, Natassa Anastasiadou, Ioanna Zouvani, Demetris Goumenos, Kyriakos Felekkis, Moin Saleem, Konstantinos Voskarides, Norbert Gretz, Constantinos Deltas
Journal: Journal of the American Society of Nephrology (2013)

Thin-basement-membrane nephropathy (TBMN) and Alport syndrome (AS) are progressive collagen IV nephropathies caused by mutations in COL4A3/A4/A5 genes. These nephropathies invariably present with microscopic hematuria and frequently progress to proteinuria and CKD or ESRD during long-term follow-up. Nonetheless, the exact molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus remain elusive. We hypothesized that defective trafficking of the COL4A3 chain causes a strong intracellular effect on the cell responsible for COL4A3 expression, the podocyte. To this end, we overexpressed normal and mutant COL4A3 chains (G1334E mutation) in human undifferentiated podocytes and tested their effects in various intracellular pathways using a microarray approach. COL4A3 overexpression in the podocyte caused chain retention in the endoplasmic reticulum (ER) that was associated with activation of unfolded protein response (UPR)–related markers of ER stress. Notably, the overexpression of normal or mutant COL4A3 chains differentially activated the UPR pathway. Similar results were observed in a novel knockin mouse carrying the Col4a3-G1332E mutation, which produced a phenotype consistent with AS, and in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation. These results suggest that ER stress arising from defective localization of collagen IV chains in human podocytes contributes to the pathogenesis of TBMN and AS through activation of the UPR, a finding that may pave the way for novel therapeutic interventions for a variety of collagenopathies.
Human lumbar apophyseal joint damage and intervertebral disc degeneration.
Authors: M W Swanepoel, L M Adams, J E Smeathers
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVES--To record the extent and location of lumbar apophyseal cartilage damage, and to ascertain if the extent of damage is correlated with the grade of disc degeneration, age, or both. METHODS--The extent and location of fibrillated areas of the apophyseal cartilage of the joint surfaces of 29 lumbar motion segments were examined using computer aided image processing of Indian ink stained areas, and degeneration of the associated intervertebral discs graded using the method of Nachemson. RESULTS--It was found that these joints showed a greater extent and prevalence of cartilage fibrillation than the knee, hip or ankle, with significant damage in specimens younger than 30 years. Damage was predominantly located peripherally, superiorly, and posteriorly in the concave superior apophyseal surfaces, and was predominantly peripheral and posterior in the inferior surfaces, with a tendency to be located inferiorly. There was a weak correlation between apophyseal joint damage and the intervertebral disc degenerative grade, but this was inconclusive, as both increased with age. CONCLUSIONS--The pattern of damage exhibited by superior joint surfaces is most probably caused by tension on collagenous joint capsule fibres which insert into the surfaces posteriorly, so producing an area of fibrocartilage unsuited to loadbearing. Tension on such fibres would be greatest during spinal flexion. The pattern of damage of the inferior surfaces lends some support to the hypothesis that their apices impact the laminae of the lumbar vertebra inferior to them, consequent upon the degeneration and narrowing of the associated intervertebral disc. The predominantly peripheral location of fibrillation of both superior and inferior surfaces may be associated with inadequate mechanical conditioning of marginal joint areas. Disc degeneration cannot be the initial cause of apophyseal fibrillation in most specimens. The study indicates a need for regular spinal exercise, starting at a young age.
Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction
Authors: Kanichiro Kobayashi, Naoyuki Takahashi, Eijiro Jimi, Nobuyuki Udagawa, Masamichi Takami, Shigeru Kotake, Nobuaki Nakagawa, Masahiko Kinosaki, Kyoji Yamaguchi, Nobuyuki Shima, Hisataka Yasuda, Tomonori Morinaga, Kanji Higashio, T. John Martin, Tatsuo Suda
Journal: The Journal of Experimental Medicine (2000)

Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.
Importance of defining loss of response before therapeutic drug monitoring
Authors: Malcolm Tan
Journal: Gut (2014)

Dear Sir,

I read with interest the study by Steenholdt et al 1 which concluded that individualised infliximab therapy was more cost effective compared with empirical dose escalation in Crohn's disease (CD) patients who developed secondary non-response to infliximab.

