An antibody-free liver cancer screening approach based on nanoplasmonics biosensing chips via spectrum-based deep learning.
The clinical needs of rapidly screening liver cancer in large populations have asked for a facile and low-cost point-of-care testing (POCT) method. We present a nanoplasmonics biosensing chip (NBC) that would empower antibody-free detection with simplified analysis procedures for POCT. The cheaply fabricable NBC consists of multiple silver nanoparticle-decorated ZnO nanorods on cellulose filter paper and would enable one-drop blood tests through surface-enhanced Raman spectroscopy (SERS) detection. In this work, utilizing such an NBC and deep neural network (DNN) modeling, a direct serological detection platform was constructed for automatically identifying liver cancer within minutes. This chip could enhance Raman signals enough to be applied to POCT. A classification DNN model was established by spectrum-based deep learning with 1140 serum SERS spectra in equal proportions from hepatocellular carcinoma (HCC) patients and healthy individuals, achieving an identification accuracy of 91% on an external validation set of 100 spectra (50 HCC versus 50 healthy). The intelligent platform, based on the biosensing chip and DNN, has the potential for clinical applications and generalizable use in quickly screening or detecting other types of cancer.


The effect of initial graft tension on postoperative clinical outcome in anterior cruciate ligament reconstruction with semitendinosus tendon.
The goal of this study is to establish the influence of tensioning the graft during anterior cruciate ligament (ACL) reconstruction, with a semitendinosus tendon graft, on postoperative stability. Prospective controlled clinical trial. Forty-eight patients were randomly allocated to three groups in which three different tensions, 8, 12, or 15 kg force, was applied on the reconstructed ACL during the operation. The patients were observed for 1 year or more after surgery (min. 1 year, max. 2 years 8 months). Clinical outcome was evaluated using the visual analogue scale, anterior knee laxity (using the KT2000 arthrometer) and the torque of the knee extensor. Postoperatively, the average side-to-side differences in anterior laxity were 1.3 mm in the 8 kg group, 2.1 mm in the 12 kg, and 2.4 mm in the 15 kg group. The visual analogue scale averaged 84, 83, and 79 mm, respectively. There were no significant differences among the three groups. There were also no significant differences between the groups for muscle strength recovery during isokinetic and isometric contraction at 1 year postoperatively. There were no significant differences among the groups in subjective clinical results, anterior laxity, and knee extensor strength in the ACL reconstructions that used the autogenous semitendinosus tendon graft.


Should patients have right heart catheterization prior to long-term oxygen treatment?
The presence of pulmonary hypertension (PH) is not an obligatory prerequisite for prescribing long-term oxygen therapy (LTO) in patients with chronic obstructive pulmonary disease (COPD), at least when PaO2 is repeatedly less than 55 mmHg in a stable state of the disease. It is generally accepted that LTO is indicated in patients whose PaO2 is in the range 55-59 mmHg, but exhibiting polycythaemia, "cor pulmonale", and (or) PH. The clinical signs of "cor pulmonale" occur late and the noninvasive diagnosis of PH is not yet satisfactory; it ensues that right heart catheterization is useful in these patients, before prescribing LTO. Pulmonary hypertension is probably the most important consequence of long-standing hypoxaemia and, in our opinion, the presence and the degree of PH should be assessed in every patient before starting such a heavy therapy as LTO.


A comparison of Mantoux and tuberculin Tine testing in a chest unit.
Simultaneous Mantoux (10 T.U.) and Tuberculin Tine tests were performed on 393 in-patients on a chest unit. The results were read by the same observer between 48 and 72 hours later. The overall agreement between the tests was 78%; this rose to 90% if patients categorised as 'doubtful' reactors were reclassified as positive. Where one test was 'doubtful' the other was more than 3 times as likely to be positive as negative. It is suggested that the 'doubtful' category by abandoned for both tests and readings in this range be reclassified as positive. In patients expected on clinical grounds to be positive reactors, over one-third were negative to both tests; in those expected to be negative over one-fifth were positive. The Tine test is convenient and gives results which seem to correlate well with the Mantoux test, although neither test appears to be highly specific.


Differential expression of two sodium channel subtypes in human brain.
Two partial human brain sodium channel cDNA sequences (designated HBSC I and II) have been cloned and mapped to chromosome 2q23-2q24 by chromosome microdissection-PCR (CMPCR). The distribution of HBSC I and II mRNA in human brain was studied by means of a novel approach based on the ligase detection reaction. These studies demonstrate that HBSC I and II mRNA is heterogeneously distributed in brain, and that the relative ratio of the two forms can vary as much as 7-fold between different regions.


The relationship between the location of pediatric intensive care unit facilities and child death from trauma: a county-level ecologic study.
To describe the relationship between the location of Pediatric Intensive Care Unit (PICU) facilities and county-level child death from trauma in the contiguous USA. We conducted a cross-sectional ecologic study using county-level data on death due to trauma in children 0 to 14 years of age from 1996 to 1998. These data were linked to 1997 county-level data on availability of PICU facilities. In 1997, PICU facilities were present in 9% of USA counties. There were 18,337 childhood deaths from trauma in the study period. The presence of PICU facilities in a county was associated with lower mortality from trauma (incidence rate ratio [IRR] = 0.72; 95% CI 0.67-0.78) compared to counties without PICU facilities. After controlling for residence in rural and low-income counties, and the presence of adult medicosurgical intensive care units, the presence of PICU facilities in a county remained associated with lower rates of death from trauma (IRR = 0.82; 95% CI 0.75-0.89). The presence of PICU facilities is related to lower mortality rates due to traumatic injuries at the county level. This finding may reflect the concentration of pediatric subspecialty care in counties with PICUs. This association merits further study with individual-level observations.


Two-dimensional polyacrylamide gel electrophoretic pattern of duodenal tumour proteins.
We investigated the protein pattern of a surgically resected tumour in a case where it was difficult to distinguish between duodenal and pancreatic cancer. The investigation was performed using two-dimensional polyacrylamide gel electrophoresis with silver staining. Samples of the duodenal tumour, normal duodenal mucosa and normal pancreatic tissue from the same patient were compared. Each gel had ca. 250-300 protein spots, and the tumour sample pattern more closely resembled that of normal duodenal mucosa than that of pancreatic tissue, suggesting that the tumour had arisen from duodenal mucosa. There were three proteins identified only in the tumour sample gel, and these may have been tumour-specific proteins.


Usefulness of power Doppler ultrasonography in evaluating erectile dysfunction.
To evaluate deep penile arterial flow after an intracavernosal injection with papaverine in patients with erectile dysfunction (ED). Twenty patients with ED were evaluated using power Doppler ultrasonography with a linear probe (8 MHz). Diagnostic tests were undertaken after an intracavernosal injection with 40 mg papaverine. The peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistive index (RI) were analysed. After injecting papaverine, seven patients had a normal erection and appropriate waveform patterns; their mean PSV was 30.7 cm/s, the EDV 4.42 cm/s and the RI 0.85. There was tumescence and elongation of the penis with no rigidity in eight patients; their mean PSV was 23.9 cm/s, the EDV 7.34 cm/s and the RI 0.72. There was no erection in five patients. The abnormal flow values showed insufficient arterial vessels in a quarter of the men, venous leakage in 15% and mixed ED in 20%. The power Doppler technique allows the accurate location and evaluation of deep penile arteries. Vascular pathology may be differentiated after an intracavernosal injection with a vasomotor agent. Recognising the pathological pattern assists in choosing the best method of treatment.


Early glycaemic control among patients with type 2 diabetes and initial glucose-lowering treatment: a 13-year population-based cohort study.
To examine real-life time trends in early glycaemic control in patients with type 2 diabetes between 2000 and 2012. We used population-based medical databases to ascertain the association between achievement of glycaemic control with initial glucose-lowering treatment in patients with incident type 2 diabetes in Northern Denmark. Success in reaching glycated haemoglobin (HbA1c) goals within 3-6 months was examined using regression analysis. Of 38 418 patients, 91% started with oral glucose-lowering drugs in monotherapy. Metformin initiation increased from 32% in 2000-2003 to 90% of all patients in 2010-2012. Pretreatment (interquartile range) HbA1c levels decreased from 8.9 (7.6-10.7)% in 2000-2003 to 7.0 (6.5-8.1)% in 2010-2012. More patients achieved an HbA1c target of <7% (<53 mmol/mol) in 2010-2012 than in 2000-2003 [80 vs 60%, adjusted relative risk (aRR) 1.10, 95% confidence interval (CI) 1.08-1.13], and more achieved an HbA1c target of <6.5% [(<48 mmol/mol) 53 vs 37%, aRR 1.07 95% CI 1.03-1.11)], with similar success rates observed among patients aged <65 years without comorbidities. Achieved HbA1c levels were similar for different initiation therapies, with reductions of 0.8% (from 7.3 to 6.5%) on metformin, 1.5% (from 8.1 to 6.6%) on sulphonylurea, 4.0% (from 10.4 to 6.4%) on non-insulin combination therapies, and 3.8% (from 10.3 to 6.5%) on insulin monotherapy. Pretreatment HbA1c levels in patients with incident type 2 diabetes have decreased substantially, which is probably related to earlier detection and treatment in accordance with changing guidelines. Achievement of glycaemic control has improved, but 20% of patients still do not attain an HbA1c level of <7% within the first 6 months of initial treatment.


Fine needle aspiration cytology in the head and neck region.
Although needle aspiration diagnosis was described over 50 years ago, many patients with neck swellings are still subjected to hazardous and unnecessary open diagnostic surgical biopsy. In a six-month period, over 200 fine needle aspirates were performed on tumours from the head and neck region, 44% of which were positive for cancer. The technique of aspiration, its advantage for the patient, clinician and cytopathologist, and the results of the study will be discussed. Close cooperation between the clinician and the cytopathologist is essential.


High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders.
Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease mediated by immune hypersensitization to multiple foods and strongly associated with atopy and esophageal remodeling. We provide clinical and molecular evidence indicating a high prevalence of EoE in patients with inherited connective tissue disorders (CTDs). We examined the rate of EoE among patients with CTDs and subsequently analyzed esophageal mRNA transcript profiles in patients with EoE with or without CTD features. We report a cohort of 42 patients with EoE with a CTD-like syndrome, representing 0.8% of patients with CTDs and 1.3% of patients with EoE within our hospital-wide electronic medical record database and our EoE research registry, respectively. An 8-fold risk of EoE in patients with CTDs (relative risk, 8.1; 95% confidence limit, 5.1-12.9; χ(2)1 = 112.0; P < 10(-3)) was present compared with the general population. Esophageal transcript profiling identified a distinct subset of genes, including COL8A2, in patients with EoE and CTDs. There is a remarkable association of EoE with CTDs and evidence for a differential expression of genes involved in connective tissue repair in this cohort. Thus, we propose stratification of patients with EoE and CTDs into a subset referred to as EoE-CTD.


