PARATHYROIDS AND CALCIUM METABOLISM.
The experiments reported in this article are in full agreement with the facts known about the action of Ca and Mg salts in tetanic animals. In the concentrations used here both Ca lactate and Mg lactate suppressed the muscular convulsions in the tetanic salamander larvae. The Mg lactate, however, appears to be more effective than the Ca lactate. At any rate the suppression of the tetanic convulsions does not seem to be a specific action of the calcium. The most important result seems to be the fact that the salts used, though they prevented the muscular convulsions, did not prevent the other symptoms of tetany which in the salamander larvae are very definite and constant. The permanent spasmodic contractions and the paralysis of the muscles developed in spite of the presence of the Ca and Mg, Furthermore, the muscular contractions and the paralysis developed even in such thymus-fed animals in which the convulsions had been suppressed completely; this was the case in one of the animals of the Mg series. From the experiments of Biedl and others it is likely that the tetanic convulsions are due to lesions of the central nervous system, since convulsions of a leg can be prevented by isolating it from the central nervous system by cutting the nerves which connect the muscles with the central nervous system. Evidently these lesions of the central nervous system are the chief factor in tetany, while the convulsions of the muscles are only an effect. In the larvae of salamanders these lesions find a definite expression in the permanent paralysis of almost the entire muscular system. In the writer's opinion, MacCallum's hypothesis that the tetany toxin has a special affinity for Ca, thereby diminishing the Ca content of the organism, cannot be disproved at present. But the present experiments seem to prove, first, that the tetany-producing substance causes permanent lesions of the nervous system, which lead to permanent spasmodic contractions and paralysis of the muscle even in the absence of tetanic convulsions, and second, that these cannot be prevented by either Ca or Mg. For the most part they result in an early death of the animals no matter whether or not Ca or Mg has been applied. In connection with this fact we wish to mention Biedl's claim that no one has yet succeeded in prolonging the life of parathyroidectomized animals by the application of Ca. From MacCallum's paper, on account of the lack of controls, it cannot be seen whether his parathyroidectomized dogs lived longer with Ca treatment than without. That in spontaneous tetany Ca treatment may effect a cure, as is evident from the report by Howland and Marriott, does not prove that in this case Ca has inhibited tetany as a disease. In spontaneous tetany the period of the action of the tetany-producing substance may be a very short one and the mere prevention of the tetanic convulsions may keep the patient alive until normal function of the glands involved has been restored. The pathological changes which the central nervous system undergoes in this short period may not be severe enough to endanger the life of the patient after the cessation of the action of the tetany toxin. In the light of the facts presented our experiments lead to the following conclusions: 1. The thymus gland excretes a tetany-producing substance which in the normal animal is antagonized in an unknown way by the parathyroids. 2. In animals devoid of parathyroids (salamander larvae, parathyroidectomized mammals) this substance may, according to MacCallum, reduce the Ca content of the organism; but by far the most dangerous and important quality of this substance is its highly injurious effect upon the central nervous system, which causes permanent spasmodic contractions of the muscles and paralysis of almost the entire muscular system. 3. It is possible to prevent the muscular contractions by introducing Ca salts into the body, though this can be done more effectively by means of Mg salts. 4. No substance, however, has been found so far to antagonize the tetany toxin and to prevent the development of the lesions of the central nervous system caused by the tetany toxin. 5. This explains why in spite of the application of Ca or Mg and in spite of the suppression by these substances of the tetanic convulsions the other symptoms of tetany develop and frequently lead to the death of the animal. 6. Accordingly the most important function of the parathyroids is to prevent the tetany toxin, by antagonizing it, from coming into contact with the central nervous system.


Comparable performance on a spatial memory task in data collected in the lab and online.
Online data collection offers a wide range of benefits including access to larger and more diverse populations, together with a reduction in the experiment cycle. Here we compare performance in a spatial memory task, in which participants had to estimate object locations following viewpoint shifts, using data from a controlled lab-based setting and from an unsupervised online sample. We found that the data collected in a conventional laboratory setting and those collected online produced very similar results, although the online data was more variable with standard errors being about 10% larger than those of the data collected in the lab. Overall, our findings suggest that spatial memory studies using static images can be successfully carried out online with unsupervised samples. However, given the higher variability of the online data, it is recommended that the online sample size is increased to achieve similar standard errors to those obtained in the lab. For the current study and data processing procedures, this would require an online sample 25% larger than the lab sample.


The Hierarchical Modular Structure of HER2+ Breast Cancer Network.
HER2-enriched breast cancer is a complex disease characterized by the overexpression of the ERBB2 amplicon. While the effects of this genomic aberration on the pathology have been studied, genome-wide deregulation patterns in this subtype of cancer are also observed. A novel approach to the study of this malignant neoplasy is the use of transcriptional networks. These networks generally exhibit modular structures, which in turn may be associated to biological processes. This modular regulation of biological functions may also exhibit a hierarchical structure, with deeper levels of modular organization accounting for more specific functional regulation. In this work, we identified the most probable (maximum likelihood) model of the hierarchical modular structure of the HER2-enriched transcriptional network as reconstructed from gene expression data, and analyzed the statistical associations of modules and submodules to biological functions. We found modular structures, independent from direct ERBB2 amplicon regulation, involved in different biological functions such as signaling, immunity, and cellular morphology. Higher resolution submodules were identified in more specific functions, such as micro-RNA regulation and the activation of viral-like immune response. We propose the approach presented here as one that may help to unveil mechanisms involved in the development of the pathology.


Heterogeneity of B cell involvement in acute nonlymphocytic leukemia.
In order to study the pattern of B cell involvement in acute nonlymphocytic leukemia (ANLL), multiple B lymphoid cell lines were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from two patients with the disease who were heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD). In one patient, the progenitor cells involved by the leukemia exhibited multipotent differentiative expression, whereas in the other patient the cells showed differentiative expression restricted to the granulocytic pathway. In the patient whose abnormal clone showed multipotent expression, the ratio of B-A G6PD in B lymphoid cell lines was skewed in the direction of type B (the enzyme characteristic of the leukemia clone) and significantly different from the 1:1 ratio expected. It is, therefore, likely that the neoplastic event occurred in a stem cell common to the lymphoid series as well as to the myeloid series. In contrast, evidence for B cell involvement was not detected in the patient whose ANLL progenitor cells exhibited restricted differentiative expression. These findings underscore the heterogeneity of ANLL. Clinically and morphologically similar malignancies in these two patients originated in progenitors with different patterns of stem cell differentiative expression. This difference may reflect differences in cause and pathogenesis.


Elephantiasis nostras verrucosa: an atypical presentation following intrapelvic lymphoma.
Elephantiasis nostras verrucosa is a progressively debilitating and disfiguring disease commonly presenting with verrucous, cobblestone-like papules, nodules, or plaques with nonpitting edema in the lower extremities. Histopathology is marked by hyperkeratosis and dermal or subcutaneous fibrosis as a result of chronic lymphedema. Risk factors include obesity, recurrent cellulitis, chronic venous insufficiency, congestive heart failure, scleroderma, radiation, trauma, and tumors. We report a 72-year-old man who presented to the dermatology clinic for an 11-year history of edematous legs, occasionally associated with ulcerations. The findings developed within a year of intrapelvic non-Hodgkin lymphoma and progressed gradually over 10 years after lymphoma remission. Physical examination revealed atypical features including compressible cysts and pitting edema extending from the lower legs to the thighs bilaterally. The patient was noncompliant for the recommended compressive devices and the condition progressively worsened over the course of 7 months of follow-up. Early interdisciplinary management using compressive devices and a lymphatic pump are recommended. Underlying causative factors should be assessed with regular follow-up to optimize treatment outcomes.


[Development of a portable electrocardiogram(ECG) and respiration monitor].
This paper is to research into a kind of portable automatic ambulatory system, which is used to monitor electrocardiograph (ECG) and respiration signals. And in the interest of meeting the requirements of continuously monitoring the patients, comprehensive consideration is given to the overall structure of the system (including the display mode and the management of power supply). With the characteristics of higher sensitivity and preferable anti-interference, this system realizes minialurization and low power dissipation.


Conformational properties of HIV-1 gp120/V3 immunogenic domains.
Infection of target host cells by the human immunodeficiency virus-1 (HIV-1) is a multi-step process involving a series of conformational changes in the viral gp120 and gp41 proteins. Gp120 binding to the main cell receptor, CD4, on the surface of cells expressing this molecule, and interaction with the cell chemokine receptors CCR5 and CXCR4, are among the key events for HIV-1 infection. These steps are crucial for the virus and offer potential therapeutic targets. For this reason, understanding the structure and the physicochemical characteristics of the gp120 in relation to these interactions has drawn much attention. This review article focuses on the biologically important V3 region of the gp120 and summarizes the functional role, the sequence variation and the conformational features of V3 peptides, which are important for co-receptor selectivity, specificity and interaction. Synthetic V3 peptides have been extensively studied by NMR spectroscopy and X-ray crystallography, in solution or in solid state, in their free or bound form, and valuable information was generated with the aim to be exploited in the design of new, effective inhibitors of HIV-1 infection. The features of the potential gp120 interacting sites on the two chemokine co-receptors, CCR5 and CXCR4, are also discussed, and co-receptor blocking molecules under clinical trial are also reported.


5-Fluoro-[β-¹¹C]-L-tryptophan is a functional analogue of 5-hydroxy-[β-¹¹C]-L-tryptophan in vitro but not in vivo.
5-Hydroxy-[β-(11)C]-L-tryptophan ([(11)C]HTP) is an established positron emission tomography (PET) imaging agent for neuroendocrine tumors (NETs). It has also been used for other clinical research purposes in neurology and diabetes. However, its widespread use is limited by the short physical half-life of the radionuclide and a difficult radiosynthesis. Therefore, a Fluorine-18 labeled analogue, 5-[(18)F]Fluoro-L-tryptophan ([(18)F]FTRP), has been proposed as a functional analogue. There is no published method for the synthesis of L-[(18)F]FTRP. We have therefore developed a synthesis of 5-fluoro-[β-(11)C]-L-tryptophan ([(11)C]FTRP), based on the existing chemo-enzymatic method for [(11)C]HTP and evaluated the potential usefulness of radiolabeled FTRP as a substitute for [(11)C]HTP. The in vitro and in vivo behavior of [(11)C]FTRP, including the dependence of key enzymes in the serotonergic metabolic pathway, was investigated in NET cell lines, NET xenograft carrying immunodeficient mice, normal rats and in non-human primate. [(11)C]HTP was used for direct comparison. Uptake of [(11)C]FTRP in NET cell lines in vitro was mediated by enzymes involved in serotonin synthesis and metabolism, similar to [(11)C]HTP. In vivo biodistribution, either in rodent or non-human primate, was not affected by selectively inhibiting enzymatic steps in the serotonergic metabolic pathway. [(11)C]FTRP has in vitro biological function similar to that of [(11)C]HTP. However, this function is not retained in vivo as shown by biodistribution and PET/CT studies. Radiolabeled FTRP is thus not likely to provide an advantage over [(11)C]HTP in PET imaging in oncology, neurology or diabetes.


