A mini dental implant-supported obturator application in a patient with partial maxillectomy due to tumor: case report.
Following a partial maxillectomy in a patient, the oral and nasal cavities remain open, providing a passageway for transmission of air and fluids between the 2 cavities. In such cases the primary aim should be the construction of an implant-supported obturator prosthesis with adequate retention, stability, and peripheral seal. In this case report, a 34-year-old female patient who underwent a class II (according to Okay et al.) partial maxillectomy 14 years before was fitted with an obturator that was supported by 5 mini dental implants. The reason for the preference of mini dental implants is the lack of adequate bone tissue for conventional implant placement in the resected area and the placement of mini dental implants with a simple surgical procedure. The treatment achieved restoration of the lost functions, which satisfied the patient, restoring her self-confidence and enhancing her quality of life. Thus, applying obturators supported by mini dental implants was successful and may be considered as an alternative to more complicated surgical techniques. Although the presented case is promising, further clinical research is needed to draw more definite conclusions.


Acute myocardial infarction with angiographically normal coronary arteries.
The authors present the case of a 51-year-old woman, with no known cardiovascular risk factors, admitted with anterior acute myocardial infarction complicated by primary ventricular fibrillation, who underwent reperfusion therapy with tenecteplase. Left heart catheterization on the sixth day showed left ventricular anteroapical akinesia and normal coronary arteries. The causes of acute myocardial infarction with normal coronary arteries and its differential diagnosis are discussed.


Whitham modulation theory for the Ostrovsky equation.
This paper derives the Whitham modulation equations for the Ostrovsky equation. The equations are then used to analyse localized cnoidal wavepacket solutions of the Ostrovsky equation in the weak rotation limit. The analysis is split into two main parameter regimes: the Ostrovsky equation with normal dispersion relevant to typical oceanic parameters and the Ostrovsky equation with anomalous dispersion relevant to strongly sheared oceanic flows and other physical systems. For anomalous dispersion a new steady, symmetric cnoidal wavepacket solution is presented. The new wavepacket can be represented as a solution of the modulation equations and an analytical solution for the outer solution of the wavepacket is given. For normal dispersion the modulation equations are used to describe the unsteady finite-amplitude wavepacket solutions produced from the rotation-induced decay of a Korteweg-de Vries solitary wave. Again, an analytical solution for the outer solution can be given. The centre of the wavepacket closely approximates a train of solitary waves with the results suggesting that the unsteady wavepacket is a localized, modulated cnoidal wavetrain. The formation of wavepackets from solitary wave initial conditions is considered, contrasting the rapid formation of the packets in anomalous dispersion with the slower formation of unsteady packets under normal dispersion.


Cardiac disease in a case of precursor B acute lymphoblastic leukaemia with eosinophilia(ALL/Eo).
Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. However, it may rarely associate with eosinophilia. Patients with ALL associated with eosinophilia (ALL/ Eo) have a grave prognosis and higher incidence of cardiac complications compared to standard lymphoblastic leukaemia. Reports of ALL/Eo disclosed a few case with cardiac involvement early in the course of leukaemia. Here, the authors report a case of 13-year-old boy who presented with peripheral eosinophilia, chest pain and a large left ventricular mass early in the course of precursor B- cell ALL associated with eosinophilia. He received multi-agent chemotherapy but succumbed to death 25 days after chemotherapy due to a refractory cardio respiratory failure.


Exercise can be pyrogenic in humans.
Exercise increases mean body temperature (T(body)) and cytokine concentrations in plasma. Cytokines facilitate PG production via cyclooxygenase (COX) enzymes, and PGE(2) can mediate fever. Therefore, we used a COX-2 inhibitor to test the hypothesis that PG-mediated pyrogenicity may contribute to the raised T(body) in exercising humans. In a double-blind, cross-over design, 10 males [age: 23 yr (SD 5), Vo(2 max): 53 ml x kg(-1) x min(-1) (SD 5)] consumed rofecoxib (50 mg/day; NSAID) or placebo (PLAC) for 6 days, 2 wk apart. Exercising thermoregulation was measured on day 6 during 45-min running ( approximately 75% Vo(2 max)) followed by 45-min cycling and 60-min seated recovery (28 degrees C, 50% relative humidity). Plasma cytokine (TNF-alpha, IL-10) concentrations were measured at rest and 30-min recovery. T(body) was similar at rest in PLAC (35.59 degrees C) and NSAID (35.53 degrees C) and increased similarly during running, but became 0.33 degrees C (SD 0.26) lower in NSAID during cycling (37.39 degrees C vs. 37.07 degrees C; P = 0.03), and remained lower throughout recovery. Sweating was initiated at T(body) of approximately 35.6 degrees C in both conditions but ceased at higher T(body) in PLAC than NSAID during recovery [36.66 degrees C (SD 0.36) vs. 36.39 degrees C (SD 0.27); P = 0.03]. Cardiac frequency averaged 6 x min(-1) higher in PLAC (P < 0.01), whereas exercising metabolic rate was similar (505 vs. 507 W x m(-2); P = 0.56). A modest increase in both cytokines across exercise was similar between conditions. COX-2 specific NSAID lowered exercising heat and cardiovascular strain and the sweating (offset) threshold, independently of heat production, indicating that PGE-mediated inflammatory processes may contribute to exercising heat strain during endurance exercise in humans.