Kawasaki disease and oxidative metabolism.
The plasmid lipid peroxidation products: malonyldialdehyde (MDA), organic hydroperoxides (OHP) and zinc peripheral values were analysed in seven children with Kawasaki disease, in the acute phase, before and after treatment with intravenous immunoglobulins. In the acute phase, plasma levels of MDA (2.95 +/- 0.30 mumol/l, control group: 2.52 +/- 0.08 mumol/l) and OHP (235 +/- 65 mumol/l, control group: 120 +/- 10) were increased (p less than 0.05 and p less than 0.01). Moreover, plasma zinc levels were significantly decreased (10 +/- 2.15 mumol/l versus 15.6 +/- 2.5 mumol/l in control group, p less than 0.05). After treatment with immunoglobulins, MDA, OHP and plasma zinc levels returned to normal. The parallel normalisation of clinical injury draws attention to the possible role of oxygen intermediates in connective tissue degradation and in the pathogenesis of vascular abnormalities in Kawasaki disease.


Antibiotic resistance, virulence and genetic characteristics of Vibrio alginolyticus isolates from aquatic environment in costal mariculture areas in China.
Vibrio alginolyticus has been the second most common Vibrio species in the world and mainly grows in the ocean or estuary environment, which can induce epidemics outbreaks under marine organisms, and causing serious economic losses in aquaculture industry. In this study, the genetic populations and evolutionary relationship analysis of V. alginolyticus isolated from different geographical locations in China with typical interannual differences were exhibited originally genetic diversity. Then the virulence genes prevalence, antibiotic resistance phenotype, and antimicrobial resistance genes risk diversity of V. alginolyticus were analyzed by phenotypic and molecular typing methods. And they were complex correlations among antibiotic phenotypes, resistance and virulence genes under different genotype of V. alginolyticus. The results provide a theoretical foundation for further understanding the genetic and metabolic diversity among V. alginolyticus in China, and lay a theoretical foundation for the transmission risk assessment and regional diagnosis of Vibrio in aquatic animals.


Low allozymic variation in the Bidens pilosa L. complex (Asteraceae).
Bidens alba, B. subalternans, and B. pilosa form a complex group based on their morphological similarities. Bidens pilosa L. and B. subalternans DC. are herbs with a wide distribution in agricultural and disturbed areas. Bidens alba (L.) DC. varies in size from herb to subshrub and has a coastal distribution. Enzyme electrophoresis was used to evaluate genetic diversity in 12 populations of Bidens. All but three loci (Lap-1, Est, and Got) were monomorphic. Est-1 and Got were polymorphic only in B. alba. Lap-1 was polymorphic only in B. pilosa and B. subalternans. The estimates of genetic variability were low for all three taxa and all of the populations studied. Genetic diversity varied from 0.01 to 0.03. Mean genetic identities were high among populations of each species (0.99 for B. alba and 1.00 for B. pilosa and B. subalternans) and among the three species (1.00). Bidens pilosa and B. subalternans could be considered a single species if the taxonomy of the group were based solely on isozyme data.


Coccidioidomycosis of the prostate gland and its therapy.
A case of disseminated coccidioidomycosis was diagnosed from a prostatic biopsy. Patients with sterile pyuria, prostatic nodules or symptoms of prostatitis who have lived in or traveled through an endemic area need careful evaluation of the lower genitourinary tract. Immunological treatment with a transfer factor currently is under investigation. Miconazole may offer a promise for future treatment of this fungal infection and, particularly, for patients with impaired renal function.


Structural and steric requirements for beta-phenethylamines as agonists of the noradrenergic cyclic AMP generating system in the rat limbic forebrain.
The present studies were undertaken to assess the structural and steric requirements for beta-phenethylamines as agonists of the noradrenergic cyclic AMP generating system in slices of the rat limbic forebrain. Significant agonist activity of beta-phenethylamines requires a beta-3,4-dihydroxyphenethylamine with a beta-hydroxyl group in the R configuration. Thus, dopamine did not stimulate the system at concentrations up to 10(-3) M. Moreover, beta-hydroxyphenethylamines without a 3,4-catechol group (octopamine, phenylephrine, p-hydroxynorephedrine, metaraminol and methoxamine) - though exerting alpha-agonist activity in peripheral tissues - lack agonist activity in this particular cyclic AMP generating system. The effects of (R)-norepinephrine and (R)-isoproterenol at maximal concentrations were not additive. The results lend further support to the view that the cyclic AMP generating system in slices of the limbic forebrain is part of a norepinephrine receptor coupled adenylate cyclase system with a subpopulation of receptors that are beta in nature.


Deployment of spatial attention to words in central and peripheral vision.
Four perceptual identification experiments examined the influence of spatial cues on the recognition of words presented in central vision (with fixation on either the first or last letter of the target word) and in peripheral vision (displaced left or right of a central fixation point). Stimulus location had a strong effect on word identification accuracy in both central and peripheral vision, showing a strong right visual field superiority that did not depend on eccentricity. Valid spatial cues improved word identification for peripherally presented targets but were largely ineffective for centrally presented targets. Effects of spatial cuing interacted with visual field effects in Experiment 1, with valid cues reducing the right visual field superiority for peripherally located targets, but this interaction was shown to depend on the type of neutral cue. These results provide further support for the role of attentional factors in visual field asymmetries obtained with targets in peripheral vision but not with centrally presented targets.


Lung Cancer Screening: New Perspective and Challenges in Europe.
Randomized-controlled trials have shown clear evidence that lung cancer screening with low-dose CT in a high-risk population of current or former smokers can significantly reduce lung-cancer-specific mortality by an inversion of stage distribution at diagnosis. This paper will review areas in which there is good or emerging evidence and areas which still require investment, research or represent implementation challenges. The implementation of population-based lung cancer screening in Europe is variable and fragmented. A number of European countries seem be on the verge of implementing lung cancer screening, mainly through the implementation of studies or trials. The cost and capacity of CT scanners and radiologists are considered to be the main hurdles for future implementation. Actions by the European Commission, related to its published Europe's Beating Cancer Plan and the proposal to update recommendations on cancer screening, could be an incentive to help speed up its implementation.


Profile of partners who completed HIV testing and received a new HIV diagnosis in Ukraine's HIV index testing program: a retrospective cohort study to inform program improvement.
Approximately one-third of people living with HIV in Ukraine are unaware of their HIV status. Index testing (IT) is an evidence-based HIV testing strategy that supports voluntary notification of partners with HIV risk, so they can receive HIV testing, prevention, and treatment services. Ukraine scaled up IT services in 2019. This observational study of Ukraine's IT program covered 39 health facilities located in 11 regions with high HIV burden. The study used routine program data from January-December 2020 to describe the profile of named partners and explore index client (IC) and partner factors associated with two outcomes: 1) completing testing; and 2) HIV case finding. Analysis used descriptive statistics and multilevel linear mixed regression models. The study included 8,448 named partners, of whom 6,959 had unknown HIV status. Among them,72.2% completed HIV testing and 19.4% of those tested were newly diagnosed with HIV. Two-thirds of all new cases were among partners of ICs who were recently diagnosed and enrolled in care (< 6 months), while one third were among partners of established ICs. In adjusted analysis, partners of ICs with unsuppressed HIV viral load (VL) were less likely to complete HIV testing (adjusted odds ratio [aOR] = 0.11, p < 0.001), but more likely to receive a new HIV diagnosis (aOR = 1.92, p < 0.001). Partners of ICs who cited injection drug use or having a known HIV + partner as their own reason for testing were more likely to receive a new HIV diagnosis (aOR = 1.32, p = 0.04 and aOR = 1.71, p < 0.001 respectively). Involving providers in the partner notification process was associated with completed testing (aOR = 1.76, p = 0.001) and HIV case finding (aOR = 1.64, p < 0.01), compared with notification by ICs. HIV case detection was highest among partners of recently diagnosed ICs, but IT participation among established ICs still yielded an important share of all newly-identified HIV cases. Areas for improvement in Ukraine's IT program include completing testing for partners of ICs with unsuppressed HIV VL, with history of injection drug use or discordant partnerships. Using intensified follow-up for the sub-groups at risk of incomplete testing may be practical. Greater use of provider-assisted notification could also accelerate HIV case finding.


Prognostic value of coronary atherosclerosis progression evaluated by coronary CT angiography in patients with stable angina.
To investigate the progression of coronary atherosclerosis burden by coronary CT angiography (CCTA) and to demonstrate its association with the incidence of major adverse cardiac events (MACE). We retrospectively studied patients with stable angina who had undergone repeat CCTA due to recurrent or worsening symptoms. Lipid-rich, fibrous, calcified and total plaque burden as well as coronary diameter stenosis were quantitatively analysed. The incidence of MACE during follow-up was determined. The final cohort consisted of 268 patients (mean age 52.9 ± 9.8 years, 71 % male) with a mean follow-up period of 4.6 ± 0.9 years. Patients with lipid-rich, fibrous, calcified and total plaque burden (%) progression, as well as coronary diameter stenosis (%) progression had a significantly higher incidence of MACE than those without (all p < 0.05). The progression of lipid-rich plaque (HR = 1.601, p = 0.021), total plaque burden (HR = 2.979, p = 0.043) and coronary diameter stenosis (HR = 4.327, p <0.001) were independent predictors of MACE (all p < 0.05). Patients presenting with recurrent or worsening symptoms associated with coronary artery disease who have coronary atherosclerosis progression on CCTA are at an increased risk of future MACE. • Repeat CCTA can provide information regarding the progression of coronary atherosclerosis. • Coronary atherosclerosis progression at CCTA is independently associated with MACE. • CCTA findings could serve as incremental predictors of MACE.


