Miracle-dz/UniFAR-FTUs huggingface dataset:
Increasing prevalence of comorbidity in patients with colorectal cancer in the South of the Netherlands 1995–2010

Comorbidity has large impact on colorectal cancer (CRC) treatment and outcomes and may increase as the population ages. We aimed to evaluate the prevalence and time trends of comorbid diseases in patients with CRC from 1995 to 2010. The Eindhoven Cancer Registry registers comorbidity in all patients with primary CRC in the South of the Netherlands. We analyzed the prevalence of serious comorbid diseases in four time frames from 1995 to 2010. Thereby, we addressed its association with age, gender and socio‐economic status (SES). The prevalence of comorbidity was registered in 27,339 patients with primary CRC. During the study period, the prevalence of comorbidity increased from 47% to 62%, multimorbidity increased from 20% to 37%. Hypertension and cardiovascular diseases were most prevalent and increased largely over time (respectively 16–29% and 12–24%). Pulmonary diseases increased in women, but remained stable in men. Average age at diagnosis increased from 68.3 to 69.5 years (p = 0.004). A low SES and male gender were associated with a higher risk of comorbidity (not changing over time). This study indicates that comorbidity among patients with CRC is common, especially in males and patients with a low SES. The prevalence of comorbidity increased from 1995 to 2010, in particular in presumably nutritional diseases. Ageing, increased life expectancy and life style changes may contribute to more comorbid diseases. Also, improved awareness among health care providers on the importance of comorbidity may have resulted in better registration. The increasing burden of comorbidity in patients with CRC emphasizes the need for more focus on individualized medicine.
Synergistic antitumor activity of the novel SN‐38‐incorporating polymeric micelles, NK012, combined with 5‐fluorouracil in a mouse model of colorectal cancer, as compared with that of irinotecan plus 5‐fluorouracil

The authors reported in a previous study that NK012, a 7‐ethyl‐10‐hydroxy‐camptothecin (SN‐38)‐releasing nano‐system, exhibited high antitumor activity against human colorectal cancer xenografts. This study was conducted to investigate the advantages of NK012 over irinotecan hydrochloride (CPT‐11) administered in combination with 5‐fluorouracil (5FU). The cytotoxic effects of NK012 or SN‐38 (an active metabolite of CPT‐11) administered in combination with 5FU was evaluated in vitro in the human colorectal cancer cell line HT‐29 by the combination index method. The effects of the same drug combinations was also evaluated in vivo using mice bearing HT‐29 and HCT‐116 cells. All the drugs were administered i.v. 3 times a week; NK012 (10 mg/kg) or CPT11 (50 mg/kg) was given 24 hr before 5FU (50 mg/kg). Cell cycle analysis in the HT‐29 tumors administered NK012 or CPT‐11 in vivo was performed by flow cytometry. NK012 exerted more synergistic activity with 5FU compared to SN‐38. The therapeutic effect of NK012/5FU was significantly superior to that of CPT‐11/5FU against HT‐29 tumors (p = 0.0004), whereas no significant difference in the antitumor effect against HCT‐116 tumors was observed between the 2‐drug combinations (p = 0.2230). Cell‐cycle analysis showed that both NK012 and CPT‐11 tend to cause accumulation of cells in the S phase, although this effect was more pronounced and maintained for a more prolonged period with NK012 than with CPT‐11. Optimal therapeutic synergy was observed between NK012 and 5FU, therefore, this regimen is considered to hold promise of clinical benefit, especially for patients with colorectal cancer. © 2008 Wiley‐Liss, Inc.
Effects of indomethacin on plasma renin activity in the conscious rat.

