Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal hypertension.
Nonselective β-blockers are useful to prevent bleeding in patients with cirrhosis and large varices but not to prevent the development of varices in those with compensated cirrhosis and portal hypertension (PHT). This suggests that the evolutionary stage of PHT may influence the response to β-blockers. To characterize the hemodynamic profile of each stage of PHT in compensated cirrhosis and the response to β-blockers according to stage, we performed a prospective, multicenter (tertiary care setting), cross-sectional study. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured in 273 patients with compensated cirrhosis before and after intravenous propranolol (0.15 mg/kg): 194 patients had an HVPG ≥10 mm Hg (clinically significant PHT [CSPH]), with either no varices (n = 80) or small varices (n = 114), and 79 had an HVPG >5 and <10 mm Hg (subclinical PHT). Patients with CSPH had higher liver stiffness (P < 0.001), worse Model for End-Stage Liver Disease score (P < 0.001), more portosystemic collaterals (P = 0.01) and splenomegaly (P = 0.01) on ultrasound, and lower platelet count (P < 0.001) than those with subclinical PHT. Patients with CSPH had lower systemic vascular resistance (1336 ± 423 versus 1469 ± 335 dyne · s · cm(-5) , P < 0.05) and higher cardiac index (3.3 ± 0.9 versus 2.8 ± 0.4 L/min/m(2) , P < 0.01). After propranolol, the HVPG decreased significantly in both groups, although the reduction was greater in those with CSPH (-16 ± 12% versus -8 ± 9%, P < 0.01). The HVPG decreased ≥10% from baseline in 69% of patients with CSPH versus 35% with subclinical PHT (P < 0.001) and decreased ≥20% in 40% versus 13%, respectively (P = 0.001). Patients with subclinical PHT have less hyperdynamic circulation and significantly lower portal pressure reduction after acute β-blockade than those with CSPH, suggesting that β-blockers are more suitable to prevent decompensation of cirrhosis in patients with CSPH than in earlier stages.


Durability of response to dapagliflozin: a review of long-term efficacy and safety.
Due to the chronic nature of type 2 diabetes (T2D), it is essential for an anti-diabetic drug to have durable efficacy and a good long-term safety profile. Dapagliflozin is a member of a unique class of anti-diabetic drugs that inhibit the sodium-glucose cotransporter 2 (SGLT-2) in the renal tubules and have an insulin-independent mechanism of action. In short-term studies (≤ 24 weeks), dapagliflozin reduced glycated hemoglobin (A1c), weight, and systolic blood pressure, and had a good safety profile. This review summarizes the findings of long-term studies that evaluated the efficacy and safety of dapagliflozin. These findings indicate that dapagliflozin is effective as monotherapy and in combination with other anti-hyperglycemic agents, including insulin and oral anti-diabetic therapies, in improving glycemic control and reducing blood pressure and weight for up to 4 years. The findings were fairly consistent across various patient populations with T2D, including those with cardiovascular disease (CVD) and mild renal impairment. Extended use of dapagliflozin was not associated with an increase in safety signals over time. Frequently observed adverse events (AEs) were consistent with the drug's mechanism of action and were generally mild in intensity. No substantial impact of dapagliflozin on renal function was observed, and findings show that the drug is safe in T2D patients with CVD or mild renal impairment, as well as elderly patients. The findings across the studies support the use of dapagliflozin for the long-term treatment of T2D across a broad spectrum of patients.


Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney.
We have analyzed the chromosome 6q21 breakpoint of a non-constitutional t(6;15)(q21;q21) rearrangement in sporadic Wilms' tumor. This identified a novel gene encoding a protein with six N-terminal ankyrin repeats linked to a C-terminal HECT ubiquitin-protein ligase domain. We therefore designated this gene HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1). HACE1 is widely expressed in human tissues, including mature and fetal kidney. We show that Hace1 protein possesses intrinsic ubiquitin ligase activity, utilizes UbcH7 as a candidate partner E2 enzyme and localizes predominantly to the endoplasmic reticulum. Although the HACE1 locus was not directly interrupted by the translocation in the index Wilms' case, its expression was markedly lower in tumor tissue compared with adjacent normal kidney. Moreover, HACE1 expression was virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney. We found no evidence of HACE1 mutations or deletions, but hypermethylation of two upstream CpG islands correlates with low HACE1 expression in tumor samples. Our findings implicate Hace1 as a novel ubiquitin-protein ligase and demonstrate that its expression is very low in primary Wilms' tumors.


Induction of Atypical Autophagy by Porcine Hemagglutinating Encephalomyelitis Virus Contributes to Viral Replication.
Autophagy is a basic biological metabolic process involving in intracellular membrane transport pathways that recycle cellular components and eliminate intracellular microorganisms within the lysosome. Autophagy also plays an important part in virus infection and propagation. However, some pathogens, including viruses, have evolved unique trick to escape or exploit autophagy. This study explores the mechanism of autophagy induction by porcine hemagglutinating encephalomyelitis virus (PHEV) in Neuro-2a cells, and examines the role of autophagy in PHEV replication. PHEV triggered autophagy in Neuro-2a cells is dependent on the presence of bulk double- or single-membrane vacuoles, the accumulation of GFP-LC3 fluorescent dots, and the LC3 lipidation. In addition, PHEV induced an incomplete autophagic effect because the degradation level of p62 did not change in PHEV-infected cells. Further validation was captured using LysoTracker and lysosome-associated membrane protein by indirect immunofluorescence labeling in PHEV-infected cells. We also investigated the change in viral replication by pharmacological experiments with the autophagy inducer rapamycin or the autophagy inhibitor 3-MA, and the lysosomal inhibitor chloroquine (CQ). Suppression of autophagy by 3-MA increased viral replication, compared with the mock treatment, while promoting of autophagy by rapamycin reduced PHEV replication. CQ treatment enhanced the LC3 lipidation in PHEV-infected Neuro-2a cells but lowered PHEV replication. These results show that PHEV infection induces atypical autophagy and causes the appearance of autophagosomes but blocks the fusion with lysosomes, which is necessary for the replication of PHEV in nerve cells.


Alveolar distraction osteogenesis: a case report involving ankylosed maxillary central incisors.
Restorative dentistry, for the optimal esthetic and functional result, at times requires innovation, exacting techniques, and employment of various treatment modalities. A case has been presented here involving a large esthetic defect in the maxillary anterior. Traditional methods of restoration may have been successful but alveolar distraction osteogenesis was determined to be the treatment of choice due to time, predictability, lack of invasiveness, and cost. It is a relatively new surgical procedure that has many applications to restore esthetic defects, ridge augmentation, and large craniofacial abnormalities. Movement of osseous sections can be made in a vertical, labial, or lingual direction. When treatment planning restorative dentistry with vertical hard and soft tissue deficiencies, alveolar distraction osteogenesis can be considered to achieve optimal esthetics and a more ideal crown-to-root ratio. Further information can be obtained from any oral surgeon, orthodontist, or from the Internet. Dr. Martin Chin, a maxillofacial surgeon from San Francisco, has done much of the clinical work regarding distraction procedures on humans and continues to be an innovator in craniofacial distraction osteogenesis. His work can be found on the Internet at www.distraction.net; other interesting Web sites include www.klsmartin.com/distract.dir/indexdistract.html and www.seattle-implants.com/articles/distost.htm.


Challenging our own practices in Indigenous health promotion and research.
At the 2006 National Conference of the Australian Health Promotion, Māori academic and public health physician Dr Papaarangi Reid challenged us to critique our own practice and asked whether health promotion needs to be de-colonised. In this paper, one Indigenous and two non-Indigenous researchers working within the Aboriginal community controlled health sector reflect on ways in which research and health promotion interventions with Indigenous populations challenge or reinforce the very values that have led to the disadvantage, neglect and apathy experienced by Indigenous populations in the first place. While our practice is framed by the principles of Aboriginal self-determination and community control, we suggest that de-colonising is not so much about the need to invent new research methods nor to search for research methods in traditional Aboriginal culture; it is much more about values, processes and relationships. We recognise the need to challenge the deficit model in health promotion and research, and we do not want to inflict any more damage to the community, through reinforcing stereotypes, creating fear, or contributing to further bad press. We argue for adopting a methodology that shifts power and enables Indigenous people to frame research in ways they want it framed, and for taking a holistic approach and focusing on community strength and resilience.


Celiac disease and dermatologic manifestations: many skin clue to unfold gluten-sensitive enteropathy.
Cutaneous manifestations of intestinal diseases are increasingly reported both in the adult and in the children, and this association cannot longer be considered a simple random. Besides the well-known association between celiac disease (CD) and dermatitis herpetiformis (DH), considered as the cutaneous manifestation of gluten-dependent enteropathy, is more frequently reported also the association with other mucocutaneous diseases. Among these there are both autoimmune, allergic, and inflammatory diseases, but also a more heterogeneous group called miscellaneous. The knowledge about pathogenic, epidemiological, clinical, and diagnostic aspects of CD is increasing in recent years as well as those about DH, but some aspects still remain to be defined, in particular the possible pathogenetic mechanisms involved in the association between both CD and DH and CD and other immunological skin diseases. The aim of this paper is to describe the skin diseases frequently associated with CD, distinguishing them from those which have a relationship probably just coincidental.


From slacktivism to activism: Improving the commitment power of e-pledges for prosocial causes.
Prosocial organizations increasingly rely on e-pledges to promote their causes and secure commitment. Yet their effectiveness is controversial. Epitomized by UNICEF's "Likes Don't Save Lives" campaign, the threat of slacktivism has led some organizations to forsake social media as a potential platform for garnering commitment. We proposed and investigated a novel e-pledging method that may enable organizations to capitalize on the benefits of e-pledging without compromising on its mass outreach potential. In two pilot studies, we first explored whether and why conventional e-pledges may not be as effective as intended. Building on those insights, we conducted one field and two lab experiments to test our proposed e-pledge intervention. Importantly, the field study demonstrated the effectiveness of the intervention for commitment behavior across a 3-month period. The laboratory experiments provided a deeper and more refined mechanism understanding of the effect and ruled out effort, novelty, and social interaction mindset as alternative explanations for why the intervention may be effective. As technological innovations continue to redefine how people interact with the world, this research sheds light on a promising method for transforming a simple virtual acknowledgment into deeper commitment-and, ideally, to action.