Clinical evaluation of carbon fiber reinforced carbon endodontic post, glass fiber reinforced post with cast post and core: A one year comparative clinical study.
Restoring endodontically treated teeth is one of the major treatments provided by the dental practitioner. Selection and proper use of restorative materials continues to be a source of frustration for many clinicians. There is controversy surrounding the most suitable choice of restorative material and the placement method that will result in the highest probability of successful treatment. This clinical study compares two different varieties of fiber posts and one cast post and core in terms of mobility of crown margin under finger pressure, recurrent caries detected at the crown margin, fracture of the restoration, fracture of the root and periapical and periodontal pathology requiring crown removal over the period of 12months as evaluated by clinical and radiographical examination. 30 root canal treated, single rooted maxillary anterior teeth of 25 patients in the age range of 18-60 years where a post retained crown was indicated were selected for the study between January 2007 and August 2007; and prepared in a standard clinical manner. It was divided into 3 groups of 10 teeth in each group. After post space preparation, the Carbon fiber and Glass fiber reinforced posts were cemented with Scotch bond multipurpose plus bonding agent and RelyX adhesive resin cement in the first and second groups respectively. The Cast post and cores were cemented with Zinc Phosphate cement in the third group. Following post- cementation, the preparation was further refined and a rubber base impression was taken for metal-ceramic crowns which was cemented with Zinc Phosphate cement. A baseline periapical radiograph was taken once each crown was cemented. All patients were evaluated after one week (baseline), 3 months, 6 months and one year for following characteristics mobility of crown margin under finger pressure, recurrent caries detected at the crown margin, fracture of the restoration, fracture of the root and periapical and periodontal pathology. Results after 12 months showed that none of the restorations among groups of cast post and core, carbon fiber reinforced post and glass fiber reinforced post with composite core restorations failed in terms of recurrent caries detected at the crown margin, fracture of the restoration, fracture of the root and periapical and periodontal pathology. One case of cast post and core and one case of carbon fiber reinforced post with composite core restorations showed slight mobility of crown margin under finger pressure at 12(th) month recall but all the cases of glass fiber post with composite core restorations did not show any signs of mobility of crown margin under finger pressure at all the recall periods on clinical and radiographical examination. From this 12 months clinical evaluation of all the cases in the 3 groups comprising of cast post and core; carbon fiber reinforced post with composite core and glass fiber reinforced post with composite core restored with porcelain fused to metal crowns, it is concluded that glass fiber reinforced post with composite core when used in single rooted upper anterior teeth are associated with a higher success rate in restoration of endodontically treated teeth.


Main Surgical Principles and Methods in Surgical Treatment of Primary Hyperparathyroidism.
The only curative treatment for primary hyperparathyroidism (pHPT) is surgery. The most important factors that increase the success rate of a parathyroidectomy are the establishment of the correct diagnosis and the surgeon's good knowledge of anatomy and embryology. The lower parathyroid glands develop from the dorsal portion of the third pharyngeal pouch, and the upper parathyroid glands from the fourth pharyngeal pouch. Humans typically have 4 parathyroid glands; however, more than 4 and fewer than 4 have been observed. Typically, the upper parathyroid glands are located in the cricothyroid junction area on the posterolateral portion of the middle and upper third of the thyroid, while the lower parathyroids are located in an area 1 cm in diameter located posterior, lateral, or anterolateral to the lower thyroid pole. Ectopic locations of parathyroid glands outside the normal anatomical regions due to the abnormal migration during embryological development or acquired ectopy due to migration of enlarged parathyroids are not uncommon. There are various surgical techniques to treat HPT; however, 2 main surgical options are used: bilateral neck exploration (BNE) and minimally invasive parathyroidectomy (MIP). While there are open, endoscopic, and video-assisted MIP (MIVAP) approaches, most often an open lateral MIP technique is used. In addition, endoscopic or robotic parathyroidectomy methods performed from remote regions outside the neck have been reported. Although currently MIP is the standard treatment option in selected patients with positive imaging, BNE remains the gold standard procedure in parathyroid surgery. In 80% to 90% of patients with pHPT, a pathological parathyroid gland can be detected with preoperative imaging methods and MIP can be applied. However, the pathological gland may not be found during a MIP procedure as a result of false positive results. The parathyroid surgeon must also know the BNE technique and be able to switch to BNE and change the surgical strategy if necessary. If the intended gland is not found in its normal anatomical site, possible embryological and acquired ectopic locations should be investigated. It should be kept in mind that MIP and BNE are not alternatives to each other, but rather complementary techniques for successful treatment in parathyroid surgery.


Myeloid and T Cell-Derived TNF Protects against Central Nervous System Tuberculosis.
Tuberculosis of the central nervous system (CNS-TB) is a devastating complication of tuberculosis, and tumor necrosis factor (TNF) is crucial for innate immunity and controlling the infection. TNF is produced by many cell types upon activation, in particularly the myeloid and T cells during neuroinflammation. Here we used mice with TNF ablation targeted to myeloid and T cell (MT-TNF-/-) to assess the contribution of myeloid and T cell-derived TNF in immune responses during CNS-TB. These mice exhibited impaired innate immunity and high susceptibility to cerebral Mycobacterium tuberculosis infection, a similar phenotype to complete TNF-deficient mice. Further, MT-TNF-/- mice were not able to control T cell responses and cytokine/chemokine production. Thus, our data suggested that collective TNF production by both myeloid and T cells are required to provide overall protective immunity against CNS-TB infection.


[Beta-mimetics and Pourcelot's index].
In a series of 20 patients presenting a threat of premature delivery, the vascular resistance index of Pourcelot, in the umbilical artery, was measured before, and then 24 hours after starting a continuous Salbutamol perfusion. A moderate but significant decreased placental vascular resistances is noted under betamimetic treatment. Relaxation of the myometrium obtained with a tocolytic treatment could be implicated in this alteration of placental resistances.


Tackling variants with antibodies.
Antibodies targeting the protein that causes placental malaria can recognise multiple variants of the protein, which may help guide the development of new vaccines to protect pregnant women from malaria.


Quantifying radiation damage in biomolecular small-angle X-ray scattering.
Small-angle X-ray scattering (SAXS) is an increasingly popular technique that provides low-resolution structural information about biological macromolecules in solution. Many of the practical limitations of the technique, such as minimum required sample volume, and of experimental design, such as sample flow cells, are necessary because the biological samples are sensitive to damage from the X-rays. Radiation damage typically manifests as aggregation of the sample, which makes the collected data unreliable. However, there has been little systematic investigation of the most effective methods to reduce damage rates, and results from previous damage studies are not easily compared with results from other beamlines. Here a methodology is provided for quantifying radiation damage in SAXS to provide consistent results between different experiments, experimenters and beamlines. These methods are demonstrated on radiation damage data collected from lysozyme, glucose isomerase and xylanase, and it is found that no single metric is sufficient to describe radiation damage in SAXS for all samples. The radius of gyration, molecular weight and integrated SAXS profile intensity constitute a minimal set of parameters that capture all types of observed behavior. Radiation sensitivities derived from these parameters show a large protein dependence, varying by up to six orders of magnitude between the different proteins tested. This work should enable consistent reporting of radiation damage effects, allowing more systematic studies of the most effective minimization strategies.