An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis.
Pouchitis is the major long-term complication of ileal pouch-anal anastomosis for ulcerative colitis. The incidence of pouchitis is as high as 50% several years after surgery. Two-thirds of pouchitis patients suffer recurrence. Of those who recur, one-quarter suffer from chronic, unremitting pouchitis. Current treatments for this disorder are disappointing. To determine whether a topically administered enema formulation of ISIS 2302 (alicaforsen), an antisense inhibitor of intercellular adhesion molecule-1, can improve the clinical symptoms, endoscopic mucosal appearance and mucosal histology in patients with chronic, unremitting pouchitis, a disorder in which this molecule is over-expressed. In an open-label, uncontrolled study, 12 patients with chronic, unremitting pouchitis were treated with 240 mg alicaforsen antisense enema nightly for 6 weeks. Clinical evaluation and endoscopy were performed at baseline and at weeks 3, 6 and 10. Pouchoscopy with biopsy was carried out at baseline and at weeks 6 and 10. The primary end-point was the reduction from baseline of the Pouchitis Disease Activity Index (PDAI) at week 6. Secondary end-points included the PDAI at week 10. Safety was evaluated by analysing the adverse events, vital signs and laboratory parameters. After 6 weeks of nightly alicaforsen enema, a statistically significant (n = 12, P = 0.001) reduction in the PDAI from baseline (11.42) to week 6 (6.83) was observed. Mean reductions in the endoscopy sub-score from baseline (5.25) to week 3 (3.08) and week 6 (2.58) were statistically significant (P = 0.0039 and P = 0.0005, respectively). The mean reductions in clinical symptom sub-score from baseline (3.75) to week 3 (2.33) and week 6 (2.25) were also statistically significant (P = 0.0156 and P = 0.0117, respectively). Ten of the 12 patients achieved a mucosal appearance score of 0 or 1 at endoscopy. Five of the 12 patients (42%) had a non-statistically significant decrease in the histology component of their PDAI from baseline to week 6. By week 6, seven of the 12 patients (58%) were in remission, as defined by PDAI < 7, with a mean decrease from baseline in PDAI score of six points. The alicaforsen enemas were well tolerated and no serious side-effects were noted. Antisense enema to intercellular adhesion molecule-1 is safe and well tolerated. In an open-label trial, it appeared to improve the PDAI score, clinical symptoms and endoscopic mucosal appearance. It may also improve the histology. In the light of the responses observed in this trial, a randomized, placebo-controlled trial is warranted.


Plasticity of seed protein composition in response to nitrogen and sulfur availability.
Seed composition is genetically programmed, but the implementation of that program is affected by many factors including the nutrition of the parent plant. In particular, seeds demonstrate a remarkable capacity to maintain nitrogen homeostasis in conditions of varying sulfur supply. They do this by altering the expression of individual genes encoding abundant storage proteins. The signal transduction pathways that modulate gene expression in seeds in response to N and S availability involve both transcriptional and post-transcriptional mechanisms.


A new method to discriminate G1, S, G2, M, and G1 postmitotic cells.
A new flow cytometric method combining light scattering measurements, detection of bromodeoxyuridine (BrdU) incorporation via fluorescent antibody, and quantitation of cellular DNA content by propidium iodide (PI) allows identification of additional compartments in the cell cycle. Thus, while cell staining with BrdU-antibodies and PI reveals the G1, S, and G2 + M phases of the cell cycle, differences in light scattering allow separation of G2 phase cells from M phase cells and subdivision of G1 phase into two compartments, i.e., G1A representing postmitotic cells which mature to G1B cells ready to initiate DNA synthesis. The method involves fixation of cells in 70% ethanol, extraction of histones with HC1, and thermal denaturation of DNA. This treatment appears to enhance the differences in chromatin structure of cells in the various phases of the cell cycle to the extent that cells could be separated on the basis of the 90 degrees scatter. Mitotic cells show much lower scatter than G2 phase cells, and G1 postmitotic cells (G1A) show lower scatter than G1 cells about to enter the S phase (G1B). Light scattering is correlated with chromatin condensation, as judged by microscopic evaluation of cells sorted on the basis of light scatter. The method has the advantage over the parental BrdU/DNA bivariate analysis in allowing the G2 and M phases of the cell cycle to be separated and the G1 phase to be analyzed in more detail. The method may also allow separation of unlabeled S phase cells from mitotic cells and distinguish between labeled and unlabeled mitotic cells.


Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis.
Endothelial dysfunction in non-insulin dependent (Type 2) diabetes mellitus (NIDDM) has implications for the pathogenesis of the two major complications, macrovascular disease and microangiopathy. Endothelial dysfunction is a consequence of a disturbance in the L-arginine/nitric oxide pathway. Its occurrence in NIDDM is well supported by both in vitro and in vivo studies. NIDDM results in diverse abnormalities in lipoprotein metabolism, the most significant being hypertriglyceridaemia which is associated with increased plasma concentrations of small dense LDL and low levels of HDL. Dysglycaemia results in hyperoxidative stress and increased formation of advanced-glycosylation endproducts, both of which enhance the oxidative modification of lipoprotein particles. Based on extensive in vitro studies and on human data, we generate the hypothesis that the development of endothelial dysfunction in NIDDM is a consequence of the effect of dyslipoproteinaemia, in particular increased circulatory concentrations of modified small dense LDL and of hyperoxidative stress on the formation, action and disposal of nitric oxide, by diverse molecular mechanisms; HDL is proposed to have a protective effect on these processes through its enzymic antioxidant properties. The hypothesis proposed is simple, testable and consistent with wide sources of evidence. The practical implications of the hypothesis and the existing opportunities for the prevention and reversal of endothelial dysfunction in NIDDM are also reviewed and discussed.


Real-life evidence of treatment with alemtuzumab in patients diagnosed with relapsing-remitting multiple sclerosis in Colombia.
Physical disability, cognitive impairment, depression, and fatigue are poorly understood in Latin American patients with multiple sclerosis following alemtuzumab infusion. To describe Sustained changes in physical disability in an average 22-month follow-up period after alemtuzumab infusion, and which demographical or clinical variables modulate change in EDSS, and adverse events, changes in cognition, fatigue, and depressive symptoms after an average 15-month follow-up period. Retrospective cohort observational study. Following the review of medical records, 23 patients with Relapsing Remitting Multiple Sclerosis treated with alemtuzumab were identified; of these, 17 had a baseline neuropsychological assessment and 12 had at least one follow-up neuropsychological assessment. Most of the patients presented a low level of physical disability, depression, fatigue, and cognitive impairment, which was more pronounced in the processing speed and visuospatial memory at baseline. Fifteen of 23 (65.2%) of patients showed disability improvement, 7 (30.1%) patients remained stable, and 1 (4.3%) patient worsened, and change was not influenced by age or baseline disability score. Twenty (87%) patients remained free of clinical relapses. Performance improved on the BVMT-R visual memory test, 9 (75%) remained stable or improved on the BICAMS, and 66.6% perceived decreased fatigue on the d-FIS. Adverse events occurred in 7 (30.1%) of patients, the most common were opportunistic infections in 2 (8.6%) patients, and one 29-year-old patient presented papillary thyroid carcinoma after infusion of the second course of alemtuzumab. Results suggest that treatment with alemtuzumab has a beneficial impact on disability, cognitive impairment, and perception of fatigue. The percentage and type of adverse events observed in the cohort are similar to those reported for other real-life studies.


Synthesis of a BSA-Le(x) glycoconjugate and recognition of Le(x) analogues by the anti-Le(x) monoclonal antibody SH1: the identification of a non-cross reactive analogue.
A Le(x) trisaccharide functionalized with a cysteamine arm was prepared and this synthesis provided additional information on the reactivity of N-acetylglucosamine O-4 acceptors when they are glycosylated with trichloroacetimidate donors activated with excess BF(3)·OEt(2). In turn, this trisaccharide was conjugated to BSA lysine side chains through a squarate-mediated coupling. This BSA-Le(x) glycoconjugate displayed 35 Le(x) haptens per BSA molecule. The relative affinity of the anti-Le(x) monoclonal antibody SH1 for the Le(x) antigen and analogues of Le(x) in which the D-glucosamine, L-fucose or D-galactose residues were replaced with D-glucose, L-rhamnose and D-glucose, respectively, was measured by competitive ELISA experiments. While all analogues were weaker inhibitors than the Le(x) antigen, only the analogue of Le(x) in which the galactose residue was replaced by a glucose unit showed no binding to the SH1 mAb. To confirm that the reduced or loss of recognition of the Le(x) analogues by the anti-Le(x) mAb SH1 did not result from different conformations adopted by the analogues when compared to the native Le(x) antigen, we assessed the conformational behavior of all trisaccharides by a combination of stochastic searches and NMR experiments. Our results showed that, indeed, the analogues adopted the same stacked conformation as that identified for the Le(x) antigen. The identification of a trisaccharide analogue that does not cross-react with Le(x) but still retains the same conformation as Le(x) constitutes the first step to the design of a safe anti-cancer vaccine based on the dimeric Le(x) tumor associated carbohydrate antigen.


Epigenetic studies and pediatric research.
The 2020 Annual Review Issue, "Preventing Disease in the 21st Century" was selected by the Editors-in-Chief of Pediatric Research to include a variety of disease entities that confront health-care practitioners entrusted to the care of infants and children. In keeping with this mandate, this article reviews the subject of epigenetics, which impacts pediatric research from bench to bedside. Epigenetic mechanisms exert their effects through the interaction of environment, various susceptibility genes, and immunologic development and include: (1) DNA methylation; (2) posttranslational modifications of histone proteins through acetylation and methylation, and (3) RNA-mediated gene silencing by microRNA (miRNA) regulation. The effects of epigenetics during fetal life and early periods of development are first reviewed together with clinical applications of cardiovascular and metabolic disorders in later life. The relationships of epigenetics to the allergic and autoimmune diseases and cancer are next reviewed. A specific focus of the article is directed to the recent recognition that many of these disorders are driven by aberrant immune responses in which immunoregulatory events are often poorly functioning and where through interventive epigenetic measures prevention may be possible by alterations in programming of DNA during fetal and early periods as well as in later life.


Plastic Shavings by Laser: Peeling Porous Graphene Springs for Multifunctional All-Carbon Applications.
Manufacturing strategies to create three-dimensional (3D) structures with multifunctional nanomaterials are of intense interest for fabricating building blocks in many electromechanical applications. A coil spring composed of graphene provides an important step toward the realization of all-carbon devices, as it is one of the essential elements for a wide range of systems. In this connection, here an unprecedented fabrication strategy to create a new type of 3D coil spring composed of laser-induced graphene springs (LIG-S) which is spontaneously produced via the pyrolytic jetting technique, is presented. Similar to wood or metal shavings observed in traditional machining processes, a pair of LIG-S with two opposite chiralities and controllable macroscopic dimensions is produced by a single scanning of a focused continuous-wave (CW) laser on a polyimide (PI) substrate. The resulting LIG-S, plastic shavings by laser, exhibits sufficient mechanical and electrical properties to enable many applications including strain-tolerant spring electrodes, antennas, supercapacitors, gas sensors, and luminescent filaments under extreme conditions. Without using any conventional fabrication techniques or other labor-intensive, time-consuming, and expensive processes, this novel approach enables a high-throughput mass production of macro-, micro-, and nanoscale featured LIG-S that can be manufactured within seconds to realize many open opportunities in all-carbon electromechanical systems.