Studies on the mechanism of chronic graft rejection in mice.
Acute and chronic types of rejection after transplantation are distinguished. The exact mechanism, however, by which the different types of rejections have been brought about are not clarified. In this study, experimental data are presented on some characteristics of the chronic type of graft rejection. Allografting was performed between isogeneic mouse strains differing at their strong histocompatibility antigens. Recipients were treated with antithymocyte serum (ATS). Those recipients which showed a chronic type of graft rejection were selected and regrafted with a second-set or a third party allograft. It was found that, in most cases, the chronic rejection of first-set allografts did not results in a sensitization (= accelerated rejection), but rather in a partial specific tolerance (= prolonged graft survival) to a second-set allograft. Furthermore, transfer of spleen cells from mice of chronic rejection into normal, adult, ATS-treated, allografted mice did not result in any significant change of the mean graft survival as compared to mice not receiving spleen cell transfer. On the other hand, transfer of spleen cells from mice with acutely rejected grafts resulted in a shortened graft survival. It is supposed that the partial specific tolerance observed after chronic graft rejection may be maintained rather by a specific suppressor mechanism than clonal deletion.


Pharmacist-initiated prior authorization process to improve patient care in a psychiatric acute care hospital.
A prior authorization (PA) is a requirement implemented by managed care organizations to help provide medications to consumers in a cost-effective manner. The PA process may be seen as a barrier by prescribers, pharmacists, pharmaceutical companies, and consumers. The lack of a standardized PA process, implemented prior to a patient's discharge from a health care facility, may increase nonadherence to inpatient prescribed medications. Pharmacists and other health care professionals can implement a PA process specific to their institution. This article describes a pharmacist-initiated PA process implemented at an acute care psychiatric hospital. This process was initiated secondary to a need for a standardized process at the facility. To date, the process has been seen as a valuable aspect to patient care. Plans to expand this process include collecting data with regards to adherence and readmissions as well as applying for a grant to help develop a program to automate the PA program at this facility.


Hydrogen attenuates sepsis-associated encephalopathy by NRF2 mediated NLRP3 pathway inactivation.
Sepsis-associated encephalopathy (SAE) is a major cause of mortality worldwide. Oxidative stress, inflammatory response and apoptosis participate in the pathogenesis of SAE. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) pathway is involved in oxidative stress and inflammatory response. We reported that hydrogen gas protected against sepsis in wild-type (WT) but not Nrf2 knockout (KO) mice. Therefore, it is vital to identify the underlying cause of hydrogen gas treatment of sepsis-associated encephalopathy. SAE was induced in WT and Nrf2 KO mice by cecal ligation and puncture (CLP). As a NLRP3 inflammasome inhibitor, MCC950 (50 mg/kg) was administered by intraperitoneal (i.p.) injection before operation. Hydrogen gas (H2)-rich saline solution (5 mL/kg) was administered by i.p. injection at 1 h and 6 h after sham and CLP operations. Brain tissue was collected to assess the NLRP3 and Nrf2 pathways by western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. SAE increased NLRP3 and Nrf2 expression in microglia. MCC950 inhibited SAE-induced NLRP3 expression, interleukin (IL)-1β and IL-18 cytokine release, neuronal apoptosis and mitochondrial dysfunction. SAE increased NLRP3 and caspase-1 expression in WT mice compared to Nrf2 KO mice. Hydrogen increased Nrf2 expression and inhibited the SAE-induced expression of NLRP3, caspase-1, cytokines IL-1β and IL-18, neuronal apoptosis, and mitochondrial dysfunction in WT mice but not Nrf2 KO mice. SAE increased NLRP3 and Nrf2 expression in microglia. Hydrogen alleviated inflammation, neuronal apoptosis and mitochondrial dysfunction via inhibiting Nrf2-mediated NLRP3 pathway.


Stimulated parotid salivary flow rates in normotensive, hypertensive, and hydrochlorothiazide-medicated.
Stimulated parotid salivary flow rates were compared in elderly normotensive, hypertensive, and controlled hypertensive African-Americans, the latter group taking hydrochlorothiazide (HCTZ). The normotensive group consisted of 15 healthy unmedicated subjects with systolic blood pressures of less than 150 mm Hg and diastolic pressures less than 90 mm Hg. The hypertensive group consisted of 10 unmedicated subjects with systolic pressures greater than 160 mm Hg and diastolic pressures greater than 100 mm Hg. The controlled hypertensive group consisted of 20 subjects taking HCTZ (50 mg, daily) with controlled blood pressures similar to the normotensive control group. Stimulated parotid salivary samples were collected from each subject. A 2% citrate solution applied to the dorsum of the tongue was used for stimulation. The results showed no significant differences in stimulated parotid flow rates between normotensive and uncontrolled hypertensive subjects. However, the medicated, controlled hypertensive subjects had a significant reduction of stimulated parotid salivary flow rates compared to both the normotensive and hypertensive groups.


[A CASE OF FAMILIAL PULMONARY AND HEPATIC ECHINOCOCCOSIS)].
Echinococcus granulosus still remains a widespread disease. Moreover, there is a large number of patients in whom it is diagnosed rather late because its clinical presentation can be unspecific and symptoms vary. We report a familial case of the disease. Its specific feature was the onset with the bilateral pulmonary process and late involvement of the liver. This excluded other pulmonary diseases, such as pneumonia, tuberculosis or cancer.


Treatment of the overactive bladder: where we stand in 2003.
The understanding and management of overactive bladder (OAB) continue to evolve. However, argument persists as to the exact incidence of the disease and the underlying pathophysiology of the symptom complex. Individual differences in symptomatic impact and, more importantly, personal coping partially account for the disparity noted among demographic estimates currently extant. Likewise, the underlying pathophysiology that leads to overt OAB syndrome is, as yet, incompletely characterized. Muscarinic receptor behavior provides partial explanation, but other complex underlying receptor and neurotransmitter interactions probably are also a component of the presentation. Current state-of-the-art therapy relies on an exclusionary diagnosis prior to the inception of therapy. Ideally, optimal therapy involves behavioral and pharmacologic interventions combined to maximize therapeutic results. Antimuscarinic therapy provides only a degree of relief from the bothersome symptoms of OAB. As yet, few options exist for patients who have previously failed oral antimuscarinic intervention. Herein, the evolving OAB landscape will be considered as it currently stands in 2003. The current lack of optimal symptom control will most assuredly lead to the development of new pathways for OAB treatment.


Symplasmic Intercellular Communication through Plasmodesmata.
Communication between cells is an essential process for developing and maintaining multicellular collaboration during plant development and physiological adaptation in response to environmental stimuli. The intercellular movement of proteins and RNAs in addition to the movement of small nutrients or signaling molecules such as sugars and phytohormones has emerged as a novel mechanism of cell-to-cell signaling in plants. As a strategy for efficient intercellular communication and long-distance molecule movement, plants have evolved plant-specific symplasmic communication networks via plasmodesmata (PDs) and the phloem.


Sexuality in Adolescents: have we Explored Enough! A Cross-sectional Study to Explore Adolescent Health in a City Slum in Northern India.
Adolescent health is a relatively new focus area of India's National health program. However, little evidence is available for the existing problems especially in adolescent slum population. A study was planned to explore the problems of adolescent pertaining to sexuality, physical health, tobacco and alcohol use in slums of Urban Meerut, and create evidence base for informed planning and decision making by the local health authorities. To study the adolescent health in the slums of Meerut City, India. Entire slums of Urban Meerut, cross-sectional study. Study was done in the slums of Meerut city, in Northern India. WHO 30 cluster sampling technique was used. Thirty slums were selected from the list of all the slums of Meerut, 210 adolescents were selected with 7 adolescents from each slum. Proportions and Chi-square test. More than one third of the (36.7%) adolescents reported to have a current health problem, however only half of these sought medical help for treatment. Tweleve percent of adolescents reported history of alcohol or tobacoo use. Nine percent adolescents complained of stressful atmosphere at home. About 10% adolescents in the surveyed population gave history of sexual activity, but only one third of them had used condom during their last sexual intercourse. This study reflects the high morbidity and poor treatment seeking behaviour among adolescents in urban slums. A significant proportion of adolescents indulge in high risk sexual behavior, tobacco and alcohol use. There were significant gender differences with regards to treatment seeking behaviour, sexual behaviour, tobacco and alcohol use. The gender nuances must be taken into account while planning interventions for this section of population.


Dynamics of reporter gene stimulation by HMG box proteins.
Overcoming local DNA rigidity is required to perform three-dimensional DNA-protein configuration at promoter regions. The abundant architectural nonhistone chromosomal HMG box proteins are nonsequence-specific; however, they have been established to specifically recognize distorted DNA. Using transient transfection to overexpress two different members of the HMGB-1/2 family of DNA architectural factors, we demonstrate that these proteins provide a general enhancement in reporter gene expression irrespective of the promoter being considered. Evidences are also provided indicating that stimulation may not be achieved by recruitment of the proteins by regulatory factors or as a consequence of major chromatin unfolding as previously suggested. Interestingly, the influence of the HMG box proteins under study was overridden when the promoters were either induced or stimulated by Trichostatin A (TSA) but recovered upon extended induction period. These results also support the concept that the architectural role of these proteins can contribute to the preinitiation complex assembly required for basal transcription, but to a much lesser extent to the poised promoter scaffolding characteristic of activated transcription.