The role of prostaglandins in the control of renin release in vivo was evaluated in the conscious rat. Indomethacin suppressed urinary prostaglandin E2 (PGE2) excretion from 5.3 +/- 0.5 to 2.6 +/- 0.5 ng/3 h (P less than 0.001). Basal plasma renin activity (PRA) fell from 6.20 +/- 1.07 to 2.98 +/- 0.45 ng . ml-1 . h-1 (P less than 0.02). Indomethacin suppressed PRA stimulated by furosemide, insulin-induced hypoglycemia, hydralazine, isoproterenol, arachidonic acid, and sodium-free diet, whereas PRA stimulated by PGE2 was not suppressed by indomethacin. The suppression of PRA by indomethacin in the sodium-deplete state rules out sodium retention as the mechanism of action of indomethacin. These results indicate that inhibition of prostaglandin synthesis by indomethacin partially blocks the renin response to several of the known stimulators, suggesting that prostaglandins may play a pivotal role in the control of renin release.
Retinal microvascular changes and target organ damage in untreated essential hypertensives

Background and purpose The clinical and prognostic significance of initial retinal alterations in hypertensive patients remains controversial. Therefore, we assessed the relationship of microvascular abnormalities with prognostically validated markers of target organ damage (TOD), such as left ventricular mass (LVM), carotid intima–media thickness (IMT) and microalbuminuria, in early stages of untreated essential hypertension. Methods A total of 437 consecutive, never-treated patients with grade 1 or 2 essential hypertension, referred to our outpatient clinic, underwent the following procedures: (1) clinical and routine laboratory examinations, (2) 24-h ambulatory blood pressure monitoring, (3) 24-h urine collection for microalbuminuria, (4) echocardiography, (5) carotid ultrasonography, (6) non-mydriatic retinography. Patients were divided into group I, with either a normal retinal pattern (n = 65, 14.9%) or arteriolar narrowing (n = 185, 42.4%) and group II with arteriovenous crossings (n = 187, 42.7%). Results The two groups were similar for gender, body mass index, smoking habit, heart rate, clinic and ambulatory blood pressure (BP) values, while mean age was slightly but significantly higher in group II than in group I (47.6 ± 10.7 versus 44.5 ± 12.5 years, P = 0.008). No differences occurred between the two groups in LVM index (101.8 ± 18.5 versus 99.9 ± 20.4 g/m2), carotid IMT (0.67 ± 0.12 versus 0.66 ± 0.20 mm), urinary albumin excretion rate (14.4 ± 27.7 versus 13.3 ± 27.7 mg/24 h) as well as in the prevalence of LV hypertrophy (14.3 versus 14.0%), IM thickening and/or plaques (26.5 versus 27.2%) (both defined according to 2003 ESH-ESC guidelines) and microalbuminuria (10.1 versus 8.7%). Furthermore, the three different retinal artery patterns were similarly distributed among tertiles of LV mass index, IMT and urinary albumin excretion rate. Conclusions These results show that: (1) a very large fraction (more than 80%) of untreated, recently diagnosed hypertensive patients have initial retinal microvascular abnormalities detectable by non-mydriatic retinography, (2) the presence of arteriovenous crossings is not associated with more prominent cardiac and extracardiac TOD, (3) fundoscopic examination has a limited clinical value to detect widespread organ involvement in early phases of grade 1 and 2 hypertension.
[Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years].

OBJECTIVE To construct the height and weight growth charts for Chinese children and adolescents from birth to 18 years for both clinical and preventive health care uses. METHODS Data from two national representative cross-sectional surveys which were The National Growth Survey of Children under 7 years in the Nine Cities of China in 2005 and The Physical Fitness and Health Surveillance of Chinese School Students in 2005. The data from 94,302 urban healthy children were used to set up the database of length/height (length was measured for children under 3 years) and weight. The LMS method was used to smooth the growth curves, with estimates of L, M, and S parameters, values of percentile and Z-score curves which were required were calculated, and then generated standardized growth charts. RESULTS The 3rd, 10th, 25th, 50th, 75th, 90th, 97th smoothed percentiles curves and -3, -2, -1, 0, +1, +2, +3 Z-scores curves of weight-for-age, length/height-for-age for boys and girls aged 0-18 years were made out respectively. Comparison with the new WHO growth charts and 2000 CDC growth charts for the United States, the results showed that there was some big difference in weight and height among the three growth charts. For boys under 15 years of age and girls under 13 years of age, the China curves are slightly higher than WHO and CDC curves, but after those ages, the China curves fall behind and the difference became larger as age progresses. At the age of 18 years, the Chinese children are 3.5 cm shorter in boys and 2.5 cm shorter in girls as compared with the U. S. children. The difference in weights are very large for the school children, especially in girls. The weight of Chinese boys was 5.9 kg less than that of the U. S. boys at 18 years, and the difference was much bigger in girls, the weight of U.S. girls between 8 to 18 years was 4.1-20.5 kg more than that of Chinese girls at the same age range. CONCLUSION The new growth charts of height and weight were based on national survey data and therefore are recommended as the China national growth standards for use in pediatric clinics and public health service. Application of the charts will promote child growth monitoring, discovering early growth disorder, and will be useful to diagnosis of diseases and assessment of therapeutic effects.
Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus

Recent observations indicate that drugs of abuse, including alcohol and opiates, impair adult neurogenesis in the hippocampus. We have studied in rats the impact of cocaine treatment (20 mg/kg, daily, i.p.) on cell proliferation, survival and maturation following short‐term (8‐day) and long‐term (24‐day) exposure. Using 5′‐bromo‐2‐deoxyuridine (BrdU) and Ki‐67 as mitotic markers at the end of the drug treatments, we found that both short‐ and long‐term cocaine exposures significantly reduced cell proliferation in the dentate gyrus (DG) of the hippocampus. By labelling mitotic cells with BrdU pulses before or during the early stages of the drug treatment, we determined that long‐term cocaine exposure did not affect the survival of newly generated cells. In register with this finding, cocaine chronic exposure did not increase the number of apoptotic cells labelled by TUNEL (terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling). Using doublecortin (DCX) immunocytochemistry and electron microscopy, we next examined the effects of cocaine exposure on the maturation of the neural precursors and on synaptic output to CA3. DCX immunocytochemistry showed that immature hippocampal cells of rats exposed to cocaine displayed normal arborization patterns and similar degrees of colocalization with BrdU at two different developmental stages. Moreover, cocaine did not produce significant morphological alterations of the mossy fibre projection system to stratum lucidum in the CA3 area of the hippocampus. The results presented demonstrate that chronic cocaine exposure impairs proliferation dynamics in the DG without significantly altering either the survival and growth of immature cells or the structural features of terminal projections to CA3.
Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma. An immunohistochemical study in early, localized, and virulent disseminated stages of disease

The distribution of carcinoembryonic antigen (CEA) and its relationship to calcitonin in early, localized, and disseminated (virulent) medullary thyroid carcinoma (MTC) have been studied using immunoperoxidase methods. Carcinoembryonic antigen can be demonstrated within C‐cells through all stages of progression of MTC. In early disease (C‐cell hyperplasia and microscopic carcinoma), CEA, and calcitonin have a similar distribution, being present in virtually every cell. Likewise, calcitonin and CEA have a similar, homogeneous distribution among cells in gross medullary carcinoma confined to the thyroid region. In both primary and metastatic tumors from patients with virulent, disseminated disease there is an inverse relationship between calcitonin and CEA distribution such that CEA expression is retained and frequently present in the greatest amounts in cells which have poor or absent staining for calcitonin, and present in the least amounts where cellular staining for calcitonin is greatest. It is postulated that in MTC expression of CEA (a marker for early epithelial differentiation), in the face of loss of calcitonin (a marker for terminal differentiation/cellular maturity), may reflect a degree of maturation block in tumors from patients with aggressive disease.
Studies in Cranial Suture Biology: Regional Dura Mater Determines Overlying Suture Biology