Human TAF(II)28 interacts with the human T cell leukemia virus type I Tax transactivator and promotes its transcriptional activity.
The Tax protein encoded by human T cell leukemia virus type I transactivates the viral promoter by forming a complex with several cellular factors bound to three repeats of a specific upstream regulatory sequence. We have shown that transactivation by Tax was correlated with its ability to interact with the C-terminal moiety of the TATA box-binding protein (TBP). In the present study, the ability of Tax to interact with several human TBP-associated factors (TAF(II)s) was analyzed. We show that Tax interacts selectively with hTAF(II)28 in transfected HeLa cells. A direct interaction between Tax and hTAF(II)28 was also observed in vitro with purified proteins. In transient expression studies we show that overexpression of hTAF(II)28 significantly increased transactivation by Tax, both in the absence and in the presence of overexpressed TBP. The ability of hTAF(II)28 to potentiate transactivation correlated with the ability of Tax to interact with hTAF(II)28 and also with the ability of hTAF(II)28 to interact with TBP. Coexpression of TBP and hTAF(II)28 resulted in an additive increase in transactivation by Tax. From these observations we propose that transcriptional activation by Tax involves multiple interactions with TFIID via its TBP and hTAF(II)28 subunits.


Short term microgravity effect on isometric hand grip and precision pinch force with visual and proprioceptive feedback.
Experiments executed on the upper limb are assuming increasing significance in the frame of the Human Physiology in space, for at least two reasons: the upper limb is the principal means of locomotion for the subject living in a space station; furthermore, fatigue can have a significant effect on the hand, for the ordinary work on board, and in particular for the extra-vehicular activities. The degradation of the performances affecting the muscular-skeletal apparatus can be easily recognized on the upper limb, by exerting specific scientific protocols, to be repeated through the permanence of the subject in weightlessness conditions. Another aspect relevant to the effect of microgravity on the upper limb is associated with the alteration of the motor control programs due to the different gravity factor, affecting not only the bio-mechanics of the subject, but in general all his/her psycho-physical conditions, induced by the totally different environment. Specific protocols on the upper limb can facilitate the studies on learning mechanisms for the motor control. The results of such experiments can be transferred to the Earth, useful for treatment of subjects with local traumas or diseases of the Central Nervous System.


Remission Effects of Dietary Soybean Isoflavones on DSS-Induced Murine Colitis and an LPS-Activated Macrophage Cell Line.
Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are chronic disorders of the gastrointestinal tract, although the exact causes of IBD remain unknown. Present treatments for IBDs have poor tolerability and insufficient therapeutic efficacy, thus, alternative therapeutic approaches are required. Soybean-derived isoflavones have multiple bioactivities such as anti-inflammation. However, the low water solubility of soybean isoflavones limits their bioavailability and practical use. Therefore, in order to study the preventive effects of water-soluble soybean isoflavones on colonic inflammatory status, we examined soybean-derived isoflavone glycosides (SIFs) in a dextran sodium sulfate (DSS)-induced murine colitis model and in lipopolysaccharide (LPS)-activated RAW264.7 macrophages. Oral administration of SIF (0.5 w/v%) attenuated DSS-induced colitis in terms of body weight decrease, colon shortening, epithelial apoptosis, histological score, mRNA levels of inflammatory cytokines, and immune cell infiltration in colon tissues. In the in vitro assessment, we observed the inhibitory effects of SIF on the production of nitric oxide and prostaglandin E2, via suppression of inducible nitric oxide synthase and cyclooxygenase-2 expression in RAW264.7 macrophages in response to LPS. Furthermore, we confirmed that the expression of inflammatory cytokines and chemokines were decreased by pre-treatment with SIF in LPS-activated RAW264.7 macrophages. Moreover, we demonstrated that SIF suppressed inflammatory mediators involved in nuclear factor-κB signaling pathway via inhibitory κB kinase phosphorylation and degradation of inhibitory κB. Our results suggested that SIF may be beneficial for the remission of colonic inflammatory status including IBDs.


Non-coding RNAs in cardiac fibrosis: Emerging biomarkers and therapeutic targets.
Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. ncRNAs are involved in cell proliferation, apoptosis, differentiation, metabolism, and other physiological processes as well as the pathogenesis of diseases. Cardiac fibrosis is increasingly recognized as a common final pathway in advanced heart diseases. Many studies have shown that the occurrence and development of cardiac fibrosis is closely related to the regulation of ncRNAs. This review will highlight recent updates regarding the involvement of ncRNAs in cardiac fibrosis, and their potential as emerging biomarkers and therapeutic targets.


A comparative analysis of postoperative pancreatic fistulas after surgery with and without hyperthermic intraperitoneal chemoperfusion.
Postoperative pancreatic fistulas (POPFs) are potentially morbid complications that often require therapeutic interventions. Distal pancreatectomy performed during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) puts patients at risk for POPF. The authors hypothesized that POPFs are more severe after CRS/HIPEC than after pancreatectomy alone. Clinicopathologic and perioperative details, including POPF by International Study Group of Pancreatic Fistula criteria (ISGPF), and oncologic outcomes for patients undergoing distal pancreatectomy during CRS/HIPEC for peritoneal carcinomatosis of appendiceal (n = 31) or colorectal (n = 23) origin (HIPEC group) were compared with those for patients undergoing minimally invasive or open distal pancreatectomy without HIPEC (n = 66) for locally resectable pancreatic adenocarcinoma (non-HIPEC group). The incidence of POPF was similar between the HIPEC and non-HIPEC groups (26 %). The severity of POPF according to the ISGPF criteria was significantly worse in the HIPEC group. The HIPEC patients had 13 grade B fistulas and 1 grade C fistula compared with 12 grade A fistulas and 4 grade B fistulas in the non-HIPEC group. The HIPEC patients with POPF did not differ in the extent of their CRS, peritoneal cancer index, length of hospital stay, or other postoperative complications from the the HIPEC patients without POPF. The HIPEC patients with colorectal carcinomatosis who experienced POPF had higher disease recurrence in the first year after CRS/HIPEC than those without POPF. The findings showed that POPFs are more severe when distal pancreatectomy is combined with CRS/HIPEC. Moreover, selective use of distal pancreatectomy is important during CRS/HIPEC because POPFs may increase early disease recurrence for patients with colorectal carcinomatosis.


Absence of androgen-mediated transcriptional effects in osteoblastic cells despite presence of androgen receptors.
Androgen excess and deficiency affect skeletal maturation and bone cell function. Understanding the molecular basis for these androgen effects could improve therapy/prevention of short stature and osteoporosis. Androgens act through binding to androgen receptors (ARs), which modulate gene transcription via interactions with DNA response elements on target genes. Because osteoblasts contain ARs at levels just below certain androgen-sensitive tissues, we sought to define the function of AR in a number of commonly used osteoblastic cell lines. Presence and quantification of AR protein and mRNA were evaluated by ligand binding assay, western blotting, and RNAse protection assay. AR-containing osteoblastic cell lines were exposed to nonaromatizable androgens and effects on gene expression were assessed. We found no evidence for direct effects of androgen on endogenous genes nor was androgen involved in modulation of parathyroid hormone effects on early gene activation. Androgen-sensitive reporter gene constructs were stimulated by androgen only when AR cDNA expression vectors were introduced into cells by cotransfection. We conclude that, in commonly used osteoblastic cell lines, the presence of AR at the levels described here does not guarantee androgen transcriptional activity. The effects of androgen on bone in vivo may involve direct stimulation of osteoblastic cells in a different setting or stage of differentiation. Alternatively, androgen may act on bone cells other than osteoblasts, or through metabolic conversion to estrogens.


[Effect of antioxidants with different antiradical activity on cornea preservation].
Changes of chemoluminescence intensity, collagen mucopolysaccaride content in the rabbit eye cornea were studied on 32 cornea of shinshilla eye conservated by dehydration under hipotenia (2 divided by 4 degrees C) for 60 days with the application of antioxidants (tocoferol, chlorhydrate 2-ethyl, 6-methyl-3-oxipyridine) having different antiradical activity. It is concluded that the application of natural antioxidant alpha-tocoferol having high antiradical activity is expedient for the conservation of cornea.


Expression of cannabinoid CB1 R-GPR55 heteromers in neuronal subtypes of the Macaca fascicularis striatum.
The cannabinoid CB1 receptor (CB1 R) is the most abundant G protein-coupled receptor in the central nervous system, consistent with the important role of endocannabinoids as neuromodulators. Cannabinoids also modulate the function of G protein-coupled receptor 55 (GPR55), which forms heteroreceptor complexes with the CB1 R in the striatum. The aim was to characterize cannabinoid CB1 R-GPR55 heteromers (CB1 R/GPR55Hets) in the basal ganglia input nuclei of nonhuman primates, Macaca fascicularis, both in projection neurons and interneurons, by the in situ proximity ligation assay. Striatal projecting neurons were identified by the retrograde neuroanatomical tracer, biotinylated dextran amine (BDA), injected into external or internal subdivisions of the globus pallidus. Triple immunofluorescent stains were carried out to visualize (1) BDA-labeled neurons, (2) CB1 R/GPR55Hets, and (3) striatal interneurons positive for choline acetyltransferase, parvalbumin, calretinin, or nitric oxide synthase. CB1 R/GPR55Hets were identified within both types of projection neurons as well as all interneurons except those that are cholinergic. Moreover, CB1 R/GPR55Hets were found specifically in the neuronal cell surface, and also in intracellular membranes. Further research efforts will be needed to confirm the intracellular occurrence of heteromers and their potential as therapeutic targets in diseases related to motor control imbalances, particularly within a parkinsonian context (with or without levodopa-induced dyskinesia).