Deep sequencing of liver explant transcriptomes reveals extensive expression from integrated hepatitis B virus DNA.
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Integration of HBV DNA into the human genome may contribute to oncogenesis and to the production of the hepatitis B surface antigen (HBsAg). Whether integrations contribute to HBsAg levels in the blood is poorly known. Here, we characterize the HBV RNA profile of HBV integrations in liver tissue in patients with chronic HBV infection, with or without concurrent hepatitis D infection, by transcriptome deep sequencing. Transcriptomes were determined in liver tissue by deep sequencing providing 200 million reads per sample. Integration points were identified using a bioinformatic pipeline. Explanted liver tissue from five patients with end-stage liver disease caused by HBV or HBV/HDV was studied along with publicly available transcriptomes from 21 patients. Almost all HBV RNA profiles were devoid of reads in the core and the 3' redundancy (nt 1830-1927) regions, and contained a large number of chimeric viral/human reads. Hence, HBV transcripts from integrated HBV DNA rather than from covalently closed circular HBV DNA (cccDNA) predominated in late-stage HBV infection, in particular in cases with hepatitis D virus co-infection. The findings support the suggestion that integrated HBV DNA can be a significant source of HBsAg in humans.


Debunking the Myth of Wool Allergy: Reviewing the Evidence for Immune and Non-immune Cutaneous Reactions.
Although wool is commonly believed to cause irritant (non-immune) and hypersensitivity (immune) cutaneous reactions, the evidence basis for this belief and its validity for modern garments have not been critically examined. Publications from the last 100 years, using MEDLINE and Google Scholar, were analysed for evidence that wool causes cutaneous reactions, both immune-mediated (atopic dermatitis exacerbation, contact urticaria, allergic contact dermatitis) and non-immune-mediated (irritant contact dermatitis, itch). Secondary aims of this paper were to examine evidence that lanolin and textile-processing additives (formaldehyde, chromium) cause cutaneous reactions in the context of modern wool-processing techniques. Current evidence does not suggest that wool-fibre is a cutaneous allergen. Furthermore, contact allergy from lanolin, chromium and formaldehyde is highly unlikely with modern wool garments. Cutaneous irritation from wool relates to high fibre diameters (≥ 30-32 µm). Superfine and ultrafine Merino wool do not activate sufficient c-fibres to cause itch, are well tolerated and may benefit eczema management.


Veggie Van Pilot Study: Impact of a Mobile Produce Market for Underserved Communities on Fruit and Vegetable Access and Intake.
We conducted a pilot evaluation of the Veggie Van, a mobile produce market that brings weekly boxes of reduced-cost locally grown fruits and vegetables (F&V) to lower-income communities and offers cooking and nutrition education to customers. We conducted surveys just prior to starting Veggie Van at each of 3 sites and again at 2-3 months. F&V intake was measured with a 2-question item and a 10-item food frequency questionnaire (FFQ) in a subset of participants. At baseline, average servings/day of F&V was 4.9 (SD = 2.6, n = 60). At follow-up, individuals who reported shopping at Veggie Van frequently (n = 32) increased their F&V consumption by 0.41 servings/day compared with a decrease of -1.19 for those who rarely/never used Veggie Van (n = 27), a total difference of 1.6 servings/day (P = .01). There were no statistically significant differences in F&V consumption between groups based on the FFQ measure. Frequent shoppers reported additional health improvements and increases in their ability to buy enough F&V. We conclude that offering weekly boxes of affordable F&V paired with education in underserved communities may improve F&V consumption for frequent program users.


A Case of Ruptured Carotid Traumatic Blood Blister-like Aneurysm.
Ruptured cerebral aneurysms that occur in the anterior wall of the internal carotid artery (ICA) are known as blood blister-like aneurysms (BBAs); they have been reported to account for 0.3% to 1% of all ruptured ICA aneurysms. In this report, we describe the treatment of an unusual traumatic BBA (tBBA) with high-flow bypass using a radial artery graft, which resulted in a favorable outcome. A 59-year-old female suffered from an acute epidural hematoma, traumatic subarachnoid hemorrhage, and traumatic carotid-cavernous sinus fistula (tCCF) after being involved in a motor vehicle accident. Her angiography results showed tCCF and a tBBA on the anterior wall of the right ICA. On the fourth day after injury, we found rebleeding from the tBBA and performed an emergency high-flow bypass using a radial artery graft with lesion trapping as a curative procedure for the tCCF and tBBA. Postoperatively, right abducens nerve palsy appeared, but no other neurological symptoms were noted; the patient was thereafter transferred to a rehabilitation hospital 49 days after injury. Traumatic ICA aneurysms commonly occur close to the anterior clinoid process, form within 1 to 2 weeks of injury, and often rupture around 2 weeks after trauma. This case was considered rare as the ICA was likely injured and bleeding at the time of injury, resulting in a form of tBBA; this allowed early detection and appropriate treatment that resulted in a good outcome.


A kinetic model of continuous radiation damage to populations of cells: comparison to the LQ model and application to molecular radiotherapy.
The linear-quadratic (LQ) model to describe the survival of irradiated cells may be the most frequently used biomathematical model in radiotherapy. There has been an intense debate on the mechanistic origin of the LQ model. An interesting approach is that of obtaining LQ-like behavior from kinetic models, systems of differential equations that model the induction and repair of damage. Development of such kinetic models is particularly interesting for application to continuous dose rate therapies, such as molecular radiotherapy or brachytherapy. In this work, we present a simple kinetic model that describes the kinetics of populations of tumor cells, rather than lethal/sub-lethal lesions, which may be especially useful for application to continuous dose rate therapies, as in molecular radiotherapy. The multi-compartment model consists of a set of three differential equations. The model incorporates in an easy way different cross-interacting compartments of cells forming a tumor, and may be of especial interest for studying dynamics of treated tumors. In the fast dose delivery limit, the model can be analytically solved, obtaining a simple closed-form expression. Fitting of several surviving curves with both this solution and the LQ model shows that they produce similar fits, despite being functionally different. We have also investigated the operation of the model in the continuous dose rate scenario, firstly by fitting pre-clinical data of tumor response to 131I-CLR1404 therapy, and secondly by showing how damage repair and proliferation rates can cause a treatment to achieve control or not. Kinetic models like the one presented in this work may be of special interest when modeling response to molecular radiotherapy.


The effect of pharmacological treatment in combination with vitamin K on healing in an experimental rat model of osteoporosis.
This study aims to compare the effects of teriparatide, zoledronic acid, and their combination therapy with vitamin K on osteoporotic rats. We divided a total of 50 female Sprague-Dawley rats into five groups: A (the control group), B and D (the teriparatide group), and C and E (the zoledronic acid group). Following ovariectomy and subcutaneous heparin administration at a dose of 2 IU/kg for four weeks, osteoporosis was created. Groups A, B, and C were fed with standard feed, while Groups D and E were fed with vitamin K-rich feed. After four weeks of treatment, sacrification was performed. The right and left femurs were separated for histopathological and biomechanical evaluation, respectively. For histopathological evaluation, the femurs were decalcified, and the sections were stained with hematoxylin-eosin and evaluated under a light microscope. Fracture healing was evaluated using the classification system as described previously. For biomechanical evaluation, the 3-point stress test and torsion stress test were applied to 10 femurs from each group. Groups B-E were histopathologically and biomechanically superior to Group A in fracture healing of osteoporotic rats; however, it was not statistically significant (p>0.05). The group that received additional vitamin K was histopathologically and biomechanically superior to the group which was fed with standard feed, although it was not statistically significant (p>0.05). Our study results indicated that both teriparatide and zoledronic acid had beneficial effects on osteoporotic fractures with comparable histological and biochemical results. Vitamin K promoted teriparatide and zoledronic acid treatment on osteoporotic fracture healing. Based on these findings, combination therapies may yield the most optimal results in biomechanical and histological examinations.


Prevalence and predictive value of anti-cyclic citrullinated protein antibodies for future development of rheumatoid arthritis in early undifferentiated arthritis.
The aim of this study is to evaluate the prevalence and predictive value of anti-cyclic citrullinated protein (CCP) antibodies as a diagnostic marker for future development of rheumatoid arthritis (RA) in a cohort of patients presenting with undifferentiated arthritis (UA). The study comprised 69 patients (22 males and 47 females) presenting with UA, and 66 healthy subjects as control group. For all patients the following parameters were assessed: swollen joint count (SJC), tender joint count (TJC), and duration of morning stiffness in minutes. Baseline laboratory investigations included erythrocyte sedimentation rate (ESR) first hour, C-reactive protein (CRP), complete blood count, complete liver and kidney function tests, urine analysis, anti-nuclear antibodies, rheumatoid factor (RF), and anti-CCP antibodies. Positive correlations were observed between anti-CCP versus SJC, TJC (p = 0.001), duration of morning stiffness (p = 0.04), ESR first hour, and bone erosive changes (p = 0.001). Anti-CCP showed sensitivity of 57%, specificity of 37.9%, positive predictive value of 65.1%, and negative predictive value of 39.3%. Sensitivity and positive predictive values of anti-CCP are close to those observed for RF. In patients presenting with UA, anti-CCP antibodies may allow prediction of RA, thereby allowing early individualized therapeutic decisions.


Double elimination protocol for synthesis of 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene.
A new method for constructing 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene is described on the basis of one-pot double elimination protocol. The target molecule, which is the smallest cyclophane with alternate arylene-ethynylene linkage, is synthesized in 61 % yield through oxidative dimerization of ortho-(phenylsulfonylmethyl)benzaldehyde. The initial carbon-carbon bond formation between sp(3) carbons followed by stepwise conversion to sp(2) and finally sp carbons bypasses the difficulty encountered in direct coupling of the sp carbon in the terminal acetylene. The mechanism of this process is discussed. The Wittig-Horner-type coupling is a key reaction employed for the carbon-carbon bond formation. Generation of (E)-vinylsulfone moiety in the first coupling between alpha-sulfonyl anion and aldehyde functions is crucial for the effective second coupling to complete the cyclization. The syn-elimination of the (E)-vinylsulfone moieties in the cyclized intermediate furnishes the acetylenic bonds.


