Cardiac Regenerative Therapy Using Human Pluripotent Stem Cells for Heart Failure: A State-of-the-Art Review.
Heart transplantation (HT) is the only definitive treatment available for patients with end-stage heart failure who are refractory to medical and device therapies. However, HT as a therapeutic option, is limited by a significant shortage of donors. To overcome this shortage, regenerative medicine using human pluripotent stem cells (hPSCs), such as human embryonic stem cells and human-induced pluripotent stem cells (hiPSCs), has been considered an alternative to HT. Several issues, including the methods of large-scale culture and production of hPSCs and cardiomyocytes, the prevention of tumorigenesis secondary to contamination of undifferentiated stem cells and non-cardiomyocytes, and the establishment of an effective transplantation strategy in large-animal models, need to be addressed to fulfill this unmet need. Although post-transplantation arrhythmia and immune rejection remain problems, the ongoing rapid technological advances in hPSC research have been directed toward the clinical application of this technology. Cell therapy using hPSC-derived cardiomyocytes is expected to serve as an integral component of realistic medicine in the near future and is being potentially viewed as a treatment that would revolutionize the management of patients with severe heart failure.


WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways.
Activation and disruption of Wnt/β-catenin signaling both result in cartilage breakdown via unknown mechanisms. Here we show that both WNT-3A and the Wnt inhibitor DKK1 induced de-differentiation of human articular chondrocytes through simultaneous activation of β-catenin-dependent and independent responses. WNT-3A activates both the β-catenin-dependent canonical pathway and the Ca(2+)/CaMKII noncanonical pathways, with distinct transcriptional targets. WNT-3A promotes cell proliferation and loss of expression of the chondrocyte markers COL2A1, Aggrecan, and SOX9; however, proliferation and AXIN2 up-regulation are downstream of the canonical pathway and are rescued by DKK1, whereas the loss of differentiation markers is CaMKII dependent. Finally, we showed that in chondrocytes, the Ca(2+)/CaMKII-dependent and β-catenin-dependent pathways are reciprocally inhibitory, thereby explaining why DKK1 can induce loss of differentiation through de-repression of the CaMKII pathway. We propose a novel model in which a single WNT can simultaneously activate different pathways with distinct and independent outcomes and with reciprocal regulation. This offers an opportunity for selective pharmacological targeting.


BTK Inhibitors in Chronic Lymphocytic Leukemia.
The treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed over the last few years with the introduction of novel targeted agents. Physicians are now faced with several equally effective therapy options when treating patients with CLL. Here, we review the role of Bruton tyrosine kinase (BTK) inhibitors in treating patients with treatment-naïve and relapsed or refractory CLL. We review recent approvals of BTK inhibitors as well as reported and ongoing clinical trial data. The approval of ibrutinib rapidly led to a paradigm shift in the management of CLL. Randomized trials have now compared ibrutinib to several chemoimmunotherapy approaches, which were in favor of ibrutinib. Second-generation more selective BTK inhibitors, including acalabrutinib and zanubrutinib, have been developed, and recent data have led to the approval of acalabrutinib in CLL. Ongoing and future studies focus on either combining BTK inhibitors with other novel agents (e.g., venetoclax, obinutuzumab, or ublituximab) or developing next-generation non-covalent reversible BTK inhibitors that may be effective in treating patients with CLL harboring BTK-resistant mutations. The field of CLL continues to evolve rapidly with new and evolving combination treatments and novel BTK agents, which will continue to change the standard of care for CLL.


Arterial 6-keto-PGF1 alpha and TxB2 release in ex vivo perfused canine vessels: effects of pulserate, pulsatility, altered pressure and flow rate.
Certain experimental conditions are known to influence the release of prostacyclin and thromboxane from the vessel wall. The specific effects of altered pulsatility, pressure, and flow rate on intraluminal release of 6-keto-PGF1 alpha and thromboxane B2 were assessed in canine arteries perfused ex vivo for five 15 min periods with arachidonic acid (AA) added during the last period. Control arteries were perfused at 100 mmHg with pulsatile flow of 90 ml/min. Experimental arteries were perfused at 7, 50 and 200 mmHg with pulsatile flow of 90 ml/min, and at 100 mmHg pressure with pulsatile flow of 20, 60, 130 and 180 ml/min, as well as at 100 mmHg with 90 ml/min nonpulsatile flow. Perfusion pump rates of 44 and 96 beats/min were also assessed. The lowest perfusion pressure, 7 mmHg, resulted in a lesser initial release of prostacyclin compared to higher pressures, and there was a tendency to a higher release of prostacyclin with increasing pressures. There was also a tendency for a lesser response to AA in arteries perfused at 200 mmHg, perhaps due to endothelial cell damage. Nonpulsatile flow was associated with a decreased initial release of prostacyclin, and diminished release following addition of AA when compared to pulsatile flow. Altered flow rate elicited no difference in prostacyclin release, although there was a tendency towards a lesser release when perfused at 20 ml/min compared to 130 ml/min or 180 ml/min. Thromboxane release was decreased by nonpulsatile flow but was otherwise unaffected by the experimental conditions tested. It is concluded that pulsatility enhances release of prostacyclin from arteries.(ABSTRACT TRUNCATED AT 250 WORDS)


A case of lung cancer metastasized to the gastrointestinal anastomosis site where the primary gastric cancer was resected 17 years ago.
Metastasis from lung cancer, often found in the adrenal glands, bone, liver, brain, and kidneys, have been thought to be rare in the digestive system. When a metastatic tumor is found in the intestine, it is most commonly metastatic melanoma or carcinoma of the cervix uteri, ovary, or breast. Yet, intestinal metastases have been described in 11% of lung cancers at autopsy. These metastases may induce gastrointestinal perforation, obstruction, or bleeding. Patients with bleeding from small intestinal metastases secondary to lung cancer almost uniformly have poor prognoses. The lung cancer metastasized to the gastrointestinal site or location where a first primary cancer was once resected is never reported in the literature. We report the case of a 76-year-old man with a history of gastric adenocarcinoma treated by subtotal gastrectomy seventeen years ago who presented with lung cancer metastatic to the bone. One month later, he developed persistent melena due to duodenal metastases. Upper gastrointestinal endoscopy showed an ulcerative duodenal mass with bleeding. The pathohistological and immunohistochemical examinations of tissue from the pathologic fracture and the endoscopic biopsy specimen revealed metastatic poorly differentiated adenocarcinoma consistent with lung origin. The diagnosis of metastatic lung cancer can be rendered based on pathologic examination and immunohistochemical analysis, even without access to the primary lung tumor. In this case, the anastomosis site where a gastrectomy for gastric cancer was once performed might be a good niche or microenvironment for cancer cells or tumor stem cells to metastasize to.


Self-contained, coaxial delivery system for intraarterial infusion of thrombolytic agents.
To facilitate continued direct intrathrombus infusion of a thrombolytic agent and yet minimize catheter exchanges and manipulations, the authors developed a simple, self-contained delivery system. It involves the use of supplies available in most angiographic suites. The system has been used in 44 patients; there have been no infectious complications, and it has been well tolerated by the patients.


PET versus PET/CT dual-modality imaging in evaluation of lung cancer.
Software coregistration of FDG-PET and CT datasets as well as integrated FDG-PET/CT enable significantly more accurate assessment of NSCLC staging than either modality alone. Integrated FDG-PET/CT has been shown to be more accurate in NSCLC staging than FDG-PET and CT read side by side. However, the benefits of anatometabolic imaging using FDG-PET/CT can only be fully exploited if optimized acquisition protocols are implemented.


Measurement of central venous pressure from a peripheral intravenous catheter in the lower extremity.
The measurement of central venous pressure (CVP) is used to assess intravascular status. Although this is usually accomplished by placement of a central venous catheter (CVC), there are circumstances when placement of a CVC may be technically difficult or impossible. The current study investigates the feasibility of measuring CVP from a peripheral intravenous catheter. CVP was simultaneously measured from a CVC and from a peripheral intravenous site. The continuity of the peripheral intravenous catheter with the central venous system was evaluated by noting the change in the pressure measured from the peripheral catheter during a sustained inspiratory effort and during occlusion of the extremity (arm or leg) above the catheter. The cohort for the study included 37 adult patients. In 8 of the 37 patients (22%), there was no increase in the peripheral venous pressure (PVP) in response to a Valsalva maneuver or occlusion of the extremity above the intravenous site. For the upper extremity intravenous sites without a PVP increase, the PVP-CVP difference was 11.2 +/- 6.2 mm Hg versus 2.7 +/- 2.2 mm Hg in the patients in whom the PVP increased with these maneuvers (P < 0.0001). For the lower extremity intravenous sites without a PVP increase, the PVP-CVP difference was 7.6 +/- 4.0 mm Hg versus 2.6 +/- 1.9 mm Hg in the patients in whom the PVP increased (P < 0.0001). No variation in the accuracy of the technique was noted, depending on the size of the intravenous cannula, its location (upper versus lower extremity), CVP value, or patient positioning (supine, prone, lateral). Provided that the PVP increases to a sustained inspiratory breath and occlusion above the intravenous site, there is a clinically useful correlation between the PVP and the CVP.


Pyrazoles as novel protein tyrosine phosphatase 1B (PTP1B) inhibitors: An in vitro and in silico study.
Type 2 diabetes mellitus (DM) is a complex chronic disorder and a major global health problem. Insulin resistance is the primary detectable abnormality and the main characteristic feature in individuals with type 2 DM. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathway, which dephosphorylates insulin receptor and insulin receptor substrates, suppressing the insulin signaling cascade. Therefore, the inhibition of PTP1B has become a potential strategy in the management of type 2 DM. In this study, a library of 22 pyrazoles was evaluated here for the first time against human PTP1B activity, using a microanalysis screening system. The results showed that 5-(2-hydroxyphenyl)-3-{2-[3-(4-nitrophenyl)-1,2,3,4-tetrahydronaphthyl]}-1-phenylpyrazole 20 and 3-(2-hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)]naphthyl}pyrazole 22 excelled as the most potent inhibitors of PTP1B, through noncompetitive inhibition mechanism. These findings suggest that the presence of additional benzene rings as functional groups in the pyrazole moiety increases the ability of pyrazoles to inhibit PTP1B. The most active compounds showed selectivity over the homologous T-cell protein tyrosine phosphatase (TCPTP). Molecular docking analyses were performed and revealed a particular contact signature involving residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. This study represents a significant beginning for the design of novel PTP1B inhibitors.