First report of genetic diversity and risk factor analysis of equine piroplasm infection in equids in Jilin, China.
Equine piroplasmosis (EP) is a tick-borne hemoprotozoan disease of equids, caused by Theileria equi and Babesia caballi. Equine piroplasmosis represents a serious challenge to the equine industry due to important economic losses worldwide. The present study aimed to evaluate the prevalence of Theileria equi and Babesia caballi infections in equids from Jilin Province, China. A total of 220 blood samples (192 horses and 28 donkeys/mules) were collected from March 2018 to October 2019 in five districts of Jilin Province and analyzed by PCR. Potential risk factors, including the region, sex, management, and host species of the animals were assessed in relation to T. equi infection. Moreover, the V4 hypervariable region of the T. equi 18S rRNA gene was analyzed to identify specific genotypes. The overall prevalence of T. equi in equids was 27.7%, whereas B. caballi infection was not identified. The district with the highest positive rate was Baicheng (43.3%), followed by Tonghua (28.9%), Yanbian (26.4%), Jilin (23.3%), and Liaoyuan (20.9%). The sex of the animals and farm management were identified as main risk factors, which were significantly associated with the prevalence of Equine piroplasmosis (P < 0.05). The risk factor analysis indicated that the females were at a higher risk (OR: 2.48, 95% CI: 1.17-5.27) of being infected compared to the males, whereas the organized farm was protective factor (OR: 0.42, 95% CI: 0.22-0.80). The phylogenetic analyses revealed that there were two T. equi genotypes (A and E) in Jilin. Our findings provided important epidemiological data for the prevention and control of T. equi infection in Jilin, China.


Fine structures of nerve fibers with corticotropin-releasing factor-like immunoreactivity in the rat lateral septum.
The fine structures of nerve fibers with corticotropin-releasing factor (CRF)-like immunoreactivity in the rat lateral septum were investigated by means preembedding immunoelectron microscopy. A number of CRF axon terminals formed synapses with cell bodies of non-immunoreactive septal neurons. They occasionally had broad terminal bulges whose subregions showed little or no immunoreactivity for CRF. CRF axon terminals were also in synaptic contact with non-immunoreactive dendrites or dendritic spines. Some dendrites with CRF were postsynaptic to non-immunoreactive axon terminals.


An androgen-associated hepatic adenoma in a trans-sexual.
A case is reported of an hepatic adenoma developing in a patient who had been taking testosterone for 3 years. There appears to be an association between various steroid preparations and hepatic neoplasia. Reports of such cases with all relevant data will allow a balanced assessment of the problem to be made.


Medicines information needs during pregnancy: a multinational comparison.
The aim was to assess the perceived needs of medicines information and information sources for pregnant women in various countries. Cross-sectional internet-based study. Multinational. Pregnant women and women with children less than 25 weeks. The need for information about medicines was assessed by a question: 'Did you need information about medicines during the course of your pregnancy?' A list of commonly used sources of information was given to explore those that are used. Altogether, 7092 eligible women responded to the survey (5090 pregnant women and 2002 women with a child less than 25 weeks). Of the respondents, 57% (n=4054, range between different countries 46-77%) indicated a need for information about medicines during their pregnancy. On average, respondents used three different information sources. The most commonly used information sources were healthcare professionals-physicians (73%), pharmacy personnel (46%) and midwifes or nurses (33%)-and the internet (60%). There were distinct differences in the information needs and information sources used in different countries. A large proportion of pregnant women have perceived information needs about medicines during pregnancy, and they rely on healthcare professionals. The internet is also a widely used information source. Further studies are needed to evaluate the use of the internet as a medicines information source by pregnant women.


X-ray microanalysis of isolated perfused rat hearts.
X-ray microanalysis was carried out on sections from isolated hearts perfused with a modified Krebs-Henseleit solution with or without isoproterenol. Changes in P, Ca and Zn concentrations could be detected after isoproterenol and some correlation with hemodynamic and morphological parameters was observed. Ratios between P/Ca in myonuclei and the ratios of interstitial cell to myofiber nucleus calcium were related directly to the state of the heart.


Emergency free flaps to the upper extremity.
Thirty-one emergency free flaps were applied to the upper extremities of patients who ranged in age from 16 to 57 years. The size of the skin defects ranged from 13 to 540 square centimeters, with an average of 145 square centimeters. A variety of flaps were used, including 14 lateral arm, seven groin, five latissimus, three first web space of the foot, one scapular and one medial arm. In patients with small defects, the operative time ranged from 3 to 9 hours, with an average of 4 hours and 54 minutes. The hospital stay was never longer than 4 days. In patients with medium size defects, the operating time ranged from 3 to 18 hours, with an average of 7 hours and 45 minutes. The hospital stay averaged 7.4 days. In large defects in which extensive reconstruction was undertaken before flap application, the operative time ranged from 3 to 20 hours, with an average of 11 hours and 54 minutes. The average hospital stay was 11.8 days. Twenty-nine of the 31 flaps survived in their entirety (93.5%). In one of the successful flaps (3.2%), exploration was required after the patient left the operating room. Severe infection occurred in only one case, that being one of the two flap failures. Twenty-seven of the 31 patients returned to work, 18 of them to their original employment.


Thyroid incidentalomas on 18FDG-PET/CT: a metabolico-pathological correlation.
Thyroid incidentaloma is defined as an unsuspected thyroid lesion found on imaging study or while performing a surgery non-related to the thyroid gland. Most recent scientific literature tends to demonstrate a detection rate of 0.1-4.3% for incidental findings of thyroid focal uptake identified by 18F-fluorodeoxyglugose Positron Emission Tomography with computed tomography (18FDG-PET/CT) initially prescribed for nonthyroid disease. From 10.3 to 80.0% of patients who underwent further evaluation are diagnosed with malignant lesions. Our first objective is to determine the risk of malignancy confined in thyroid incidentalomas(IT) detected on 18FDG-PET/CT in patients treated in a tertiary care center (Centre Hospitalier Universitaire de Sherbrooke). Second, we want to identify a cut-off value for SUVmax in order to distinguish benign from malignant IT. Third, we look for predictive criterion that can be outlined to help in their management. We retrospectively reviewed 40 914 charts of patients who had a 18FDG-PET/CT done in a tertiary center from 2004 to 2014. For each patient where a thyroid incidentaloma has been identified, Maximum Standardized Uptake Value (SUVmax), ultrasound report, cytology and histopathological results as well as oncologic outcomes were compiled and analyzed. In this study, the incidence for thyroid incidentaloma detected with 18FDG-PET/CT is 0.74%. The rate of malignancy present in IT is 8.2% based on histopathological results. Of the patients who underwent surgery, thyroid malignancy was identified in 54.3% of them. Cytoponction showed a strong correlation with final histopathological results (p = 0.009). Thyroid incidentalomas detected with 18FDG-PET/CT are relatively infrequent, but the potential risk of malignancy remains elevated. Fine needle aspiration biopsy is the investigation of choice to rule out a malignant incidentaloma when there is no other element in the clinical portrait to preclude such additional work up.


Spontaneous intraperitoneal hemorrhage in the third trimester of pregnancy: Clinical suspicion made the difference.
A case of spontaneous hemoperitoneum resulting from ruptured vessels in the uterine-ovarian plexus, in the third trimester of pregnancy is described. This is a rare and challenging obstetric emergency. Acute abdominal pain is the main presenting symptom. Clinical suspicion and rapid intervention consisting of emergency cesarean section with ligation of bleeding vessels resulted in favorable outcomes for both mother and baby. The importance of prompt action in the case of deteriorating vital signs is emphasized to achieve success in their management.


Xyloglucan-based hybrid nanocomposite with potential for biomedical applications.
Natural polymer-based hybrid nanocomposites have been proposed as one of the most promising tools for biomedical applications, including disease treatment and diagnosis procedures. Xyloglucan nanocapsules can simultaneously load magnetic iron oxide nanoparticles and bioactive for a specific tissue, reducing the processes of degradation and metabolic inactivation of molecules with biological activity. In this work, magnetic nanocapsules of xyloglucan loaded with hydrophilic sulfated quercetin (MNXQ_SO3) were successfully synthesized by inverse miniemulsion process through interfacial polymerization. The polymeric shell formation of nanocapsules was evidenced by Fourier Transform Infrared spectroscopy and Transmission Electron Microscopy. The ferrofluid (Fe3O4@PAAS) incorporated into the xyloglucan nanocapsules was synthesized by hydrothermal method, using polyacrylic acid sodium salt as coating. Dynamic Light Scattering technique confirmed the nanomeric dimensions (202.3 nm) and the good colloidal stability (-40.2 mV) of MNXQ_SO3. The saturation magnetization analyses pointed out the superparamagnetic behavior of Fe3O4@PAAS (48 emu/g) and MNXQ_SO3 (4.2 emu/g). MNXQ_SO3 was able to modify the release profile of sulfated quercetin (67%) when compared to the free bioactive (100%), exhibiting a release profile compatible with the zero-order kinetic model. The results showed that the development of MNXQ_SO3 presents a new perspective for biomedical applications, including studies of targeted drug delivery.


1D lattice distortions as the origin of the (2 x 2)p4gm reconstruction in gamma'-Fe4N(100): a magnetism-induced surface reconstruction.
The (100) surface of magnetic gamma'-Fe4N films epitaxially grown on Cu(100) shows a (2 x 2)p4gm reconstruction. The atom positions determined experimentally are properly accounted for by first-principles total energy calculations, which further reveal that the (2 x 2)p4gm reconstruction requires the topmost Fe4N2 plane to be magnetic and effectively decoupled from the rest of the crystal and that it originates from the perpendicular crossing of one-dimensionally dimerized Fe chains.


A biphasic response of urinary prostaglandin E2 excretion to water deprivation in conscious diabetes insipidus Brattleboro rats.
The effects of water deprivation on the urinary excretion rate of prostaglandin E2 (PGE2) were examined in conscious Brattleboro rats. In order to study the time course of the changes in the PGE2 excretory rate, urine was collected in 6 periods, 0-1 hour (h.). 1: 3-4.5 h., 8-10 h., III: 12-15 h., IV: 24-28 h. and V: 32-36 h. after removal of water and food. It was found that the PGE2 excretion rate changed in a biphasic pattern. During the first 2 experimental periods it increased. Thereafter it decreased towards the control value. There was an increase in PGE2 excretion with urinary flows down to 3 microliter/(min*100 g b. wt). At further reductions in urinary flow rate, PG excretion decreased towards basal levels.