Prevention trials: their place in how we understand the value of prevention strategies.
Several key factors bear on the interpretation of prevention trials and observational studies that inform prevention strategies. These factors include the underlying disease process and aspects of the intervention: sustainability of behavior change, the time course of the intervention within the disease process, dose and duration of exposure needed to effect risk reduction, durability of the impact of intervention, and methodological problems in implementing and interpreting randomized trials and observational studies to evaluate prevention strategies. The question asked through an intent-to-treat analysis of a randomized controlled trial (RCT) differs from that in the observational setting. Furthermore, the long duration necessary to conduct prevention trials and the resulting lack of adherence to therapy can bias results toward the null. A broader range of approaches to evaluate prevention interventions and programs with improved knowledge synthesis and translation to public health practice will speed our progress toward achieving public health and prevention of chronic diseases.


Spectroscopic features of ultrahigh-pressure impact glasses of the Kara astrobleme.
The state of substances under ultrahigh pressures and temperatures (UHPHT) now raises a special interest as a matter existing under extreme conditions and as potential new material. Under laboratory conditions only small amounts of micrometer-sized matter are produced at a pressure up to 100 GPa and at room temperature. Simultaneous combination of ultrahigh pressures and temperatures in a lab still requires serious technological effort. Here we describe the composition and structure of the UHPHT vein-like impact glass discovered by us in 2015 on the territory of the Kara astrobleme (Russia) and compare its properties with impact glass from the Ries crater (Germany). A complex of structural and spectroscopic methods presents unusual high pressure marks of structural elements in 8-fold co-ordination that had been described earlier neither in synthetic nor natural glasses. The Kara natural UHPHT glasses being about 70 Ma old have well preserved initial structure, presenting some heterogeneity as a result of partial liquation and crystallization differentiation where an amorphous component is proposed to originate from low level polymerization. Homogeneous parts of the UHPHT glasses can be used to deepened fundamental investigation of a substance under extreme PT conditions and to technological studies for novel material creations.


Thrombosis in pediatric malignancy: a review and future perspectives with focus on management.
: Venous thromboembolism (VTE) result in significant morbidity and mortality in children with cancer. The cause of VTE in children with cancer is multifactorial and includes genetic predisposition (thrombophilia), disease-related factors, and treatment-related factors including use of central venous catheter (CVC), surgery, and chemotherapy. This review aims to examine current knowledge regarding the incidence, risk factors, clinical manifestation, evaluation, prevention, and management of thromboembolic events in children with cancer.


[Erik Vio, surgeon from Rijeka at history's crossroad].
The fact that many famous denizens of Rijeka belong to different nationalities confirms this city's historic multicultural image. The life story of Erik Vio (1910-1966), renowned surgeon of international reputation, reflects the fate of many displaced residents of Rijeka who left to live in exile. After graduating in Rome, Vio worked as a medical doctor in Hong Kong for almost three decades. The question is weather a surgeon from Rijeka chose to live in Hong Kong because it reminded him of his hometown? The author finds the root of this thesis in Vio's novel The Pathways of Freedom (˝Irwege der Freiheit˝, Köln 1978), a particular medical-philosophic diagnosis of the contemporary civilization's spiritual state. Rare fragments dedicated to Rijeka confirm Vio's actual detachment; faced with his own identity, but also with the others' with whom he shared his living space, a surgeon from Rijeka became a true citizen of the world and at the same time a stateless person with no roots of his own. Through the projection of Hong Kong one can detect the novel's identification backbone: writer's provocation of the ideological perspective on socio-cultural relations. By engaging in the interpretation of Vio's The Pathways of Freedom the author seeks to dissect a sociological dimension of descriptions of dual identities in border space. This leads to the issue of understanding and tolerance toward the others.


Perioperative use of modified thrombelastography in factor XI deficiency: a helpful method to assess drug effects.
Factor XI deficiency is a rare, hereditary bleeding disorder associated with a trauma-related bleeding tendency, caused by insufficient generation of the thrombin activatable fibrinolysis inhibitor (TAFI) evoking increased fibrinolysis. We present the case of a five year old girl with homozygote, severe factor XI deficiency presenting for surgery on two occasions. Modified thrombelastography (ROTEM) was used to assess effects of factor XI deficiency on coagulation, endogenous fibrinolysis, and potential effects of tranexamic acid, aprotinin and recombinant, activated Factor VII in an in vitro model of hyperfibrinolysis. According to our data and in consideration of the mechanisms of factor XI deficiency we decided on prophylactic use of tranexamic acid.


Systemic sclerosis-associated interstitial lung disease.
In this review, the authors discuss systemic sclerosis-associated interstitial lung disease (SSc-ILD) with a focus on recent developments in diagnosis, surveillance, and management. With advances in the management of SSc, the importance of ILD has been increasingly recognized and is the leading cause of mortality. Early detection is essential, and a combination of lung function testing and chest imaging are key tools in diagnosis and surveillance. The foundation of treatment is immunomodulation with recent studies identifying several potential new agents. The use of therapies targeting pro-fibrotic pathways have demonstrated significant effects on lung function decline and represent the latest advance in therapy for SSc-ILD. Recent studies support the use of newer therapies in SSc-ILD including antifibrotic agents. The identification and management of comorbidities is important, and lung transplantation is a viable option for patients with advanced disease.


Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation.
Short chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are produced at high concentration by bacteria in the gut and subsequently released in the bloodstream. Basal acetate concentrations in the blood (about 100 microm) can further increase to millimolar concentrations following alcohol intake. It was known previously that SCFAs can activate leukocytes, particularly neutrophils. In the present work, we have identified two previously orphan G protein-coupled receptors, GPR41 and GPR43, as receptors for SCFAs. Propionate was the most potent agonist for both GPR41 and GPR43. Acetate was more selective for GPR43, whereas butyrate and isobutyrate were more active on GPR41. The two receptors were coupled to inositol 1,4,5-trisphosphate formation, intracellular Ca2+ release, ERK1/2 activation, and inhibition of cAMP accumulation. They exhibited, however, a differential coupling to G proteins; GPR41 coupled exclusively though the Pertussis toxin-sensitive Gi/o family, whereas GPR43 displayed a dual coupling through Gi/o and Pertussis toxin-insensitive Gq protein families. The broad expression profile of GPR41 in a number of tissues does not allow us to infer clear hypotheses regarding its biological functions. In contrast, the highly selective expression of GPR43 in leukocytes, particularly polymorphonuclear cells, suggests a role in the recruitment of these cell populations toward sites of bacterial infection. The pharmacology of GPR43 matches indeed the effects of SCFAs on neutrophils, in terms of intracellular Ca2+ release and chemotaxis. Such a neutrophil-specific SCFA receptor is potentially involved in the development of a variety of diseases characterized by either excessive or inefficient neutrophil recruitment and activation, such as inflammatory bowel diseases or alcoholism-associated immune depression. GPR43 might therefore constitute a target allowing us to modulate immune responses in these pathological situations.


Rapid onsite evaluation uses a very small proportion of total material aspirated at endobronchial or endoscopic ultrasound in the investigation of suspected thoracic malignancy.
The objectives were: to measure the proportion of aspirated material used to make direct slides for rapid onsite evaluation (ROSE) at endobronchial (EBUS) and endoscopic ultrasound (EUS) in suspected thoracic malignancy; and to correlate pass weights with ROSE category and needle size. All EBUS and EUS cases for possible thoracic malignancy October 2018-May 2019 were included. All material from each pass was expelled into a Petri dish. One drop of material was placed on each of two slides; one used for ROSE, the other fixed and remaining material processed to cell block. Dish and slides were weighed before and after this procedure on a sensitive balance and weight of aspirate and slide material calculated. When ROSE identified malignancy, slide production ceased but target sampling for ancillary studies continued. ROSE accuracy was 96.8%. Mean percentage by target of aspirated material used to make direct slides for ROSE was 1.9% in malignant cases and 3.6% in non-malignant cases (P = .027 for difference). Mean percentage by pass was 5.9%. Mean weight of a single aspirate was 128.8 mg. Mean weight of aspirates insufficient on ROSE (175.7 mg) was significantly higher than the mean weight of benign or malignant aspirates (117.1 and 114.0 mg, respectively). Mean weight of aspirates using 22G needles (132.6 mg) was significantly higher than that for 25G needles (87.1 mg). Material made into direct slides at EBUS and EUS and used in part for ROSE uses a tiny proportion of aspirated material with over 98% processed to cell block and available for ancillary testing in malignant cases.


Resveratrol ameliorates cisplatin-induced oxidative injury in New Zealand rabbits.
This study investigated the preventive role of resveratrol in cisplatin-induced nephrotoxicity. The study used groups of New Zealand rabbits that were treated as follows: group C (cisplatin treated), group R (resveratrol treated), group R+C (resveratrol + cisplatin treatment), and group E (control group). Kidney levels of glutathione were significantly lower in group C than in groups E and R, whereas glutathione levels in group R+C were found to be similar to the control values. Malondialdehyde levels in group C were significantly higher than in groups E and R. However, malondialdehyde levels in group R+C were similar to group E. Kidney levels of nitric oxide were significantly higher in the cisplatin group than in the control, whereas nitric oxide levels were at basal values in group R+C. Cisplatin treatment significantly reduced kidney levels of glutathione peroxidase, superoxide dismutase, and catalase activity compared with those of group E, whereas resveratrol treatment significantly increased levels of glutathione peroxidase, superoxide dismutase, and catalase activity in group R+C. However, cisplatin injection did not affect mRNA levels of glutathione peroxidase, superoxide dismutase, or catalase enzymes. Histopathological and immunohistochemical analyses indicated that cisplatin caused kidney damage, which was mostly prevented by resveratrol treatment. In conclusion, resveratrol ameliorates cisplatin-induced oxidative injury in the kidney of rabbit.