Laparoscopic resection of presacral benign tumors with rectum preservation.
Multiple surgical approaches are available for the treatment of presacral tumors. In patients with presacral tumors, surgical resection is currently the only curative treatment option. However, the anatomical structures of the pelvis are not readily accessible using traditional approaches. Herein, we present a surgical technique for laparoscopic presacral benign tumor resection with rectal preservation. Surgical videos of two patients were used to introduce the laparoscopic procedure. First, the tumor of a 30-year-old woman with presacral cysts was observed during physical examination. As the tumor continued to enlarge, it increased rectal compression and altered bowel habits. The patient's surgical video was used to present complete laparoscopic presacral resection. Several video clips of a second 30-year-old woman with cysts were used to present the details and precautions of the resection. Neither of the patients required conversion to an open surgical approach. Complete surgical excision of the tumors was achieved, without rectal injury. Both patients had no postoperative complications and were discharged on postoperative 5-6 days. The laparoscopic approach for presacral benign tumors is superior in terms of manipulability compared with the conventional approach. Therefore, we recommend that the laparoscopy approach should be considered as the standard surgical approach for presacral benign tumors.


Tannic acid alleviates experimental pulmonary fibrosis in mice by inhibiting inflammatory response and fibrotic process.
Pulmonary fibrosis (PF) is a chronic and irreversible scarring disease in the lung with limited treatment options. Therefore, it is critical to identify new therapeutic options. This study was undertaken to identify the effects of tannic acid (TA), a naturally occurring dietary polyphenol, in a mouse model of PF. Bleomycin (BLM) was intratracheally administered to induce PF. Administration of TA significantly reduced BLM-induced histological alterations, inflammatory cell infiltration and the levels of various inflammatory mediators (nitric oxide, leukotriene B4 and cytokines). Additionally, treatment with TA also impaired BLM-mediated increases in pro-fibrotic (transforming growth factor-β1) and fibrotic markers (alpha-smooth muscle actin, vimentin, collagen 1 alpha and fibronectin) expression. Further investigation indicated that BLM-induced phosphorylation of Erk1/2 (extracellular signal-regulated kinases 1 and 2) in lungs was suppressed by TA treatment. Findings of this study suggest that TA has the potential to mitigate PF through inhibiting the inflammatory response and fibrotic process in lungs and that TA might be useful for the treatment of PF in clinical practice.


Precision control of mTORC1 is crucial for the maintenance and IL-13 responsiveness of alveolar macrophages.
Alveolar macrophages (AMs) are the lung resident macrophages critically involved in pulmonary homeostasis and immune response. Recent researches have uncovered a diversity of regulators responsible for the development, maintenance, and function of AMs. Nevertheless, the molecular underpinnings that determine the developmental and functional specification of AMs remain incompletely understood. Here, we investigated the role of the TSC1-mTOR pathway in murine AMs by genetic ablating Tsc1 or mTor alleles through Cd11c-Cre or LysM-Cre. Flow cytometry analyses revealed a prominent decrease in AMs in Tsc1f/f-Cd11c-Cre and Tsc1f/f/-LysM-Cre mice. Moreover, a reduction in AMs was also noted in mTorf/f-Cd11c-Cre or Rptorf/f-Cd11c-Cre mice. Further evidence implicated that elevation in cell death, most likely aberrant apoptosis or/and necroptosis, might be attributable to disrupted AM homeostasis. Whereas a diversity of cytokines involved in AM homeostasis and function triggered mTOR activation, only the IL-13 signaling, particularly Jak1 and Stat3 activation, was affected by TSC1 in macrophages. Further, select genes induced by IL-13, including AM surface markers such as Pparg, Fabp4/5, Nfil3 and Car4, and M2 hallmarks such as Arg1, Fizz, Ym1 and Clec7a were fine-tuned by the TSC1-mTOR pathway. Therefore, our results demonstrated that the TSC1-mTOR pathway has a crucial role in the homeostasis and functional specification of AMs through integrating cytokine signaling with metabolic cues.


Alcohol use by patients admitted to hospital emergency rooms for treatment of drug overdose and misuse.
Persons admitted to hospital emergency rooms for treatment of drug misuse with concomitant alcohol use were generally found to be heavy drinkers.


Modification of CeO2-ZrO2 catalyst by potassium for NOx-assisted soot oxidation.
Potassium-modified ceria-zirconia catalyst was synthesized by wetness impregnation method. The ageing treatment was performed in static air at 800degrees C for 20 hr to evaluate the thermal stability of the catalyst. The catalysts were characterized by X-ray diffraction, BET surface area, oxygen storage capacity, NO(x)-temperature programmed desorption and soot-temperature programmed oxidation measurements. By introduction of potassium, the maximum soot oxidation rate temperature (T(m)) of the ceria-zirconia based catalyst decreased from 525 to 428 degrees C in the presence of NO under a loose contact mode. The shift of T(m) of the K-modified catalyst after ageing is only 15 degrees C. The enhanced activity of the aged catalyst mainly lies in the promotional effect of potassium on the NO(x)/oxygen storage capacity as well as the soot-catalyst contact.


On the Eulerian formulation of a stress induced platelet activation function.
This paper introduces a general concept of Eulerian reformulation of Langrangian particle tracking methods in evaluation of platelet damage and activation. It is applied to formulation of a new multistage algorithm describing the delayed activation of platelets due to excessive exposure to supra-critical stress. This new class of multistage Eulerian activation models allows for numerous extensions and generalizations, while preserving its simplicity and flexibility.


Replication of varicella zoster virus in Raji cells.
This report provides evidence for the replication of varicella zoster virus (VZV) in Raji cells. Infection was achieved by co-cultivation of Raji cells with VZV-infected human fibroblasts. Replication of VZV, as assessed by immunofluorescence using monoclonal antibodies against VZV-glycoproteins, ranged from 18 to 24% of the cells. Electron microscopy detected complete virions within the membrane-bound cytoplasmic vesicles and free viral particles in the nuclear matrix as late as 12 days post-infection. Western blot analysis of infected Raji cells demonstrated VZV-specific glycoproteins. The availability of a VZV-susceptible cell line growing in suspension culture provides a useful model for future studies.


A deep learning algorithm to detect chronic kidney disease from retinal photographs in community-based populations.
Screening for chronic kidney disease is a challenge in community and primary care settings, even in high-income countries. We developed an artificial intelligence deep learning algorithm (DLA) to detect chronic kidney disease from retinal images, which could add to existing chronic kidney disease screening strategies. We used data from three population-based, multiethnic, cross-sectional studies in Singapore and China. The Singapore Epidemiology of Eye Diseases study (SEED, patients aged ≥40 years) was used to develop (5188 patients) and validate (1297 patients) the DLA. External testing was done on two independent datasets: the Singapore Prospective Study Program (SP2, 3735 patients aged ≥25 years) and the Beijing Eye Study (BES, 1538 patients aged ≥40 years). Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min per 1·73m2. Three models were trained: 1) image DLA; 2) risk factors (RF) including age, sex, ethnicity, diabetes, and hypertension; and 3) hybrid DLA combining image and RF. Model performances were evaluated using the area under the receiver operating characteristic curve (AUC). In the SEED validation dataset, the AUC was 0·911 for image DLA (95% CI 0·886 -0·936), 0·916 for RF (0·891-0·941), and 0·938 for hybrid DLA (0·917-0·959). Corresponding estimates in the SP2 testing dataset were 0·733 for image DLA (95% CI 0·696-0·770), 0·829 for RF (0·797-0·861), and 0·810 for hybrid DLA (0·776-0·844); and in the BES testing dataset estimates were 0·835 for image DLA (0·767-0·903), 0·887 for RF (0·828-0·946), and 0·858 for hybrid DLA (0·794-0·922). AUC estimates were similar in subgroups of people with diabetes (image DLA 0·889 [95% CI 0·850-0·928], RF 0·899 [0·862-0·936], hybrid 0·925 [0·893-0·957]) and hypertension (image DLA 0·889 [95% CI 0·860-0·918], RF 0·889 [0·860-0·918], hybrid 0·918 [0·893-0·943]). A retinal image DLA shows good performance for estimating chronic kidney disease, underlying the feasibility of using retinal photography as an adjunctive or opportunistic screening tool for chronic kidney disease in community populations. National Medical Research Council, Singapore.


COVID-19 morbidity and mortality associated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers use among 14,129 patients with hypertension from a US integrated healthcare system.
Although recent evidence suggests no increased risk of severe COVID-19 outcomes associated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) use, the relationship is less clear among patients with hypertension and diverse racial/ethnic groups. This study evaluates the risk of hospitalization and mortality among patients with hypertension and COVID-19 in a large US integrated healthcare system. Patients with hypertension and COVID-19 (between March 1- September 1, 2020) on ACEIs or ARBs were compared with patients on other frequently used antihypertensive medications. Among 14,129 patients with hypertension and COVID-19 infection (mean age 60 years, 48% men, 58% Hispanic), 21% were admitted to the hospital within 30 days of COVID-19 infection. Of the hospitalized patients, 24% were admitted to intensive care units, 17% required mechanical ventilation, and 10% died within 30 days of COVID-19 infection. Exposure to ACEIs or ARBs prior to COVID-19 infection was not associated with an increased risk of hospitalization or all-cause mortality (rate ratios for ACEIs vs other antihypertensive medications = 0.98, 95% CI: 0.88, 1.08; ARBs vs others = 1.00, 95% CI: 0.90, 1.11) after applying inverse probability of treatment weights. These associations were consistent across racial/ethnic groups. Use of ACEIs or ARBs during hospitalization was associated with a lower risk of all-cause mortality (odds ratios for ACEIs or ARBs vs others = 0.50, 95% CI: 0.34, 0.72). Our study findings support continuation of ACEI or ARB use for patients with hypertension during the COVID-19 pandemic and after COVID-19 infection.


Double neuraxial catheter (Subarachnoid and epidural) in obese patient cancer surgery: A case report.
Morbid obesity is one of the major concerns when performing surgeries, due to higher risks of anesthetic complications. Combined spinal and epidural (CSE) anesthesia technique is used effectively in variety of surgical procedures. Our patient is a 58-year old female with a Body Mass Index (BMI) of 44.53 who presented to the emergency department complaining of an abdominal pain of a renal nature. She was found to have an abdominal mass suggestive of anexial mass or a Gastro Intestinal Stromal Tumor (GIST) and was scheduled for surgery. Due to the risks associated with general anesthesia, a double neuraxial catheter (subarachnoid and epidural) was the anesthitic method of choice. Overweight and obesity represent a rapidly growing threat to the health of populations in an increasing number of countries. The first report using the double catheter technique described a parturient with a BMI of 76 kg/m2 who had a lumbar Combined Spinal Epidural (CSE) catheter placed for intraoperative anesthesia and postoperative pain management. In the published literature CSE technique use is limited to obstetric procedure of obese females. In our case it is highlighted how an obese patient, with severe comorbidities that can jeopardize the success of the treatments, can be discharged in a few days by performing an "unconventional" but effective anesthetic technique.