Binary toxicity of polystyrene nanoplastics and polybrominated diphenyl ethers to Arctic Cyanobacteria under ambient and future climates.
Cyanobacteria are the predominant biota in the Arctic. Interactive effects on Arctic cyanobacteria between climate-change-shifting parameters and anthropogenic contaminants are largely unknown. We utilized a fractional factorial experiment and Arctic cyanobacteria Pseudanabaena biceps Strain PCCC_O-153 to capture the complexity of interacting climate factors, nano-polystyrene (nano-PS) and 2,2´,4,4´-tetrabromodipenyl ether (BDE-47). The short-term binary toxicity of nano-PS and BDE-47 was then examined through experiments, toxicity units, and reference models. The toxic mechanism was further revealed through biochemical analyses and multivariate statistics. We found that BDE-47 and nano-PS had more hazardous effects than changing climate conditions. The mixture had antagonistic effects on PCCC_O-153, attributing to the aggregation of nano-PS, the adsorption of BDE-47, and the wrapping of both contaminants by released extracellular polymeric substances. Binary toxicity was caused by the chain reactions triggered by combining individual contaminants. Total protein was a sensitive target and positively correlated to chlorophyll pigment. Oxidative stress for the mixture mainly resulted from the presence of nano-PS. This is the first study to access the hazardous effects of a mixture of anthropogenic contaminants on Arctic cyanobacteria under ambient and future climates.


Soft and stretchable organic bioelectronics for continuous intraoperative neurophysiological monitoring during microsurgery.
In microneurosurgery, it is crucial to maintain the structural and functional integrity of the nerve through continuous intraoperative identification of neural anatomy. To this end, here we report the development of a translatable system leveraging soft and stretchable organic-electronic materials for continuous intraoperative neurophysiological monitoring. The system uses conducting polymer electrodes with low impedance and low modulus to record near-field action potentials continuously during microsurgeries, offers higher signal-to-noise ratios and reduced invasiveness when compared with handheld clinical probes for intraoperative neurophysiological monitoring and can be multiplexed, allowing for the precise localization of the target nerve in the absence of anatomical landmarks. Compared with commercial metal electrodes, the neurophysiological monitoring system allowed for enhanced post-operative prognoses after tumour-resection surgeries in rats. Continuous recording of near-field action potentials during microsurgeries may allow for the precise identification of neural anatomy through the entire procedure.


Fabrication and characterization of zein nanoparticles by dextran sulfate coating as vehicles for delivery of curcumin.
Zein nanoparticles (ZNPs) have limited use as a result of its poor colloidal stability. The goal of this paper is to stabilize ZNPs using a sulfated anionic polysaccharide-dextran sulfate (DS). Zein/DS composite nanoparticles (ZDSNPs) were fabricated by antisolvent precipitation method at pH 4.0 with an optimal zein-to-DS ratio of 1:2 (w/w). ZDSNPs exhibited good stability to pH, heating and storage. Additionally, ZDSNPs showed spherical structures formed primarily by electrostatic attractions, hydrogen bonding and hydrophobic interactions. The incorporation of DS led to the change in secondary structure of zein. The surface hydrophobicity of ZNPs reduced owing to the deposition of DS. And ZDSNPs were basically nontoxic to normal colonic epithelial cell lines-NCM460 cell lines. ZDSNPs were successfully used to encapsulate curcumin. The encapsulation efficiency of curcumin-loaded ZDSNPs (ZDSCNPs) was 85.37%, which was significantly higher than that of curcumin-loaded ZNPs. In addition, ZDSCNPs exhibited improved storage stability and bioaccessibility of curcumin.


Iodine absorption in burn patients treated topically with povidone-iodine.
Providone-iodine is used as a topical antimicrobial in burn patients. Although absorption of iodine has been thought to be negligible, several patients have recently been noted with substantial elevations of serum free iodide. Unexplained abnormalities occurred in several of these patients, renal failure, metabolic acidosis, and elevation of serum glutamic oxaloacetic transaminase. It is conceivable that the large iodide loads noted were at least in part responsible for these abnormalities.


Toxicity of historically metal(loid)-contaminated soils to Folsomia candida under the influence of climate change alterations.
Global warming is drastically altering the climate conditions of our planet. Soils will be among the most affected components of terrestrial ecosystems, especially in contaminated areas. In this study we investigated if changes in climate conditions (air temperature and soil moisture) affect the toxicity of historically metal(loid)-contaminated soils to the invertebrate Folsomia candida, followed by an assessment of its recovery capacity. Ecotoxicity tests (assessing survival, reproduction) were performed in field soils affected by metal(loid)s under different climate scenarios, simulated by individually changing air temperature or soil moisture conditions. The scenarios tested were: standard conditions (20°C + 50% soil water holding capacity-WHC); increased air temperature (daily fluctuation of 20-30°C + 50% WHC); soil drought (20°C + 25% WHC); soil flood (20°C + 75% WHC). Recovery potential was assessed under standard conditions in clean soil. Increased temperature was the major climate condition negatively affecting collembolans performance (decreased survival and reproduction), regardless of metal(loid) contamination. Drought and flood conditions presented less pronounced effects. When it was possible to move to the recovery phase (enough juveniles in exposure phase), F. candida was apparently able to recover from the exposure to metal(loid) contamination and/or climate alterations. The present study showed that forecasted climate alterations in areas already affected by contamination should be considered to improve environmental risk assessment.


A cutback in Imiquimod cutaneous toxicity; comparative cutaneous toxicity analysis of Imiquimod nanotransethosomal gel with 5% marketed cream on the BALB/c mice.
Herein, Imiquimod (IMQ) was incorporated in nanotransethosomes (nTES) to develop the IMQ-nTES nano-drug delivery system. IMQ-nTES was optimized using 23 factorial design. The optimized formulation was expressed with a particle size of 192.4 ± 1.60 nm, Poly-dispersibility of 0.115 ± 0.008, and IMQ percent entrapment efficiency of 91.05 ± 3.22%. Smooth and round morphology of IMQ-nTES vesicles was confirmed by TEM micrographs. Moreover, FTIR results have shown drug-excipient compatibility. The IMQ-nTES was laden inside the low molecular weight chitosan gel, which exhibited easy application, spreadability and no irritation to the applied skin. The release pattern has clearly exhibited improved dissolution properties of IMQ with the provision of the sustain release pattern. Higher IMQ content was deposited in deeper epidermis and dermis with IMQ-nTES gel, in contrast to ALDARA. In vivo, comparative toxicity study on BALB/c mice has shown significantly reduced (p < 0.001) psoriatic area severity index (PASI) score and less increment in ear thickness. Epidermal hyperplasia was an obvious finding with ALDARA which was, providentially, minimal in IMQ-nTES gel-treated skin. FTIR analysis of skin tissue has shown an enhancement of lipid and protein content in the ALDARA group, however, in the IMQ-nTES group no such change was observed. With ALDARA application, CD4+ T-cells and constitutive NF-κβ expression were significantly elevated, in comparison to the IMQ-nTES gel treated group. Moreover, the adequate expression of IFN-γ and cytotoxic CD8+ T-cells were suggesting the preserved IMQ efficacy with IMQ-nTES gel. Quantification of cutaneous as well as systemic inflammatory markers has also suggested the reduced psoriatic potential of IMQ-nTES gel. In essence, IMQ-nTES gel can be a suitable alternative to ALDARA owing to its better safety profile.


[Checkpoint inhibitors-indications and application in melanoma patients].
Since its introduction in 2011 the checkpoint inhibitor ipilimumab, has revolutionized the whole of oncology. After this first major step more checkpoint inhibitors, such as the PD‑1 antibodies nivolumab and pembrolizumab have been developed. The results are groundbreaking, especially in advanced malignant melanoma, which only a few years ago led to certain death in most cases after only a few months. Currently, the application of checkpoint inhibitors has been extended to many more tumor entities, with very promising results.


Signet ring carcinoma parotid gland: a case report.
Signet ring adenocarcinoma is a recently characterized entity occurring in the minor salivary glands. All reported cases have occurred in minor salivary gland. Pure signet ring adenocarcinoma of a major salivary gland has not been reported in the literature. A 38-year-old woman presented with a mass in the parotid region. Microscopy showed signet ring cells positive for mucicarmine. Immunohistochemistry showed cytokeratin and focal smooth muscle actin (SMA) positivity; an exhaustive search for primary elsewhere did not reveal any suspicious focus. A diagnosis of low-grade signet ring adenocarcinoma of the parotid gland was made. On 6-month follow-up the patient was alive and well. The present case highlights a rare occurrence of this tumor in the parotid gland, which until now was labeled as a tumor exclusive to minor salivary glands. Thus this entity should be kept as a differential while investigating mucinous tumors of parotid.


The role of combined magnetic field bone growth stimulation as an adjunct in the treatment of neuroarthropathy/Charcot joint: an expanded pilot study.
This study was designed to assess the value of combined magnetic field (CMF) bone growth stimulation in the treatment of acute, phase 1, Charcot neuroarthopathy. Thirty-one subjects were studied. Initially 10 controls and 11 study patients were examined. When the initial results were analyzed, 10 additional study patients were added. The result was a statistically significant reduction in time to consolidation, 23.8 weeks for the control versus 11 weeks for the study group. Additionally, less destruction of the bony architecture was noted in the study group as compared to the control. Thus the results of this expanded pilot study demonstrate the efficacy of CMF in accelerating the consolidation process of acute, phase 1, Charcot joint, and decreasing the amount of residual deformity.


Chronic lymphocytic leukemia showing pituitary tumor with massive leukemic cell infiltration, and special reference to clinicopathological findings of CLL.
An autopsy case of a 33 years old doctor with chronic lymphocytic leukemia (CLL) was reported. Two remissions were noted with chemotherapy and irradiation. The special characteristic of this case was the tumor formation in the sellar fossa similating a pituitary tumor which was considered as a type of meningeal leukemia, showing visual disturbance. Leukemic cell infiltration was hardly observed in any other organs. From the analysis of five cases of CLL, the author proposes that CLL may be classified into two types: the one is the severe type showing a short clinical course and the other is a mild one, showing a long clinical course. Details such as histopathological findings, cause of death and clinical findings were discussed.