The ideas about advanced life support and affecting factors at the end-stage of life in a hospital in Turkey.
The participation of the people in health decisions may be structured in various levels. One of these is participation in decisions for the treatment. "Advanced directives" is one of the examples for the participation in decisions for the treatment. We wanted to determine the decisions on advanced life support at the end-stage of life in case of a life-threatening illness for the people themselves and their first degree relatives and the factors effecting these decisions. The cross-sectional study was conducted with volunteers among patients and patient relatives who applied to all polyclinics of the Ankara Numune Training and Research Hospital except the emergency, oncology and psychiatry polyclinics between 15.12.2012 and 15.03.2013. A questionnaire, the Hospital Anxiety Depression (HAD) scale, and Templer's Death Anxiety Scale (TDA) were applied to all individuals. SPSS for Win. Ver. 17.0 and MS-Excel 2010 Starter software bundles were used for all statistical analysis and calculations. The participants want both themselves and their first degree relatives included in end-stage decision-making process. Therefore, the patients and their families should be informed adequately during decision making process and quality communication must be provided. Participants who have given their end-stage decisions previously want to be treated according to these decisions. This desire can just be possible by advanced directives.When moral and material loads of end-stage process are taken into consideration, countries, in which advanced directives are practiced, should be examined well and participants' desire should be evaluated in terms of practicability.


Bipolar Electrodes with 100% Current Efficiency for Sensors.
A bipolar electrode (BPE) is an electron conductor that is embedded in the electrolyte solution without the direct connection with the external power source (driving electrode). When the sufficient voltage was provided, the two poles of BPE promote different oxidation and reduction reactions. During the past few years, BPEs with wireless feature and easy integration showed great promise in the various fields including asymmetric modification/synthesis, motion control, targets enrichment/separation, and chemical sensing/biosensing combined with the quantitative relationship between two poles of BPE. In this perspective paper, we first describe the concept and history of the BPE for analytical chemistry and then review the recent developments in the application of BPEs for sensing with ultrahigh current efficiency (ηc = iBPE/ichannel) including the open and closed bipolar system. Finally, we offer the guide for possible challenge faced and solution in the future.


Intervention for the prevention and control of hypertension and atherosclerotic diseases: United States and international experience.
Intervention to control hypertension and prevent coronary heart disease was initially undertaken in the United States in the late 1950s. It was conducted along three lines: randomized controlled trials, community demonstration projects, and broad public health and medical care efforts involving both the general population and its high-risk strata. This article reviews findings from the United States trials, particularly those on the primary prevention of coronary heart disease by unifactorial means (such as fat-modified diet, serum cholesterol-lowering drugs, antihypertensive drug treatment) and by multifactorial interventions. Results of unifactorial and multifactorial trials are discussed with reference to the prevention of high blood pressure. Studies in the United States are compared with research abroad, and current research needs are reviewed together with the implications for medical practice and public health. The United States population as a whole has a large high-risk segment. Since the late 1950s, significant population-wide changes have occurred in life-styles (diet, smoking, exercise habits), and this is especially true of the more educated. The proportion of persons with detected, treated, and controlled high blood pressure has risen markedly in all population strata. Consequently, a favorable shift has occurred in the population distribution of the major established risk factors: "rich" diet, hypercholesterolemia, high blood pressure, and cigarette smoking. It can be reasonably inferred that the steady and marked declines in death rates in the United States from coronary heart disease, stroke, all cardiovascular diseases, and all causes since 1968 are related to reductions in these risk factors.


Disopyramide for Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterized by hypertrophy of a nondilated left ventricle without any other cardiac or systemic disease that could account for observed hypertrophy. We present a female patient with the diagnosis of obstructive HCM, which is rare because sudden death is frequently the first clinical presentation. Her symptoms were resistant to medical treatment and the patient did not want invasive procedures. Disopyramide was added, and it improved her symptoms. Disopyramide is a safe and effective medication that reduces symptoms and delays the need for invasive therapy. Disopyramide was added to the treatment of the patient and it improved her symptoms.


Horizontal Alveolar Ridge Augmentation with Allogeneic Bone Block Graft Compared with Autogenous Bone Block Graft: a Systematic Review.
The objective of the present systematic review was to test the hypothesis of no difference in implant treatment outcome after horizontal ridge augmentation with allogeneic bone block compared with autogenous bone block. A MEDLINE (PubMed), Embase and Cochrane Library search in combination with a hand-search of relevant journals was conducted including human studies published in English through March 13, 2019. Comparative and non-comparative studies evaluating horizontal ridge augmentation with allogeneic bone block were included. Cochrane risk of bias tool and Newcastle-Ottawa Scale were used to evaluate risk of bias. One comparative study with high quality and 12 non-comparative studies fulfilled the inclusion criteria. Considerable heterogeneity prevented meta-analysis from being performed. The comparative retrospective short-term study demonstrated no significant difference in implant treatment outcome between the two treatment modalities. Non-comparative long-term studies revealed high implant survival, gain in alveolar ridge width and bone regeneration with allogeneic bone block. However, non-comparative studies disclosed high incidence of complications including dehiscence, exposure of allogeneic bone block and partial or total loss of the grafts. There seemed to be no difference in implant treatment outcome after horizontal ridge augmentation with allogeneic bone block compared with autogenous bone block. However, increased risk of complications was frequently reported with allogeneic bone block.