Enovid-induced exacerbation of high blood pressure in stroke-prone rats (SHR).
Male and female, normotensive Wistar:Kyoto rats, spontaneously hypertensive rats (SHR), and Stroke-prone SHR (SHR/SP) with severe hypertension were treated with a contraceptive drug (Enovid) from the time of weaning until they became 180 days old. Although the Envoid-treated SHR and SHR/SP had exacerbations of their high blood pressure, none of the animals developed renal or cerebral damage. Chronic treatment with Enovid caused testicular and ovarian atrophy and a significant increase in circulating corticosterone. It is suggested that the potentially deleterious effects, e.g., stroke, hypertension, hyperglycemia, hyperlipidemia, etc., of chronic treatment with contraceptive drugs is largely determined by pre-existing genetically endowed proneness or resistance.


Factors influencing outcome and incidence of late complications in children who underwent allogeneic hematopoietic stem cell transplantation for hemoglobinopathy.
Hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for severe hemoglobinopathy (HGP). Late complications (LCs) are all events occurring beyond two years post-HSCT. We retrospectively analyzed prevalence, factors influencing occurrence, and prognosis of LCs post-HSCT for HGP. Between 2000 and 2011, 47 patients (21 males, 26 females; 43 with beta thalassemia major, four with sickle cell disease) who had survived more than two years post-HSCT for HGP were retrospectively reviewed. Mean age at HSCT was 7.7 years (1.1-32 years); mean follow-up was 7.1 years (2-11.6 years); 11 patients were splenectomized; mean ferritin level was 3022 ng/mL (350-10900); and seven patients underwent a second HSCT. Endocrinological complications were observed with primary gonadal failure in 16/20 mature females and 4/11 mature males, in five patients with primary hypothyroidism and in four with insulin-dependent diabetes mellitus (DM). Skeletal complications were observed in 10 with secondary osteoporosis; 22 patients had elevated transaminase levels; two had hepatitis B reactivation. Neurological, cardiac and ocular manifestations were relatively rare. A higher incidence of LCs was observed in splenectomized than in nonsplenectomized patients: cGVHD -64% versus 13% (P = .003); endocrine abnormalities -91% versus 30.5%, (P = .001); elevated transaminase levels -73% versus 33% (P = .043); mortality -18% versus 2.7% (NS). LCs post-HSCT for HGP are common and heterogeneous. Etiology is multifactorial with iron overload (IO), class, splenectomy, age, chronic GVHD, and corticosteroid (CS) treatment. Our data may help build follow-up guidelines to limit, detect, and treat any LCs and improve quality of life.


Estrogen receptor β2 (ERβ2)-mediated upregulation of hsa_circ_0000732 promotes tumor progression via sponging microRNA-1184 in triple-negative breast cancer (TNBC).
The role of estrogen receptor β (ERβ) in the pathogenesis and development of breast cancer (BC) is controversial, and it is currently considered to play contradictory roles in different phenotypes. ERβ2 is thought to promote the BC process, but its role in triple-negative breast cancer (TNBC) has not been reported. In this study, we collected tumor tissues from 15 patients with TNBC and obtained a variety of TNBC cell lines as research objects. The plasmid vectors and RNA interference techniques were used to change the level of target genes in cells, quantitative PCR and Western Blots were used to detect gene expression levels, CCK-8 and EdU assay were used to detect cell growth, and Transwell was used to detect cell migration and invasion. Dual-luciferase gene reports and RNA immunoprecipitation (RIP) were used to verify gene targeting relationships. ERβ2 was up-regulated in TNBC tissues and promoted the growth, migration, and invasion of TNBC cells. ERβ2 regulated hsa_circ_0000732 expression by binding to SCARF1 promoter. Knockdown of hsa_circ_0000732 inhibited TNBC cell proliferation, migration, and invasion by upregulating miR-1184. Our present study found that ERβ2 is upregulated in some TNBC cells and promotes TNBC cell growth, migration and invasion by regulating hsa_circ_0000732 targeting miR-1184. The special role of ERβ2 in TNBC may be the breakthrough of a targeted treatment strategy for TNBC.


Hepatic necrosis in aged mice by oral administration of microcystin-LR.
Aged mice (32 weeks) were orally administered microcystin-LR at 500 micrograms/kg, and injuries of the liver were estimated by microscopy 2 hr after treatment. Sixty-two per cent of aged mice proved to be sensitive to microcystin-LR, whereas such changes in the liver were not found in young mice (5 weeks). Uptake of the toxin into the liver was confirmed by high-performance liquid chromatography and frit-fast atom bombardment liquid chromatograph/mass spectrometry after clean-up with an immunoaffinity column. To verify the difference in sensitivity to microcystin-LR between aged and young mice, non-treated mice were examined, and among them aged mice were confirmed to have a rough surface of the stomach and small intestinal mucosa. These results suggested that the hepatotoxicity by oral administration of microcystin-LR is deeply related to aging, and particularly to conditions in the small intestine such as the permeability of capillaries in the villi.


Serum antiendometrial antibodies and diagnosis of endometriosis.
The purpose of the present prospective multi-center study is to investigate the relationship between laparoscopic diagnosis of endometriosis and results of a serum antiendometrial antibody (AEA) assay. Indirect immunofluorescence detection of AEA was performed on serum specimens from patients presenting with dysmenorrhea or chronic pelvic pain and infertility (n = 2609) utilizing frozen sections of endometrium acquired on cycle days 18-21 from normally cycling women without endometriosis. Diagnostic laparoscopy was performed within 1 year of AEA assay on 527 tested women. The relationship between the serum AEA and laparoscopic verification was characterized by a positive predictive value = 88%, negative predictive value = 86%, sensitivity = 87% and specificity = 87%. The AEA assay is a very good screening test for patients suspected of having endometriosis and should be utilized prior to laparoscopy in diagnostic categories of dysmenorrhea or chronic pelvic pain and infertility.


Heritable changes in division speed accompany the diversification of single T cell fate.
Rapid clonal expansion of antigen-specific T cells is a fundamental feature of adaptive immune responses. It enables the outgrowth of an individual T cell into thousands of clonal descendants that diversify into short-lived effectors and long-lived memory cells. Clonal expansion is thought to be programmed upon priming of a single naive T cell and then executed by homogenously fast divisions of all of its descendants. However, the actual speed of cell divisions in such an emerging "T cell family" has never been measured with single-cell resolution. Here, we utilize continuous live-cell imaging in vitro to track the division speed and genealogical connections of all descendants derived from a single naive CD8+ T cell throughout up to ten divisions of activation-induced proliferation. This comprehensive mapping of T cell family trees identifies a short burst phase, in which division speed is homogenously fast and maintained independent of external cytokine availability or continued T cell receptor stimulation. Thereafter, however, division speed diversifies, and model-based computational analysis using a Bayesian inference framework for tree-structured data reveals a segregation into heritably fast- and slow-dividing branches. This diversification of division speed is preceded already during the burst phase by variable expression of the interleukin-2 receptor alpha chain. Later it is accompanied by selective expression of memory marker CD62L in slower dividing branches. Taken together, these data demonstrate that T cell clonal expansion is structured into subsequent burst and diversification phases, the latter of which coincides with specification of memory versus effector fate.


Wide temperature-tolerant polyaniline/cellulose/polyacrylamide hydrogels for high-performance supercapacitors and motion sensors.
Herein, we report a simple approach to fabricate PANI/cellulose/PAAM conductive hydrogels with interpenetrating structure by in-situ polymerization of PANI into the acid tolerant cellulose/PAAM hydrogel. The obtained conductive hydrogels not only can achieve high flexibility and excellent conductivity, but also can be directly sandwiched between carbon clothes to fabricate all-in-one configured supercapacitors. Such supercapacitors show excellent electrochemical performances with a large areal capacitance of 835.0 mF/cm2 (corresponding to 4.175 F/cm3), a high energy density of 74.22 μWh/cm2 and an enhanced cycling performance with 96% capacitance retention after 5000 cycles. What's more, the supercapacitors can withstand large bending/compressing deformations and wide temperature-tolerant from -60 to 80 °C. In addition, the PANI/cellulose/PAAM hydrogels can be fabricated into wearable motion sensors to monitor various human movements, such as finger bending and pressing, subtle clenching fist, swallowing and phonation in real-time. The obtained multifunctional performances may provide intriguing opportunities for practical applications.


Development and Validation of a Hybrid Nuss Procedure Surgical Simulator and Trainer.
This work presents the development and validation of an interactive simulation training platform for the minimally invasive repair of pectus excavatum, otherwise known as the Nuss procedure. The challenges and implications of developing both an all-virtual and an all-physical version of the simulator are investigated in a training context. A hybrid system is then developed that integrates virtual and physical constituents and a haptic interface to reproduce the primary steps of the procedure and to satisfy clinically relevant prerequisites for its training system. Furthermore, this work carries out a study to investigate the system's face, content, and construct validity. Objective and subjective evaluations of the system demonstrate its utility for surgical training and establish various levels of its validity. A hybrid virtual/physical configuration of the trainer can efficiently and realistically reproduce the primary steps of the procedure. Outside of this work, a simulation and training platform for the Nuss procedure is not available. This system was developed in close collaboration with the pioneers of this surgical technique.


Synthesis, purification, and characterization of oligoribonucleotides that act as agonists of TLR7 and/or TLR8.
Viral single-stranded (ss) RNA is the natural ligand for TLR7 and TLR8. Synthetic ssRNA has been shown to act as a ligand for TLR7 and TLR8. We have previously reported a novel RNA structure, referred to as stabilized immune modulatory RNA (SIMRA), in which two short phosphorothioate oligoribonucleotides were linked through their 3'-ends via a linker. SIMRA compounds had greater stability in serum than unmodified ssRNA and induced immune responses via TLR7 and/or TLR8. SIMRA compounds were synthesized using phosphoramidite chemistry on controlled-pore glass solid support derivatized with a linker. After cleavage from the solid support and removal of protecting groups, SIMRA compounds were purified on an anion-exchange HPLC followed by desalting/dialysis, and lyophilization. SIMRA compounds were characterized for their purity and sequence integrity by anion-exchange HPLC, capillary gel electrophoresis, polyacrylamide gel electrophoresis, and MALDI-TOF mass spectrophotometric analysis. As SIMRA compounds induce TLR7- and/or TLR8-mediated Th1-type immune responses, they have potential utility as therapeutic agents for a broad range of diseases, including cancer, infectious diseases, asthma, and allergies, and as adjuvants with vaccines.