Epigenetic and replacement roles of histone variant H3.3 in reproduction and development.
The nucleosomal organization of eukaryotic chromatin is generally established during DNA replication by the deposition of canonical histones synthesized in S phase. However, cells also use a Replication Independent (RI) nucleosome assembly pathway that allows the incorporation of non-canonical histone variants in the chromatin. H3.3 is a conserved histone variant that is structurally very close to its canonical counterpart but nevertheless possesses specific properties. In this review, we discuss the dual role of H3.3 which functions as a neutral replacement histone, but also participates in the epigenetic transmission of active chromatin states. These properties of H3.3 are also explored in the light of recent studies that implicate this histone and its associated chromatin assembly factors in large scale, replication-independent chromatin remodeling events. In particular, H3.3 appears as a critical player in the transmission of the paternal genome, from sperm to zygote.


Deep hypothermia with reduced flow rates for correction of ventricular septal defects in infants. An alternative approach.
In this presentation our experience of the correction of large ventricular septal defects (VSD) under deep hypothermia (DH) and reduced flow rates in infants is reported. Sixty patients with VSD and pulmonary hypertension were operated. The age of the patients varied from 1.5 to 12 months and body weight from 3.0 to 8.7 kg. Deep hypothermia was achieved by cooling the patient using a heart-lung machine after aortic and right atrial cannulation. At a rectal temperature of 18 degrees C, pump flow was reduced to 0.28 l . min-1 . m-2 and cardiotomy was performed. Venous blood from the right atrium was aspirated with a single coronary sucker. The aorta was not clamped. After completion of the intracardiac repair, pump flow was increased and the patient was rewarmed to a rectal temperature of 36 degrees C. In all cases cardiac rhythm was restored spontaneously during rewarming. In every patients, the VSD was closed with a xenopericardial patch (in 42 patients from a right atrial approach and in 18 patients through the ventriculotomy). In 5 patients a patent ductus was also ligated and in 37 patients an atrial septal defect was sutured. The hospital mortality was 5% (3 patients). In the remaining 57 patients the cardiac index during the first 48 hours after operation was 2.5-4.2 l . min-1 . m-2. Patients were extubated between 18 and 44 hours after the operation. Deep hypothermia with reduced flow rates during intracardiac repair provides excellent myocardial protection and exposition in infants with VSD.


The quality of notification of congenital malformations.
The United Kingdom Congenital Malformations Notification Scheme began in 1964. It is based on notes added to birth notification forms. In Birmingham, a local scheme based on multiple sources has been run in parallel for the last 20 years. The national notification scheme records malformations noted up to the age of 7 days, whereas the Birmingham scheme collects information up to the age of 5 years. A case by case record linkage of the two registers was carried out. This operation revealed the essential completeness of the multiple-source register but gross defects among notifications. The extent and nature of the deficiencies are described. They include defects of ascertainment of malformed infants and of major additional malformations in those infants who are in fact notified, overnotification of infants without significant malformations, and misclassification of the major malformations that were, in fact, notified. The defects arise partly from the defective design of the national scheme and partly from defective implementation and a lack of designated supervisory responsibilities. The main requirements for a scheme that could indeed be relied upon to meet its monitoring objectives are set out.


Compensation of FM-to-AM conversion in high-power lasers.
FM-to-AM conversion in the ninth beam of the Shen Guang II laser system with sinusoidal phase-modulated spectra is calculated and analyzed. The simulations show that the intensity modulation at 3ω is much more serious compared to the other wavebands and it is mostly induced by the frequency conversion system rather than the amplification chain. The compensation effects of FM-to-AM conversion in the frequency conversion system by angular dispersion grating and cascaded crystals are numerically simulated and compared. Compared to the cascaded crystals, the angular dispersion grating could maintain higher frequency conversion efficiency with wide spectral width and offer a higher dynamic range of compensation effectiveness versus fundamental laser intensity. Combined with a precompensation filter before the amplification chain, FM-to-AM conversion at 3ω could be eliminated.


The role of the dorsal and ventral hippocampus in fear and memory of a shock-probe experience.
The roles of the dorsal and ventral hippocampus in fear and memory are unclear. This study examined the effects of temporary inactivation of the dorsal or ventral hippocampus on unconditioned and conditioned fear, using the shock-probe test. In Experiment 1, rats received either dorsal or ventral hippocampal infusions of lidocaine or saline, before exposure to an electrified shock-probe (acquisition I). In Experiment 2, rats received lidocaine or saline infusions after exposure to the shock-probe (acquisition II). In both experiments, a retention test in the same apparatus was given 24 h later, at which time the hippocampus was no longer inactivated, and the probe was disconnected from the shock-source. Because ventral hippocampal inactivation impaired fear behaviour during acquisition, and dorsal hippocampal inactivation impaired fear behaviour (probe avoidance) during retention, we concluded that 1) the ventral hippocampus plays a role in the expression of untrained fear reactions whereas 2) the dorsal hippocampus plays a role in encoding memory of the fearful experience.


Older people at the beginning of the COVID-19 pandemic: A scoping review.
This scoping review focuses on evidence gaps regarding the effects on health, social participation and life contexts of older people at the beginning of the COVID-19 pandemic. It is based on a systematic search strategy of the international literature covering a period between December 2019 and June 2020. The review is supplemented by a search of the websites of selected organisations in Germany (cut-off date: 29 June 2020). Search hits were differentiated by types of publication (empirical study, review, discussion paper). The contents were summarised in tabular form according to topic. The publications mainly discussed the high risks of suffering severe courses of COVID-19 faced by older people, specifically those belonging to certain subgroups. In addition, further main topics were the pandemic's indirect impacts on physical and mental health, physical and cognitive functions and participation in society. Social isolation, loneliness, reduced levels of physical activity and difficulties in maintaining care were discussed as major health risks. Ageism was an issue that was addressed across all of the identified topics. The publications highlighted the need, but also the opportunity, for raising public awareness of the needs of older people in various life contexts. Publications pointed to the urgent need for research into the biological and social causes of older peoples' high infection risk and how measures could be adapted in a differentiated manner (infection prevention and control measures, social support, medical and nursing care).


Iron oxide nanoparticle targeted chemo-immunotherapy for triple negative breast cancer.
Triple negative breast cancer is difficult to treat effectively, due to its aggressiveness, drug resistance, and lack of the receptors required for hormonal therapy, particularly at the metastatic stage. Here, we report the development and evaluation of a multifunctional nanoparticle formulation containing an iron oxide core that can deliver doxorubicin, a cytotoxic agent, and polyinosinic:polycytidylic acid (Poly IC), a TLR3 agonist, in a targeted and simultaneous fashion to both breast cancer and dendritic cells. Endoglin-binding peptide (EBP) is used to target both TNBC cells and vasculature epithelia. The nanoparticle demonstrates favorable physicochemical properties and a tumor-specific targeting profile. The nanoparticle induces tumor apoptosis through multiple mechanisms including direct tumor cell killing, dendritic cell-initiated innate and T cell-mediated adaptive immune responses. The nanoparticle markedly inhibits tumor growth and metastasis and substantially extends survival in an aggressive and drug-resistant metastatic mouse model of triple negative breast cancer (TNBC). This study points to a promising platform that may substantially improve the therapeutic efficacy for treating metastatic TNBC.


Very distal radial osteotomy for Madelung's deformity.
Madelung's deformity results from arrested or slowed growth of the volar-palmar portion of the distal radial epiphysis. The deformity is characterized by increased volar and ulnar tilt of the articular surface of the radius and a bow of the distal radius in a palmar direction. When Madelung's deformity produces pain and interferes with function, correction of the deformity of the radius and secondary overgrowth of the ulna is desirable. Although osteotomy of the radius near the junction of the middle and distal thirds allows correction of the bow of the radius and limited correction of palmar tilt, it does not permit correction of ulnar tilt. We describe a very distal radial osteotomy that permits correction of the 3 deformities of the distal radius independently; correction of palmar tilt, ulnar tilt, and the bow of the radius are selected individually. The inherent flexibility makes the procedure technically challenging but allows for maximum independent correction of the components of Madelung's deformity. Early results indicate the procedure provides relief of pain and improved appearance with few complications.


Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues.
Racemic fluoxetine is a widely used SSRI antidepressant compound having also anticonvulsant effect. In addition, it was shown that it blocked several types of voltage gated ion channels including neural and cardiac calcium channels. In the present study the effects of enantiomers of fluoxetine (R(-)-fluoxetine and S(+)-fluoxetine) were compared on neuronal and cardiac voltage-gated Ca2+ channels using the whole cell configuration of patch clamp techniques, and the anticonvulsant action of these enantiomers was also evaluated in a mouse epilepsy model. In isolated pyramidal neurons of the dorsal cochlear nucleus of the rat the effect of fluoxetine (S(+), R(-) and racemic) was studied on the Ca2+ channels by measuring peak Ba2+ current during ramp depolarizations. All forms of fluoxetine reduced the Ba2+ current of the pyramidal cells in a concentration-dependent manner, with a Kd value of 22.3+/-3.6 microM for racemic fluoxetine. This value of Kd was higher by one order of magnitude than found in cardiac myocytes with fluoxetine enantiomers (2.4+/-0.1 and 2.8+/-0.2 microM). Difference between the effects of the two enantiomers on neuronal Ba2+ current was observed only at 5 microM concentration: R(-)-fluoxetine inhibited 28+/-3% of the peak current, while S(+)-fluoxetine reduced the current by 18+/-2% (n=13, P<0.05). In voltage clamped canine ventricular cardiomyocytes both enantiomers of fluoxetine caused a reversible concentration-dependent block of the peak Ca2+ current measured at 0 mV. Significant differences between the two enantiomers in this blocking effect was observed at low concentrations only: S(+)-fluoxetine caused a higher degree of block than R(-)-fluoxetine (56.3+/-2.2% versus 49.1+/-2.2% and 95.5+/-0.9% versus 84.5+/-3.1% block with 3 and 10 microM S(+) and R(-)-fluoxetine, respectively, P<0.05, n=5). Studied in current clamp mode, micromolar concentrations of fluoxetine shortened action potential duration of isolated ventricular cells, while higher concentrations also suppressed maximum velocity of depolarization and action potential amplitude. This shortening effect was significantly greater in the case of S(+) than R(-)-fluoxetine at 1 and 3 microM concentrations, whereas no differences in their effects on depolarization were observed. In pentylenetetrazole-induced mouse epilepsy model fluoxetine pretreatment significantly increased the 60 min survival rate, survival duration and seizure latency. These effects were more pronounced with the R(-) than the S(+) enantiomer. The results indicate that fluoxetine exerts much stronger suppressive effect on cardiac than neuronal calcium channels. At micromolar concentrations (between 1 and 10 microM) R(-)-fluoxetine is more effective than the S(+) enantiomer on neuronal, while less effective on cardiac calcium channels. The stronger anticonvulsant effect of the R(-) enantiomer may, at least partially, be explained by these differences. Used as an antidepressant or anticonvulsant drug, less severe cardiac side-effects are anticipated with the R(-) enantiomer.