The study methodology has a number of questions that require attention.

First, 80% of the patients recruited for the study had non-fistulising disease, and the study entry criterion for them was having a Crohn's Disease Activity Index (CDAI) score of ≥220. Furthermore, the endpoint for clinical response …
Validation of a Cell-Cycle Progression Gene Panel to Improve Risk Stratification in a Contemporary Prostatectomy Cohort
Authors: Matthew R. Cooperberg, Jeffry P. Simko, Janet E. Cowan, Julia E. Reid, Azita Djalilvand, Satish Bhatnagar, Alexander Gutin, Jerry S. Lanchbury, Gregory P. Swanson, Steven Stone, Peter R. Carroll
Journal: Journal of Clinical Oncology (2013)

We aimed to validate a previously described genetic risk score, denoted the cell-cycle progression (CCP) score, in predicting contemporary radical prostatectomy (RP) outcomes.RNA was quantified from paraffin-embedded RP specimens. The CCP score was calculated as average expression of 31 CCP genes, normalized to 15 housekeeper genes. Recurrence was defined as two prostate-specific antigen levels ≥ 0.2 ng/mL or any salvage treatment. Associations between CCP score and recurrence were examined, with adjustment for clinical and pathologic variables using Cox proportional hazards regression and partial likelihood ratio tests. The CCP score was assessed for independent prognostic utility beyond a standard postoperative risk assessment (Cancer of the Prostate Risk Assessment post-Surgical [CAPRA-S] score), and a score combining CAPRA-S and CCP was validated.Eighty-two (19.9%) of 413 men experienced recurrence. The hazard ratio (HR) for each unit increase in CCP score (range, -1.62 to 2.16) was 2.1 (95% CI, 1.6 to 2.9); with adjustment for CAPRA-S, the HR was 1.7 (95% CI, 1.3 to 2.4). The score was able to substratify patients with low clinical risk as defined by CAPRA-S ≤ 2 (HR, 2.3; 95% CI, 1.4 to 3.7). Combining the CCP and CAPRA-S improved the concordance index for both the overall cohort and low-risk subset; the combined CAPRA-S + CCP score consistently predicted outcomes across the range of clinical risk. This combined score outperformed both individual scores on decision curve analysis.The CCP score was validated to have significant prognostic accuracy after controlling for all available clinical and pathologic data. The score may improve accuracy of risk stratification for men with clinically localized prostate cancer, including those with low-risk disease.
Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure
Authors: C. L. Shovlin, H. C. Tighe, R. J. Davies, J. S. R. Gibbs, J. E. Jackson
Journal: European Respiratory Journal (2008)

Increasing evidence supports the use of embolisation to treat pulmonary arteriovenous malformations (AVMs). Most pulmonary AVM patients have hereditary haemorrhagic telangiectasia (HHT), a condition that may be associated with pulmonary hypertension. The current authors tested whether pulmonary AVM embolisation increases pulmonary artery pressure ( P pa ) in patients without baseline severe pulmonary hypertension. P pa was measured at the time of pulmonary AVM embolisation in 143 individuals, 131 (92%) of whom had underlying HHT. Angiography/embolisation was not performed in four individuals with severe pulmonary hypertension, whose systemic arterial oxygen saturation exceeded levels usually associated with dyspnoea in pulmonary AVM patients. In 143 patients undergoing pulmonary AVM embolisation, P pa was significantly correlated with age, with the most significant increase occurring in the upper quartile (aged &gt;58 yrs). In 43 patients with repeated measurements, there was no significant increase in P pa as a result of embolisation. In half, embolisation led to a fall in P pa . The maximum rise in mean P pa was 8 mmHg: balloon test occlusion was performed in one of these individuals, and did not predict the subsequent rise in P pa following definitive embolisation of the pulmonary AVMs. In the present series of patients, which excluded those with severe pulmonary hypertension, pulmonary artery pressure was not increased significantly by pulmonary arteriovenous malformation embolisation.
Treatment-Related Mortality in Patients With Advanced-Stage Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group
Authors: Diana Wongso, Michael Fuchs, Annette Plütschow, Beate Klimm, Stephanie Sasse, Bernd Hertenstein, Georg Maschmeyer, Tom Vieler, Ulrich Dührsen, Walter Lindemann, Walter Aulitzky, Volker Diehl, Peter Borchmann, Andreas Engert
Journal: Journal of Clinical Oncology (2013)