Height after photon craniospinal irradiation in pediatric patients treated for central nervous system embryonal tumors.
We modeled height after craniospinal irradiation (CSI) in pediatric patients with central nervous system (CNS) embryonal tumors to identify factors that impair stature. During 1996-2012, 212 pediatric patients (131 male) with CNS embryonal tumors received postoperative CSI: 23.4 Gy (n = 147) or ≥36 Gy (n = 65), similar postirradiation chemotherapy, and were followed for at least 5 years without tumor progression or other event. The group was further characterized by age at CSI and hormone-replacement therapy received. Models were developed to identify factors associated with growth impairment and estimate final height. With median follow up of 10.2 years (range 5.0-20.4 years), the mean final height z-scores at 18 years of age, compared to United States standards, were -1.3 for female and -1.5 for male survivors. Younger age at the time of CSI, higher CSI dose, and female sex were associated with height impairment. Factors associated with higher growth rates before 15 years of age were older age at CSI, male sex, CSI dose < 36 Gy, replacement therapy for growth hormone (GH) and central adrenal insufficiency, and white race. Growth after age 15 in male survivors was associated with treatment of gonadotropin deficiency. Linear mixed-effects models were developed using clinical factors to estimate final height, demonstrate the unique growth curve of this cohort, and interactions between clinical variable and radiation dose. CSI significantly impaired height at current doses used to treat standard- or high-risk CNS embryonal tumors. Measures to reduce the impact of CSI on height should be sought, with our models serving as benchmarks.


The relationship between CYP17 -34T/C polymorphism and acne in Chinese subjects revealed by sequencing.
Although many arguments have been raised on the role of heredity in the etiology of acne, the relevant genetic elements in the pathogenesis of the disease are not well established. The aim of our study was to evaluate the association between a genetic polymorphism in the promoter region of the CYP17 gene and the development of acne. 206 acne patients and 200 controls were included in the study. A polymerase chain reaction (PCR) sequencing technique was used to reveal a CYP17 gene polymorphism in its promoter region. A chi2 test was used for data analysis. CYP17 -34T/C polymorphism was found and the frequency distribution of the C/C homozygotes and C allele in the male patients with severe acne (33.3 and 60.9%, respectively) were statistically significantly different from those of the control samples (18.2 and 46.6%; p < 0.05). No significant difference was observed between the female patients, mild + moderate male patients and their controls, respectively. The CYP17 -34C/C homozygote Chinese men are at a significantly increased risk of developing severe acne.


[Use of an new modular revision arthroplasty system for the knee reconstruction].
Reconstruction of stable knee joint kinematics using modular axis-guided revision implants after failed knee arthroplasty surgery. Revision implant for bone defects (type Anderson Orthopaedic Research Institute [AORI] III) in case of revision arthroplasty. Primary implant in case of mediolateral instability (>grade I) or multidirectional instability. Persistent or current joint infection, general infection (e.g. pneumonia), missing metaphysis femoral and/or tibial, insufficient extensor apparatus. Standard approach extending the previously used skin incision. Arthrotomy, synovectomy and collection of multiple samples for microbiological and histopathological analyses. Preparation of the femur with reamers of increasing diameter. Subsequently, a reference stem is anchored and after referencing the correct rotation and joint line height; the femoral osteotomy is performed after fixation of the 5‑in‑1 cutting block. Following the femoral osteotomy, the box of the femoral prosthesis is prepared. In addition, the tibia is prepared using an intramedullary reference system. Level of constraint and additional tibial augmentation is chosen according to the amount of defect bone and according to ligament stability. Full load bearing; standard wound control and sterile dressings; limitation of active/passive range of motion only in case of weakened extensor apparatus. Between 03/2011 and 05/2018, a total of 48 patients underwent revision arthroplasty using the described system. The mean follow-up was 24 months (range 21-35 months). In 30 of the 48 cases, a rotating hinge variant was implanted, while in 18 cases a semiconstrained variant was implanted. Indications to revision arthroplasty: infection (n = 22), aseptic loosening (n = 11), instability (n = 11), periprosthetic fracture (n = 3) and PMMA allergy (n = 1). In 11 cases, revision had to be performed due to persistent infection (n = 6) and aseptic loosening (n = 5): 9 cases could be successful treated by a two-step revision procedure, while in 2 cases it was necessary to perform an arthrodesis. The 2‑year implant survival rate was 77%.


Genetic markers of the immune response of Atlantic salmon (Salmo salar) to infectious salmon anemia virus (ISAV).
Infectious diseases among fish present an important economic burden for the aquaculture and fisheries industries around the world. For example, the infectious salmon anemia virus (ISAV) infects farmed Atlantic salmon (Salmo salar), and results in millions of dollars of lost revenue to salmon farmers. Although improved management and husbandry practices over the last few years have minimized the losses and the number of outbreaks, the risk of new virulent strains emerging is a looming threat to the viability and sustainability of this industry. A greater understanding of the host-pathogen interactions at the molecular level during the course of an infection thus remains of strategic importance for the development of molecular tools and efficient vaccines capable of minimizing losses in the eventual case of a new outbreak. Using a 32 k cDNA microarray platform (cGRASP), we have identified various signaling pathways and immune regulated genes, which are activated or repressed in Atlantic salmon head-kidney during the course of an ISAV infection. Gene expressions were measured at five different time-points: 6 h, 24 h, 3 d, 7 d and 16 d post-injection. The earliest time points showed only a few differentially expressed genes in ISAV injected fish, relative to sham injected controls, although as time progressed, many additional genes involved in key defense pathways were up-regulated including MHC type I, beta-2 microglobulin, TRIM 25 and CC chemokine 19. During the latest stage of the infection process, many genes related to oxygen transportation were under-expressed, which correlates well with the observed anemia that occurs prior to death in Atlantic salmon infected with virulent strains of ISAV.


Regression analysis of recent changes in cardiovascular morbidity and mortality in The Netherlands.
To test whether recent declines in mortality from coronary heart disease were associated with increased mortality from other cardiovascular diseases. Poisson regression analysis of national data on causes of death and hospital discharges. Population of the Netherlands, 1969-93. Annual changes in mortality from coronary heart disease, stroke, and other cardiovascular diseases and annual changes in hospital discharge rates for acute coronary events, stroke, and congestive heart failures. Patterns of cardiovascular mortality changed abruptly in 1987-93. Annual decline in mortality from coronary heart disease increased sharply for women and men: from -1.9% (95% confidence interval -2.2% to -1.6%) and -1.7% (-1.9% to -1.4%) respectively in 1979-86 to -3.1% (-3.5% to -2.6%) and -4.2% (-4.6% to -3.9%) in 1987-93. The longstanding decline in mortality from stroke levelled off: from annual change of -3.3% (-3.7% to -2.8%) and -3.2% (-3.7% to -2.8%) in 1979-86 to -0.1% (-0.7% to 0.4%) and -1.1% (-1.7% to -0.5%) in 1987-93. Mortality from other cardiovascular diseases, however, started to increase: from -2.0% (-2.4% to -1.6%) and -0.2% (-0.5% to 0.2%) in 1979-86 to 1.5% (1.0% to 2.0%) and 1.9% (1.5% to 2.3%) in 1987-93. Hospital discharge rates for acute coronary heart disease, congestive heart failure, and stroke increased during 1980-6. During 1987-93 discharge rates for stroke and coronary heart disease stabilised but rates for congestive heart failure increased. Improved management of coronary heart disease seems to have reduced mortality, but some of the gains are lost to deaths from stroke and other cardiovascular diseases. The increasing numbers of patients with coronary heart disease who survive will increase demands on health services for long term care.


[Serological and molecular studies of a rare A subgroup].
To determine the genotype of an individual suspected for Aw through DNA sequencing. Serologic testing was carried out with standard methods. Exons 6 and 7 of the ABO genes were amplified by PCR and subjected to direct sequencing or sequenced after gene cloning. Serological testing showed that the forward typing and reverse typing were Aw and A, respectively. DNA sequencing revealed that the individual has carried an Aw allele and an O allele. Haplotype sequencing of each allele has revealed a nt543 variant (543G>C) in the Aw allele. The individual was verified as a rare A subtype, which was previously unreported in mainland China.


Screening for atrial fibrillation in the elderly: A network meta-analysis of randomized trials.
Randomized controlled trials (RCTs) investigating the optimal screening strategy for atrial fibrillation (AF) have yielded conflicting results. To examine the comparative efficacy of different AF screening strategies in older adults. We searched MEDLINE, EMBASE and Cochrane without language restrictions through January 2022, for RCTs evaluating the outcomes of non-invasive AF screening approaches among adults ≥65 years. We conducted a pairwise meta-analysis comparing any AF screening approach versus no screening, and a network meta-analysis comparing systematic screening versus opportunistic screening versus no screening. The primary outcome was new AF detection. The final analysis included 9 RCTs with 85,209 patients. The weighted median follow-up was 12 months. The mean age was 73.4 years and men represented 45.6%. On pairwise meta-analysis, any AF screening (either systematic or opportunistic) was associated with higher AF detection (1.8% vs. 1.3%; risk ratio [RR] 2.10; 95% confidence interval [CI] 1.20-3.65) and initiation of oral anticoagulation (RR 3.26; 95%CI 1.15-9.23), compared with no screening. There was no significant difference between any AF screening versus no screening in all-cause mortality (RR 0.97; 95%CI 0.93-1.01) or acute cerebrovascular accident (CVA) (RR 0.92; 95%CI 0.84-1.01). On network meta-analysis, only systematic screening was associated with higher AF detection (RR 2.73; 95% CI 1.62-4.59) and initiation of oral anticoagulation (RR 5.67; 95% CI 2.68-11.99), but not with the opportunistic screening, compared with no screening. Systematic AF screening using non-invasive tools was associated with higher rate of new AF detection and initiation of OAC, but opportunistic screening was not associated with higher detection rates. There were no significant differences between the various AF screening approaches with respect to rates of all-cause mortality or CVA events. However, these analyses are likely underpowered and future RCTs are needed to examine the impact of systematic AF screening on mortality and CVA outcomes. None.