Competition between deferiprone, desferrioxamine and other chelators for iron and the effect of other metals.
Competition for iron between the leading oral iron chelator deferiprone (L1, 1,2-dimethyl-3-hydroxypyrid-4-one) and desferrioxamine (DF), and the effect of other metals has been studied. Visible spectroscopy was used to estimate the displacement of iron from DF-iron(III) and L1-iron(III) complexes, respectively, by varying quantities of up to 100 molar equivalent of a competing metal ion M+ (Mg2+, Al3+, Ca2+, Mn2+, Co2+, Cu2+, Zn2+ and Pb2+) at physiological pH. Copper and aluminium showed the greatest competition against iron, while magnesium, calcium and manganese had little or no effect and the other metals an intermediate effect. DF showed greater selectivity for iron than L1 under these conditions. An analogous series of experiments carried out using a competing chelator of up to 50 molar equivalent in a place of a competing metal ion showed that 8-hydroxyquinoline, diethylenetriamine-pentaacetic acid (DTPA) and tropolone were more effective at displacing iron from DF-Fe and (L1)3Fe complexes than maltol or omadine. Desferrioxamine was the most efficient competitor against L1. Stoichiometric studies of the L1 complexes of aluminium and copper at pH 7.4 using Job Plots, suggested the formation of (L1)3Al and (L1)2Cu complexes, respectively.


Lateral cortical Cdca7 expression levels are regulated by Pax6 and influence the production of intermediate progenitors.
We studied whether regulation of Cdca7 (Cell division cycle associated 7) expression by transcription factor Pax6 contributes to Pax6's cellular actions during corticogenesis. The function of Cdca7 in mediating Pax6's effects during corticogenesis has not been explored. Pax6 is expressed by radial glial progenitors in the ventricular zone of the embryonic cortical neuroepithelium, where it is required for the development of a normal complement of Tbr2-expressing intermediate progenitor cells in the subventricular zone. Pax6's expression levels are graded across the ventricular zone, with highest levels laterally where Tbr2-expressing progenitors are generated in greatest numbers at early stages of corticogenesis. We used in situ hybridization and immunohistochemistry to analyse patterns of Cdca7 and Pax6 expression in cortical tissue from wild-type and Pax6 -/- embryos. In each genotype we compared the graded expression of the two genes quantitatively at several ages. To test whether defects in Cdca7 expression in lateral cortical cells might contribute to the cellular defects in this region caused by Pax6 loss, we electroporated a Cdca7 expression vector into wild-type lateral cortex and examined the effect on the production of Tbr2-expressing cells. We found that Cdca7 is co-expressed with Pax6 in cortical progenitors, at levels opposite to those of Pax6. Lowest levels of Cdca7 are found in the radial glial progenitors of lateral cortex, where Pax6 levels are highest. Higher levels of Cdca7 are found in ventral telencephalon, where Pax6 levels are low. Loss of Pax6 causes Cdca7 expression to increase in the lateral cortex. Elevating Cdca7 in normal lateral cortical progenitors to levels close to those normally found in ventral telencephalon reduces their production of Tbr2-expressing cells early in lateral cortical formation. Our results suggest that Pax6 normally represses Cdca7 expression in the lateral cortex and that repression of Cdca7 in cells of this region is required for their production of a normal complement of Tbr2-expressing intermediate progenitors.


Effects of flutamide and finasteride on rat testicular descent.
The endocrine control of descent of the testis in mammalian species is poorly understood. The androgen dependency of testicular descent was studied in the rat using an antiandrogen (flutamide) and an inhibitor of the enzyme 5 alpha-reductase (finasteride). Androgen receptor blockade inhibited testicular descent more effectively than inhibition of 5 alpha-reductase activity. Moreover, its inhibitory effect was limited to the outgrowth phase of the gubernaculum testis, particularly the earliest stages of outgrowth. Gubernacular size was also significantly reduced in fetuses exposed to flutamide during the outgrowth period. In contrast, androgen receptor blockade or 5 alpha-reductase inhibition applied after the initiation of gubernacular outgrowth or during the regression phase did not affect testicular descent. Successful inhibition of the development of epididymis and vas by prenatal flutamide did not correlate with ipsilateral testicular maldescent, suggesting that an intact epididymis is not required for descent of the testis. Plasma androgen assays confirmed significant inhibition of dihydrotestosterone formation in finasteride-treated rats. These data suggest that androgens, primarily testosterone, are required during the early phases of gubernacular outgrowth for subsequent successful completion of testicular descent.


Roles of voltage‑gated potassium channels in the maintenance of pancreatic cancer stem cells.
The targeting of membrane proteins that are activated in cancer stem cells (CSCs) represents one of the key recent strategies in cancer therapy. The present study analyzed ion channel expression profiles and functions in pancreatic CSCs (PCSCs). Cells strongly expressing aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were isolated from the human pancreatic PK59 cell line using fluorescence‑activated cell sorting, and PCSCs were identified based on tumorsphere formation. Microarray analysis was performed to investigate the gene expression profiles in PCSCs. ALDH1A1 messenger RNA levels were higher in PCSCs compared with non‑PCSCs. PCSCs were resistant to 5‑fluorouracil and capable of redifferentiation. The results of the microarray analysis revealed that gene expression related to ion channels, including voltage‑gated potassium channels (Kv), was upregulated in PCSCs compared with non‑PCSCs. 4‑Aminopyridine (4‑AP), a potent Kv inhibitor, exhibited greater cytotoxicity in PCSCs compared with non‑PCSCs. In a xenograft model in nude mice, tumor volumes were significantly lower in mice inoculated with PK59 cells pre‑treated with 4‑AP compared with those in mice injected with non‑treated cells. The present results identified a role of Kv in the persistence of PCSCs and suggested that the Kv inhibitor 4‑AP may have potential as a therapeutic agent for pancreatic carcinoma.


Virion-associated transcriptase activity of influenza recombinant and mutant strains.
A comparative study of the in vitro reaction kinetics of the virion RNA polymerase of influenza A strains WS and WSN was conducted to establish phenotypic differences for enzyme activity that might be exchanged as genetic markers among recombinants of these viruses. Characteristically, the RNA polymerase activity of WS virus showed an initial rate of synthesis about two- to threefold higher than that of WSN when assayed at 32 C. The two strains were also distinguishable by comparing the transcription rates of each strain at 32 and 37 C. The initial rate of WS was invariably higher at 37 than at 32 C, whereas the opposite was found with WSN. When a series of recombinants obtained from mixed infections with the WS and WSN viruses were examined for virion transcriptase activity, it was found that the two polymerase related markers behaved as properties which segregated independently of each other and of additional nonselective markers that were scored. Seven temperature-sensitive mutants of WSN virus representing distinct recombination-complementation groups were found to show a diminished transcriptase activity as compared to wild-type virus, and one of these clones (ts 24) was largely deficient for this function. None of these mutants appeared to possess a heat-liable virion polymerase.