&NA; The influence of dura mater on adjacent cranial sutures is significant. By better understanding the mechanisms of normal suture fusion and the role of the dura mater, it may be possible to delineate the events responsible for the premature suture fusion seen in craniosynostosis. In the Sprague‐Dawley rat, the posterior frontal suture normally fuses between 12 and 20 days of postnatal life and has proved to be an excellent model to describe normal suture fusion. The purpose of this study was to document the critical role that the dura mater‐suture complex may play on cranial suture biology. Forty Sprague‐Dawley rats at 8 days of age were divided into two groups of 20 animals each. The control group (group A) had surgical disruption of the dura matercalvarial interface. This was accomplished by elevating a strip of cranium inclusive of the posterior frontal and sagittal sutures and replacement of the cranial strip back to its anatomic position, all with the dura mater left intact. The experimental group (group B) had the same calvarial elevation (strip craniectomy), but the sutural anatomy/alignment was rotated 180 degrees. This rotation placed the posterior frontal suture into the sagittal suture's anatomic position and the sagittal suture into the posterior frontal suture's anatomic position. All of these procedures were accomplished by leaving the underlying dura mater intact. Animals were killed at 20, 30, 40, and 50 days (12, 22, 32, and 42 days postoperatively), and tissue sections were examined with hematoxylin and eosin staining. Group A (control) showed normal but delayed suture activity. The posterior frontal suture fused, and the sagittal suture remained patent. Fusion was delayed, not beginning before 20 days (12 days postoperative) and showing complete fusion between 30 and 40 days. Group B (180degree calvarial rotation) demonstrated that the suture in the posterior frontal anatomic position (actual sagittal suture) fused between 20 and 40 days, whereas the suture in the sagittal anatomic position (actual posterior‐frontal suture) remained patent throughout the study. This study demonstrates that the location of the dura mater‐suture complex is important in determining either suture patency or closure in this model. Normal closure of the suture overlying the posterior frontal dura mater demonstrates that the dura mater itself, or forces derived in specific cranial locations, determines the overlying suture biology. (Plast. Reconstr. Surg. 101: 1441, 1998.)
Mutant Huntingtin in Glial Cells Exacerbates Neurological Symptoms of Huntington Disease Mice*

Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) repeat (>37Q) in huntingtin (htt), and age of onset is inversely correlated with the length of the polyQ repeat. Mutant htt with expanded polyQ is ubiquitously expressed in various types of cells, including glia, but causes selective neurodegeneration. Our recent study demonstrated that expression of the N-terminal mutant htt with a large polyQ repeat (160Q) in astrocytes is sufficient to induce neurological symptoms in mice (Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Li, X.-J., and Li, S. H. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 22480–22485). Because glia-neuron interactions are critical for maintaining the normal function and survival of neurons in the brain and because mutant htt is more abundant in neurons than in glial cells, it is important to investigate whether glial htt can still contribute to HD pathology when mutant htt is abundantly expressed in neuronal cells. We generated transgenic mice that express mutant htt with 98Q in astrocytes. Unlike our recently generated htt-160Q transgenic mice, htt-98Q mice do not show obvious neurological phenotypes, suggesting that the length of the polyQ repeat determines the severity of glial dysfunction. However, htt-98Q mice show increased susceptibility to glutamate-induced seizure. Mice expressing mutant htt in astrocytes were mated with N171-82Q mice that express mutant htt primarily in neuronal cells. Double transgenic mice expressing mutant htt in both neuronal and glial cells display more severe neurological symptoms and earlier death than N171-82Q mice. These findings indicate a role of glial mutant htt in exacerbating HD neuropathology and underscore the importance of improving glial function in treating HD.
Exploratory Study on the Effects of a Robotic Hand Rehabilitation Device on Changes in Grip Strength and Brain Activity after Stroke

Abstract Background: The brain mechanisms underlying successful recovery of hand fuenction after stroke are still not fully understood, although functional MRI (fMRI) studies underline the importance of neuronal plasticity. Methods: We explored potential changes in brain activity in 7 patients with subacute to chronic stroke (69 ± 8 years) with moderate- to high-grade distal paresis of the upper limb (Motricity Index: 59.4) after standardized robotic finger-hand rehabilitation training, in addition to conventional rehabilitation therapy for 3 weeks. Behavioral and fMRI assessments were carried out before and after training to characterize changes in brain activity and behavior. Results: The Motricity Index (pre: 59.4, post: 67.2, P < .05) and grip force (pre: 7.26, post: 11.87, P < .05) of the paretic hand increased significantly after rehabilitation. On fMRI, active movement of the affected (left) hand resulted in contralesional (ie, ipsilateral) activation of the primary sensorimotor cortex prior to rehabilitation. After rehabilitation, activation appeared “normalized,” including the ipsilesional primary sensorimotor cortex and supplementary motor area (SMA). No changes and no abnormalities of activation maps were seen during movement of the unaffected hand. Subsequent region-of-interest analyses showed no significant ipsilesional activation increases after rehabilitation. Conclusion: Despite behavioral improvements, we failed to identify consistent patterns of functional reorganization in our sample. This warrants caution in the use of fMRI as a tool to explore neural plasticity in heterogeneous samples lacking sufficient statistical power.
Expression pattern of membrane‐associated guanylate kinases in interneurons of the visual cortex