Cost-effectiveness of topiramate in migraine prevention: results from a pharmacoeconomic model of topiramate treatment.
Patients whose migraines are frequent, cause disruptions of daily routines, or are unresponsive to acute treatment are primary candidates for preventive migraine therapy. This cost-effectiveness model assesses the clinical and economic impact of topiramate (TPM) therapy versus no preventive treatment for migraine headache in the United States. Despite significant progress in treatment options, the economic burden of migraine to patients, employers, health systems, and society is substantial. Treatment strategies for migraine are directed toward managing acute episodes. However, preventive therapy should be used for patients with frequent migraine attacks (>2 per month) or those experiencing attacks that disrupt daily routines. Data for the model were obtained from the published literature and pooled results of two randomized, double-blinded, placebo-controlled trials of TPM in migraine prevention. Model inputs included baseline migraine frequency (the base case assumed 6 per month, consistent with the average rate in the TPM trials), treatment discontinuation (including discontinuation due to adverse events), treatment response (ie, > or = 75%, 50% to 75%, and <50% reduction in migraine frequency), cost of preventive therapy (TPM plus physician visits for medication titration), cost of acute treatment per attack (including pharmacy and medical service costs), hours of disability per attack, hourly wage, and quality-of-life (utility) weights. Model outcomes included the number of migraines averted, disability hours, total cost of acute and preventive treatment, and lost wages. Results were expressed as cost per migraine averted and cost per quality-adjusted life years (QALY). All costs were stated as 2002 U.S. dollars. We also conducted sensitivity analyses to assess the robustness of model findings with respect to variation in key parameters. We estimated that the use of TPM would prevent 1.85 migraines per patient and almost 5 hours of disability per month versus no preventive treatment. Resulting savings in cost of acute treatment (dollar 27) and work loss (dollar 51) offset 68% of the expected monthly cost of TPM (dollar 113). The incremental cost per migraine averted was dollar 19, while the incremental cost per QALY was estimated to be dollar 10,888 (dollar 26,191 when indirect costs were excluded from the analysis). Model results were sensitive to baseline migraine rate and gain in health utility from migraine prevention. Economic savings associated with reduced migraine frequency offset approximately two thirds of the cost of preventive TPM therapy. The cost-effectiveness of TPM depends on utility gains associated with a reduced frequency of migraine headaches, which is the subject of ongoing research. However, results from our model suggest that the use of TPM in prevention of migraine may offer reasonable value for money relative to many well-accepted medical interventions.


Fall in pulmonary vascular resistance in patients awaiting heart transplantation.
Raised pulmonary vascular resistance is associated with decreased survival after orthotopic heart transplantation and patients with this risk factor are usually denied transplantation. In a proportion of cases raised pulmonary vascular resistance may fall with time and medical treatment. Seven patients with high pulmonary vascular resistance (range 3.9-6.6 Wood units) at initial assessment for cardiac transplantation were restudied by right heart catheterisation after a period of seven to 17 months. In five of the seven patients the pulmonary vascular resistance had fallen, allowing orthotopic heart transplantation to be performed in four. In one patient the resistance was static and in one it had risen. The mean fall in pulmonary vascular resistance for the group was (mean (SD)) 2.6 (2.7) Wood units, p < 0.05. Patients who have been denied transplantation on the basis of their raised pulmonary vascular resistance should be reassessed after four to six months if they remain otherwise clinically suitable.


[Structural and serologic characteristics of O-specific polysaccharides of Hafnia alvei PCM 1185 and 1199].
This work describes results of studies of O-specific oligosaccharide repeating units from lipopolysaccharides of two related Hafnia alvei serotypes. The linkage between O-antigen and the core region in PCM 1199 LPS has been also established. The O-acetyl residues present in the polysaccharides are involved in formation of epitopes.


Bilateral calcified stylohyoid ligament: an incidental autopsy finding with medicolegal significance.
Eagle's syndrome occurs due to elongation of the styloid process or calcification of the stylohyoid ligament, which then may produce a pain sensation due to pressure exerted on various structures in the head and neck region. A case report of calcified stylohyoid ligament found incidentally at autopsy and further confirmed by computed tomography scan and histopathology is herein discussed with associated medicolegal significance.


Early and mid-term results of transcatheter aortic valve implantation and valve durability assessment.
This study aimed to evaluate the early and mid-term outcomes of transcatheter aortic valve implantation (TAVI) and to assess valve durability. A total of 146 consecutive patients who underwent TAVI for severe aortic stenosis between October 2013 and August 2018 were retrospectively reviewed. All patients (mean age, 84 ± 6 years; age range 53-98 years; 42 males [28.7%]) had multiple comorbidities, with a mean logistic EuroSCORE of 30.9 ± 17.4%. Eighteen patients (12.3%) were aged 90 years or over. Five in-hospital deaths (3.4%) occurred, and 36 patients (24.7%) experienced major TAVI-related complications. With the transfemoral approach, 10 patients had major vascular complications, which mostly occurred with first-generation devices (n = 9) but less commonly with new-generation low-profile devices (P = 0.0078). During a follow-up period of 580 ± 450 (11-1738) days, 29 late deaths occurred. The survival rate was 86.0%, 78.0%, and 61.7% at 1, 2, and 3 years, respectively. Multivariate Cox hazard regression analysis revealed that more-than-moderate tricuspid regurgitation was the only independent risk factor for late deaths due to any cause (hazard ratio, 3.145; 95% confidence interval, 1.129-8.762; P = 0.0283). No statistically significant differences between post-TAVI before discharge from the hospital and at 4 years after TAVI were observed with respect to aortic valve area (1.76 ± 0.49 cm2 vs. 1.64 ± 0.38 cm2; P = 0.1871) and mean pressure gradient (10.0 ± 4.6 mmHg vs. 7.9 ± 3.3 mmHg; P = 0.5032). TAVI was a feasible method with acceptable early and mid-term outcomes and valve durability for at least 4 years in poor-risk patients. Further close follow-up is essential to evaluate late outcomes and valve durability.


High Seroprevalence of SARS-CoV-2 (COVID-19)-Specific Antibodies among Healthcare Workers: A Cross-Sectional Study in Guilan, Iran.
This study was conducted to evaluate the anti-SARS-CoV-2 IgM and IgG antibodies among healthcare workers in Guilan. This cross-sectional study was conducted on 503 healthcare workers. Between April and May 2020, blood samples were collected from the healthcare workers of Razi Hospital in Rasht, Guilan, Iran. Enzyme-linked immunosorbent assay (ELISA) was used for the detection and quantitation of anti-SARS-CoV-2 IgM/IgG antibodies by using kits made by Pishtaz Teb Company, Tehran, Iran. From a total of 503 participants, the result of the anti-SARS-CoV-2 IgM antibody test was positive in 28 subjects (5.6%) and the anti-SARS-CoV-2 IgG antibody test was positive in171 subjects (34%). Participants in the age group of 35-54 years were significantly more likely to have a positive anti-SARS-CoV-2 antibody test than the age group of 20-34 years (odds ratio = 1.53, 95% CI: 1.04-2.25, P=0.029). Also, physicians were significantly more likely to have a positive antibody test than office workers (odds ratio = 1.92, 95% CI: 1.04-3.54, P=0.037). The wide range of symptoms was significantly associated with the positive anti-SARS-CoV-2 antibody test. The most significant association was observed between fever and a positive anti-SARS-CoV-2 antibody test (odds ratio = 3.03, 95% CI: 2.06-4.44, P < 0.001). The results of the current study indicated that the seroprevalence of COVID-19 was high among healthcare workers of Guilan Province. It seems that this finding was due to the earlier exposure to COVID-19 and the lack of awareness and preparedness to deal with the pandemic in Iran, compared to other countries.


Magnetic charge propagation upon a 3D artificial spin-ice.
Magnetic charge propagation in spin-ice materials has yielded a paradigm-shift in science, allowing the symmetry between electricity and magnetism to be studied. Recent work is now suggesting the spin-ice surface may be important in mediating the ordering and associated phase space in such materials. Here, we detail a 3D artificial spin-ice, which captures the exact geometry of bulk systems, allowing magnetic charge dynamics to be directly visualized upon the surface. Using magnetic force microscopy, we observe vastly different magnetic charge dynamics along two principal directions. For a field applied along the surface termination, local energetics force magnetic charges to nucleate over a larger characteristic distance, reducing their magnetic Coulomb interaction and producing uncorrelated monopoles. In contrast, applying a field transverse to the surface termination yields highly correlated monopole-antimonopole pairs. Detailed simulations suggest it is the difference in effective chemical potential as well as the energy landscape experienced during dynamics that yields the striking differences in monopole transport.


Preterm infants with severe extrauterine growth retardation (EUGR) are at high risk of growth impairment during childhood.
Extrauterine growth retardation (EUGR) seriously affects premature newborns and is related to the impairment of growth during childhood. There are very limited data available concerning the growth outcome of EUGR children. Our aim was to assess the growth outcome in a cohort of children born before 34 weeks of gestation with severe EUGR. This was a retrospective multicenter study, performed in outpatient endocrinology clinic. A total of 103 premature children with weight and/or length below -2 standard deviation score (SDS) of "intrauterine" growth expectation at the time of discharge from hospital (within 42 weeks of postmenstrual age) were included in the study. The study participants underwent a thorough anthropometric assessment at a mean age of 3.9 years ± 1.7 SD. Of the EUGR children, 12.6 % showed a height below -2 SDS and 7.7 % even below -2.5 SDS. Growth impairment was more common in males than in females (17 vs. 8 %). The prevalence of subnormal weight (below -2 SDS) was 13.6 %, being higher in males than in females (17 vs. 10 %). BMI values below -2 SDS were found in 18.4 % of our study population (22.7 % in males and 12 % in females). The 19.6 % of EUGR children did not catch up in head circumference during early childhood. Length at term was the major predictor of height in childhood (P < 0.001). A significant proportion of children born prematurely with severe EUGR show growth retardation in childhood thus suggesting the need for a close clinical follow-up to determine their growth potential and implement effective intervention strategies.


Simulating an exclusion zone for vapour intrusion of TCE from groundwater into indoor air.
This paper is an extension of the work by Yu et al. (2009) to examine exposure pathways of volatile organic compounds (VOCs) originating from a NAPL source zone located below the water table, and their potential impact on multiple residential dwellings down-gradient of the source zone. The three-dimensional problem geometry is based on the Rivett (1995) field experiment in the Borden aquifer, and contains houses located both above and adjacent to the groundwater plume in order to define an exclusion zone. Simulation results using the numerical model CompFlow Bio indicate that houses which are laterally offset from the groundwater plume are less affected by vapour intrusion than those located directly above the plume due to limited transverse horizontal flux of TCE within the groundwater plume, in agreement with the ASTM (2008) guidance. Uncertainty in the simulated indoor air concentration is sensitive to heterogeneity in the permeability structure of a stratigraphically continuous aquifer, with uncertainty defined as the probability of simulated indoor air concentrations exceeding the NYSDOH (2005) regulatory limit. Within this uncertainty framework, this work shows that the Johnson and Ettinger (1991), ASTM (2008) and CompFlow Bio models all delineate an identical exclusion zone at a 99.9% confidence interval of indoor air concentrations based on the probability of exceedence.