The introduction of BEACOPP(escalated) (escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has significantly improved tumor control and overall survival in patients with advanced-stage Hodgkin lymphoma. However, this regimen has also been associated with higher treatment-related mortality (TRM). Thus, we analyzed clinical course and risk factors associated with TRM during treatment with BEACOPP(escalated).In this retrospective analysis, we investigated incidence, clinical features, and risk factors for BEACOPP(escalated)-associated TRM in the German Hodgkin Study Group trials HD9, HD12, and HD15.Among a total of 3,402 patients, TRM of 1.9% (64 of 3,402) was mainly related to neutropenic infections (n = 56; 87.5%). Twenty of 64 events occurred during the first course of BEACOPP(escalated) (31.3%). Higher risk of TRM was seen in patients age ≥ 40 years with poor performance status (PS) and in patients age ≥ 50 years. PS and age were then used to construct a new risk score; those with a score ≥ 2 had TRM of 7.1%, whereas patients who scored 0 or 1 had TRM of 0.9%.The individual risk of TRM associated with BEACOPP(escalated) can be predicted by a simple algorithm based on age and PS. High-risk patients should receive special clinical attention.
Pulmonary tumour with high carcinoembryonic antigen titre caused by chronic propolis aspiration
Authors: W-C. Lin, Y-T. Tseng, Y-L. Chang, Y-C. Lee
Journal: European Respiratory Journal (2007)

Carcinoembryonic antigen (CEA) titre elevation is sometimes found in benign diseases, such as gastro-intestinal tract inflammatory disease and chronic obstructive pulmonary disease; however, very high CEA titre is rarely encountered in benign pulmonary disease. A 36-yr-old female, who had suffered from body weight loss, was found to have high serum CEA titre (60.8 ng·mL<sup>−1</sup>). Image studies revealed one pulmonary tumour at the left lower lobe, satellite nodules and mediastinal lymphadenopathy. Left lower lobectomy and lymph node dissection were performed for suspicious pulmonary malignancy. The pathological examination revealed that the tumourous lesion was composed of small and fragmented foreign bodies, fibrinopurulent exudate and heavy eosinophils. The bronchial epithelium was characterised by goblet cell hyperplasia and CEA overexpression. The remaining lung parenchyma possessed similar foreign body reaction. The patient’s medical history was reviewed and it was found that she had spread propolis topically on nasal mucosa as an adjuvant therapy to asthma for 6 months prior to this medical event. The CEA titre decreased after the operation to 14.2 and 7.88 ng·mL<sup>−1</sup> after 2 weeks and 6 months, respectively. Propolis is used widely in folk medicine but it also has strong sensitising potential. One rare case of propolis aspiration is reported with presentation mimicking lung cancer.
Schizophrenia as a Long-Term Outcome of Pregnancy, Delivery, and Perinatal Complications: A 28-Year Follow-Up of the 1966 North Finland General Population Birth Cohort
Authors: Peter B. Jones, Paula Rantakallio, Anna-Liisa Hartikainen, Matti Isohanni, Pirkko Sipila
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The 1966 North Finland general population birth cohort was studied to determine whether abnormalities during pregnancy, delivery, and the neonatal period are associated with adult-onset schizophrenia. METHOD: The authors included all 11,017 subjects alive in Finland at age 16. For each individual, standardized assessments made during pregnancy, delivery, and infancy were linked to national psychiatric case registers covering the period up to age 28. Subjects with DSM-III-R schizophrenia were identified by using a two-stage screen that included perusal of individual case records. Associations (adjusted odds ratios) between schizophrenia and specific pregnancy, delivery, and neonatal characteristics were calculated. RESULTS: Within this cohort, 76 cases of DSM-III-R schizophrenia arose by age 28 years; 51 (67.1%) of these persons were men. Demographic characteristics and previous obstetric histories of the mothers were similar in the case and unaffected comparison groups, although the former were more likely to have been more depressed than usual during pregnancy. Low birth weight (<2500 g) and the combination of low birth weight and short gestation (<37 weeks) were more common among the schizophrenic subjects. Being small for gestational age (<10th percentile) was not more common. Of 125 survivors of severe perinatal brain damage, six (4.8%) later developed schizophrenia. CONCLUSIONS: The spectrum of adverse outcomes after fetal and perinatal insults unfolded beyond childhood and included adult-onset schizophrenia. The findings have implications for understanding the mechanisms involved in the development of schizophrenia and, possibly, for its prevention.
Food intolerance in rheumatoid arthritis.
Authors: M Abuzakouk, C O'Farrelly
Journal: Annals of the Rheumatic Diseases (1993)