Qualitative Exploration of Geospatially Identified Bright Spots and Priority Areas to Improve Diabetes Management.
Type 2 diabetes (T2DM) results in significant morbidity and mortality and is associated with disparities in prevalence, treatment, and outcomes. GIS can identify geographically based disparities. In the focused Rapid Assessment Process (fRAP)-a novel mixed-method study design-GIS is combined with qualitative inquiry to inform practice interventions and policy changes. Using fRAP, areas with poor T2DM outcomes (priority areas) as well as areas with positive T2DM outcomes (bright spots) were identified, focus groups were conducted, and responses analyzed for intervention opportunities. Focus group participants were English- and Spanish-speaking patients with T2DM living in one of the identified areas. Qualitative analysis consisted of initial coding with a priori themes from the focus group question guide, followed by identification of emergent themes within each defined category. The a priori categories included Facilitators, Barriers, Strategies, and Impact of Diabetes Diagnosis. Emerging recurrent themes were Interactions with Medical Professionals, Medications, Lifestyle Management, Family Motivators and Support, Self-Efficacy, and Social Needs and Community Resources. Thematic results from focus groups can be used by practices to improve T2DM care through educating patients about chronic disease and nutrition, connecting them to diabetes-specific services, learning how diabetes fits in the context of patient lives, and eliciting patient values and motivations to improve diabetes self-management. Findings also may be used by health care professionals to inform community-based advocacy efforts, interventions, and future research.


In vivo "MRI phenotyping" reveals changes in extracellular matrix transport and vascularization that mediate VEGF-driven increase in breast cancer metastasis.
To gain new insights into the relationship between angiogenic factors in breast cancer and their effect on extracellular matrix (ECM) remodeling and metastasis, we characterized and validated the "metastatic signature" of human breast cancer cell lines engineered to overexpress VEGF in terms of in vivo MRI-derived angiogenesis and ECM transport parameters. MRI was used to evaluate the effects of overexpressing VEGF-A (VEGF165) on tumor angiogenesis and ECM remodeling in vivo, for two differentially metastatic human breast cancer cell lines: MCF-7 and MDA-MB-231. Overexpression of VEGF elevated vascular volume in both MCF-7-VEGF and MDA-MB-231-VEGF tumors relative to their wild-type counterparts, but vascular permeability was elevated only in MCF-7-VEGF tumors. A significant increase in the volume of extravascular fluid drained as well as the number of ECM drainage voxels was detected in MCF-7-VEGF tumors relative to MCF-7 tumors, but not in MDA-MB-231-VEGF versus MDA-MB-231 tumors. The angiogenic effects of VEGF overexpression in both MCF-7-VEGF and MDA-MB-231-VEGF tumors were validated histologically. MCF-7-VEGF tumors exhibited enhanced invasion and a greater fraction of cancer positive lungs and lymph nodes relative to MCF-7 tumors. In vivo MRI and histological data demonstrate that VEGF overexpression results in the progression of noninvasive MCF-7 and invasive MDA-MB-321 tumors to a more angiogenic phenotype. However, VEGF overexpression significantly altered ECM integrity only in MCF-7 tumors, causing them to progress to an invasive and metastatic phenotype. This study for the first time demonstrates the concurrent effects of VEGF overexpression and ECM remodeling on metastasis in vivo. Collectively, these findings demonstrate that in vivo MRI can non-invasively monitor changes in the tumor microenvironment that can potentially predict a cancer's ability to metastasize.


Gar1p binds to the small nucleolar RNAs snR10 and snR30 in vitro through a nontypical RNA binding element.
The nucleolar proteins Gar1p and fibrillarin possess a typical nucleolar glycine/arginine-rich domain and belong to ribonucleoprotein particles. Both proteins are essential for yeast cell growth and are required for pre-rRNA processing. In addition, Gar1p is involved in pre-rRNA pseudouridylation, whereas fibrillarin is required for pre-rRNA methylation. Gar1p and fibrillarin are each associated with a different subset of the small nucleolar RNAs (snoRNAs). Gar1p is co-immunoprecipitated with the H/ACA family of snoRNAs, whereas fibrillarin is co-immunoprecipitated with the C/D family. However, attempts to demonstrate direct interactions between fibrillarin and snoRNAs have failed, and such interactions between Gar1p and the H/ACA snoRNAs had not yet been reported. Among the H/ACA snoRNAs associated with Gar1p, one can distinguish a large group of snoRNAs that are not essential in yeast and serve as guides for pseudouridine synthesis onto the pre-rRNA molecule. In contrast, the two snoRNAs snR10 and snR30 are required for normal cell growth and for pre-rRNA cleavage. We show here that Gar1p interacts in vitro directly and specifically with these two snoRNAs. Deletion analysis of Gar1p indicates that a major RNA binding element, which is extremely well conserved throughout evolution, lies in the middle of the protein. However, this domain alone binds poorly to the target RNAs and an accessory domain is required to restore efficient binding. The accessory domain can be either one of the glycine/arginine-rich domains or a second element of the core of the protein that is highly conserved between different species.


[Lipoprotein metabolism in arterial walls and its relationship with the genesis of atheromatous lesion].
In this review we have concentrated on the ways in which modification of LDL structure may account for foam cell formation. We have presented in vivo evidence as well as in vitro evidence supporting the proposition that modification of native LDL is a prerequisite for foam cell formation and atherogenesis. If further research supports the importance of LDL modification in atherogenesis, a whole new array of possibilities opens itself to us for intervention. At the moment, the only intervention that appears to be feasible is prevention of LDL oxidation; conceivably we might be able to interfere with the aggregation of LDL with itself or with other complexes in the artery wall that appear also to favor initiation of the atherogenic process.


The effect of thyrotropin releasing hormone on carbon dioxide laser induced lesion of the cerebral artery.
Carbon dioxide laser which is used widely in neurosurgery has less traumatic effect on the tissue beside the lesion than other types of laser. There has been little study on the changes to the vascular tissue, following laser application. We performed a study on 4 groups of dogs; comprising craniectomy only, craniectomy and thyrotropin releasing hormone (TRH), craniectomy and laser, and craniectomy, laser and TRH. We applied CO2 laser on the angular artery of two groups of dogs. To one group we infused TRH for 15 days following the laser application and to the other group we did not. We investigated the ultrastructural and biochemical changes and the effect of TRH on the tissue 15 days following laser application. In our study, we observed an increase in superoxide dismutase activity and a decrease in ATP-ase activities in the degenerated tissue on which CO2 laser was applied. TRH partially prevented the vascular degeneration of CO2 laser but did not significantly change superoxide dismutase and Adenosine-5'-triphosphatase activities.


Nucleotide sequence and functional properties of a sodium-dependent citrate transport system from Klebsiella pneumoniae.
The gene of the sodium-dependent citrate transport system from Klebsiella pneumoniae (citS) is located on plasmid pES3 (Schwarz, E., and Oesterhelt, D. (1985) EMBO J. 4, 1599-1603) and encodes a 446-amino acid protein. Transport of citrate via this citrate transport protein (CitS) is dependent on the presence of sodium ions and is inhibited by magnesium ions. The delta pH (pH gradient across the membrane) is the major driving force for uptake. It is postulated that, in analogy with the proton-dependent citrate carrier (CitH) of K. pneumoniae (van der Rest, M. E., Abee, T., Molenaar, D., and Konings, W. N. (1990) Eur. J. Biochem. 195, 71-77), only one of the protonated species of citrate is recognized by CitS and that citrate is translocated across the membrane in symport with protons and sodium ions. The hydrophobicity profile of CitS suggests that the protein is very hydrophobic and contains 12 membrane-spanning segments. These segments are not centered around a hydrophilic core as has been suggested for other transport proteins, but the protein is asymmetrical with seven transmembrane segments in front of a large hydrophilic loop and five after this loop. The amino acid sequence is highly similar to a citrate transport system of Lactococcus lactis subsp. lactis var. diacetylactis (CitP) (David, S., van der Rest, M. E., Driessen, A. J. M., Simons, G., and de Vos, W. M. (1990) J. Bacteriol. 172, 5789-5794) and less similar to CitH of K. pneumoniae. We conclude that the citS gene of K. pneumoniae encodes a sodium-dependent citrate transport system that belongs to a novel subclass of transport proteins.


Recent and Rapid Transmission of HIV Among People Who Inject Drugs in Scotland Revealed Through Phylogenetic Analysis.
Harm reduction has dramatically reduced HIV incidence among people who inject drugs (PWID). In Glasgow, Scotland, <10 infections/year have been diagnosed among PWID since the mid-1990s. However, in 2015 a sharp rise in diagnoses was noted among PWID; many were subtype C with 2 identical drug-resistant mutations and some displayed low avidity, suggesting the infections were linked and recent. We collected Scottish pol sequences and identified closely related sequences from public databases. Genetic linkage was ascertained among 228 Scottish, 1820 UK, and 524 global sequences. The outbreak cluster was extracted to estimate epidemic parameters. All 104 outbreak sequences originated from Scotland and contained E138A and V179E. Mean genetic distance was <1% and mean time between transmissions was 6.7 months. The average number of onward transmissions consistently exceeded 1, indicating that spread was ongoing. In contrast to other recent HIV outbreaks among PWID, harm reduction services were not clearly reduced in Scotland. Nonetheless, the high proportion of individuals with a history of homelessness (45%) suggests that services were inadequate for those in precarious living situations. The high prevalence of hepatitis C (>90%) is indicative of sharing of injecting equipment. Monitoring the epidemic phylogenetically in real time may accelerate public health action.