The exchange factor and diacylglycerol receptor RasGRP3 interacts with dynein light chain 1 through its C-terminal domain.
RasGRP3 is an exchange factor for Ras-like small GTPases that is activated in response to the second messenger diacylglycerol. As with other diacylglycerol receptors, RasGRP3 is redistributed upon diacylglycerol or phorbol ester binding. Several factors are important in determining the pattern of translocation, including the potency of the diacylglycerol analog, the affinity of the receptor for phospholipids, and in some cases, protein-protein interactions. However, little is known about the mechanisms that play a role in RasGRP3 redistribution aside from the nature of the ligand. To discover potential protein binding partners for RasGRP3, we screened a human brain cDNA library using a yeast two-hybrid approach. We identified dynein light chain 1 as a novel RasGRP3-interacting protein. The interaction was confirmed both in vitro and in vivo and required the C-terminal domain encompassing the last 127 amino acids of RasGRP3. A truncated mutant form of RasGRP3 that lacked this C-terminal domain was unable to interact with dynein light chain 1 and displayed a dramatically altered subcellular localization, with a strong reticular distribution and perinuclear and nuclear localization. These findings suggest that dynein light chain 1 represents a novel anchoring protein for RasGRP3 that may regulate subcellular localization of the exchange factor and, as such, may participate in the signaling mediated by diacylglycerol through RasGRP3.


Culture of Adult Transgenic Zebrafish Retinal Explants for Live-cell Imaging by Multiphoton Microscopy.
An endogenous regeneration program is initiated by Müller glia in the adult zebrafish (Danio rerio) retina following neuronal damage and death. The Müller glia re-enter the cell cycle and produce neuronal progenitor cells that undergo subsequent rounds of cell divisions and differentiate into the lost neuronal cell types. Both Müller glia and neuronal progenitor cell nuclei replicate their DNA and undergo mitosis in distinct locations of the retina, i.e. they migrate between the basal Inner Nuclear Layer (INL) and the Outer Nuclear Layer (ONL), respectively, in a process described as Interkinetic Nuclear Migration (INM). INM has predominantly been studied in the developing retina. To examine the dynamics of INM in the adult regenerating zebrafish retina in detail, live-cell imaging of fluorescently-labeled Müller glia/neuronal progenitor cells is required. Here, we provide the conditions to isolate and culture dorsal retinas from Tg[gfap:nGFP]mi2004 zebrafish that were exposed to constant intense light for 35 h. We also show that these retinal cultures are viable to perform live-cell imaging experiments, continuously acquiring z-stack images throughout the thickness of the retinal explant for up to 8 h using multiphoton microscopy to monitor the migratory behavior of gfap:nGFP-positive cells. In addition, we describe the details to perform post-imaging analysis to determine the velocity of apical and basal INM. To summarize, we established conditions to study the dynamics of INM in an adult model of neuronal regeneration. This will advance our understanding of this crucial cellular process and allow us to determine the mechanisms that control INM.


Involvement of the ADP/ATP carrier in permeabilization processes of the inner mitochondrial membrane.
The effect of different agents on inner-mitochondrial-membrane permeabilization and lipoperoxidation induced by Ca2+ and the pyridine-nucleotide oxidant t-butylhydroperoxide or inorganic phosphate was investigated. Comparing the protection conferred by ADP, a substrate of the ADP/ATP carrier, dithiothreitol, a disulfide reductant and butylhydroxytoluene, a radical scavenger, it was found that ADP was always the most effective against mitochondrial damage, when present in the incubation medium from the beginning. Moreover, carboxyatractyloside, a specific inhibitor of the ADP/ATP carrier, abolished completely the protective effect of ADP on both the lipoperoxidation and mitochondrial swelling processes. Experiments where deenergized mitochondria were previously incubated with Ca2+ showed a decrease in the content of active ADP/ATP carrier, indicating a direct involvement of this protein in the formation of a non-specific Ca(2+)-dependent pore. Our results also eliminate the possibility of an attack of oxygen radicals on lipids or proteins of the mitochondrial membrane as the primary event triggering the permeability transition of the inner mitochondrial membrane.


Lineage specific composition of cyclin D-CDK4/CDK6-p27 complexes reveals distinct functions of CDK4, CDK6 and individual D-type cyclins in differentiating cells of embryonic origin.
This article is to study the role of G(1)/S regulators in differentiation of pluripotent embryonic cells. We established a P19 embryonal carcinoma cell-based experimental system, which profits from two similar differentiation protocols producing endodermal or neuroectodermal lineages. The levels, mutual interactions, activities, and localization of G(1)/S regulators were analysed with respect to growth and differentiation parameters of the cells. We demonstrate that proliferation parameters of differentiating cells correlate with the activity and structure of cyclin A/E-CDK2 but not of cyclin D-CDK4/6-p27 complexes. In an exponentially growing P19 cell population, the cyclin D1-CDK4 complex is detected, which is replaced by cyclin D2/3-CDK4/6-p27 complex following density arrest. During endodermal differentiation kinase-inactive cyclin D2/D3-CDK4-p27 complexes are formed. Neural differentiation specifically induces cyclin D1 at the expense of cyclin D3 and results in predominant formation of cyclin D1/D2-CDK4-p27 complexes. Differentiation is accompanied by cytoplasmic accumulation of cyclin Ds and CDK4/6, which in neural cells are associated with neural outgrowths. Most phenomena found here can be reproduced in mouse embryonic stem cells. In summary, our data demonstrate (i) that individual cyclin D isoforms are utilized in cells lineage specifically, (ii) that fundamental difference in the function of CDK4 and CDK6 exists, and (iii) that cyclin D-CDK4/6 complexes function in the cytoplasm of differentiated cells. Our study unravels another level of complexity in G(1)/S transition-regulating machinery in early embryonic cells.


Ferrocenyl chiral bisphosphorus ligands for highly enantioselective asymmetric hydrogenation via noncovalent ion pair interaction.
A new class of ferrocenyl chiral bisphosphorus ligand, Wudaphos, was developed, and exhibits excellent ee and activity (ee up to 99%, TON up to 20 000) for the asymmetric hydrogenation of both 2-aryl and 2-alkyl acrylic acids through ion pair noncovalent interaction under base free and mild reaction conditions. Well-known anti-inflammatory drugs such as naproxen and ibuprofen together with the intermediate for the preparation of Roche ester and some bioactive compounds were also efficiently obtained with excellent ee. Control experiments were conducted and revealed that the ion pair noncovalent interaction and chain length played important roles.


Development and in-vivo evaluation of insulin-loaded chitosan phthalate microspheres for oral delivery.
Novel chitosan phthalate microspheres containing insulin were prepared by emulsion cross-linking technique. The feasibility of these microspheres as oral insulin delivery carriers was evaluated. The pH-responsive release behaviour of insulin from microspheres was analysed. The ability of chitosan phthalate-insulin microspheres to enhance intestinal absorption and improve the relative pharmacological availability of insulin was investigated by monitoring the plasma glucose and insulin level of streptozotocin-induced diabetic rats after oral administration of microspheres at insulin dose of 20 IU kg(-1). In simulated gastric fluid (pH 2.0), insulin release from the microspheres was very slow. However, as the pH of the medium was changed to simulated intestinal fluid (pH 7.4), a rapid release of insulin occurred. The relative pharmacological efficacy for chitosan phthalate microspheres (18.66 +/- 3.84%) was almost four-fold higher than the efficacy of the chitosan phthalate-insulin solution administration (4.08 +/- 1.52%). Chitosan phthalate microspheres sustained the plasma glucose at pre-diabetic level for at least 16 h. These findings suggest that the microsphere is a promising carrier as oral insulin delivery system.


Myrsinoic acid E, an anti-inflammatory compound from Myrsine seguinii.
The methanolic extract of Myrsine seguinii yielded the novel anti-inflammatory compound, myrsinoic acid E (1), whose structure was elucidated to be 3,5-digeranyl-4-hydroxy benzoic acid. We synthesized 1- and its 3,5-diprenyl (2) and 3,5-difarnesyl analogues (3). Compounds 1-3 suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation of mouse ears by 59%, 14%, and 69% at a dose of 1.4 micromol.


Enabling valley selective exciton scattering in monolayer WSe2 through upconversion.
Excitons, Coulomb bound electron-hole pairs, are composite bosons and their interactions in traditional semiconductors lead to condensation and light amplification. The much stronger Coulomb interaction in transition metal dichalcogenides such as WSe2 monolayers combined with the presence of the valley degree of freedom is expected to provide new opportunities for controlling excitonic effects. But so far the bosonic character of exciton scattering processes remains largely unexplored in these two-dimensional materials. Here we show that scattering between B-excitons and A-excitons preferably happens within the same valley in momentum space. This leads to power dependent, negative polarization of the hot B-exciton emission. We use a selective upconversion technique for efficient generation of B-excitons in the presence of resonantly excited A-excitons at lower energy; we also observe the excited A-excitons state 2s. Detuning of the continuous wave, low-power laser excitation outside the A-exciton resonance (with a full width at half maximum of 4 meV) results in vanishing upconversion signal.


[Lipid metabolism and castration resistant prostate cancer].
Epidemiological studies showed the inverse association between statin use and prostate cancer incidence, especially advanced stages, or mortality. Recent report on association of postdiagnostic use of statin with reduction of prostatic or all-cause mortality strengthened the evidence in this subject. Our basic research findings demonstrated multiple mechanisms of lipid on prostate cancer proliferations. We also showed the mechanism of statin action on prostate cancer cells via IGF1-receptor or LDL receptor cascades. These findings will serve the new strategy for progressive and castration resistant prostate cancer management.


Vestibular and balance issues following sport-related concussion.
To review relevant literature regarding the effect of concussion on vestibular function, impairments, assessments and management strategies. REASONING: Dizziness and balance impairments are common following sport-related concussion. Recommendations regarding the management of sport-related concussion suggest including tests of balance within the multifactorial assessment paradigm for concussive injuries. The literature was searched for guidelines and original studies related to vestibular impairments following concussion, oculomotor and balance assessments and treatment or rehabilitation of vestibular impairments. The databases searched included Medline, CINAHL, Sport Discus and the Cochrane Database of Systematic Reviews through October 2013. Dizziness following concussion occurs in ∼67-77% of cases and has been implicated as a risk factor for a prolonged recovery. Balance impairments also occur after concussion and last 3-10 days post-injury. Assessments of balance can be done using both clinical and instrumented measures with success. Vestibular rehabilitation has been shown to improve outcomes in patients with vestibular impairments, with one study demonstrating success in decreasing symptoms and increasing function following concussion. Best practices suggest that the assessment of vestibular function through cranial nerve, oculomotor and balance assessments are an important aspect of concussion management. Future studies should evaluate the effectiveness of vestibular rehabilitation for improving patient outcomes.


Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors.
Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor (CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Delta24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor (EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.


Polar Localization of the NIP5;1 Boric Acid Channel Is Maintained by Endocytosis and Facilitates Boron Transport in Arabidopsis Roots.
Boron uptake in Arabidopsis thaliana is mediated by nodulin 26-like intrinsic protein 5;1 (NIP5;1), a boric acid channel that is located preferentially on the soil side of the plasma membrane in root cells. However, the mechanism underlying this polar localization is poorly understood. Here, we show that the polar localization of NIP5;1 in epidermal and endodermal root cells is mediated by the phosphorylation of Thr residues in the conserved TPG (ThrProGly) repeat in the N-terminal region of NIP5;1. Although substitutions of Ala for three Thr residues in the TPG repeat did not affect lateral diffusion in the plasma membrane, these substitutions inhibited endocytosis and strongly compromised the polar localization of GFP-NIP5;1. Consistent with this, the polar localization was compromised in µ subunit mutants of the clathrin adaptor AP2. The Thr-to-Ala substitutions did not affect the boron transport activity of GFP-NIP5;1 in Xenopus laevis oocytes but did inhibit the ability to complement boron translocation to shoots and rescue growth defects in nip5;1-1 mutant plants under boron-limited conditions. These results demonstrate that the polar localization of NIP5;1 is maintained by clathrin-mediated endocytosis, is dependent on phosphorylation in the TPG repeat, and is necessary for the efficient transport of boron in roots.


The karyotypes of two bark-lice species (Psocoptera, Psocomorpha, Amphipsocidae): the first description of the neo-XY sex chromosome system in Psocoptera.
Karyotypes of two bark-lice species Amphipsocus japonicus End. and Dasypsocus japonicus End. (Amphipsocidae, Psocomorpha, Psocoptera) were studied for the first time. D. japonicus displayed 2n = 16 (14 + XX/X0). The XX/X0 sex chromosome system observed in this species is characteristic of the order Psocoptera. A. japonicus showed 2n = 16 (14 + neo-XY). This is the first observation of the neo-XY sex determination system in Psocoptera. In this species a large amount of constitutive heterochromatin was found in the original X-part of the neo-X chromosome.


Chemical synthesis of a gene for human cystatin C and its expression in E. coli.
A DNA containing the coding sequence for the human cysteine proteinase inhibitor protein cystatin C has been obtained by enzymatic ligation of chemically synthesized deoxyoligonucleotides, using the Khorana ligation method. The 375 bp synthetic gene carries signals for the translation initiation and termination and was expressed in E. coli as a beta-galactosidase fusion protein as well as a secreted protein under the control of the E. coli alkaline phosphatase signal sequence. The secreted hybrid protein was shown to have similar biological properties as the authentic protein isolated from human plasma.


Use of pharmaceuticals amongst athletes tested by Anti-Doping Norway in a five-year period.
The aim of the study was to map the use of pharmaceuticals by Norwegian athletes registered on doping control forms (DCFs) in a five-year period to examine general and some class specific use of pharmaceuticals across sports and athlete levels. Anonymous data from DCFs collected in 2015-2019 were manually entered into a database using the Anatomical Therapeutic Chemical (ATC) system for classification of the pharmaceuticals. Variables entered were year of control, gender, age group, athlete level, sport, test type, nationality, and pharmaceuticals (and dietary supplements) used. Pain killers in the ATC groups M01 A (Nonsteroidal anti-inflammatory drugs - NSAIDs) and N02 B (other analgesics), and anti-asthmatics in ATC groups R03 A and R03 B were the most frequently used pharmaceuticals. National level athletes reported more use of pharmaceuticals (1.4 ± 1.7 pharmaceuticals per form) than recreational level athletes (0.9 ± 1.2). The highest proportion of DCFs containing information about at least one pharmaceutical were found in speed skating (79.1%), alpine skiing (74.0%), rowing (72.4%) and cross-country skiing (71.7%). Painkillers were most frequently used in muscular endurance sports (30.4% and 21.2 % for M01A and N02 B, respectively) and ball and team sports (17.9% and 17.0%). Use of hypnotics was reported from ice-hockey players and alpine skiers in around 8% of the cases. Use of anti-asthmatics was most often reported amongst athletes specially exposed to cold, chemicals and heavy endurance training. Athletes in specialized sports requiring high levels of strength and/or endurance reported a higher use of pharmaceuticals out-of-competition compared to in-competition, while there was no such difference in complex sports, such as team, gymnastic, aiming and combat sports.


Are life-saving anticancer drugs reaching all patients? Patterns and discrepancies of trastuzumab use in the European Union and the USA.
The development of trastuzumab is considered to be one of the greatest improvements in breast cancer treatment in recent years. This study aims to evaluate changes in the uptake of trastuzumab over the last 12 years and to determine whether its use is proportional to patient needs in the European Union and the USA. Using national registry data, the number of new cases of HER2-positive breast cancer patients per year was estimated. The number of likely trastuzumab treatments per year was estimated using trastuzumab procurement data for each country. Western Europe and the USA show increasing procurement level of trastuzumab over the years studied, reaching proportional of use of trastuzumab few years after its marketing authorization in the early 2000's. After the approval in the adjuvant setting, in the year 2006, it was observed underuse of trastuzumab given the increase of the number of patients in need of treatment. Proportional use was shortly met after a couple of years. Few countries in Eastern Europe acquired the needed quantity of trastuzumab, with procurement levels starting to increase only after approval in the adjuvant setting in 2006. Significant differences in trastuzumab procurement are observed between Western Europe, the USA and Eastern Europe, with the latter geographic region acquiring insufficient amounts of the drug required to treat all patients in need.


Antigen-specific immune response impairment in the chick as influenced by dietary vitamin A.
The effects of a broad range of dietary vitamin A levels on antigen-specific immune responses of the chick were studied. Vitamin A deficiency and long-term excess caused impairment of the immune response as demonstrated by antigen-specific antibody production and T-lymphocyte proliferation in vitro. Immune responsiveness was correlated with both hepatic and blood vitamin A levels, and was affected prior to other physiological manifestations of hypo- or hypervitaminosis. In contrast to the effects of long-term vitamin excess, a large vitamin A bolus did not cause immune response impairment and, on the contrary, restored normal immune functions in previously vitamin A-depleted chicks. This finding implied a regulatory role for vitamin A in the immune system rather than a constitutive one.


Peritoneal sclerosis in chronic peritoneal dialysis patients: analysis of clinical presentation, risk factors, and peritoneal transport kinetics.
To analyze clinical features of peritoneal sclerosis (PS) in a group of peritoneal dialysis (PD) patients, and to compare potential risk factors and peritoneal transport characteristics with a control group matched for duration of PD. Study 1: Retrospective study of 16 PD patients with PS. Study 2: Case-control study comparing 10 patients with evident PS to 30 control patients who were matched for duration of PD. Continuous Ambulatory Peritoneal Dialysis unit in the Academic Medical Centre in Amsterdam. The incidence of PS was 3.5 per 1000 patient years. PS was diagnosed either during PD (n = 10), in patients on hemodialysis (n = 2), or after successful transplantation (n = 4). Presenting symptoms were bowel obstruction, ascites, blood-stained effluent, and impaired net ultrafiltration. Macroscopic confirmation of the diagnosis was possible in 13 patients. Sclerotic encapsulation was present in 8 of them. Patients with PS were divided into three groups based on clinical symptoms and typical macroscopical findings. In category I the diagnosis PS was obvious (10 patients), in category II the diagnosis was highly suggestive (3 patients), and in category III it was doubtful (3 patients). Treatment was conservative in most patients. Surgical treatment was only possible in four and immunosuppressive therapy was given in 5 patients. Peritoneal sclerosis was the direct cause of death in 1 patient. Five patients died during follow-up due to other causes. At present, 7 patients are well and 3 patients (all from category I) still have recurrent bowel obstruction. Compared to matched controls, no difference existed in peritonitis incidence, or in the percentage of patients with former renal transplantations. The number of patients treated with beta-blocking agents and the number of previous abdominal surgeries were not different. The number of catheter-related surgical procedures was higher in the PS patients than in the control group. The mass transfer area coefficient (MTAC) of creatinine was higher in PS patients and net ultrafiltration with 1.36% glucose was lower. The estimated cumulative glucose exposure until the diagnosis of PS was made was larger in PS patients than in their controls. This difference was already present in the first year of PD treatment in 8 of 10 patients. The initial values for the MTAC creatinine were similar in both groups. The presenting symptoms of PS were bowel obstruction, ascites, and blood-stained effluent, often in combination with loss of net ultrafiltration. Peritoneal sclerosis is a complication of long-duration PD and could also become manifest after a successful renal transplant. Treatment should be conservative unless complications require surgical intervention. Patients with PS had lower net ultrafiltration and higher transport rates compared to controls who were matched for duration of PD. Although peritonitis incidence was similar, a relation of PS with severe peritonitis may be present in some patients. Glucose exposure is likely to be an important risk factor for PS.


[Use of the urinary trypsin inhibitor ulinastatin for acute Kawasaki disease].
Intravenous immunoglobulin (IVIG) therapy is widely recognized as standard treatment for Kawasaki disease(KD). However, about 20 % of KD patients are resistant to IVIG and are considered to be a high risk group for coronary artery lesions (CAL). Ulinastatin(UTI) is one of the neutrophil elastase inhibitors used for patients with pancreatitis or circulatory shock, and several studies have shown its efficacy for KD. Recently, we demonstrated that initial UTI treatment combined with IVIG decreased the number of patients requiring addi- tional rescue treatment and the occurrence of CAL. In this study, no severe adverse events occurred. Further research and a prospective trial are needed to prove the clinical efficacy and demonstrate the limits of UTI in patients with KD.