Food intolerance in rheumatoid arthritisSir: We read with interest the two papers by Drs van de Laar and van der Korst on food intolerance in rheumatoid arthritis (RA). 1 2 It appears from this extensive but short study of patients with seropositive RA that rheumatoid disease in a small subgroup is sensitive to dietary manipulation.Identification of these patients is, however, a problem.We have previously shown that significant gut abnormalities are associated with raised levels of IgA rheumatoid factor (RF) and dietary protein specific IgG in patients with RA and suggested that these changes might identify patients who would respond to dietary manipulation.3Gendre and colleagues have described villous atrophy and other histological abnormalities of the small intestine in patients with RA.4These changes were more significant among IgM RF negative patients (who are often IgA RF positive).In the recent study the number of patients examined histologically was small, therefore a firm conclusion cannot be reached.Moreover, it is likely that by excluding IgM RF negative patients with RA some food intolerant patients might have been missed.Furthermore, investigation of intestinal structure and function in RA is severely hampered by the damaging effects of non-steroidal anti-inflam- matory drugs, which are so often used by patients with RA.Thus a fundamental question remains extremely difficult to answer-that is, whether gut abnormalities and any of the manifestations associated with these abnor- malities in patients with RA are secondary to the disease process and its treatment or are of primary pathogenic significance.
Ancient DNA Enables Timing of the Pleistocene Origin and Holocene Expansion of Two Adelie Penguin Lineages in Antarctica
Authors: P. A. Ritchie
Journal: Molecular Biology and Evolution (2003)

The timing of divergent events in history is one of the central goals of contemporary evolutionary biology. Such studies are however dependent on accurate evolutionary rates. Recent developments in ancient DNA analysis enable the estimation of more accurate evolutionary rates and therefore more accurate timing of divergence events. Consequently, this leads to a better understanding of changes in populations through time. We use an evolutionary rate calculated from ancient DNA of Adélie penguins (Pygoscelis adeliae) to time divergent events in their history. We report the presence of two distinct and highly variable mitochondrial DNA lineages and track changes in these lineages through space and time. When the ancient DNA and the phylogenetic rates are used to estimate the time of origin of the lineages, two very different estimates resulted. In addition, these same rates provide very different estimates of the time of expansion of these lineages. We suggest that the rate calculated from ancient DNA is more consistent with the glacial history of Antarctica and requires fewer assumptions than does a narrative based on the phylogenetic rate. Finally, we suggest that our study indicates an important new role for ancient DNA studies in the timing of divergent events in history.