Dynamic and thermodynamic properties of porous vortex matter in Bi(2)Sr(2)CaCu(2)O(8) in an oblique magnetic field.
Vortex matter in Bi(2)Sr(2)CaCu(2)O(8) with a low concentration of tilted columnar defects (CDs) was studied using magneto-optical measurements and molecular dynamics simulations. It is found that while the dynamic properties are significantly affected by tilting the magnetic field away from the CDs, the thermodynamic transitions are angle independent. The simulations indicate that vortex pancakes remain localized on the CDs even at large tilting angles. This preserves the vortex thermodynamics, while vortex pinning is considerably weakened due to kink sliding.


Biochemical properties, enterohaemolysin production and plasmid carriage of Shiga toxin-producing Escherichia coli strains.
Thirty-eight strains of Shiga toxin-producing Escherichia coli (STEC) were characterised in terms of biochemical properties, enterohaemolysin production and plasmid carriage. A wide variation in the biochemical properties was observed among the STEC, with 14 distinct biotypes identified. Biotype 1 was the most common, found in 29% of the strains. Enterohaemolysin production was detected in 29% of the strains. Most of the bacterial strains (95%) carried one or more plasmids and considerable heterogeneity in size and combinations was observed. Seven distinct plasmid profiles were identified. The most common profile, characterised by the presence of a single plasmid of ~90 kb, was found in 50% of these strains. These data indicate extensive diversity among STEC strains. No correlation was found among biotype, serotype, enterohaemolysin production and plasmid profile.


Intravenous Lipid Emulsions to Deliver Bioactive Omega-3 Fatty Acids for Improved Patient Outcomes.
Lipids used in intravenous nutrition support (i.e., parenteral nutrition) provide energy, building blocks, and essential fatty acids. These lipids are included as emulsions since they need to be soluble in an aqueous environment. Fish oil is a source of bioactive omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid). Lipid emulsions, including fish oil, have been used for parenteral nutrition for adult patients post-surgery (mainly gastrointestinal). This has been associated with alterations in biomarkers of inflammation and immune defense, and in some studies, a reduction in length of intensive care unit and hospital stay. These benefits, along with a reduction in infections, are emphasized through recent meta-analyses. Perioperative administration of fish oil may be superior to postoperative administration, but this requires further exploration. Parenteral fish oil has been used in critically ill adult patients. Here, the influence on inflammatory processes, immune function, and clinical endpoints is less clear. However, some studies found reduced inflammation, improved gas exchange, and shorter length of hospital stay in critically ill patients if they received fish oil. Meta-analyses do not present a consistent picture but are limited by the small number and size of studies. More and better trials are needed in patient groups in which parenteral nutrition is used and where fish oil, as a source of bioactive omega-3 fatty acids, may offer benefits.


[STERNAL CLEFT – REPORT OF THREE CASES].
During the last 25 years we surgically treated three patients with sternal cleft anomaly, aged from 6 weeks to 2 years. The aim of this case series is to present this extremely rare congenital anomaly and differences in the operative treatment of sternal cleft (SC) depending on patients age due to flexibility of the chest wall. Patients presented to us with signs of sternal cleft; displaced sternoclavicular articulations and paradoxical motion of the skin over the defect. Preoperatively we performed X-ray and computed tomography of the chest which revealed displaced sternoclavicular articulations with superior incomplete sternal cleft and echocardiography which showed orthotopic heart without malformations of the great vessels. Surgical treatment included primary closure in two infants and Sabiston's technique in a two-year-old girl. All three patients were successfully operated without complications.


Predictors of Functional Outcomes and Recovery Time Following Tympanoplasty.
Objectives: To identify the predictors of tympanoplasty success including graft success, hearing outcomes, and recovery time. Methods: Patients who underwent a tympanoplasty between January 2019 and July 2022 were enrolled. Hearing outcomes were measured by air-bone gap from pure tone. Demographic data of the patient, surgical parameters, and Ossiculoplasty Outcome Parameter Staging (OOPS) were reviewed and evaluated to predict the success of tympanoplasty using univariate and multivariate logistic or Cox regression analyzes. Results: Of 138 patients, 151 procedures were studied. At the 6-month follow-up visit, the overall graft success was 90.7% and the overall hearing success was 40.4%. There was a correlation between the OOPS index and postoperative hearing success (Spearman r = 0.322). Blood loss > 10 ml and OOPS ≥ 4 were independent predictors of hearing failure. Blocked aditus ad antrum and blood loss > 10 ml were independent predictors of prolonged recovery time. Conclusions: The OOPS index exhibits a strong predictive influence on hearing outcomes after tympanoplasty. A predictive model that combines the amount of blood loss and blockage of aditus ad antrum can serve as a useful tool in predicting postoperative recovery time.


Epidemiological studies of UK test veterans: I. General description.
This review gives a general account of how and why epidemiological studies of UK participants in the nuclear weapons test programme were set up. There is a short description of the circumstances in which the tests were planned and executed and a discussion of the general considerations involved in designing studies to show whether the health of test participants suffered as a result of the tests. The companion review article summarises the results of the epidemiological studies.


Considerations for de-escalating universal masking in healthcare centers.
Three years after the beginning of the COVID-19 pandemic, better knowledge on the transmission of respiratory viral infections (RVI) including the contribution of asymptomatic infections encouraged most healthcare centers to implement universal masking. The evolution of the SARS-CoV-2 epidemiology and improved immunization of the population call for the infection and prevention control community to revisit the masking strategy in healthcare. In this narrative review, we consider factors for de-escalating universal masking in healthcare centers, addressing compliance with the mask policy, local epidemiology, the level of protection provided by medical face masks, the consequences of absenteeism and presenteeism, as well as logistics, costs, and ecological impact. Most current national and international guidelines for mask use are based on the level of community transmission of SARS-CoV-2. Actions are now required to refine future recommendations, such as establishing a list of the most relevant RVI to consider, implement reliable local RVI surveillance, and define thresholds for activating masking strategies. Considering the epidemiological context (measured via sentinel networks or wastewater analysis), and, if not available, considering a time period (winter season) may guide to three gradual levels of masking: (i) standard and transmission-based precautions and respiratory etiquette, (ii) systematic face mask wearing when in direct contact with patients, and (iii) universal masking. Cost-effectiveness analysis of the different strategies is warranted in the coming years. Masking is just one element to be considered along with other preventive measures such as staff and patient immunization, and efficient ventilation.


Effect of Mass Drug Administration with a Single Dose of Albendazole on Ascaris lumbricoides and Trichuris trichiura Infection among Schoolchildren in Yangon Region, Myanmar.
Soil-transmitted helminths, including Ascaris lumbricoides and Trichuris trichiura, are important intestinal parasites mostly affecting younger people in developing countries. In 2014-2015, we performed mass fecal examinations targeting a total of 2,227 schoolchildren in 3 districts (South Dagon, North Dagon, and Hlaing-thar-yar) of Yangon Region, Myanmar, using the Kato-Katz thick smear technique. The egg positive children were subjected to a mass drug administration (MDA) using a single oral dose of 400 mg albendazole. The pre-treatment egg positive rate (EPG/person) of A. lumbricoides averaged 17.2% (15,532); it was 25.2% (21,796), 14.2% (11,816), and 12.8% (12,983) in 3 districts, respectively, and that of T. trichiura averaged 19.4% (1,074), and was 24.1% (1,040), 12.3% (852), and 21.2% (1,330) in 3 districts, respectively. Follow-up fecal examinations performed 4 months post-MDA revealed considerable decreases of A. lumbricoides prevalence (EPG/person) to av. 8.3% (12,429), and 13.7% (17,640), 8.0% (7,797), and 4.5% (11,849) in 3 districts, respectively. However, T. trichiura did not show any recognizable decrease in the prevalence (EPG/person) remaining at av. 18.2% (862), and 18.5% (888), 11.5% (812), and 23.3% (887) in 3 districts, respectively. The results demonstrated difficulty in short-term control of T. trichiura by MDA using albendazole and suggested necessity of either a long-term MDA (>10 years) or changing the albendazole regimen into 2~3-day course (total 800 or 1,200 mg), or using an alternative drug/drug combination.


Tissue prints for the rapid diagnosis of malignancy in lung cancer.
Rapid diagnosis of malignancy during oncological surgery is crucial for making decisions related to the extension of the resection. The tissue prints, used initially for plant biology but also for prostate or breast cancer diagnosis, might be useful as a rapid cytological diagnosis. Tissue prints were done from freshly sectioned excised tissue fragments in patients operated between March 2010 and February 2012 in the Department of Surgery for cancer or benign lesions. Tissue prints were examined by a cytologist and considered as malignant or benign. Same fragments were then processed in the pathology laboratory using the typical paraffin-embedding method. All slides were examined by the same pathologist and considered the golden standard for malignancy and histological type. Three hundred and eleven fragments were examined, obtained from lung masses, lymph nodes, pleura and mediastinal masses, pathology showed 208 malignant and 103 benign. Tissue prints identified 227 malignant and 84 benign. For identifying malignancy, tissue prints had a sensibility of 0.91, specificity 0.64. Positive predictive value was 0.86 and negative predictive value 0.78. For lymph nodes, the specificity was better. In lymphomas and adenocarcinomas, tissue prints identified also the histology type in most cases. Tissue prints are rapid, easy to perform, cheap, with high sensibility but specificity lower than literature data on frozen sections. This might be improved by a better selection of cases where tissue prints are used for rapid diagnosis.


Genetic studies of sulfadiazine-resistant and methionine-requiring Neisseria isolated from clinical material.
Deoxyribonucleate (DNA) preparations were extracted from Neisseria meningitidis (four isolates from spinal fluid and blood) and N. gonorrhoeae strains, all of which were resistant to sulfadiazine upon primary isolation. These DNA preparations, together with others from in vitro mutants of N. meningitidis and N. perflava, were examined in transformation tests by using as recipient a drug-susceptible strain of N. meningitidis (Ne 15 Sul-s Met(+)) which was able to grow in a methionine-free defined medium. The sulfadiazine resistance typical of each donor was introduced into the uniform constitution of this recipient. Production of p-aminobenzoic acid was not significantly altered thereby. Transformants elicited by DNA from the N. meningitidis clinical isolates were resistant to at least 200 mug of sulfadiazine/ml, and did not show a requirement for methionine (Sul-r Met(+)). DNA from six strains of N. gonorrhoeae, which were isolated during the period of therapeutic use of sulfonamides, conveyed lower degrees of resistance and, invariably, a concurrent methionine requirement (Sul-r/Met(-)). The requirement of these transformants, and that of in vitro mutants selected on sulfadiazine-agar, was satisfied by methionine, but not by vitamin B(12), homocysteine, cystathionine, homoserine, or cysteine. Sul-r Met(+) and Sul-r/Met(-) loci could coexist in the same genome, but were segregated during transformation. On the other hand, the dual Sul-r/Met(-) properties were not separated by recombination, but were eliminated together. DNA from various Sul-r/Met(-) clones tested against recipients having nonidentical Sul-r/Met(-) mutant sites yielded Sul-s Met(+) transformants. The met locus involved is genetically complex, and will be a valuable tool for studies of genetic fine structure of members of Neisseria, and of genetic homology between species.