Influence of intralaryngeal CO2 on the response of laryngeal afferents to upper airway negative pressure.
Effects of intralaryngeal CO2 on the response of superior laryngeal afferents to negative pressure were investigated in 20 anesthetized spontaneously breathing adult cats. Single-fiber action potentials were recorded from the peripheral cut end of the superior laryngeal nerve. The larynx was exposed to negative pressure during inspiration when the animal breathed against an occluded upper airway. Among the 99 receptors evaluated, 54 were respiratory modulated and 45 were nonmodulated endings. The effect of intralaryngeal CO2 on the response of 39 receptors responding to negative pressure was determined by exposure of the larynx to CO2 or air for 1 min followed immediately by upper airway occlusion. The mean discharge frequency of 22 fibers inhibited by negative pressure was 32.4 +/- 2.6 Hz during air trials compared with 29.9 +/- 2.6 Hz during CO2 trials (P < 0.005). During occlusion of the upper airway after the warm humidified air trial, the discharge frequency of these endings decreased to 24.2 +/- 2.3 Hz compared with 17.5 +/- 2.2 Hz after CO2 trial (P < 0.001). The mean discharge frequencies of 17 fibers stimulated by negative pressure were 3.7 +/- 2.6 and 4.4 +/- 1.8 Hz, respectively, during air and CO2 trials. The mean frequencies increased to 14.7 +/- 3.5 Hz (air) and 18.6 +/- 4.0 Hz (CO2) during upper airway occlusions (P < 0.01). We conclude that intralaryngeal CO2 can alter the response of pressure-sensitive laryngeal afferents, thereby having a role in the maintenance of upper airway patency.(ABSTRACT TRUNCATED AT 250 WORDS)


Diagnostic performance and description of morphological features of focal nodular hyperplasia in Gd-EOB-DTPA-enhanced liver magnetic resonance imaging: results of a multicenter trial.
The aim of this prospective study was to evaluate the diagnostic performance of magnetic resonance imaging (MRI) of the liver with the hepatocellular-specific contrast agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) in comparison to precontrast MRI and spiral computed tomography (CT) in the specific diagnosis of focal nodular hyperplasia (FNH) and to describe morphologic features and enhancement pattern of FNH. In 176 patients from a phase III multicenter trial, 59 confirmed FNHs were present (13 = histopathology; 46 = imaging follow-up within 12 months before or 3 months after the MRI study). MR examination consisted of precontrast T1- and T2-w sequences, T1-weighted (w) dynamic sequences after bolus-injection of 0.025 mmol Gd-EOB-DTPA (Primovist; Bayer Schering Pharma)/kg bodyweight and T1-w sequences with fat saturation in the hepatocyte-phase after 20 minutes. The number of correctly characterized FNHs was evaluated and compared with that determined on spiral CT in an on-site reading (clinical study) and an off-site reading (3 blinded readers). The morphologic appearance and enhancement patterns of the FNHs were evaluated. Characterization with combined pre- and post-MRI (88.1%) was superior to that achieved with biphasic-enhanced spiral CT (84.7%, not significant) and precontrast MRI (67.8%, P < 0.05) in the clinical study and significantly superior to both precontrast MRI and spiral CT for 2 of 3 blinded readers. Complete or partial enhancement of the lesions was present in the early dynamic phase (arterial and portovenous dynamic phase) in 94% and 85%, respectively. The pattern of lesion enhancement in the early dynamic phase was mainly homogenous (78%-80%); the median contrast-to-noise ratio was -5.9 in T1-w precontrast images, 14.0 in the arterial phase, 2.4 in the portovenous phase, and 2.9 in the equilibrium phase. Enhancement in the hepatocyte-phase after 10 and 20 minutes was observed in 88% and 90% of lesions, respectively. Characterization of FNH provided by Gd-EOB-DTPA-enhanced MRI is superior to that provided by precontrast MRI alone or spiral CT. FNHs show very similar enhancement characteristics to those of other extracellular contrast agents in the early dynamic phase after bolus injection of Gd-EOB-DTPA, after 20 minutes in the liver-specific phase enhancement is regularly seen.


Transplantation of Human Gingiva-Derived Mesenchymal Stem Cells Ameliorates Neurotic Erectile Dysfunction in a Rat Model.
Cavernous nerve injury (CNI) is the main cause of erectile dysfunction (ED) following pelvic surgery. Our previous studies have demonstrated that transplantation of different sources of mesenchymal stem cells (MSCs) was able to alleviate ED induced by CNI in rat models. However, little is known about the therapeutic effects of human gingiva-derived MSCs (hGMSCs) in CNI ED rats. Herein, we injected the hGMSCs around the bilateral major pelvic ganglia (MPG) in a rat model of CNI and evaluated their efficacy. The results showed that treatment of hGMSCs could significantly promote the recovery of erectile function, enhance smooth muscle and endothelial content, restore neuronal nitric oxide synthase (nNOS) expression, and attenuate cell apoptosis in penile tissue. Moreover, penile fibrosis was significantly alleviated after hGMSC administration. In addition, potential mechanism exploration indicated that hGMSCs might exert its functions via skewed macrophage polarity from M1 toward M2 anti-inflammatory phenotype. In conclusion, this study found that transplantation of hGMSCs significantly improved CNI-related ED, which might provide new clues to evaluate their pre-clinical application.


Clinical Response with intralesional Amphotericin B in the treatment of old world cutaneous leishmaniasis: a preliminary report.
Cutaneous leishmaniasis (CL) is a vector-borne tropical disease caused by a heterogeneous group of protozoan parasites that belong to the genus Leishmania. With an annual incidence of 1.5 million new cases, CL is a global health concern mainly in developing countries. The treatment options for CL are numerous but none is optimal. Pentavalent antimonials despite their side effects remain the preferred choice since decades. Alternate new treatment options are being explored to expand the therapeutic armamentarium of CL. In this study, we intend to describe our therapeutic experience with intralesional amphotericin B in the treatment of CL in a series of Indian patients, hitherto not commonly used in old world CL (OWCL). We also endeavour to review the literature on the use of amphotericin B in OWCL. Five consecutive patients diagnosed with cutaneous leishmansis at the out-patient department of Dermatology, Government Medical College, Jammu were treated with weekly injections of intralesional amphotericin B (2.5 mg/mL). Treatment response was assessed at each visit and the cases were followed up for 6 months. All the five patients responded well to the treatment and remained recurrence-free during follow-up. Intralesional amphotericin B was found to be safe and effective treatment for OWCL. Large randomized control trials need to be conducted to establish its efficacy.