Pulmonary O2 toxicity in lambs: physiological and biochemical effects of endotoxin infusion.
Hyperoxic adult rats have prolonged survival and reduced morphological evidence of lung injury when treated with a single dose of bacterial endotoxin; this effect is mediated by an augmentation of antioxidant enzyme activity in lung homogenate. To determine whether endotoxin would prolong survival and influence antioxidant enzyme levels in lambs whose physiological response to O2 breathing can be serially measured, we administered a single intravenous dose of endotoxin (0.75 microgram/kg body wt) to 13 lambs before exposing them to greater than 95% O2 (n = 11) or air (n = 2). Seven additional lambs were placed in O2 after receiving only saline vehicle. All lambs had been instrumented to measure pulmonary vascular pressures and cardiac output, and 10 lambs had lung lymph fistulas. O2-exposed control lambs developed noncardiogenic pulmonary edema and respiratory failure within 85 +/- 10 h (range 76-110 h); antioxidant enzymes were not increased, but reduced glutathione (GSH) levels fell and oxidized glutathione (GSSG) increased, reflecting the oxidant stress of O2 exposure. By contrast, endotoxin-treated O2-exposed lambs had a delayed increase in microvascular permeability to protein, a reduced rate of lung edema formation, normal gas exchange after 72 h in O2, and prolonged survival (136 +/- 15 h; range 90-160 h; all variables P less than 0.05). Despite prolonged survival, postmortem lung water content was no greater in the lambs that received endotoxin. Treatment with endotoxin did not increase antioxidant enzyme levels in lung homogenate, but levels of GSH relative to GSSG were significantly elevated.(ABSTRACT TRUNCATED AT 250 WORDS)


DIRECTIONAL MOVEMENT AND HORIZONTAL EDGE DETECTORS IN THE PIGEON RETINA.
There are ganglion cells in the pigeon retina that respond selectively, some to any edge moving in a particcular direction only, others to any vertically moving horizontal edge. This selective response to a specific stimulus arises from the selective sensitivity of each neuron to a particular spatiotemporal configuration in its afferent influences, and is independent of specific pathways.


Ovarian serous cystadenofibroma with stromal sex cord elements: report of a unique case.
This report describes an ovarian serous cystadenofibroma, in a postmenopausal woman, which exhibited extensive sex cord differentiation, in the form of solid and hollow tubules resembling Sertoli cell elements, within the stroma. The sex cord elements, which were located just beneath the epithelium, were positive with both alpha inhibin and calretinin and negative with epithelial membrane antigen. They were also CD56 positive but negative with other neuroendocrine markers. True sex cord structures or sex cord-like elements have been described in ovarian adenosarcomas and pure stromal tumors, especially fibromas. However, as far as we are aware, these elements have not been reported in a serous cystadenofibroma. The endometrium exhibited simple hyperplasia, perhaps secondary to estrogenic activity of the sex cord elements. We discuss the significance of CD56 positivity of the sex cord elements.


Analysis of workplace injuries in a dental school environment.
Workplace injuries at the University of Queensland Dental School during the period 1992-1994 were assessed to determine their incidence, and the associated indirect costs, causal factors, and appropriate preventive strategies. Overall, dental chairside assistants experienced a higher incidence of injuries than students both on a per worker and per time basis. Of the injuries with a low risk of cross-infection, burns and scalds from sterilizing equipment, and eye injuries in laboratories were the most common. This emphasizes the importance of wearing appropriate protective equipment in areas outside the treatment zone, and the need for signage and education. Common causes of sharps injuries were burs left in handpieces, two-handed needle recapping, and cleaning of probes in the sterilizing room. Changes to techniques and equipment would prevent such incidents. A range of factors which contribute to the calculation of indirect costs following injuries in the dental workplace are identified.


[Phimosis can be treated with local steroids].
The effectiveness of topical steroid application in relieving phimosis was studied in 41 boys treated with a potent steroid ointment. 35 patients showed improvement initially but in 12 of them the phimosis recurred completely and in seven of them partly. There was significantly less recurrence in the patients who improved within one month. Most of the families were satisfied with the treatment. We recommend topical steroids as first treatment of choice for phimosis, when treatment is necessary.


Water soluble porphyrin as optical sensor for the toxic heavy metal ions in an aqueous medium.
Here we report the photophysical and sensing properties of the aqueous solution of meso-tetra(N-methyl-4-pyridyl)porphyrin toluene sulfonate (TMPP) for simultaneous detection of toxic metal ions in an aqueous medium by using different physiochemical methods such as UV-vis absorption, steady state and time resolved fluorescence, stopped flow, and cyclic voltammetry. The steady-state absorption and fluorescence spectra in organic solvents (EtOH, DMSO, DMF, MeOH and ACN) showed the formation of monomer form (λmaxabs = 426 nm and λmaxflu = 654 and 715 nm). In THF and water, different spectral features were recorded suggested the formation of aggregated forms in both solvents. The formation of aggregated form in water was confirmed by recording the remarkable fluorescence quenching of the singlet excited TMPP with increasing the concentrations of TMPP. In cationic micelles (CTAB), both the absorption and fluorescence spectra were significantly decreased with increasing the concentrations of CTAB with a break at CMC value at 6.0 × 10-5 M. In an anionic micelle (SDS), the CMC value was found to be 1.0 × 10-4 M. Upon interacting with different metal ions, the absorption and fluorescence spectra of TMPP showed different features depending on the metal ions. While the optical studies of TMPP showed no significant interaction in the presence of Mn+2, Co+2, Ba2+, and Ni+2, TMPP showed that it can function as a single optical chemical sensor for the toxic metal ions in water, particularly Hg+2, Pb+2, Cu+2, and Cd+2 ions.


Co-creation of educational commons spaces to reverse inequalities: project SMOOTH and the Children's Club.
This article presents an action-research project from the EU-funded SMOOTH project, which focuses on the potential of Educational Commons to address educational inequalities. The project adopts an emergent paradigm that views spaces for collaboration, content co-creation, socialization, governance, and play as catalysts for reversing inequalities. The action-research, conducted in a disadvantaged non-formal education setting in northern Portugal, involved children aged 8-10 years old. Over a span of 10 months, the innovative action-research program aimed to achieve several objectives: (1) reversing inequalities faced by vulnerable social groups, (2) strengthening inter-cultural and inter-generational dialogue and social integration, (3) developing essential social and personal skills, and (4) creating smooth spaces of democratic citizenship based on equality, collaboration, sharing, and caring. By understanding the tensions and conflicts that emerge in children's everyday situations, the project sought to build and foster community through embracing differences. This article analyzes the characteristics, behaviors, challenges, and strengths observed during the 30 sessions. The results provide insights into the dimensions of Children as commoners, in terms of sharing and care, cooperation and collective creativity and active citizenship. This research contributes to the exploration of Educational Commons as a means to promote equity and transform educational contexts.


Solvent Extraction as a Method of Recovery and Separation of Platinum Group Metals.
Platinum group metals (PGMs) are a group of six metals with high market value and key importance to many industrial sectors. Due to their low prevalence in the Earth's crust and high demand, these metals have been recognized as critical materials for many years. Along with economic development, the natural resources of the platinum group metals are gradually depleting, which is accompanied by the need to recover PGMs from secondary sources. The solutions resulting from the processing of such materials are characterized by high content of impurities and low content of precious metals. For this reason, in order to obtain pure metals, it is extremely important to choose an effective, selective method for the recovery and separation of the platinum group metals. This review focuses on the most important aspects of the characteristics of the PGMs, including their properties and occurrence, the processing of natural and secondary raw materials and the role of liquid-liquid extraction in the selective separation of metals from this group, not only on a laboratory scale but, above all, on an industrial scale. In addition, this study collects information on the most commonly used, commercially available extractants, based on current reports, taken from the scientific literature.


New L-dopa codrugs as potential antiparkinson agents.
This paper reports the synthesis and preliminary evaluation of new L-dopa (LD) conjugates (1 and 2) obtained by joining LD with two different natural antioxidants, caffeic acid and carnosine, respectively. The antioxidant efficacy of compounds 1 and 2 was assessed by evaluating plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the rat. Rat striatal concentration of LD and dopamine (DA), and central nervous effects were evaluated after oral administration of the codrugs 1 and 2. The results suggest that, though our codrugs are devoid of significant antioxidant activity, they are able to induce sustained delivery of DA in rat striatum and can improve LD and DA release in the brain.


Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity.
Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), patients who fail R-CHOP have a dismal outcome. Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective. Advances in molecular genetics have vastly improved our understanding of the biological diversity of DLBCL and have led to the discovery of key oncogenic pathways. In addition to the major molecular designations of germinal center B-cell and activated B-cell subtypes, next-generation sequencing technologies have unveiled the remarkable complexity of DLBCL and identified unique molecular targets that may be differentially exploited for therapeutic benefit. These findings have translated into a growing list of promising novel agents. Moving forward, it is of paramount importance to recognize the heterogeneity of DLBCL and to investigate these targeted agents within patient populations who are most likely to benefit. It will be necessary to prioritize drugs that affect key driver pathways and to combine them rationally to optimize their benefit. Improved prognostication and the availability of predictive biomarkers will be crucial to allow for the possibility of individualized risk-adapted therapy.


Qualitative evaluation of the adesive interface between lithium disilicate, luting composite and natural tooth.
Aim of this work was to qualitatively evaluate the interface between tooth, luting composite and lithium disilicate surface using a scanning electron microscope (SEM). An extracted restoration-free human molar was stored in physiological solution until it was embedded in an autopolimerysing acrylic resin. A standard preparation for overlay was completed and after preparation an anatomic overlay was waxed on the tooth and then hot pressed using lithium disilicate ceramic. After cementation the sample was dissected and the section was analysed using an Automatic Micromet (Remet s.a.s) and the section was analyzed using a scanning electron microscope (SEM). SEM evaluation of the tooth showed the three layers seamlessly; by increasing the enlargement the interface did not change.