Breast Cancer-Related Lymphedema Risk-Management Behaviors Among Chinese Breast Cancer Survivors and Relationships with Socio-Demographic and Clinical Characteristics: A Longitudinal Study.
We sought to determine changes in breast cancer-related lymphedema (BCRL) risk-management behaviors in the six-month period after surgery among Chinese breast cancer survivors and to explore the relationship between their socio-demographic and clinical characteristics and these behaviors. A longitudinal study design was adopted. Females aged ≥18 years with a first breast cancer diagnosis and who had undergone modified radical mastectomy were recruited from a cancer hospital in China. Respondents with a history of other malignant tumors, mental illness, or cognitive impairment were excluded from the study. Socio-demographic and clinical factors were assessed at baseline. BCRL risk-management behaviors were assessed with the Lymphedema Risk-Management Behavior Questionnaire (LRMBQ) and Functional Exercise Adherence Scale (FEAS) in the first, third, and sixth months after surgery. Repeated-measures analysis of variance was used to examine changes in BCRL risk-management behaviors over the three study time periods, and a generalized linear mixed model was used to determine socio-demographic and clinical factors associated with BCRL risk-management behaviors. A total of 166 participants completed all three assessments. The scores of the total LRMBQ and its "Skin care" and "Lifestyle" subscales did not change significantly, but those of the "Avoidance of limb compression and injury" and "Other matters requiring attention" subscales changed over the three study time periods. Additionally, scores of the total FEAS and most of its subscales changed over the three study time periods. Furthermore, BCRL risk-management behaviors were significantly related to patients' geographic residence, education level, and tumor stage. Some dimensions of BCRL risk-management behaviors changed over time, and several socio-demographic and clinical factors are related to BCRL risk-management behaviors. It is recommended that health care professionals consider the dynamic nature of BCRL risk-management behaviors and related factors when planning health education and promotion interventions.


The effects of several oligosaccharides on true amino acid digestibility and true metabolizable energy in cecectomized and conventional roosters.
Prebiotics, such as indigestible oligosaccharides, are considered to be possible dietary alternatives to antibiotic growth promoters in poultry. The effects of indigestible oligosaccharides on nutrient digestibility in poultry are largely unknown. Therefore, an experiment was conducted to evaluate the effects of several oligosaccharides on amino acid digestibility and TMEn in roosters. The dietary treatments consisted of a corn-isolated soy protein control diet or that diet supplemented with 4 or 8 g/kg of inulin, oligofructose, mannanoligosaccharide (MOS), short-chain fructooligosaccharide, or transgalactooligosaccharide (TOS). Each of the 11 diets was tube-fed (30 g) to 4 cecectomized and 4 intact Single Comb White Leghorn roosters that had been fasted for 24 h. Excreta were then collected for the following 48 h, freeze-dried, and analyzed for amino acid content. The true digestibility of lysine and valine was increased (P<0.05) in cecectomized roosters fed 8 g/kg of MOS or TOS when compared with roosters fed the control diet. In addition, methionine digestibility was improved (P<0.05) in cecectomized roosters fed 4 g/kg of MOS or short-chain fructooligosaccharide and by 8 g/kg of oligofructose or TOS. The true digestibility of isoleucine was increased (P<0.05) in cecectomized roosters fed 8 g/kg of MOS or 4 or 8 g/kg of TOS. The magnitude of the increases in amino acid digestibility coefficients for cecectomized roosters ranged from 3 to 9 percentage units. Feeding either 4 or 8 g/kg of inulin to intact roosters decreased (P<0.05) the true digestibility of methionine. The oligosaccharides generally had no significant effect on TMEn. The results of this study indicated that the indigestible oligosaccharides had no significant effect on the digestibility of most amino acids in a corn-isolated soy protein diet. The digestibility of a few amino acids, however, was increased by some oligosaccharides in cecectomized roosters but not in intact roosters.


A thermal threshold assay to measure the nociceptive response to morphine sulphate in cattle.
A thermal threshold measurer (TTM) apparatus was developed and tested in 12 dry, nonpregnant, culled cows with the purpose of measuring the thermal nociceptive threshold and of finding the response to morphine sulphate dosages. The cows received a cumulative dose (from 0.00 to 0.40 mg/kg BW) of morphine sulphate through a catheter in the jugular vein. The interval between doses was 20 min, and a nociceptive test was performed 15 min after each injection. The TTM device consisted of a 60 W halogen bulb mounted in a 15 cm PVC tube, with a 0.6 s response time probe attached to its end, connected to a thermocouple. The probe measured the response temperature on the skin over the middle phalanges on the dorsum of the forefoot. The radiating heat stimulus from the bulb was instantaneously terminated with the foot-lift response of the tested animal. The nociceptive response to the 0.00 mg/kg dose was considered the baseline and subsequent measurements were expressed in difference from it. Data were evaluated in a regression analysis using the GLM procedure. A significant elevation (P < 0.0001) in the nociceptive threshold of the cows with cumulative dosing of morphine sulphate was noticed. A high variability (P < 0.0001) in the response among animals was also detected, suggesting that a 2-step dose of morphine sulphate is necessary to achieve a certain degree of induced analgesia in all cows. The nociceptive assay described, using the TTM device, was able to detect an elevation of the thermal threshold of cows due to morphine sulphate induced analgesia. An increase in locomotory behaviour or other side effects due to morphine sulphate were not noticed.


Long-term antihypertensive therapy with beta-blockers: submaximal exercise capacity and metabolic effects during exercise.
The effects of long-term (6 months) antihypertensive treatment with three different types of beta-blockers (propranolol, nonselective without ISA; pindolol, nonselective with ISA; metoprolol, beta 1-selective without ISA) on submaximal exercise capacity and metabolic variables during submaximal endurance exercise were studied in seven subjects with essential hypertension. Exercise tests were performed on a bicycle ergometer at 70% of estimated VO2 max. Similar reductions of resting and exercise blood pressure and exercise heart rate were obtained with the three beta-blockers. Exercise time was significantly reduced by all three beta-blockers during chronic antihypertensive therapy. The reduction tended to be more pronounced after 5-6 months of treatment than after 1 week (P = 0.06). During exercise, the plasma glycerol and nonesterified fatty acid concentrations were reduced. Plasma glucose concentration was reduced at the end of the exercise test during propranolol treatment only. Plasma lactate concentrations tended to be increased, but the difference was significant during pindolol treatment only. Oxygen uptake tended to decrease and respiratory exchange ratio to increase. Plasma potassium concentrations during exercise were significantly increased with all three beta-blockers. The effects on the metabolic variables during exercise were similar after 1 week and during long-term (20/24 weeks) beta-blocker treatment. The study shows that submaximal endurance exercise capacity is impaired in patients with essential hypertension on beta-blocker therapy and that the impairment is maintained during long-term antihypertensive beta-blocker treatment.


Phytotherapeutic effects of the fruits of Poncirus trifoliata (L.) Raf. on cancer, inflammation, and digestive dysfunction.
Poncirus trifoliata (L.) Raf. belongs to the family Rutaceae in the genus Poncirus. Its fruits are widely used to alleviate symptoms of various disorders. The mature fruit (MF) possesses anticancer and antiinflammatory activities. Extracts of the dried, immature fruit, Poncirus fructus (PF) are widely used as a traditional medicine for ameliorating symptoms of digestive dysfunction in East Asia. Molecular and cellular mechanisms underlying the effects of MF and PF extracts on cancer, inflammation, and gastrointestinal disorders have been extensively studied in the past decade. This review summarizes recent findings on the anticancer and antiinflammatory effects of MF and the prokinetic effects of PF. Although the therapeutic effects of MF and PF have been clearly elucidated, in-depth further clinical studies are still required to completely verify the clinical efficacy and safety of the fruits of P. trifoliata (L.) Raf.


Simple Quantitative Sensory Testing Reveals Paradoxical Co-existence of Hypoesthesia and Hyperalgesia in Diabetes.
Background: Diabetic neuropathy is characterized by the paradoxical co-existence of hypo- and hyperalgesia to sensory stimuli. The literature shows consistently sensory differences between healthy and participants with diabetes. We hypothesized that due to differences in pathophysiology, advanced quantitative sensory testing (QST) might reveal sensory discrepancies between type 1 (T1D) and type 2 diabetes (T2D). Furthermore, we investigated whether vibration detection thresholds (VDT) were associated with sensory response. Method: Fifty-six adults with T1D [43 years (28-58)], 99 adults with T2D [65 years (57-71)], and 122 healthy individuals [51 years (34-64)] were included. VDT, pressure pain detection thresholds (pPDT) and tolerance (pPTT), tonic cold pain (hand-immersion in iced water), and central pain mechanisms (temporal summation and conditioned pain modulation) were tested and compared between T1D and T2D. VDT was categorized into normal (< 18 V), intermediary (18-25 V), or high (> 25 V). Results: In comparison to healthy, analysis adjusted for age, BMI, and gender revealed hypoalgesia to tibial (pPDT): p = 0.01, hyperalgesia to tonic cold pain: p < 0.01, and diminished temporal summation (arm: p < 0.01; abdomen: p < 0.01). In comparison to participants with T2D, participants with T1D were hypoalgesic to tibial pPDT: p < 0.01 and pPTT: p < 0.01, and lower VDT: p = 0.02. VDT was not associated with QST responses. Conclusion: Participants with T1D were more hypoalgesic to bone pPDT and pPTT independent of lower VDT, indicating neuronal health toward normalization. Improved understanding of differentiated sensory profiles in T1D and T2D may identify improved clinical endpoints in future trials.