State-of-the-art of minimally invasive treatments of bone metastases.
Bone metastases is a common manifestation of advanced malignant tumors. With the recent advances in medical technology, the survival period of patients with malignant tumors is prolonged, and the probability of bone metastases is significantly increased. Approximately 70% to 80% of patients with breast or prostate cancer will eventually develop bone metastases. In addition, thyroid, lung, and kidney carcinomas are all known to cause bone metastases, with a 30% to 40% incidence upon postmortem assessment. Bone metastases often lead to severe pain, pathological fractures, and nerve damage and have become a critical factor affecting the quality of life and life expectancy of cancer patients. Although treatments for bone metastases are diverse, choosing the appropriate treatment is difficult. Both conservative treatment and open surgery have certain drawbacks and may not be appropriate for all patients. Interventional procedures have the advantages of less trauma with quicker recovery and represent a viable alternative. This review provides updates on the progress of research on the interventional treatment of bone metastases and directions regarding relevant further studies.


Corrigendum to "Exposure assessment of Bisphenol A intake from polymeric babybottles in formula-fed infants aged less than one year" [Toxicology Reports 2 (2015) 1273-1280].
[This corrects the article DOI: 10.1016/j.toxrep.2015.09.002.].


Specific changes in the expression of imprinted genes in prostate cancer--implications for cancer progression and epigenetic regulation.
Epigenetic dysregulation comprising DNA hypermethylation and hypomethylation, enhancer of zeste homologue 2 (EZH2) overexpression and altered patterns of histone modifications is associated with the progression of prostate cancer. DNA methylation, EZH2 and histone modifications also ensure the parental-specific monoallelic expression of at least 62 imprinted genes. Although it is therefore tempting to speculate that epigenetic dysregulation may extend to imprinted genes, expression changes in cancerous prostates are only well documented for insulin-like growth factor 2 (IGF2). A literature and database survey on imprinted genes in prostate cancer suggests that the expression of most imprinted genes remains unchanged despite global disturbances in epigenetic mechanisms. Instead, selective genetic and epigenetic changes appear to lead to the inactivation of a sub-network of imprinted genes, which might function in the prostate to limit cell growth induced via the PI3K/Akt pathway, modulate androgen responses and regulate differentiation. Whereas dysregulation of IGF2 may constitute an early change in prostate carcinogenesis, inactivation of this imprinted gene network is rather associated with cancer progression.


Antimicrobial resistance in Neisseria gonorrhoeae in China: a meta-analysis.
Neisseria gonorrhoeae (N. gonorrhoeae) resistance to antimicrobial has been a major concern in China, and epidemiological data on N. gonorrhoeae resistance are not well understood. This meta-analysis was aimed at summarizing the evidence on N. gonorrhoeae resistance to penicillin, tetracycline, ciprofloxacin, ceftriaxone and spectinomycin in China. Two researchers independently searched five databases to identify studies on N. gonorrhoeae resistance to antimicrobials from the databases' inception to November 7, 2014. A random-effects model was used to estimate the antimicrobial resistance rates and their corresponding 95% confidence intervals (CIs). Publication bias was assessed with the Begg rank correlation test and the Egger test. We included 127 studies in our synthesis reporting antimicrobial resistance. Our analyses demonstrated that N. gonorrhoeae resistance to penicillin and tetracycline respectively increased from 74.41% (95% CI: 64.1-84.7%) and 68.3% (95% CI: 58.7-78.0%) in 2000 to 84.2% (95% CI: 79.7-88.8%) and 82.4% (95% CI: 79.9-84.7%) in 2012. N. gonorrhoeae resistance to ciprofloxacin experienced a steady increase from 12.7% (95% CI, 8.6-16.7%) in 1995 and reached 93.8% (95% CI: 91.9-95.7%) in 2003. N. gonorrhoeae resistance to ceftriaxone was 1.7% (95% CI: 0.5-5.7%) before 1995 and 0.5% (95% CI: 0.2-1.4%) in 2012, and N. gonorrhoeae resistance to spectinomycin was less than 2% from 1995 to 2012. N. gonorrhoeae resistance rates to penicillin, tetracycline and ciprofloxacin were high in China. Ceftriaxone and spectinomycin remained effective therapy for the treatment of gonorrhea. It is essential to strengthen N. gonorrhoeae resistance surveillance and update treatment guidelines timely.


Radiation exposure to family members of patients with thyrotoxicosis treated with iodine-131.
The purpose of this study was twofold: (1) to measure the radiation exposure to family members of out-patients with thyrotoxicosis treated with radioiodine, 131I, using the recommendations from the European Commission (EC) guidance and age-specific periods for behaviour restrictions; (2) to use the results to identify necessary restrictions to ensure recommended dose constraints. The study population comprised 76 family members (46 adults and 30 children below the age of 18) of 42 patients. The patients were treated with an average activity of 417 MBq (range 260-600 MBq). They received oral and written EC recommendations about behaviour restrictions (translated into Norwegian). On the day of treatment we repeated the oral instructions to the patient and an adult family member. The time periods for restrictions were 14 days for children aged 0-10 years, 7 days for persons aged 11-59 years and 3 days for persons aged 60 years and older. Family members wore a thermoluminescent dosimeter (TLD) on each wrist day and night for 2 weeks. The doses received were adjusted to give an estimate of the expected values if the TLDs had been worn indefinitely. Radiation doses well below the recommended dose constraints were measured for all adult family members and children, except one 2-year-old child; in the latter case the mother probably did not comply with the instructions given. The radiation dose to family members of thyrotoxic patients treated with up to 600 MBq of radioiodine is well below recommended dose constraints if EC instructions are given and compliance is adequate. The duration of restrictions for various age groups used in this study may be considered when establishing guidelines in Norway.


Surgical access to primary orbital tumors.
The basics of evaluation and surgical access to primary orbital tumors as well as paranasal or intracranial neoplasms that invade the orbit are presented.


Behaviour modification.
The first part of the article outlines how behaviour, both normal and 'abnormal', is a learned phenomenon and briefly looks at the various contingencies of learning that determine which behaviours develop. Many types of psychological disorder can be accounted for by such an approach, and several examples of how behavioural disorders develop are outoined. Finally, a rationale for treating certain types of these behavioural disorders is presented.


A test of a competition model with reference to three species of small mammals in south-eastern Australia.
This study tests the hypothesis that competition occurs in a community of three species of small mammals (Antechinus stuartii and A. swainsonii, Marsupialia; Rattus fuscipes, Rodentia) in south-eastern Australia. The hypothesis was tested by using a simple model of competition that is based on two premises: I. competition results in a negative numerical or a negative spatial association between species, and II. competition is more intense where the densities of the competing species are relatively high. The model combines both premises and predicts that measures of association between competing species will be more negative where the species exist at high population densities than derived from the model and applied to data gathered in two study areas with contrasting mean animal densities. There was no evidence of numerical association among the species (three tests), but evidence of negative spatial association (three tests our of four). These latter findings were consistent with the predictions of the model. All species preferred the same broad kinds of habitat (macrohabitat), but they segregated into smaller, finer grained patches (microhabitat) when their numbers were relatively high. Such segregation was more evident between the two species of marsupials than between either species of marsupial and the eutherian rat. These findings suggested that competition occurs by interference, and reinforce the idea that an understanding of the behaviour of individuals is important to understanding competition between species.


Melatonin retards senescence via regulation of the electron leakage of postharvest white mushroom (Agaricus bisporus).
Currently, melatonin (N-acetyl-5-methoxytrytamine) is recognized as a potential scavenger of free radicals. In this study, the effect of exogenous melatonin at various concentrations (0.05, 0.1, and 0.2 mM) on the texture, sensory qualities, and electron leakage in white mushrooms was evaluated at 3 ± 1 °C. It was observed that mushrooms treated with 0.1 mM melatonin were of good quality and their electron leakage was dramatically dampened. The results showed that 0.1 mM melatonin retained a higher adenosine triphosphate level and also prevented the release of cytochrome c into the cytoplasm. More significantly, it prominently inhibited electron leakage by increasing the activities of complexes I and III by the upregulation of AbNdufB9 and AbRIP1. It also regulated respiratory states in mushrooms; delayed the decline of respiratory state 3; enhanced respiratory state 4; boosted the oxidative phosphorylation and efficiency of mitochondria; and ultimately retarded the senescence of the white mushrooms.


Malignancy rates in Crohn's disease patients with perianal fistula: A German retrospective cohort study.
Patients with inflammatory bowel disease are at increased risk of colorectal and extra-intestinal cancer. However, the overall cancer risk in patients with Crohn's disease (CD) with perianal fistulas (PF) (CPF) and those with CD without PF (non-PF CD) is unclear. To describe the prevalence and incidence of cancer in patients with CPF and non-PF CD, and to estimate incidence rate ratio (IRR) of cancer between CPF and non-PF CD groups. A retrospective cohort study was conducted using the German InGef (Institute for Applied Health Research Berlin) research database. Patients with a CD record and PF from 1 January 2013 to 31 December 2014 were identified and followed up from 1 January 2015 until the first occurrence of cancer, end of health insurance contributing data, death, or end of study period (31 December 2020). Prevalence of any type of cancer including patients with CD diagnosed with cancer in the selection period and incidence of cancer excluding patients with CD diagnosed with cancer in the selection period were calculated. In total, 10,208 patients with CD were identified. Of 824 patients with CPF (8.1%), 67 had had a malignancy (6-year period crude malignancy prevalence 8.13% [95% confidence interval (CI) 6.36%-10.21%]), which was lower than patients with non-PF CD (19.8% [95% CI 19%-20.6%]). Incidence (per 100,000 person-years) in patients with CPF was 1184 (95% CI 879-1561) and in non-PF CD was 2365 (95% CI 2219-2519). There was no significant difference in the adjusted IRR of cancer for the CPF group compared with the non-PF CD group (0.83 [95% CI 0.62-1.10]; p = 0.219). There was no significant difference in the incidence of any cancer in patients with CPF compared with non-PF CD. However, patients with CPF had a higher numerical risk of cancer than the general German population.


Beneficial effects of endoscopic screening on gastric cancer and optimal screening interval: a population-based study.
BACKGROUND : The effectiveness of endoscopic screening on gastric cancer has not been widely investigated in China and the screening interval of repeated screening has not been determined. METHODS : In a population-based prospective study, we included 375,800 individuals, 14,670 of whom underwent endoscopic screening (2012-2018). We assessed the associations between endoscopic screening and risk of incident gastric cancer and gastric cancer-specific mortality, and examined changes in overall survival and disease-specific survival following screening. The optimal screening interval for repeated endoscopy for early detection of gastric cancer was explored. RESULTS : Ever receiving endoscopic screening significantly decreased the risk of invasive gastric cancer (age- and sex-adjusted relative risk [RR] 0.69, 95 % confidence interval [CI] 0.52-0.92) and gastric cancer-specific mortality (RR 0.33, 95 %CI 0.20-0.56), particularly for noncardia gastric cancer. Repeated screening strengthened the beneficial effect on invasive gastric cancer-specific mortality of one-time screening. Among invasive gastric cancers, screening-detected individuals had significantly better overall survival (RR 0.18, 95 %CI 0.13-0.25) and disease-specific survival (RR 0.18, 95 %CI 0.13-0.25) than unscreened individuals, particularly for those receiving repeated endoscopy. For individuals with intestinal metaplasia or low grade intraepithelial neoplasia, repeated endoscopy at an interval of < 2 years, particularly within 1 year, significantly enhanced the detection of early gastric cancer, compared with repeated screening after 2 years (P-trend = 0.02). CONCLUSION : Endoscopic screening prevented gastric cancer occurrence and death, and improved its prognosis in a population-based study. Repeated endoscopy enhanced the effectiveness. Screening interval should be based on gastric lesion severity.