Image-guided placement of the Bonebridge™ without surgical navigation equipment.
Most of the current Bonebridge surgeries undergo preoperative simulation planning in a computer. However, surgeons usually use the landmarks on the bone surface to determine the location where to implant the device, using the simulation image in the computer only as a reference (conventional method). We developed an image-guided method for precisely replicating simulation surgery upon performing Bonebridge implantation. Based on our previous development of the surface template-assisted marker positioning (STAMP) method for performing image-guided otologic surgery, we fabricated templates that fit only at the designated location on the patient's temporal bone surface. The Bonebridge STAMP (BB-STAMP) plate shows the exact location where to start drilling. The BB-STAMP was also combined with a perforator-guiding sleeve, so that the location, direction and depth of the cylindrical well could be precisely replicated as simulated. We also created a STAMP plate for confirmation that fits only after sufficient drilling at the correct location is finished. To evaluate the proposed methods, we performed simulation surgery on four cadaveric temporal bones and their 12 replicas (three each for four bones). The time used and the degree of mismatch between the simulated location and the drilled location were compared. A feasibility study was successfully conducted using the proposed BB-STAMP methods and the conventional method. The amount of time required for the procedure did not differ significantly between the surgical methods, although using the BB-STAMP and perforator guide was always quicker. The degree of mismatch between the simulation and resected models had tendency to be smaller when the surgery was guided by the BB-STAMP with or without a perforator guide, although the difference was not statistically significant. The proposed BB-STAMP is a promising method for replicating exactly what is performed during simulation without using a surgical navigation system.


Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat.
Rats were trained to run on a horizontal treadmill for 2 h at 20 m/min. This activity considerably increased plasma free tryptophan (TRP) (+70%) but did not alter plasma total TRP levels and had little or no effect on plasma concentrations of the other large neutral amino acids (LNAAs) that compete with TRP for entry into the brain. Brain TRP levels increased by 80%. The only other brain LNAA to be affected by exercise was threonine, which rose moderately. The results indicate that increased plasma free TRP was specifically responsible for the increase of brain TRP after 2 h of exercise. Brain lysine was also increased whereas glycine, alanine, and gamma-aminobutyric acid were decreased. The differences between the present findings and those previously obtained following 2 h immobilization stress are discussed.


[The evolution of the Italian Code of Medical Deontology: a historical-epistemological perspective].
The Italian Code of Medical Deontology is a set of self-discipline rules prefixed by the medical profession, that are mandatory for the members of the medical registers, who must conform to these rules. The history of the Italian Code of Medical Deontology dates back to the beginning of the twentieth century. In 1903 it appeared in the form of a "Code of Ethics and Deontology" and was prepared by the Board of the Medical Register of Sassari (Sardinia). This Board inserted the principles inspiring the correct practice of the medical profession in an articulated and self-normative system, also foreseeing disciplinary measures. About ten years later, in 1912, the Medical Register of Turin (Piedmont) elaborated a Code which constituted the basis for a subsequent elaboration leading to a Unified Code of Medical Ethics (1924). After World War II the idea prevailed in Italy that the codes of medical deontology should undergo periodical review, updating and dissemination, and the new 1947 text (Turin) was for the first time amply diffused among Italian physicians. The next national code dates back to 1958, and twenty years later a revision was published. In the 1989 Code new topics appeared, including organ transplantation, artificial in vitro insemination and the role of police doctors; these and other issues were later developed in the 1995, 1998 and 2006 versions of the Code. The last available edition of the Italian Code of Medical Deontology is that of May 2014.


WITHIN- AND BETWEEN-GENERATION EFFECTS OF TEMPERATURE ON THE MORPHOLOGY AND PHYSIOLOGY OF DROSOPHILA MELANOGASTER.
We investigated the effects of developmental and parental temperatures on several physiological and morphological traits of adult Drosophila melanogaster. Flies for the parental generation were raised at either low or moderate temperature (18°C or 25°C) and then mated in the four possible sex-by-parental temperature crosses. Their offspring were raised at either 18°C or 25°C and then scored as adults for morphological (dry body mass, wing size, and abdominal melanization [females only]), physiological (knock-down temperature, and thermal dependence of walking speed), and life history (egg size) traits. The experiment was replicated, and the factorial design allows us to determine whether and how paternal, maternal, and developmental temperatures (as well as offspring sex) influence the various traits. Sex and developmental temperature had major effects on all traits. Females had larger bodies and wings, higher knock-down temperatures, and slower speeds (but similar shaped performance curves) than males. Development at 25°C (versus at 18°C) increased knock-down temperature, increased maximal speed and thermal performance breadth, decreased the optimal temperature for walking, decreased body mass and wing size, reduced abdominal melanization, and reduced egg size. Parental temperatures influenced a few traits, but the effects were generally small relative to those of sex or developmental temperature. Flies whose mother had been raised at 25°C (versus at 18°C) had slightly higher knock-down temperature and smaller body mass. Flies whose father had been raised at 25°C had relatively longer wings. The effects of paternal, maternal, and developmental temperatures sometimes differed in direction. The existence of significant within- and between-generation effects suggests that comparative studies need to standardize thermal environments for at least two generations, that attempts to estimate "field" heritabilities may be unreliable for some traits, and that predictions of short-term evolutionary responses to selection will be difficult.