GABAergic interneurons are key elements regulating the activity of local circuits, and abnormal inhibitory circuits are implicated in certain psychiatric and neurodevelopmental diseases. The glutamatergic input that interneurons receive is a key determinant of their activity, yet its molecular structure and development, which are often distinct from those of glutamatergic input to pyramidal cells, are poorly defined. The membrane‐associated guanylate kinase (MAGUK) homologs PSD‐95/SAP90, PSD‐93/chapsyn110, SAP97, and SAP102 are central organizers of the postsynaptic density at excitatory synapses on pyramidal neurons. We therefore studied the cell‐type‐specific and developmental expression of MAGUKs in the nonoverlapping parvalbumin (PV)‐ and somatostatin (SOM)‐positive interneurons in the visual cortex. These interneuron subtypes account for the vast majority of interneurons in the cortex and have different functional properties and postsynaptic structures, being either axodendritic (PV+) or axospinous (SOM+). To study cell‐type‐specific MAGUK expression, we used DIG‐labeled riboprobes against each MAGUK along with antibodies against either PV or SOM and examined tissue from juvenile (P15) and adult mice. Both PV+ and SOM+ interneurons express mRNA for PSD‐95, PSD‐93, and SAP102 in P15 and adult tissue. In contrast, these interneuron subtypes express SAP97 at P15, but for adult visual cortex we found that most PV+ and SOM+ interneurons show low or no expression of SAP97. Given the importance of SAP97 in regulating AMPA receptor GluA1 subunit and NMDA receptor subunits at glutamatergic synapses, these results suggest a developmental shift in glutamate receptor subunit composition and regulation of glutamatergic synapses on PV+ and SOM+ interneurons. J. Comp. Neurol. 518:4842–4854, 2010. © 2010 Wiley‐Liss, Inc.
Parametric Adversarial Divergences are Good Task Losses for Generative Modeling

Generative modeling of high dimensional data like images is a notoriously difficult and ill-defined problem. In particular, how to evaluate a learned generative model is unclear. In this position paper, we argue that adversarial learning, pioneered with generative adversarial networks (GANs), provides an interesting framework to implicitly define more meaningful task losses for generative modeling tasks, such as for generating "visually realistic" images. We refer to those task losses as parametric adversarial divergences and we give two main reasons why we think parametric divergences are good learning objectives for generative modeling. Additionally, we unify the processes of choosing a good structured loss (in structured prediction) and choosing a discriminator architecture (in generative modeling) using statistical decision theory; we are then able to formalize and quantify the intuition that "weaker" losses are easier to learn from, in a specific setting. Finally, we propose two new challenging tasks to evaluate parametric and nonparametric divergences: a qualitative task of generating very high-resolution digits, and a quantitative task of learning data that satisfies high-level algebraic constraints. We use two common divergences to train a generator and show that the parametric divergence outperforms the nonparametric divergence on both the qualitative and the quantitative task.
Classification of Brachyspira spp. isolated from Swedish dogs

Abstract Brachyspira spp. were isolated from 21 of 32 sampled dogs (66%) in a colony of Swedish beagle dogs with a history of diarrhea and from 3 of 17 Swedish pet dogs (17%) with diarrhea. All Swedish isolates were weakly β-hemolytic and gave a negative indole reaction. Eighty-eight percent showed negative α-galactosidase and hippurate reactions, but a positive β-glucosidase reaction. Two isolates were hippurate positive with a negative β-glucosidase reaction. One additional German isolate diverged by showing a positive indole reaction in combination with a positive hippurate reaction. Sequencing of 16S rDNA indicated that the hippurate-positive isolates belonged to the species Brachyspira pilosicoli. Four representative isolates were examined using pulsed-field gel electrophoresis (PFGE) and compared with six reference strains and five porcine isolates of Brachyspira spp. The canine isolates clustered together in the PFGE analysis. Necropsy examination of a culture-positive B. pilosicoli colony-raised beagle dog revealed macro- and microscopical lesions of colitis with numerous spiral-shaped bacteria in the lumens of the crypts, in goblet cells and within the colonic epithelium.