Glycosyl-Substituted Dicarboxylates as Detergents for the Extraction, Overstabilization, and Crystallization of Membrane Proteins.
To tackle the problems associated with membrane protein (MP) instability in detergent solutions, we designed a series of glycosyl-substituted dicarboxylate detergents (DCODs) in which we optimized the polar head to clamp the membrane domain by including, on one side, two carboxyl groups that form salt bridges with basic residues abundant at the membrane-cytoplasm interface of MPs and, on the other side, a sugar to form hydrogen bonds. Upon extraction, the DCODs 8 b, 8 c, and 9 b preserved the ATPase function of BmrA, an ATP-binding cassette pump, much more efficiently than reference or recently designed detergents. The DCODs 8 a, 8 b, 8 f, 9 a, and 9 b induced thermal shifts of 20 to 29 °C for BmrA and of 13 to 21 °C for the native version of the G-protein-coupled adenosine receptor A2A R. Compounds 8 f and 8 g improved the diffraction resolution of BmrA crystals from 6 to 4 Å. DCODs are therefore considered to be promising and powerful tools for the structural biology of MPs.


Temporal indication of cannabis use by means of THC glucuronide determination.
According to the regulations of the World Anti-Doping Agency (WADA), the use of cannabinoids is forbidden in competition. In doping controls, the detection of cannabinoid misuse is based on the analysis of the non-psychoactive metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (carboxy-THC). The determination of values greater than 15 ng/mL in urine represents an adverse analytical finding; however, no accurate prediction of the time of application is possible as the half-life of carboxy-THC ranges between three and four days. Consequently the detection of carboxy-THC in doping control urine samples collected in competition might also result from cannabis use in out-of-competition periods. The analysis of the glucuronide of the pharmacologically active delta 9-tetrahydrocannabinol (THC-gluc) may represent a complementary indicator for the detection of cannabis misuse in competition.An assay for the determination of THC-gluc in human urine was established. The sample preparation consisted of liquid-liquid extraction of urine specimens, and extracts were analysed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Authentic doping-control urine samples as well as specimens obtained from a controlled smoking study were analysed and assay characteristics such as specificity, detection limit (0.1 ng/mL), precision (>90%), recovery ( approximately 80%), and extraction efficiency (90%) were determined.


Subclinical leishmaniasis associated with infertility and chronic prostatitis in a dog.
A stud dog was presented for acquired infertility. Haematospermia and teratozoospermia were found on two ejaculates 2 weeks apart. A presumptive diagnosis of prostatitis was made follo-wing ultrasound examination. An ultrasound-guided needle core biopsy was performed under general anaesthesia, revealing a mild chronic macrophagic and plasma cell prostatitis with intracytoplasmic amastigotes consistent with Leishmania spp. infection. Presence of Leishmania infantum, Leishmania donovani or Leishmania chagasi was confirmed by polymerase chain reaction in seminal plasma. Serology and serum protein electrophoresis confirmed the diagnosis of a subclinical active systemic leishmaniasis. A meglumine antimoniate and allopurinol treatment was given which clearly improved within 3 months both general condition and the quality of sperm. To the authors' knowledge, this is the first reported case of a prostatitis secondary to a Leishmania spp. infection. Subclinical systemic leishmaniasis should be considered in the differential diagnosis of infertility in dogs suffering from semen alterations.


N-acetyltransferase and hydroxyindole-O-methyltransferase activity in intraocular pineal transplants: diurnal thythm as evidence for functional sympathetic adrenergic innervation.
Immature rat pineal grafts were transplanted bilaterally to the anterior eye chamber of adult male rats. The transplants matured and became sympathetically innervated from the host iris and synthesized 5-hydroxytryptamine as revealed by fluorescence histochemistry. Transplants were used to investigate whether the newly formed nerve terminals were functional and thus could induce a rhythm in pineal N-acetyltransferase (NAT) enzyme activity and hydroxyindole-O-methyl transferase (HIOMT) enzyme activity. The in situ pineal glands from the recipient animals exhibited NAT and HIOMT levels and diurnal variations of enzyme activities no different from control rats without transplants. Sympathetically innervated transplants showed lower NAT enzyme activity than the in situ pineals but did yield a highly significant increase in darkness NAT activity as compared to light NAT activity (20:1). Sympathetically denervated transplants showed a much smaller rise in darkness NAT enzyme activity as compared to light values (1.8:1) but the rhythm was still statistically significant (p less then 0.01). Sympathetically innervated transplants had a higher HIOMT activity in darkness than in light (2.7:1)9 The HIOMT activity of the sympathetically denervated grafts was invariably low. Protein contents of transplants were found to be significantly lower than in situ pineal protein content but failed to show a diurnal variation.


Non-high-density lipoprotein cholesterol versus low-density lipoprotein cholesterol as a risk factor for a first nonfatal myocardial infarction.
Low-density lipoprotein (LDL) cholesterol is the primary lipid parameter targeted to prevent myocardial infarction. Alternatively, non-high-density lipoprotein (HDL) cholesterol includes LDL cholesterol and other atherogenic particles but does not require a fasting sample. Non-HDL cholesterol and LDL cholesterol as predictors of first nonfatal myocardial infarction were compared in 303 patients and 297 controls matched for age, gender, and community within the Boston Area Health Study. Patients were white men or women aged <76 years living in the Boston area, without a history of myocardial infarction or angina pectoris, in whom symptoms of confirmed myocardial infarction began during the 24 hours before admission. After multivariate adjustment for coronary risk factors in unmatched analyses, the corresponding odds ratios (ORs) of a first nonfatal myocardial infarction for non-HDL cholesterol in the second, third, and fourth quartiles were 1.83 (95% confidence interval [CI] 1.07 to 3.14), 2.07 (95% CI 1.23 to 3.49), and 2.33 (95% CI 1.39 to 3.90) (p trend <0.01). For LDL cholesterol, the ORs were 1.10 (95% CI 0.67 to 1.81), 0.87 (95% CI 0.52 to 1.46), and 1.45 (95% CI 0.90 to 2.35) (p trend = 0.16). Including HDL cholesterol in the model increased the ORs and strengthened the test for a trend for LDL cholesterol, whereas the ORs were decreased and the test for a trend was weakened for non-HDL cholesterol. In conclusion, given that non-HDL cholesterol accounts for LDL cholesterol plus other atherogenic particles but does not require a fasting sample, this study suggests that non-HDL cholesterol may be at least as useful as LDL cholesterol to initially screen patients for risk of a first nonfatal myocardial infarction.


Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation.
How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.


Prevalence of Pulmonary Embolism and Deep Venous Thromboembolism in Patients With Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) increases the risk of pulmonary embolism (PE) and deep venous thrombosis (DVT). AECOPD combined with PE and DVT poses challenges for treatment and management. This necessitates prevention and management to estimate the overall prevalence of PE and DVT among patients with AECOPD and to identify the risk factors. We searched the PubMed, Embase, and Cochrane Library databases from their inception to January 9, 2021 and extracted the data from the included studies. The risk of bias was assessed for each study. We separately calculated the prevalence of PE and DVT in patients with AECOPD. Subgroup analysis and meta-regression analyses were performed to determine the sources of heterogeneity. Furthermore, we assessed the publication bias. The meta-analysis included 20 studies involving 5,854 people. The overall prevalence of PE and DVT among patients with AECOPD was 11% (95% CI: 0.06-0.17) and 9% (95% CI: 0.06-0.12), respectively. Subgroup analysis demonstrated that the prevalence of PE among patients with AECOPD was 12, 2, 7, and 16% in the European, South-East Asia, Western Pacific, and Eastern Mediterranean regions, respectively, and the DVT was 10, 9, 9, and 4%, respectively. The prevalence of PE among patients with AECOPD aged ≥ 70 and <70 years old was 6 and 15%, respectively, and the DVT was 8 and 9%, respectively. The prevalence of PE among patients with AECOPD diagnosed within 48 h and other times (beyond 48 h or not mentioned) was 16 and 6%, respectively, and DVT was 10 and 7%, respectively. The pooled prevalence of PE and DVT among patients with AECOPD was insignificantly different between the different age groups and the WHO regions. However, the early diagnosis was associated with a higher prevalence of PE. Clinicians and the public need to further improve the awareness of prevention and management for PE and DVT among patients with AECOPD. PROSPERO, identifier CRD42021260827.


Extra- and intracranial cerebral vasculitis in giant cell arteritis: an observational study.
Recognizing giant cell arteritis (GCA) in patients with stroke may be challenging. We aimed to highlight the clinical spectrum and long-term follow-up of GCA-specific cerebrovascular accidents. Medical charts of all patients followed in a French Department of Internal Medicine for GCA between January 2008 and January 2014 were retrospectively reviewed. Patients with cerebrovascular accidents at GCA diagnosis were included. Diagnosis of GCA was based on American College of Rheumatology criteria. Transient ischemic attacks and stroke resulting from an atherosclerotic or cardioembolic mechanism were excluded. Clinical features, GCA-diagnosis workup, brain imaging, cerebrospinal fluid (CSF) study, treatment, and follow-up data were analyzed. From January 2008 to January 2014, 97 patients have been followed for GCA. Among them, 8 biopsy-proven GCA patients (mean age 70±7.8 years, M/F sex ratio 3/1) had stroke at GCA diagnosis. Six patients reported headache and visual impairment. Brain MR angiography showed involvement of vertebral and/or basilar arteries in all cases with multiple or unique ischemic lesions in the infratentorial region of the brain in all but one case. Intracranial cerebral arteries involvement was observed in 4 cases including 2 cases with cerebral angiitis. Long lasting lesions on diffusion-weight brain MRI sequences were observed in 1 case. All patients received steroids for a mean of 28.1±12.8 months. Side effects associated with long-term steroid therapy occurred in 6 patients. Relapses occurred in 4 patients and required immunosuppressive drugs in 3 cases. After a mean follow-up duration of 36.4±16.4 months, all but 1 patient achieved complete remission without major sequelae. The conjunction of headache with vertebral and basilar arteries involvement in elderly is highly suggestive of stroke associated with GCA. Intracranial cerebral arteries involvement with cerebral angiitis associated with long lasting brain lesions on diffusion-weight brain MRI sequences may occur in GCA. Both frequent relapses and steroid-induced side effects argue for the use of immunosuppressive agents combined with steroids as first-line therapy.