Crystal structures of human Fabs targeting the Bexsero meningococcal vaccine antigen NHBA.
Neisserial heparin-binding antigen (NHBA) is a surface-exposed lipoprotein from Neisseria meningitidis and is a component of the meningococcus B vaccine Bexsero. As part of a study to characterize the three-dimensional structure of NHBA and the molecular basis of the human immune response to Bexsero, the crystal structures of two fragment antigen-binding domains (Fabs) isolated from human monoclonal antibodies targeting NHBA were determined. Through a high-resolution analysis of the organization and the amino-acid composition of the CDRs, these structures provide broad insights into the NHBA epitopes recognized by the human immune system. As expected, these Fabs also show remarkable structural conservation, as shown by a structural comparison of 15 structures of apo Fab 10C3 which were obtained from crystals grown in different crystallization conditions and were solved while searching for a complex with a bound NHBA fragment or epitope peptide. This study also provides indirect evidence for the intrinsically disordered nature of two N-terminal regions of NHBA.


Neonatal thyroid function in congenital hypothyroidism.
In the cord blood of seven infants with congenital hypothyroidism detected in our newborn screening programs, thyroxine values ranged from 2.5 to 6.7 mug/dl and thyrotropin, from 105 to 975 muU/ml; triiodothyronine values were normal. On follow-up, T3 levels increased to normal in five infants, there was a significant negative correlation between the T3 value and the severity of thyroprevia as reflected in the TSH levels and the number of clinical features present. This increase in T3 may explain in part why the diagnosis of this disease is difficult during the first few months of life and why early treatment is effective. This observation provides further rationale for the widespread institution of newborn screening programs for congenital hypothyroidism.


The causal role of intestinal microbiome in development of pre-eclampsia.
The correlation of pre-eclampsia (PE) and intestinal microbiome has been widely demonstrated in existing research, whereas their causal relationship has been rarely explored. The causal relationship between intestinal microbiome and PE risk was examined using large-scale genome-wide association studies (GWAS) summary statistics. To be specific, the causal microbial taxa for PE were identified using the two-sample Mendelian randomization (MR) method. The results were verified to be robust through comprehensive sensitive analyses, and the independence of causal relationship was ensured through novel multivariable MR analyses. The possibility of reverse relationships was ruled out through reverse-direction MR analyses. Lastly, the biofunction was explored through enrichment analysis, and a series of validations of PE results in a second GWAS were performed to confirm the results. After correction, four microbial taxa, including Streptococcus genus for PE (FDR q = 0.085), Olsenella genus for PE (FDR q = 0.085), Enterobacteriales order for PE (FDR q = 0.0134), and Akkermansia genus for PE (FDR q = 0.015), had a causal relationship to diverse joint PE (FDR q < 0.15). Moreover, when three different methods were employed on basis of the nominal significance (P < 0.05), five suggestive microbial taxa took on significance. The effect of heterogeneity and horizontal pleiotropy was excluded through sensitive analysis, and the possibility of horizontal pleiotropy of BMI was ruled out through multivariable MR analysis. The protective mechanism of the identified taxa against PE was illustrated through GO enrichment analysis and KEGG pathways. A number of microbial taxa had a causal relationship to PE. The result of this study provides more insights into intestinal microbiome in the pathology of PE.


c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity.
The Smad proteins are key intracellular effectors of transforming growth factor-beta (TGF-beta) cytokines. The ability of Smads to modulate transcription results from a functional cooperativity with the coactivators p300/cAMP-response element-binding protein-binding protein (CBP), or the corepressors TGIF and Ski. The c-Jun N-terminal kinase (JNK) pathway, another downstream target activated by TGF-beta receptors, has also been suggested to inhibit TGF-beta signaling through interaction of c-Jun with Smad2 and Smad3. Here we show that c-Jun directly interacts with Ski to enhance the association of Ski with Smad2 in the basal state. Interestingly, TGF-beta signaling induces dissociation of c-Jun from Ski, thereby relieving active repression by c-Jun. Moreover, activation of JNK pathway suppressed the ability of TGF-beta to induce dissociation of c-Jun from ski. Thus, the formation of a c-Jun/Ski complex maintains the repressed state of Smad2-responsive genes in the absence of ligand and participates in negative feedback regulation of TGF-beta signaling by the JNK cascade.


The Intergenerational Effects of Relocation Policies on Indigenous Families.
This research utilizes life-course perspective concepts of linked lives and historical time and place to examine the multigenerational effects of relocation experiences on Indigenous families. Data were collected from a longitudinal study currently underway on four American Indian reservations in the Northern Midwest and four Canadian First Nation reserves where residents share a common Indigenous cultural heritage. This paper includes information from 507 10 - 12 year old Indigenous youth and their biological mothers who participated in the study. Results of path analysis revealed significant direct and indirect effects whereby grandparent-generation (G1) participation in government relocation programs negatively impacts not only G1 well being, but also ripples out to affect subsequent generations.


Cyanidin-3-glucoside suppresses the progression of lung adenocarcinoma by downregulating TP53I3 and inhibiting PI3K/AKT/mTOR pathway.
The aim of this study is to unravel the role of Cyanidin-3-glucoside (C3G) and its potential mechanisms in lung adenocarcinoma (LUAD). The cell clones, proliferation, apoptosis, migration, and invasion in H1299 and A549 cells were determined by colony formation assay, 5-ethynyl-20 deoxyuridine (EdU) assay, flow cytometry, and transwell assay, respectively. The expression of p53-induced gene 3 (TP53I3) was assessed and the prognostic values of TP53I3 in LUAD via the dataset from the Cancer Genome Atlas (TCGA). In addition, the mRNA and protein expressions were detected by quantitative real-time PCR (qRT-PCR) and western blot. C3G inhibited the proliferation, migration, and invasion of, and also promoted the apoptosis in H1299 and A549 cells. The database of TCGA showed TP53I3 was highly expressed in LUAD tissues and correlated with the poor prognosis of LUAD patients. Moreover, we also found that C3G inhibited the proliferation, migration and invasion, and promoted apoptosis in H1299 and A549 cells by downregulating TP53I3. Additionally, C3G could inhibit the activation of phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in H1299 and A549 cells by downregulating TP53I3. This study demonstrated that C3G could inhibit the proliferation, migration and invasion, and also facilitate the apoptosis through downregulating TP53I3 and inhibiting PI3K/AKT/mTOR pathway in LUAD.


Regional gastrointestinal absorption of ranitidine in the rat.
Ranitidine absorption from isolated segments of rat small intestine (duodenum, midgut, and terminal ileum) was investigated to examine the influence of pH and 50% bile, and to determine if ranitidine is absorbed preferentially from a specific region. Ranitidine (50 mg/kg) was administered into each segment in pH 5 or pH 7 buffer, or in 50% bile. Venous blood was collected at various times for 40 min from the right jugular vein. When ranitidine was administered in pH 7 buffer or in 50% bile, Cmax and AUC0-40 were significantly greater after administration into the terminal ileum compared to the duodenum and midgut. AUC0-40 was significantly greater when ranitidine was administered in pH 5 buffer or in 50% bile into the duodenum compared to the midgut. Cmax was significantly different between administration into the duodenum and midgut only when ranitidine was administered in 50% bile. Ranitidine administration in pH 5 buffer significantly decreased AUC0-40 and Cmax after administration into the midgut, and AUC0-40 after administration into the terminal ileum compared to administration with pH 7 buffer or in 50% bile. Bile had no significant effect on AUC0-40 after ranitidine administration into the duodenum and midgut compared to administration in pH 7 buffer. However, bile significantly increased AUC0-40 and Cmax after ranitidine administration into the terminal ileum compared to administration with pH 7 and pH 5 buffer. Results suggest that ranitidine is absorbed from the entire small intestine. However, the terminal ileum is the optimal site of gastrointestinal absorption. Furthermore, bile enhances ranitidine absorption from the terminal ileum.


The spectrum of Spitz nevi: a clinicopathologic study of 83 cases.
To achieve a clinicopathologic classification of Spitz nevi by comparing their clinical, dermoscopic, and histopathologic features. Eighty-three cases were independently reviewed by 3 histopathologists and preliminarily classified into classic or desmoplastic Spitz nevus (CDSN, n = 11), pigmented Spitz nevus (PSN, n = 14), Reed nevus (RN, n = 16), or atypical Spitz nevus (ASN, n = 14); the remaining 28 cases were then placed into an intermediate category (pigmented Spitz-Reed nevus, PSRN) because a unanimous diagnosis of either PSN or RN was not reached. University dermatology and pathology departments and general hospital pathology departments. A sample of subjects with excised melanocytic lesions. Frequency of dermoscopic patterns within the different histopathologic subtypes of Spitz nevi. Overlapping clinical, dermoscopic, and histopathologic findings were observed among PSN, RN, and PSRN, thereby justifying their inclusion into the single PSRN diagnostic category. Asymmetry was the most frequent indicator of histopathologic ASN (79%; n = 11); in only 4 cases did dermoscopic asymmetry show no histopathologic counterpart, and in those cases the discrepancy was probably the result of an artifact of the gross sampling technique carried out with no attention to the dermoscopic features. Among Spitz nevi, histopathologic distinction between PSN and RN is difficult, not reproducible, and may be clinically useless. A simple clinicopathologic classification of these neoplasms might therefore be structured as CDSN, PSRN, and ASN. Asymmetry should be assessed using both dermoscopic and histopathologic analysis, and reliability in histopathologic diagnosis may be enhanced by the simultaneous evaluation of the corresponding dermoscopic images.


Clinical perspective: Linking psychosocial care to the disease continuum in patients with multiple myeloma.
A model of psychosocial care specific for patients with multiple myeloma and their caregivers has not yet been proposed. We sought to develop a model of care that considers the specific profile of this disease. The authors, representing a multidisciplinary care team, met in December of 2012 to identify a model of psychosocial care for patients with multiple myeloma and their caregivers. This model was determined by consensus during the meeting and via total agreement following the meeting. The meeting was sponsored by Onyx Pharmaceuticals. The need for targeted psychosocial care for the multiple myeloma patient and caregiver throughout the disease process is essential to ensure quality of life and optimal treatment outcomes. We propose herein the first known model of care for the treatment of multiple myeloma that engages both the patient and their caregivers. Innovative partnerships between psychosocial providers and other entities such as pharmaceutical companies can maximize resources for comprehensive program development. This manuscript proposes a model of care that promotes active engagement in therapies for multiple myeloma while engaging the individual patient and their family caregivers. This treatment approach must be evidence based in terms of distress screening tools, comprehensive psychosocial assessments, and, most importantly, in the interventions and measurements of response that clinicians apply to this population.