Inhalation toxicity studies on cigarette smoke. V. Deposition of smoke particles in the respiratory system of rats under various exposure conditions.
This paper describes a dosimetry experiment on rats which was designed to make a contribution towards the optimisation of exposure conditions for inhalation toxicology studies with smoke aerosols. The main conclusions drawn from the work are: (i) Under continuous exposure conditions the deposition of total particulate matter (TPM) in the respiratory system and carboxyhaemoglobin (COHb) levels in blood were linearly dependent on the concentration of smoke in the exposure chamber. (ii) Intermittent exposure gave relatively lower TPM deposition compared to continuous exposure, even after allowing for differences in actual exposure times. (iii) For arithmetically equivalent exposure levels, short exposure to high concentration gave greater TPM deposition than long exposures to low smoke concentrations. (iv) There was a good correlation between lower respiratory system (LRS) and lung deposition of TPM and blood COHb level for both continuous and intermittent exposure conditions. These findings are discussed in relation to the conduct of inhalation studies with tobacco smoke.


Accuracy of molecular diagnostic methods for the detection of bovine brucellosis: A systematic review and meta-analysis.
Bovine brucellosis is a disease of global socio-economic importance caused by Brucella abortus. Diagnosis is mainly based on bacterial culture and serology. However, these methods often lack sensitivity and specificity. A range of molecular diagnostic methods has been developed to address these challenges. Therefore, this study aims to investigate the diagnostic accuracy of molecular tools, in comparison to gold standard bacterial isolation and serological assays for the diagnosis of bovine brucellosis. The systematic review and meta-analysis were conducted based on analyses of peer-reviewed journal articles published between January 1, 1990, and June 6, 2020, in the PubMed, Science Direct, Scopus, and Springer Link databases. Data were extracted from studies reporting the use of molecular diagnostic methods for the detection of B. abortus infections in animals according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The quality of included journal articles was assessed using the quality assessment of diagnostic-accuracy studies assessment tool and meta-analysis was carried out using Review Manager. From a total of 177 studies, only 26 articles met the inclusion criteria based on PRISMA guidelines. Data from 35 complete studies were included in the meta-analysis and used to construct 2 × 2 contingency tables. Improved diagnostic performance was observed when tissue (sensitivity 92.7% [95% confidence interval (CI) 82.0-98.0%]) and serum samples (sensitivity 91.3% [95% CI 86.0-95.0%]) were used, while the BruAb2_0168 locus was the gene of preference for optimal assay performance (sensitivity 92.3% [95% CI 87.0-96.0%] and specificity 99.3% [95% CI 98.0-100.0%]). Loop-mediated isothermal amplification (LAMP) had a higher diagnostic accuracy than polymerase chain reaction (PCR) and real-time quantitative PCR with sensitivity of 92.0% (95% CI 78.0-98.0%) and specificity of 100.0% (95% CI 97.0-100.0%). The findings of this study assign superior diagnostic performance in the detection of B. abortus to LAMP. However, due to limitations associated with decreased specificity and a limited number of published articles on LAMP, the alternative use of PCR-based assays including those reported in literature is recommended while the use of LAMP for the detection of bovine brucellosis gains traction and should be evaluated more comprehensively in future.


Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients.
The present study was conducted to determine the concentration of amino acids in the cerebrospinal spinal fluid (CSF) and the activities of two tramsaminases: glutamic oxaloacetate transaminase (GOT) and glutamic pyruvate transaminase (GPT) in human Alzheimer disease (AD) and normal brain. L-glutamic acid, L-glutamine and L-alanine are the most abundant amino acids in the CSF (50-55% of total amino acids). L-glutamine occurs at much higher levels in Alzheimer CSF compared to the normal CSF (229+/-91.8 nmol/ml in AD versus 107+/-47.2 nmol/ml in normal; P=0.0041). In contrast, L-aspartate occurs at significantly lower concentrations in Alzheimer CSF than normal CSF (46.1+/-25.7 nmol/ml in Alzheimer versus 95.2+/-52.6 nmol/ml in normal; P=0.020). In Alzheimer brain (frontal, parietal and occipital cortices) GOT is present at significantly higher activities than in normal brain cortices (about 1.5 times higher; P<0.01). No significant differences for GPT activity occurred between normal and AD brain. Since CSF receives amino acids from brain tissues, and since GOT catalyzes the conversion of L-aspartate to L-glutamate, the higher concentrations of L-glutamine (which is derived from L-glutamate), and the lower concentrations of L-aspartate found in Alzheimer CSF could be considered as a consequence of the higher activity of GOT that occurs in Alzheimer brain.


A novel pathway for the induction of DNA damage in human spermatozoa involving extracellular cell-free DNA.
DNA damage is a common feature of human spermatozoa associated with an impaired capacity to fertilize the oocyte and an increased mutational load in the offspring. However, the etiology of this damage remains poorly defined. In this study we demonstrate that a major pathway for the induction of DNA damage in mammalian spermatozoa is triggered by exposure to exogenous cell free DNA (cfDNA). Exposure of human and mouse spermatozoa to cfDNA (calf thymus, mouse liver and salmon testes) in vitro induced a dose-dependent increase in sperm DNA damage that could be effectively suppressed by the concomitant presence of DNase. The induction of such damage was not accompanied by any concomitant change in sperm motility or vitality and was not directly associated with the induction of oxidative stress. In vivo the injection of exogenous DNA again precipitated an increase in sperm DNA fragmentation that could be reversed by the prior administration of DNase. Similarly, the induction of a transient unilateral testicular ischemia induced an increase in DNA fragmentation that was evident within 24 h and sustained for at least 14 days via mechanisms that could be completely suppressed by the prior administration of DNase. We conclude that exogenous cfDNA activates a defensive response in human spermatozoa associated with the nuclease-mediated induction of DNA fragmentation, possibly involving the participation of TLR9 and CD4. These novel insights have significant implications for our understanding of DNA fragmentation in the male germ line and open up new pathways for the remediation of this condition.


Radioimmunological and biological measurement of prostaglandins in rabbit urine: decrease of PGE2 excretion at high NaCl intake.
The estimation of prostaglandin (PG) E2 and of PGF2alpha by radioimmunoassay is described in detail. PGE2 was measured after conversion to either PGB2 or PGF2alpha and the results compared to bioassay. The methods were used to follow the excretion of PGE2 and PGF2alpha after salt loading in rabbits. A marked reduction of PGE2 levels was observed at high NaC1 intake, while PGF2alpha excretion remained unchanged.


Increased Lung Cancer Risk and Associated Risk Factors in Tuberculosis Survivors: A Korean Population-Based Study.
Few studies have comprehensively evaluated the risk of lung cancer in tuberculosis survivors with consideration of smoking status and chronic obstructive pulmonary disease (COPD). Furthermore, little is known about lung cancer risk factors in tuberculosis survivors. This population-based cohort study enrolled tuberculosis survivors (n = 75 467) between 2010 and 2017 and 1:1 age- and sex-matched controls. Subjects were followed up for 1 year from the date of tuberculosis diagnosis to the date of the incident lung cancer, death, or December 2018, whichever came first. The risk of lung cancer was evaluated according to smoking and COPD status. We also evaluated the risk factors for lung cancer and developed an individualized lung cancer prediction model for tuberculosis survivors. During a median follow-up duration of 4.8 years, the incident lung cancer risk was 1.72-fold higher in tuberculosis survivors than in the controls. Among tuberculosis survivors, those who were current smokers with ≥20 pack-years showed the highest risk of lung cancer (adjusted hazard ratio, 6.78) compared with never-smoker, non-tuberculosis-infected controls. tuberculosis survivors with COPD had a higher risk (2.43) than non-COPD, non-tuberculosis-infected controls. Risk factors for lung cancer in tuberculosis survivors were pulmonary tuberculosis, age >60 years, smoking, and the presence of COPD or asthma. The individualized lung cancer risk model showed good discrimination (concordance statistic = 0.827). Previous tuberculosis infection is an independent risk factor regardless of smoking status or amount and COPD. Closer monitoring of tuberculosis survivors, especially heavy smokers or those with COPD, is needed for early lung cancer diagnosis.


[Uterine arteriovenous malformations: diagnosis and treatment in 2011].
Uterine arteriovenous malformations (UAVM) are rare. They mostly occur after endo-uterine trauma, or are less often congenital. When symptomatic, they may be a cause of uterine recurrent and massive bleeding. Diagnosis should be evoked in these cases, to avoid haemostatic curettage which will be useless and injurious. UAVM is often suspected by Doppler ultrasound, but pelvic MRI seems to be also relevant. Angiography confirms the diagnosis and allows concomitant embolization. Uterine embolization seems to be currently the best treatment, however surgery should still be performed in case of failure or hemodynamic instability. In this work, we aim to evaluate diagnosis and therapeutic modalities for UAVM.


Cutaneous malignant melanoma after immunosuppressive therapy.
Malignant neoplasm after immunosuppressive therapy is a well-known entity. Though a considerable number of such lesions are cutaneous in origin, melanoma has rarely been reported. In this communication, six such melanoma cases are reported.