[Diaphragmatic eventration in the adult: repair with Gore-Tex surgical mesh].
The Authors report the case of a fifty-nine-year-old patient, affected by complete eventration of the left diaphragm and cranial stomach dislocation with axial volvulus, associated with an upward movement of part of the left colon and some jejunal loops. The subclinical condition had been occasionally discovered during a routine chest X-ray at the age of eighteen and the patient remained without symptoms up to five years ago, when he began to show significant digestive and cardiorespiratory symptoms. The patient has been successfully treated via thoracotomy with phrenic alloplastic using Gore-Tex patch and has obtained an immediate remission of the symptoms. Left diaphragmatic eventration of the adult is a rare pathology, either congenital or acquired, with few and definite surgical indications such as severe digestive and cardiorespiratory symptoms. Different surgical techniques including the use of patches are herein illustrated.


Inertial Microfluidic Purification of Floating Cancer Cells for Drug Screening and Three-Dimensional Tumor Models.
Floating cancer cells can survive the programmed death anoikis process after detaching from the extracellular matrix for the anchorage-dependent cells. Purification of viable floating cancer cells is essential for many biomedical studies, such as drug screening and cancer model development. However, the floating cancer cells are mixed with dead cells and debris in the medium supernatant. In this paper, we developed an inertial microfluidic device with sinusoidal microchannels to continuously remove dead cells and debris from viable cells. First, we characterized the differential inertial focusing properties of polystyrene beads in the devices. Then, we investigated the effects of flow rate on inertial focusing of floating MDA-MB-231 cells. At an optimal flow condition, purification of viable cells was performed and the purity of live cells was increased significantly from 19.9% to 76.6%, with a recovery rate of 69.7%. After separation, we studied and compared the floating and adherent MDA-MB-231 cells in terms of cell proliferation, protrusive cellular structure, and the expression of cyclooxygenase (Cox-2) which is related to epithelial-mesenchymal transition (EMT) changes. Meanwhile, drug screening of both floating and adherent cancer cells was conducted using a chemotherapeutic drug, doxorubicin (Dox). The results revealed that the floating cancer cells possess 30-fold acquired chemoresistance as compared to the adherent cancer cells. Furthermore, a three-dimensional (3D) double-cellular coculture model of human mammary fibroblasts (HMF) spheroid and cancer cells using the floating liquid marble technique was developed.


Computational approaches in detecting non- coding RNA.
The important role of non coding RNAs (ncRNAs) in the cell has made their identification a critical issue in the biological research. However, traditional approaches such as PT-PCR and Northern Blot are costly. With recent progress in bioinformatics and computational prediction technology, the discovery of ncRNAs has become realistically possible. This paper aims to introduce major computational approaches in the identification of ncRNAs, including homologous search, de novo prediction and mining in deep sequencing data. Furthermore, related software tools have been compared and reviewed along with a discussion on future improvements.


A multitrajectory, competition model of emergent complexity in human social organization.
The repeated pattern of emergent human organization at a societal level going from small-scale, egalitarian decentralized societies to complex, stratified, and centralized societies is well-documented in the archaeological record of past societies. In this paper, I outline a multitrajectory model that relates to the broad features of this sequence of societal change. Competition is shown to play a critical role in the way interaction--among decision making, demographic parameters, and social units that organize resource ownership and procurement--either promotes or inhibits change in social organization. Multiagent simulation is discussed as a way to link culturally embedded decision making to emergent properties in the multitrajectory model.


Physical Properties of E143 Food Dye as a New Organic Semiconductor Nanomaterial.
Organic semiconductors (OSCs) have attracted considerable attention for many promising applications, such as organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs), and organic photovoltaics (OPVs). The present work introduced E143 food dye as a new nanostructured organic semiconductor that has several advantages, such as low cost, easy fabrication, biocompatibility, and unique physical properties. The material was characterized using a transmission electron microscope (TEM), Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), and optical absorption spectroscopy. The study of X-ray diffraction (XRD) showed that E143 dye has a monoclinic polycrystalline structure. Electrical and dielectric properties were performed by impedance spectroscopy at frequencies (20 Hz-1 MHz) in the temperature range (303-473 K). The values of interband transitions and activation energy recommended the application of E143 dye as a new organic semiconductor material with promising stability, especially in the range of hot climates such as KSA.


Enhancing the efficiency of graphene-based THz modulator by optimizing the Brewster angle.
The gate-controllable electronical property of graphene provides a possibility of active tuning property for THz modulator. However, the common modulation technology which only depends on voltage cannot solve the problem of power consumption limitation in communication applications. Here, we demonstrated a Brewster angle-controlled graphene-based THz modulator, which could achieve a relatively high modulation depth with low voltage. First, we explored the complex relationships among the Brewster angles, reflection coefficients and the conductivities of graphene. Then, we further investigated the optimal incident angle selection based on the unusual reflection effect which occurs at Brewster angle. Finally, an improved scheme by dynamically adjusting the incident angle was proposed in this paper. It would make it possible that the modulator could achieve a modulation depth of more than 90% with a Fermi level as low as 0.2eV at any specific frequency in the range of 0.4THz-2.2THz. This research will help to realize a THz modulator with high-performance and ultra-low-power in quantities of applications, such as sensing and communication.


Edifoligide: a transcription factor decoy to modulate smooth muscle cell proliferation in vein bypass.
The era of genomics and recombinant DNA technology has ushered in an entirely new class of therapeutic agents designed to influence disease progression at a genetic level. The scope and utility of this technology is not fully realized. However, multiple trials of therapeutic agents have been completed and many more are ongoing. Here we report on edifoligide, a double-stranded oligodeoxynucleotide (ODN) that competitively inhibits the transcription factor E2F, a critical regulator of the cell cycle. Edifoligide has undergone extensive clinical testing for the treatment of intimal hyperplasia following vascular bypass procedures. In this review we address the rationale for targeting E2F in vascular disease, the pharmacology of edifoligide, and the results of preclinical and clinical studies using this novel compound.


Breast-conserving therapy and sentinel lymph node biopsy are feasible in cancer patients with previous implant breast augmentation.
Breast-conserving therapy (BCT) is reported to result in a significant rate of complications and local recurrences in patients with prior implant breast augmentation. The role of sentinel lymph node (SLN) biopsy in these patients is unknown. Retrospective review of patients with prior breast augmentation treated with BCT or SLN biopsy. Nineteen breast cancers were treated with BCT. Of 17 breasts undergoing adjuvant radiotherapy, 11 (64.7%) retained favorable aesthetic results. Of 9 subpectoral implants, capsular contracture developed in only 1 (11.1%). During follow-up (median 3 years), 1 local recurrence (5.3%) occurred in a patient who refused adjuvant radiotherapy and systemic therapy. Eleven patients underwent SLN biopsy with an identification rate of 100% and a false-negative rate of 0%. Breast-conserving therapy inclusive of radiotherapy after implant breast augmentation produced acceptable cosmetic results in nearly two-thirds of patients. Sentinel lymph node mapping in the setting of prior implant augmentation was highly successful and accurate.


Hydrogen peroxide acts on sensitive mitochondrial proteins to induce death of a fungal pathogen revealed by proteomic analysis.
How the host cells of plants and animals protect themselves against fungal invasion is a biologically interesting and economically important problem. Here we investigate the mechanistic process that leads to death of Penicillium expansum, a widespread phytopathogenic fungus, by identifying the cellular compounds affected by hydrogen peroxide (H(2)O(2)) that is frequently produced as a response of the host cells. We show that plasma membrane damage was not the main reason for H(2)O(2)-induced death of the fungal pathogen. Proteomic analysis of the changes of total cellular proteins in P. expansum showed that a large proportion of the differentially expressed proteins appeared to be of mitochondrial origin, implying that mitochondria may be involved in this process. We then performed mitochondrial sub-proteomic analysis to seek the H(2)O(2)-sensitive proteins in P. expansum. A set of mitochondrial proteins were identified, including respiratory chain complexes I and III, F(1)F(0) ATP synthase, and mitochondrial phosphate carrier protein. The functions of several proteins were further investigated to determine their effects on the H(2)O(2)-induced fungal death. Through fluorescent co-localization and the use of specific inhibitor, we provide evidence that complex III of the mitochondrial respiratory chain contributes to ROS generation in fungal mitochondria under H(2)O(2) stress. The undesirable accumulation of ROS caused oxidative damage of mitochondrial proteins and led to the collapse of mitochondrial membrane potential. Meanwhile, we demonstrate that ATP synthase is involved in the response of fungal pathogen to oxidative stress, because inhibition of ATP synthase by oligomycin decreases survival. Our data suggest that mitochondrial impairment due to functional alteration of oxidative stress-sensitive proteins is associated with fungal death caused by H(2)O(2).


Metabolic effects of antihypertensive treatment with beta-blockers.
The beneficial effects of beta-blockers on morbidity and mortality have been demonstrated in several prospective long-term trials. The suspected negative metabolic effects of low-dose beta 1-selective-blockers do not appear to be relevant to daily clinical practice, and do not restrict the use of these agents as first choice antihypertensive drugs in diabetic or non-diabetic patients.


Exercise-induced second-degree atrioventricular block.
In this report we describe 2 patients with exercise-induced, second-degree atrioventricular (AV) block. Case 1 was a 49-year-old man with normal AV conduction at rest but who developed dyspnea on exertion. Treadmill testing showed an exercise-induced 2:1 AV block. Electrophysiologic study (EPS) demonstrated rate-dependent, presumably intrahissian, AV block. Case 2 was a 31-year-old woman with first-degree AV block and complete right bundle branch block with dyspnea on exertion and occasional syncope. She had twice undergone surgical patch closure of an ostium primum atrial septal defect. Exercise testing induced type II second-degree AV block. Atrial pacing during EPS did not disclose rate-dependent type II AV block, but disopyramide induced second-degree AV block.