A low mortality model of chronic pulmonary hypertension in sheep.
Pulmonary hypertension and right ventricular failure are major contributors to morbidity and mortality in chronic lung disease. Therefore, large animal models of pulmonary hypertension and right ventricular hypertrophy are needed to study underlying disease mechanisms and test new treatment modalities. The objective of this study was to create a low-mortality model of chronic pulmonary hypertension and right ventricular hypertrophy in sheep. The vena cavae of nine sheep weighing 62 ± 2 (SEM) kg were injected with 0.375 g of dextran beads (sephadex) every day for 60 d. Pulmonary hemodynamics were assessed via pulmonary artery catheterization prior to the first injection and again on d 14, 28, 35, 42, 49, and 56. At the end of the experiment, the heart was removed, dissected, and weighed to determine the ratio of right ventricular mass to left ventricle plus septal mass (RV:LV+S). All sheep survived to 60 d. The average pulmonary artery pressure rose from 17 ± 1 mmHg at baseline to 35 ± 3 mmHg on d 56 with no significant change in cardiac output (8.7 ± 0.7 to 9.8 ± 0.7 L/min, P = 0.89). The RV:LV+S was significantly higher (0.42 ± 0.01, P < 0.001) than a historic group of untreated normal animals (0.35 ± 0.01, n = 13). This study provides a low-mortality large animal model of moderate chronic pulmonary hypertension and right ventricular hypertrophy.


Changes of Effective Connectivity in the Alpha Band Characterize Differential Processing of Audiovisual Information in Cross-Modal Selective Attention.
Cross-modal selective attention enhances the processing of sensory inputs that are most relevant to the task at hand. Such differential processing could be mediated by a swift network reconfiguration on the macroscopic level, but this remains a poorly understood process. To tackle this issue, we used a behavioral paradigm to introduce a shift of selective attention between the visual and auditory domains, and recorded scalp electroencephalographic signals from eight healthy participants. The changes in effective connectivity caused by the cross-modal attentional shift were delineated by analyzing spectral Granger Causality (GC), a metric of frequency-specific effective connectivity. Using data-driven methods of pattern-classification and feature-analysis, we found that a change in the α band (12 Hz-15 Hz) of GC is a stable feature across different individuals that can be used to decode the attentional shift. Specifically, auditory attention induces more pronounced information flow in the α band, especially from the parietal-occipital areas to the temporal-parietal areas, compared to the case of visual attention, reflecting a reconfiguration of interaction in the macroscopic brain network accompanying different processing. Our results support the role of α oscillation in organizing the information flow across spatially-separated brain areas and, thereby, mediating cross-modal selective attention.


Aedes albopictus in the Solomon and Santa Cruz Islands, South Pacific.
Surveys of mosquitoes in the South Pacific up until 1977 have shown the presence of Aedes albopictus only as far east as Papua New Guinea. During the visit to the Solomon Islands in 1978 to collect members of the Aedes (Stegomyia) scutellaris complex, Ae. albopictus was found in large numbers on Guadalcanal and was also present in the Santa Cruz Islands. This species has been incriminated as a vector of dengue haemorrhagic fever.


Maternal deprivation in neonatal rats alters the expression of circadian system under light-dark cycles and restricted daily feeding in adulthood.
Effects of maternal deprivation (MD) with different conditions were examined on the circadian rhythms in plasma corticosterone and locomotor activity in adult rats under ad libitum and restricted daily feeding (RF), in which rats had free access to food for 2 h for 3 weeks. Three different types of MD were performed from postnatal day 1 (P1) to day 6 (P6); MD for 12 h/day (MD12), for 3 h/day in the morning (MD3am) and in the afternoon (MD3pm). Under ad libitum feeding, corticosterone levels at 08:00 h and 24:00 h were significantly increased in MD12 rats. A similar increase was detected in MD3am rats, but not in MD3pm rats. Under the RF, corticosterone levels at 08:00 h, 24:00 h, and 04:00 h were significantly increased in MD12 rats. Similar elevations were detected in MD3am rats, but not in MD3pm rats. Furthermore, prefeeding locomotor activities under the RF increased significantly in MD12 rats. A similar increase was observed in MD3am rats, but not in MD3pm rats. Keeping ambient temperature and humidity at 37 degrees C and 70-80% during MD attenuated the effects of MD on the corticosterone rhythmicities under RF as well as ad lib feeding. It is concluded that MD in the early postnatal period influences the expressions of circadian rhythms in plasma corticosterone and locomotor activity in adult rats. Not only the length but also the time of day of MD seems to be critical for these effects. Ambient temperature and/or humidity are suggested to be one of the factors by which MD exerts its effect.


The effect of Optune™ Tumor Treating Fields transducer arrays on skin radiation dose during radiotherapy.
A Phase 3 clinical study demonstrated that the addition of 200kHz Tumor Treating Fields (TTF) to temozolomide in the post-radiation (RT) phase of therapy in newly diagnosed glioblastoma increases progression free and overall survival (resulting in FDA and European Union approval). Preclinical studies have demonstrated the ability of TTF to act as a radiosensitizer, suggesting concurrent TTF and RT may have clinical utility. The removal and replacement of TTF transducer arrays from the scalps of patients on a daily basis, i.e., just before and after RT treatments, would be extremely cumbersome. Based on these considerations, phantom studies of the effect of Optune (TM) transducer arrays on radiation dose distribution were performed to evaluate the feasibility of leaving arrays in place during RT. Film measurements were performed using Gafchromic EBT3 film and an Epson 11000XL scanner. Film calibration was done based on the ratio of the red to blue color channel data. A Siemens Oncor linear accelerator operating at 6MV, 10cm×10cm field size, and 100cm source-to-film distance was used for all measurements. For each exposure, two films were stacked, providing planes of measurement that were ∼0.1 and 0.4mm in depth. Data accrued demonstrated that radiation attenuation should not be a clinically significant issue. However, TTF transducer arrays were found to cause both a radiation bolus effect, as well as an increased exit dose effect. These studies predict increased skin toxicity, which merits significant caution for further clinical development of this combination.


Future prospects for oncolytic therapy.
Viruses have been engineered to replicate selectively in cancer cells, based on a number of innovative principles. Several of these viruses have entered clinical trials and have proven relatively safe, and have shown evidence of efficacy. However, further research is required to enable these agents to function systemically. This might involve attempts to suppress immune responses to virus antigens, and re-targeting of viruses to favor tumor infection and increased potency. When these barriers are overcome, oncolytic viruses could enter the mainstream of clinical oncology.


Accuracy of quantitative diffusion-weighted imaging for differentiating benign and malignant pancreatic lesions: a systematic review and meta-analysis.
A variety of imaging techniques can be used to evaluate diffusion characteristics to differentiate malignant and benign pancreatic lesions. The diagnostic performance of diffusion parameters has not been systematic assessed. We aimed to investigate the diagnostic efficacy of quantitative diffusion-weighted imaging (DWI) for pancreatic lesions. A literature search was conducted using the PubMed, Embase, and Cochrane Library databases for studies from inception to March 30, 2020, which involves the quantitative diagnostic performance of diffusion-weighted imaging (DWI) and intravoxel incoherent motion (IVIM) in the pancreas. Studies were reviewed according to inclusion and exclusion criteria. The quality of articles was evaluated by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUATAS-2). A bivariate random-effects model was used to evaluate pooled sensitivities and specificities. Univariable meta-regression analysis was used to test the effects of factors that contributed to the heterogeneity. A total of 31 studies involving 1558 patients were ultimately eligible for data extraction. The lowest heterogeneity was found in specificity of perfusion fraction (f) with the I2 value was 17.97% and Cochran p value was 0.28. However, high heterogeneities were found for the other parameters (all I2 > 50%). There was no publication bias found in funnel plot (p = 0.30) for the apparent diffusion coefficient (ADC) parameter. The pooled sensitivities for ADC, f, pure diffusion coefficient (D), and pseudo diffusivity coefficient (D*) were 83%, 81%, 76%, and 84%, respectively. The pooled specificities for ADC, f, D, and D* were 87%, 83%, 69%, and 81% respectively. The areas under the curves for ADC, f, D, and D* were 0.92, 0.87, 0.79, and 0.87 respectively. Quantitative DWI and IVIM have a good diagnostic performance for differentiating malignant and benign pancreatic lesions. • IVIM has high sensitivity and specificity (84% and 83%, respectively) for differential diagnosis of pancreatic lesions, which is comparable to that of the ADC (83% and 87%, respectively). • The ADC has an excellent diagnostic performance for differentiating malignant from benign IPMNs (sensitivity, 0.83; specificity, 0.92); the f has the best diagnostic performance for differentiating pancreatic carcinoma from PNET (sensitivity, 0.85; specificity, 0.85). • For the ADC, using a maximal b value < 800 s/mm2 has a higher diagnostic accuracy than ≥ 800 s/mm2; performing in a high field strength (3.0 T) system has a higher diagnostic accuracy than a low field strength (1.5 T) for pancreatic lesions.


Dose-Response Effect of Consuming Commercially Available Eggs on Wintertime Serum 25-Hydroxyvitamin D Concentrations in Young Australian Adults: a 12-Week Randomized Controlled Trial.
Vitamin D deficiency is a common health concern during winter. Eggs are one of the few rich dietary sources of vitamin D, containing cholecalciferol (vitamin D-3) and 25-hydroxyvitamin D-3 [25(OH)D3], with the latter reported to be 5 times more potent at increasing serum 25(OH)D concentrations, the major circulating form of vitamin D. However, whether there is an optimal dose of eggs to increase or maintain 25(OH)D concentrations during wintertime is not known. To evaluate the dose-response effect of consuming 2, 7, or 12 commercially available eggs per week on serum 25(OH)D concentrations during the autumn-winter months in young adults. Secondary aims were to investigate changes in serum lipids, and the feasibility (adherence) and acceptability to consuming the eggs. In a 12-wk randomized controlled trial, 51 adults aged 25-40 y were randomly assigned to consume 2 eggs/wk (control, n = 17), 7 eggs/wk (n = 17), or 12 eggs/wk (n = 17). Change in serum 25(OH)D was the primary outcome as assessed by LC/MS/MS. Serum lipids were assessed using standard techniques, and acceptability to consuming the eggs was assessed via a questionnaire. Forty-two (82%) participants completed the study. Mean adherence to the eggs was 83% for controls, 86% for 7 eggs/wk, and 83% for 12 eggs/wk. Mean serum 25(OH)D concentrations did not change significantly in either the 7-eggs/wk (-8.3 nmol/L; 95% CI: -17.0, 0.4 nmol/L) or 12-eggs/wk (-7.2 nmol/L; 95% CI: -18.6, 4.3 nmol/L) groups, but decreased by 28.6 nmol/L (95% CI: -38.1, -18.9 nmol/L) in controls, which led to a significant (P = 0.003) between-group difference for the change after 12 wk. Serum lipids did not differ between the groups, and acceptability profiles to consuming the eggs were positive and similar for all 3 groups. Consuming 7 commercially available eggs per week for 12 wk was effective for attenuating the wintertime decline in circulating vitamin D concentrations in young Australian adults, with 12 eggs/wk not providing any additional benefits.