In vitro and in vivo replication for scanning electron microscopy of the cervical region of human teeth.
A replica technique for scanning electron microscopy (SEM) of the cervical region of human teeth was evaluated on extracted premolar teeth by comparing the replicas and the original specimens in the SEM. For in vivo application, the technique was modified to circumvent contamination by saliva and gingival exudate. Impressions were taken with an addition silicone polyvinylsiloxane material and the replicas were poured in epoxy resin die material. A surface active dentine conditioner facilitated flow of the impression material into irregular surface areas; in vivo a scavenger impression was used to remove surface debris. Custom trays were made of light-cured acrylic resin for the in vivo impressions. The method faithfully reproduced surface detail in the amelocemental region. In vivo the scavenger impression followed by application of the surface-active conditioner effectively cleaned the tooth surface. The custom tray allowed selection and inclusion of landmarks and ensured reproducibility. The method meets the requirements of a simple, reproducible, non-invasive means of documenting the micromorphology of the cervical region of the teeth.


Adipose-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage: A Systematic Review on Preclinical and Clinical Evidence.
Among the current therapeutic approaches for the regeneration of damaged articular cartilage, none has yet proven to offer results comparable to those of native hyaline cartilage. Recently, it has been claimed that the use of mesenchymal stem cells (MSCs) provides greater regenerative potential than differentiated cells, such as chondrocytes. Among the different kinds of MSCs available, adipose-derived mesenchymal stem cells (ADSCs) are emerging due to their abundancy and easiness to harvest. However, their mechanism of action and potential for cartilage regeneration are still under investigation, and many other aspects still need to be clarified. The aim of this systematic review is to give an overview of in vivo studies dealing with ADSCs, by summarizing the main evidence for the treatment of cartilage disease of the knee.


Characterization of the blood brain barrier in pediatric central nervous system neoplasms.
The normal blood-brain barrier (BBB) is composed of tight junctions between endothelial cells and surrounding astrocyte foot processes. Breakdown of the physiological astrocyte-endothelial cell relationship occurs in adult metastatic and primary brain tumors. However, the astrocyte-endothelial cell relationship has not been studied in pediatric tumors. Utilizing specimens from cases of pilocytic astrocytoma (n = 5), medulloblastoma (n = 5), and low-grade diffuse astrocytoma (n = 1), immunofluorescence were performed using primary antibodies against CD31, glial fibrillary acidic protein (GFAP), and aquaporin 4 (AQ4). Clinical, magnetic resonance imaging, operative, and histopathological findings were analyzed. Strongly-enhancing areas of medulloblastoma exhibited complete BBB breakdown with sparse GFAP and AQ4 staining around CD31-positive vessels. Moderately enhancing regions of pilocytic astrocytomas exhibited regions of intact BBB and vasculature surrounded by dense GFAP staining but reduced and disorganized AQ4 staining, suggesting tumor cells could not fulfill physiological BBB support. Non-enhancing low-grade diffuse astrocytoma demonstrated intact BBB with intense peri-microvasculature GFAP and AQ4 staining. AQ4 stained so strongly that AQ4 visualization alone delineated CD31-positive vessels. Taken together, BBB breakdown in pediatric tumors corresponds to a loss of normal endothelial cell-astrocyte foot process relationships. Further development of pharmaceutical agents capitalizing on this disrupted BBB is warranted in medulloblastoma and pilocytic astrocytoma. However, BBB integrity remains a challenge in treating low-grade diffuse astrocytoma before progression toward secondary glioblastoma.


In-plane illuminated metallic annular aperture array for sensing application.
We propose here an application to sensing of annular aperture arrays (AAA). We theoretically investigate the optical properties of the reflective AAA device when illuminated in-plane. The cavity presents almost perfect absorption due to the waveguide mode resonance with strong field localization in the aperture. Additionally, the reflective cavity is modeled to be available for on-chip sensing with a theoretically expected sensitivity of 764 nm/RIU(refractive index unit).


The early 1990s cigarette price decrease and trends in youth smoking in Ontario.
Youth are especially vulnerable to fluctuations in cigarette price, and both the smuggling increase during the early 1990s and the 1994 tax decrease made purchasing easier for youth. The purpose of this study is to examine the relation between these price decreases, and trends in smoking prevalence and amount smoked among Ontario youth. Data from the Ontario Student Drug Use Survey were analyzed for trend using: 1) polynomial regression, and 2) discontinuity regression with an "event time" of 1993 to capture effects of both pre-tax cut smuggling and the tax cut. Overall, smoking prevalence decreased from 1977 to 1993, jumped upward at this time, and decreased after 1993. Among daily smokers, mean number of cigarettes smoked daily showed an increase followed by a decrease over the 24 years, and a negative quadratic trend. Trends for subgroups are also reported. These findings suggest that the early 1990s cigarette price decrease may have played a role in increasing youth smoking in Ontario.


Nanoscale inhomogeneity and the evolution of correlation strength in FeSe[Formula: see text]S[Formula: see text].
We report a comprehensive study of the nanoscale inhomogeneity and disorder on the thermoelectric properties of FeSe[Formula: see text]S[Formula: see text] ([Formula: see text]) single crystals and the evolution of correlation strength with S substitution. A hump-like feature in temperature-dependent thermpower is enhanced for x = 0.12 and 0.14 in the nematic region with increasing in orbital-selective electronic correlations, which is strongly suppressed across the nematic critical point and for higher S content. Nanoscale Se/S atom disorder in the tetrahedral surroundings of Fe atoms is confirmed by scanning transmission electron microscopy measurements, providing an insight into the nanostructural details and the evolution of correlation strength in FeSe[Formula: see text]S[Formula: see text].


Transdermal selegiline: the new generation of monoamine oxidase inhibitors.
The clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to concerns about food and drug interactions and waning physician experience. Evidence indicates that MAOIs are effective in depressive disorders, in particular depression with atypical features. Efforts to address safety issues have led to the development of more selective and reversible MAOIs, such as moclobemide. Selegiline, a selective monoamine oxidase B inhibitor, has been approved for the adjunctive treatment of Parkinson's disease at low doses. At higher doses, oral selegiline is also effective in major depressive disorder (MDD) but loses its selectivity and has the potential for tyramine interactions. To overcome these problems, a transdermal formulation of selegiline, the selegiline transdermal system (STS), was developed with novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production. In addition, STS allows targeted inhibition of central nervous system monoamine A (MAO-A) and monoamine B isoenzymes with minimal effects on MAO-A in the gastrointestinal and hepatic systems, thereby reducing the risk of interactions with tyramine-rich foods (the "cheese-reaction"). Clinical trials have found 6 mg/24 hours of STS to be effective in MDD without the need for dietary restrictions. The efficacy and safety profile of STS supports its use in MDD. It is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants. However, more research is needed. Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs.


Relationship between the change in tumour-infiltrating lymphocyte level and residual tumour after neoadjuvant chemotherapy in patients with locally advanced breast cancer.
To evaluate the tumour-infiltrating lymphocyte (TIL) rates in breast tissue before and after neoadjuvant chemotherapy (NAC) and their impact on survival, eighty-four patients with locally advanced breast cancer (LABC) were assessed. Pre- and post-NAC TIL levels were determined using biopsy and surgical specimens, respectively. The median TIL rate was significantly different before (17.5%) and after (5%) NAC. Pre- and postoperative Ki-67 index, molecular subtype, pre- and post-NAC TIL concentration, and preoperative residual-cancer-burden TIL were significantly associated with pathological complete response (pCR). Specifically, higher pre-NAC TIL levels were associated with higher pCR rates. Postoperative Ki-67 index and pCR, and postoperative Ki-67 index were significant predictors of disease-free (DFS) and overall survival, respectively. The independent prognostic factors for DFS were postoperative Ki-67 score (hazard ratio [HR]: 6.16; p = 0.012), post-NAC TIL score (HR: 0.42; P = 0.041), and pCR (HR: 0.10; P = 0.038). Our study confirms that higher pre-NAC and lower postoperative TIL levels may be surrogate factors for longer DFS, and postoperative TIL rate may predict post-NAC pCR in patients with LABC.


Strengthening health systems in low-income countries by enhancing organizational capacities and improving institutions.
This paper argues that the global health agenda tends to privilege short-term global interests at the expense of long-term capacity building within national and community health systems. The Health Systems Strengthening (HSS) movement needs to focus on developing the capacity of local organizations and the institutions that influence how such organizations interact with local and international stakeholders. While institutions can enable organizations, they too often apply requirements to follow paths that can stifle learning and development. Global health actors have recognized the importance of supporting local organizations in HSS activities. However, this recognition has yet to translate adequately into actual policies to influence funding and practice. While there is not a single approach to HSS that can be uniformly applied to all contexts, several messages emerge from the experience of successful health systems presented in this paper using case studies through a complex adaptive systems lens. Two key messages deserve special attention: the need for donors and recipient organizations to work as equal partners, and the need for strong and diffuse leadership in low-income countries. An increasingly dynamic and interdependent post-Millennium Development Goals (post-MDG) world requires new ways of working to improve global health, underpinned by a complex adaptive systems lens and approaches that build local organizational capacity.


Adiponectin is required for PPARγ-mediated improvement of endothelial function in diabetic mice.
Rosiglitazone is a PPARγ agonist commonly used to treat diabetes. In addition to improving insulin sensitivity, rosiglitazone restores normal vascular function by a mechanism that remains poorly understood. Here we show that adiponectin is required to mediate the PPARγ effect on vascular endothelium of diabetic mice. In db/db and diet-induced obese mice, PPARγ activation by rosiglitazone restores endothelium-dependent relaxation of aortae, whereas diabetic mice lacking adiponectin or treated with an anti-adiponectin antibody do not respond. Rosiglitazone stimulates adiponectin release from fat explants, and subcutaneous fat transplantation from rosiglitazone-treated mice recapitulates vasodilatation in untreated db/db recipients. Mechanistically, adiponectin activates AMPK/eNOS and cAMP/PKA signaling pathways in aortae, which increase NO bioavailability and reduce oxidative stress. Taken together, these results demonstrate that adipocyte-derived adiponectin is required for PPARγ-mediated improvement of endothelial function in diabetes. Thus, the adipose tissue represents a promising target for treating diabetic vasculopathy.