Analysis of protein profiles in human epithelial ovarian cancer tissues by proteomic technology.
Screening in ovarian cancer is progressively finding out candidate genes and proteins which may work as screening biomarkers and play a role in tumor progression. We examined the protein expression patterns of ovarian cancer tissues using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of fight mass spectrometry (MALDI-TOF MS). Tissues from 36 ovarian cancers and 20 normal ovaries were examined by 2-DE. The images of silver stained gels were analyzed by ImageMaster 2D Elite. The peptide mixtures, after in-gel digestion, were determined by MALDI-TOF MS for fingerprinting. The de-isotope tryptic peptide profiles were matched by using the Mascot search engine based on the entire NCBI and Swiss-Prot protein databases. Western/dot blots were then applied to verify the findings. In ovarian cancer, 12 proteins that showed differential expressions were identified unequivocally. Among these proteins, five proteins (galectin-1, cathepsin B, ubiquitin carboxy-terminal hydrolase L1, HLA class II antigen DRB1-11 and heat shock protein 27) were up-regulated and seven proteins (cellular retinol-binding protein, transthyretin, SH3 binding glutamic-rich-like protein, tubulin-specific chaperone A, DJ-1, gamma-actin and tropomyosin 4) were down-regulated. The present study is the first to report the up-regulation of ubiquitin carboxy-terminal hydrolase L1 and the down-regulation of SH3 binding glutamic-rich-like protein, tubulin-specific chaperone A, and tropomyosin 4 in human ovarian cancer tissues. Further cloning and functional analysis of these salient proteins will provide more information on their pathophysiologic roles in ovarian cancer.


Active nanodiamond hydrogels for chemotherapeutic delivery.
Nanodiamond materials can serve as highly versatile platforms for the controlled functionalization and delivery of a wide spectrum of therapeutic elements. In this work, doxorubicin hydrochloride (DOX), an apoptosis-inducing drug widely used in chemotherapy, was successfully applied toward the functionalization of nanodiamond materials (NDs, 2-8 nm) and introduced toward murine macrophages as well as human colorectal carcinoma cells with preserved efficacy. The adsorption of DOX onto the NDs and its reversible release were achieved by regulating Cl- ion concentration, and the NDs were found to be able to efficiently ferry the drug inside living cells. Comprehensive bioassays were performed to assess and confirm the innate biocompatibility of the NDs, via real-time quantitative polymerase chain reaction (RT-PCR), and electrophoretic DNA fragmentation as well as MTT analysis confirmed the functional apoptosis-inducing mechanisms driven by the DOX-functionalized NDs. We extended the applicability of the DOX-ND composites toward a translational context, where MTT assays were performed on the HT-29 colon cancer cell line to assess DOX-ND induced cell death and ND-mediated chemotherapeutic sequestering for potential slow/sustained released capabilities. These and other medically relevant capabilities enabled by the NDs forge its strong potential as a therapeutically significant nanomaterial.


"Trophic" effect of transferrin on amphibian limb regeneration blastemas.
In light of the recent demonstration that one "neurotrophic factor" of peripheral nerves is the iron-transport glycoprotein transferrin, we tested the effects of heterologous transferrin on cellular events in cultured newt forelimb blastemas. Addition of transferrin to medium containing 1% fetal bovine serum resulted in DNA labeling and mitotic activity approximately twice as high as that of blastemas cultured in medium with 1% serum alone. Blastemas maintained for 24 hr in medium with 1% serum were stimulated to increased levels of DNA synthesis by the addition of transferrin, and this response was dose-dependent. Varying the concentrations of iron and transferrin in the medium gave results indicating that the glycoprotein's trophic effect is due to its ability to furnish iron to the cells in an appropriate manner. Results of the study are consistent with the hypothesis that blastema cell proliferation is promoted by transferrin or transferrin-like factors released from nerves.


[Evaluation of cases of metastatic liver tumors resected following intra-arterial infusion chemotherapy].
We encountered four cases whose unresectable metastatic liver tumors could be resected by operation after intra-arterial infusion chemotherapy using an implantable reservoir. Metastatic lesions were thus markedly reduced and localized. Three cases were metastases of colorectal cancer and one of gastric cancer. All cases of liver metastases were synchronous and more than H2 stage. In these cases, metastatic lesions were reduced at an early stage of this chemotherapy after resection of the primary lesions. Resection of metastases was carried out from 4 to 14 months after the first operation. Effects of this chemotherapy were also observed histologically; necrosis and fibrosis were found in the cancer nest, which paralleled the reduction in tumor size. Our results indicate that this chemotherapy could be a neoadjuvant chemotherapy for unresectable metastatic liver tumors which may become resectable after this chemotherapy as seen in our cases. However, lung metastases and peritoneal dissemination influenced the prognosis of our cases. Treatment of extra-hepatic recurrence seemed important to improve the prognosis of these patients.


EVALUATING A HYPOTHESIS ABOUT HETEROCHRONY: LARVAL LIFE-HISTORY TRAITS AND JUVENILE HIND-LIMB MORPHOLOGY IN HYLA CRUCIFER.
This paper reports the results of an investigation into whether selection on genetically based differences in the timing or rate of development (heterochrony) can give rise to nonadaptive morphological differences among individual frogs. We used a quantitative-genetics approach to examine the relationships among the life-history characters time to metamorphosis and larval-growth rate and a functionally significant morphological features, relative hind-limb length, in the spring peeper, Hyla crucifer. Time to metamorphosis and growth rate had low heritabilities in our population. Morphological traits had moderate heritabilities. There were positive genetic correlations between the life-history traits and the components of relative hind-limb length but no significant correlations with the shape variable itself. We used field observations of pond-drying time and experimental results of selection on growth rate to simulate the correlated responses of hind-limb shape to four reasonable selection regimes on the life-history traits. We found little evidence to suggest that relative hind-limb length would display much of a correlated response to such selection. The differences in relative hind-limb length seen among closely related species or among populations of a single species that appear to be unrelated to performance differences are not obviously explicable as neutral correlated responses to selection on larval traits.