Design, synthesis, and biological evaluation of pyrazolopyrimidine-sulfonamides as potent multiple-mitotic kinase (MMK) inhibitors (part I).
A novel class of pyrazolopyrimidine-sulfonamides was discovered as selective dual inhibitors of aurora kinase A (AKA) and cyclin-dependent kinase 1 (CDK1). These inhibitors were originally designed based on an early lead (compound I). SAR development has led to the discovery of potent inhibitors with single digit nM IC(50)s towards both AKA and CDK1. An exemplary compound 1a has demonstrated good efficacy in an HCT116 colon cancer xenograft model.


Review of the metabolism and mode of action of cyclophosphamide.
A review of recent studies of the pharmacology of cyclophosphamide is presented. Particular attention is paid to the use of mass spectrometry in the identification of the active compound phosphoramide mustard as a circulating human metabolite of cyclophosphamide, the development of an assay method for cyclophosphamide, phosphoramide mustard, and nornitrogen mustard, and a demonstration that alkylation by phosphoramide mustard proceeds through a symmetrical aziridinium ion.


Measurements of knee morphometrics using MRI and arthroscopy: a comparative study between ACL-injured and non-injured subjects.
The primary purpose of this study was as follows: (1) to compare bony morphology in subjects with and without ACL injury. The secondary purposes were the following: (2) to compare bony morphology between men and women and (3) to determine whether MRI measurements of the notch correlate with intra-operative measurements. MRI measurements of NW, bicondylar width, medial condyle size and lateral condyle size, and medial-to-lateral condyle ratio (M:L) were taken from 45 subjects with ACL injury and 44 subjects without ACL injury, by two independent observers. In addition, notch width measurements were taken arthroscopically in the 45 injured subjects. Knee morphometrics were compared between men and women. Additionally, values of ACL-injured and non-injured subjects were compared for male and female subjects separately. Correlations between notch measurements taken from MRI and measured arthroscopically were determined. Reliability of the MRI measurements was calculated. Significant differences were found for bicondylar width (P = 0.001), medial condyle width (P = 0.002), and lateral condyle width (P = 0.002) between male and female subjects. When bony morphology was compared between ACL-injured and non-injured subjects, the male subjects showed significant differences for bicondylar width (P = 0.002) and medial condyle width (P = 0.008). For the female subjects, significant differences were found for bicondylar width (P = 0.009) and lateral condyle width (P = 0.002). There was no correlation between notch width measured on the MRI's and NW measured intra-operatively. The intra- and inter-observer reliability of the MRI measurements was satisfactory. There were differences in bony morphology between men and women and between subjects with and without ACL injury. The bony morphology that was different between ACL-injured and non-injured subjects varied between male and female subjects.


A FRAX® model for the assessment of fracture probability in Belgium.
A country-specific FRAX® model was developed from the epidemiology of fracture and death in Belgium. Fracture probabilities were identified that corresponded to currently accepted reimbursement thresholds. The objective of this study was to evaluate a Belgian version of the WHO fracture risk assessment (FRAX®) tool to compute 10-year probabilities of osteoporotic fracture in men and women. A particular aim was to determine fracture probabilities that corresponded to the reimbursement policy for the management of osteoporosis in Belgium and the clinical scenarios that gave equivalent fracture probabilities. Fracture probabilities were computed from published data on the fracture and death hazards in Belgium. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck bone mineral density (BMD). Fracture probabilities were determined that were equivalent to intervention (reimbursement) thresholds currently used in Belgium. Fracture probability increased with age, lower BMI, decreasing BMD T-score and all clinical risk factors used alone or combined. The 10-year probabilities of a major osteoporosis-related fracture that corresponded to current reimbursement guidelines ranged from approximately 7.5% at the age of 50 years to 26% at the age of 80 years where a prior fragility fracture was used as an intervention threshold. For women at the threshold of osteoporosis (femoral neck T-score = -2.5 SD), the respective probabilities ranged from 7.4% to 15%. Several combinations of risk-factor profiles were identified that gave similar or higher fracture probabilities than those currently accepted for reimbursement in Belgium. The FRAX® tool has been used to identify possible thresholds for therapeutic intervention in Belgium, based on equivalence of risk with current guidelines. The FRAX® model supports a shift from the current DXA-based intervention strategy, towards a strategy based on fracture probability of a major osteoporotic fracture that in turn may improve identification of patients at increased fracture risk. The approach will need to be supported by health economic analyses.


Emission factors and characteristics of volatile organic compounds (VOCs) from adhesive application in indoor decoration in China.
Adhesive application in indoor decoration is an important anthropogenic volatile organic compound (VOC) emission source of both indoors and outdoors. However, few studies have been conducted on VOC emission factors and characteristics from indoor decorating adhesives. In this study, the VOC emission factors were obtained by measurement of VOCs in 210 adhesives. The results showed that the VOC emission factors were 41.23 g/L for wall and ground solidify, 33.49 g/L for tile adhesive, 76.88 g/L for white glue, 52.36 g/L for wallcovering adhesive, 132.28 g/L for sealant glue, 49.33 g/kg for foaming adhesive, 654.23 g/L for all-purpose adhesive, 251.93 g/L for free nails adhesive, 152.01 g/L for marble glue, and 136.79 g/L for beautiful sealant. Methodology for calculating activity data of decorating adhesive consumptions was developed and a VOC emission inventory from adhesive application in indoor decoration was developed using a bottom-up estimation methodology. The VOC emissions from 2012 to 2017 in China were 235,987.76, 246,230.47, 250,981.62, 249,849.48, 227,150.33 and 212, 433.07 t, respectively. The beautiful sealant, wall and ground solidify, sealant glue and all-purpose adhesive contributed the most of the total emissions, collectively accounting for 78.14%. Shandong, Jiangsu, Zhejiang, Sichuan and Guangdong ranked as the top five provinces for VOC emissions, together contributing 39.10% to the national total emissions. Shandong and Jiangsu reached up to 17,057.95 t/year and 15,207.92 t/year, respectively. Priority should be given to four types of adhesives with pretty high VOC contents for designing effective VOC control measures, including solvent-based all-purpose adhesive, solvent-based free nails adhesive, solvent-based sealant glue, and solvent-based beautiful sealant. Future emission trends are projected through 2030 based on current emission control policies and real estate trend. It may be possible to reduce VOC emissions by 60.81% and 69.37% by 2030 under the two scenarios, respectively, compared with the VOC emissions in 2017.


Multidisciplinary Virtual Three-Dimensional Planning of a Forequarter Amputation With Chest Wall Resection.
We present the case of a 74-year-old man with a history of a squamous cell carcinoma in the left axilla. The patient underwent a multidisciplinary surgical resection through an extended forequarter amputation with thoracic wall resection and reconstruction. With regard to the complexity of the case, three-dimensional virtual reality-based patient-specific reconstructions were used as a supplemental tool to conventional computed tomography imaging to plan the procedure. With this report, we aim to stimulate further research to improve and automate the workflow and to bring virtual and augmented reality reconstructions into the surgical theater of the future.


A rare case of spontaneous otogenic pneumocephalus with pictorial illustration of temporal evolution.
Pneumocephalus is commonly seen on imaging in the setting of craniofacial trauma, skull base tumours, intracranial infection and after neurological intervention. Spontaneous pneumocephalus in the absence of these conditions is exceedingly rare, with only approximately 30 cases reported in the literature to date. Spontaneous otogenic pneumocephalus (SOP) is believed to occur as a result of anomalous communication between the intracranial space and a hyper-pneumatised temporal bone, with either positive extra-to-intracranial pressure or negative intracranial pressure gradient. These anomalous communicating channels may only become clinically apparent when triggered by episodes of acute increase in middle ear pressure during coughing, sneezing, Valsalva manoeuvre or significant change in atmospheric pressure. Patients may exhibit a wide range of neurological symptoms and the aim of treatment is to reduce the risk of complications such as infection and intracranial hypertension. Both conservative and neurosurgical approaches have been described. We report a case of SOP in which the patient was conservatively managed, and spontaneous resolution of pneumocephalus was documented on serial computed tomography (CT) scans. This unique case clearly demonstrates the natural history and temporal evolution of SOP without surgical intervention. This knowledge may potentially obviate the need for surgery, thus reducing morbidity and mortality in patients who are poor surgical candidates.


Dodecanol, metabolite of entomopathogenic fungus Conidiobolus coronatus, affects fatty acid composition and cellular immunity of Galleria mellonella and Calliphora vicina.
One group of promising pest control agents are the entomopathogenic fungi; one such example is Conidiobolus coronatus, which produces a range of metabolites. Our present findings reveal for the first time that C. coronatus also produces dodecanol, a compound widely used to make surfactants and pharmaceuticals, and enhance flavors in food. The main aim of the study was to determine the influence of dodecanol on insect defense systems, i.e. cuticular lipid composition and the condition of insect immunocompetent cells; hence, its effect was examined in detail on two species differing in susceptibility to fungal infection: Galleria mellonella and Calliphora vicina. Dodecanol treatment elicited significant quantitative and qualitative differences in cuticular free fatty acid (FFA) profiles between the species, based on gas chromatography analysis with mass spectrometry (GC/MS), and had a negative effect on G. mellonella and C. vicina hemocytes and a Sf9 cell line in vitro: after 48 h, almost all the cells were completely disintegrated. The metabolite had a negative effect on the insect defense system, suggesting that it could play an important role during C. coronatus infection. Its high insecticidal activity and lack of toxicity towards vertebrates suggest it could be an effective insecticide.


1,5-Anhydroglucitol attenuates cytokine release and protects mice with type 2 diabetes from inflammatory reactions.
1,5-anhydroglucitol (1,5-AG) decreases in diabetic patients and is used as a marker of glycemic control. Type 2 diabetic patients are susceptibile to lipopolysaccharides (LPS), which stimulate macrophages to release large quantities of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. This study examines the effects of 1,5-AG on lung inflammation induced by LPS and consequent systemic inflammation to determine whether the decrease of 1,5-AG concentration induces susceptibility to LPS. Before the challenge with LPS (1 mg/kg in vivo and 500 ng/ml in vitro), we pretreated db/db mice and RAW264.7 cells with 1,5-AG at 38.5 mg/kg and 500 microg/ml, respectively. The levels of IL-6, TNF-alpha, macrophage chemoattractant protein (MCP)-1 and IL-1beta in the serum and in the cell supernatants were measured. We also measured macrophage recruitment and the expression of inducible nitric oxide synthase (iNOS) in pulmonary tissues. We found that 1,5-AG attenuated serum cytokine release and protected db/db mice from LPS-induced pulmonary inflammation. In addition, 1,5-AG suppressed cytokine release and iNOS expression by suppressing Akt/NF-kB activity in RAW264.7 cells. These results suggest that 1,5-AG may be a mediator in, as well as marker for diabetes, and 1,5-AG intake may confer tolerance to LPS in patients with type 2 diabetes.