Differential rearing effects on rat visual cortex synapses. III. Neuronal and glial nuclei, boutons, dendrites, and capillaries.
Morphological measures of neurons, astrocytes, oligodendrocytes, presynaptic boutons, dendrites and capillaries were examined in the upper 4 layers of occipital cortex in rats reared for 30 days postweaning in complex (EC), social (SC) or individual cage (IC) environments. EC rats had a lower numerical density of neuronal nuclei with a comparable volume fraction to SC and IC rats. The volume fraction of astrocyte and oligodendrocyte nuclei was significantly greater for EC rats than IC littermates, and IC rats also had more synapses and neurons/micron3 of glial nuclei. Environmental groups did not differ in the numerical density of presynaptic boutons but the number of boutons per neuron was greater in EC than in IC or SC rats. This result parallels the findings that EC rats have more synapses per neuron than IC rats. Electron microscopic estimates of dendritic volume fraction confirmed estimates from Golgi-impregnated neurons that there is more dendrite per neuron in the occipital cortex of EC rats than IC or SC rats. EC rats also had a larger capillary volume than SC or IC and these capillaries were closer together and had fewer synapses/micron3 of capillary in ECs. Another indicator of metabolic activity, mitochondria volume per neuron, gave similar results with ECs having a greater volume than ICs and SCs intermediate. These results indicate that not only are there more synapses per neuron in the visual cortex of rats from more complex environments but also that the brain appears to adjust to the metabolic requirements of its synapses or neurons, in terms of vascular, mitochondrial and glial support.


Involucrin, a marker of squamous and urothelial differentiation. An immunohistochemical study on its distribution in normal and neoplastic tissues.
Involucrin is a soluble protein precursor of the cross-linked envelope present in the submembranous zone of human stratum corneum, and subsequently demonstrated in stratified squamous epithelia. The immunoperoxidase technique was used to assess the distribution of involucrin in 107 normal and 318 abnormal tissues. With few exceptions, involucrin was restricted to squamous epithelia, urothelium, some skin appendages and thymic Hassall's corpuscles. In normal squamous epithelium and normal urothelium, staining was most intense in the superficial layers where it was concentrated at the cell periphery and gradually decreased toward the basal layer. This orderly staining pattern was maintained in benign squamous and urothelial lesions and in grade I papillary urothelial carcinomas. Higher grade papillary urothelial carcinomas, infiltrating urothelial and squamous carcinomas, and in situ urothelial and squamous carcinomas demonstrated abnormal staining patterns for involucrin that are described. Foci of squamous differentiation in adenocarcinomas and other epithelial malignancies stained intensely for involucrin. Brenner tumours of the ovary and Walthard rests of the fallopian tube, lesions of uncertain histogenesis but possibly urothelial-related, also stained for involucrin. Results of this study suggest that involucrin is a sensitive and specific marker for squamous and urothelial differentiation, staining patterns for involucrin may be helpful in distinguishing benign from malignant urothelial and squamous lesions, and presence of involucrin may be helpful in determining the histogenesis of selected lesions.


Studies of cAMP metabolism in cultured hepatoma cells: presence of functional adenylate cyclase despite low cAMP content and lack of hormonal responsiveness.
The ability of isoproterenol, glucagon, PGE1 and cholera toxin to stimulate the synthesis of cAMP and protein kinase activity in line of liver cells (BRL) and a line of rat hepatoma cells (H35) has been determined. The concentration of cAMP in BRL cells (approximately 10 pmoles/mg protein) is in the range reported for other cultured cell lines but H35 cells contain extraordinarily low amounts of this cyclic nucleotide (approximately 0.05 pmoles/mg protein). Isoproterenol and PGE1 caused an increase in cAMP content, and protein kinase activation in BRL cells, although glucagon was ineffective. H35 cells, in contrast, were completely insensitive to all hormonal agonists. Despite this fact, cholera toxin was able to produce a marked increase in cAMP content, adenylate cyclase activity and protein kinase activation in H35 cells. binding studies with [125 I]-iodohydroxybenzylpindolol, a specific beta-adrenergic receptor antagonist, revealed that each H35 cell possesses fewer than 10 beta-adrenergic receptors whereas BRL cells contain 2-5,000 receptors per cell. The low level of cAMP in H35 cells appears to result from a combination of totally unstimulated adenylate cyclase and apparently elevated phosphodiesterase activities.


Risk of lung cancer in pre- and post-menopausal women with ano-genital malignancies.
Women diagnosed during the period 1943-1990 and reported to the Danish Cancer Registry with invasive squamous-cell carcinomas of the uterine cervix, vulva, vagina or anus, together with those having pre-cancerous lesions (CIN III or carcinoma in situ) of the uterine cervix diagnosed in the period 1958-1990, were followed for the occurrence of subsequent lung cancer over 762,000 person-years. Overall, these patients developed 2 to 2 1/2 times more lung cancers than women in the general Danish population. Women in whom cervical cancer was diagnosed recently, and before the age of 45 years, had a 4.6 times elevated risk of developing lung cancer, while young women with vulvar or vaginal cancer were at a 4.0-fold elevated risk. Similarly, women in whom anal cancer was diagnosed before the age of 60 years were at a 3.5-fold increased risk of developing lung cancer. The present study supports the hypothesis that smoking is involved in the aetiology of ano-genital malignancies. The particularly high risk of developing subsequent lung cancers seen in women who were pre-menopausal (< 45 years) at the time of the ano-genital cancer diagnosis suggests that the effect of smoking in ano-genital carcinogenesis might be partly mediated through alterations in oestrogen metabolism. Alternatively, patients who developed their initial ano-genital cancer at a young age might harbour some genetic susceptibility which could explain their excess lung-cancer risk.


Global comparative transcriptomes uncover novel and population-specific gene expression in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and is one of the deadliest gastrointestinal malignancies. Despite numerous transcriptomics studies to understand its molecular basis, the impact of population-specific differences on this disease remains unexplored. This study aimed to investigate the population-specific differences in gene expression patterns among ESCC samples obtained from six distinct global populations, identify differentially expressed genes (DEGs) and their associated pathways, and identify potential biomarkers for ESCC diagnosis and prognosis. In addition, this study deciphers population specific microbial and chemical risk factors in ESCC. We compared the gene expression patterns of ESCC samples from six different global populations by analyzing microarray datasets. To identify DEGs, we conducted stringent quality control and employed linear modeling. We cross-compared the resulting DEG lists of each populations along with ESCC ATLAS to identify known and novel DEGs. We performed a survival analysis using The Cancer Genome Atlas Program (TCGA) data to identify potential biomarkers for ESCC diagnosis and prognosis among the novel DEGs. Finally, we performed comparative functional enrichment and toxicogenomic analysis. Here we report 19 genes with distinct expression patterns among populations, indicating population-specific variations in ESCC. Additionally, we discovered 166 novel DEGs, such as ENDOU, SLCO1B3, KCNS3, IFI35, among others. The survival analysis identified three novel genes (CHRM3, CREG2, H2AC6) critical for ESCC survival. Notably, our findings showed that ECM-related gene ontology terms and pathways were significantly enriched among the DEGs in ESCC. We also found population-specific variations in immune response and microbial infection-related pathways which included genes enriched for HPV, Ameobiosis, Leishmaniosis, and Human Cytomegaloviruses. Our toxicogenomic analysis identified tobacco smoking as the primary risk factor and cisplatin as the main drug chemical interacting with the maximum number of DEGs across populations. This study provides new insights into population-specific differences in gene expression patterns and their associated pathways in ESCC. Our findings suggest that changes in extracellular matrix (ECM) organization may be crucial to the development and progression of this cancer, and that environmental and genetic factors play important roles in the disease. The novel DEGs identified may serve as potential biomarkers for diagnosis, prognosis and treatment.


Atorvastatin reduces renal interstitial fibrosis caused by unilateral ureteral obstruction through inhibiting the transcriptional activity of YAP.
Renal interstitial fibrosis is the primary pathological basis for the progression and development of various chronic kidney diseases, ultimately leading to renal failure. Obstructive kidney disease caused by conditions such as kidney stones, is a common cause of renal fibrosis. The Hippo pathway is a crucial signaling pathway that senses mechanical forces and is involved in the pathophysiology of fibrosis. In this study, we established a mouse model of obstructive kidney disease induced by unilateral ureteral obstruction (UUO). The UUO procedure significantly upregulated YAP and fibrosis-related gene expression in a time-dependent manner. Morphologically, the renal fibrotic lesions associated with hydronephrosis progressively worsened over time in the UUO group. Atorvastatin, which is widely used to lower blood cholesterol levels, has recently been shown to inhibit Yes1 associated protein (YAP). We treated UUO mice with atorvastatin for 3 and 10 days and observed a decrease in the expression of YAP and fibrosis-related genes at the mRNA and protein levels, along with a reduction in the renal fibrosis analyzed by Masson's staining. These findings suggest that atorvastatin may serve as a preventive agent for fibrosis associated with obstructive kidney disease.


Dynamically stable and amplified circularly polarized excimer emission regulated by solvation of chiral co-assembly process.
Chiral supramolecular assembly has been assigned to be one of the most favorable strategies for the development of excellent circularly polarized luminescent (CPL)-active materials. Herein, we report our study of an achiral boron-containing pyrene (Py)-based chromophore (PyBO) as a circularly polarized excimer emission (CPEE) dye induced by chiral co-assemblies containing chiral binaphthyl-based enantiomers (R/S-M). Chiral co-assembly R/S-M-(PyBO)4 fresh film spin-coated from toluene solution can exhibit orderly nanofibers and strong green CPEE (λem = 512 nm, gem = ±0.45, ΦFL = 51.2 %) resulting from an achiral PyBO excimer. In contrast, only a very weak blue CPL was observed (λem = 461 nm, gem = ± 0.0125, ΦFL = 19.0 %) after 187 h due to PyBO monomer emission as spherulite growth. Interestingly, this kind of chiral co-assembly R-M-(PyBO)4-T film from tetrahydrofuran (THF) solution retains uniform morphology and affords the most stable and strongest CPEE performance (λem = 512 nm, gem = + 0.62, ΦFL = 53.3 %) after 10 days.


Diagnostic performance of magnetic resonance arthrography of the shoulder in children.
No reported data demonstrate the usefulness of magnetic resonance arthrography of the shoulder in children. To evaluate the sensitivity, specificity and accuracy of MR arthrography in the assessment of superior labral anteroposterior (SLAP) tears of the shoulder, Bankart-type injuries and Hill-Sachs lesions in children as compared to arthroscopy. We retrospectively interpreted 66 MR arthrograms of the shoulder and compared them with surgical findings. Assessment included evaluation of the osseous structures, labral-ligamentous complex and determination of skeletal maturity. We calculated sensitivity, specificity and accuracy and compared sensitivity and specificity between skeletally mature and immature children. MR arthrography demonstrated a sensitivity, specificity and accuracy of 88%, 98% and 94%, respectively, for depiction of SLAP tears; 94%, 92% and 94% for detection of Bankart-type injuries; and 100%, 94% and 97% for diagnosing Hill-Sachs lesions. There was no statistical difference between the skeletally immature and skeletally mature groups. There is no significant difference in the diagnostic accuracy of MR arthrography in skeletally immature versus skeletally mature children. MR shoulder arthrography is an effective method for the detection of labral and bone pathology.