Environmental and physiological factors affecting the succinate product ratio during carbohydrate fermentation by Actinobacillus sp. 130Z.
Actinobacillus sp. 130Z fermented glucose to the major products succinate, acetate, and formate. Ethanol was formed as a minor fermentation product. Under CO2-limiting conditions, less succinate and more ethanol were formed. The fermentation product ratio remained constant at pH values from 6.0 to 7.4. More succinate was produced when hydrogen was present in the gas phase. Actinobacillus sp. 130Z grew at the expense of fumarate and l-malate reduction, with hydrogen as an electron donor. Other substrates such as more-reduced carbohydrates (e.g., d-sorbitol) resulted in higher succinate and/or ethanol production. Actinobacillus sp. 130Z contained the key enzymes involved in the Embden-Meyerhof-Parnas and the pentose-phosphate pathways and contained high levels of phosphoenolpyruvate (PEP) carboxykinase, malate dehydrogenase, fumarase, fumarate reductase, pyruvate kinase, pyruvate formate-lyase, phosphotransacetylase, acetate kinase, malic enzyme, and oxaloacetate decarboxylase. The levels of PEP carboxykinase, malate dehydrogenase, and fumarase were significantly higher in Actinobacillus sp. 130Z than in Escherichia coli K-12 and accounted for the differences in succinate production. Key enzymes in end product formation in Actinobacillus sp. 130Z were regulated by the energy substrates.


[HRV-Spectral analysis of Pain, by 3D Evaluation and by Balance Index in the Pain Rehabilitation Field].
Pain signaling is achieved by electrical impulses in the body; however, some electrical abnormalities can cause pain in the body without generating any visible symptoms. This phenomenon is sensed by the brain and a signal that may affect cardiac rhythms is immediately transmitted to the heart. To evaluate heart rate variability (HRV), the balance correction between an increase and decrease of heart rate was recorded in real time. Using a special method for spectral-analysis of the HRV, techniques for analyzing the essence of pain were developed, namely, the 'Balance index' and the '3D spectrum evaluation method'. Using these techniques, an alpha wave-like factor or a beta wave-like reaction can be obtained, and the nature and strength of pain can be displayed as spectral zones, as in a rainbow. The balance reaction can be shown by analyzing data in the frequency band using a 1/f-like spectral-analysis method. Additionally, emotional reactions can be detected using a 'Balance index' that can demonstrate imbalance responding to the pain. The mental state of the subject can also be inferred because this technique is adapted from the 1/f fluctuation theory related to the best balanced 1/f-sound wave in nature that comforts the human mind, similar to music (artificial sound wave). In this study, the variety and intensity of pain were determined from the frequency band resulting from the 1/f-spectral analysis of HRV fluctuation. These techniques could explain several situations related to medication or anesthesia and can be helpful in preventative treatment and/or explaining the differences in the effectiveness of various techniques for the rehabilitation of chronic pain.


Motivating forces of human actions. Neuroimaging reward and social interaction.
In neuroeconomics, reward and social interaction are central concepts to understand what motivates human behaviour. Both concepts are investigated in humans using neuroimaging methods. In this paper, we provide an overview about these results and discuss their relevance for economic behaviour. For reward it has been shown that a system exists in humans that is involved in predicting rewards and thus guides behaviour, involving a circuit including the striatum, the orbitofrontal cortex and the amygdala. Recent studies on social interaction revealed a mentalizing system representing the mental states of others. A central part of this system is the medial prefrontal cortex, in particular the anterior paracingulate cortex. The reward as well as the mentalizing system is engaged in economic decision-making. We will discuss implications of this study for neuromarketing as well as general implications of these results that may help to provide deeper insights into the motivating forces of human behaviour.


Chromatin appearance in intermediate cells from patients with uterine cancer.
This paper presents the differences found by the computer analysis of digitized images of visually apparently normal intermediate cells from patients with normal cytology and patients with uterine cancer. There exist differences in the absolute amount of nuclear staining, the average density of staining, cell shape and size and also differences in spectral contrasts of the nuclear chromatin. Visual cytologic detection of these changes became more conspicuous when the photomicrographs were arranged in order of their discriminant function scores.


Operating vibrating tools and prevalence of subjective complaints in vibration syndrome.
The aim of this paper is to evaluate the prevalence of subjective symptoms and signs related to vibration syndrome in various groups of subjects exposed to hand-arm vibration (HAV). In 9 groups of subjects occupationally exposed to HAV, one group of subjects previously exposed to HAV, one control group, and 2 groups of general population (males and females), the prevalence of finger blanching, numbness in the hands, stiffness in the hands, and pain in the hands were investigated. The age of subjects ranged from 25 to 59 years. In subjects exposed to HAV, hand-transmitted vibration levels (HTVLs) were measured by means of vibration dosimeters, and the frequency-weighted acceleration levels [(Lh,w)eq,t] were determined as the vibration levels. The prevalence of vibration-induced white finger (VWF) in the exposed subjects was in the range of 0.0-9.6%, and that in subjects who were previously exposed to HAV was 4.1%. The prevalence rates of finger blanching in males and females of the general population were 2.7 and 3.4%, respectively. The highest prevalence rate of VWF was observed among subjects exposed to HTVLs of 2.7-5.1 m/s2. The prevalence of numbness of the hands fluctuated among the groups; i.e., in the exposed groups: in the range of 6.5-30.4%; in those previously exposed to HAV: 16.4%; and was 13.4% in males and 29.5% in females of the general population. The prevalence rates of stiffness in the hands were in the range of 7.6-65.2% in the exposed workers, 13.7% in those previously exposed to HAV, and was 5.5% in males and 20.9% in females of the general population. The prevalence of pain in the hands was between 7.4 and 17.4% in the exposed groups, 1.4% in those who stopped exposure to vibration, and 1.2% in subjects without segmental vibration exposure. Among the subjective symptoms, only VWF showed a significant positive correlation with the measured vibration acceleration; Y = -0.9 + 1.9 X, r = 0.8, P = 0.01. It was concluded that VWF is the most appropriate signs in decisions concerning quantitative recommendations for segmental vibration exposure.


Digital holography for in situ real-time measurement of plasma-facing-component erosion.
In situ, real time measurement of net plasma-facing-component (PFC) erosion/deposition in a real plasma device is challenging due to the need for good spatial and temporal resolution, sufficient sensitivity, and immunity to fringe-jump errors. Design of a high-sensitivity, potentially high-speed, dual-wavelength CO2 laser digital holography system (nominally immune to fringe jumps) for PFC erosion measurement is discussed.


High-risk AML complicated by pulmonary aspergillosis: successful treatment with nonmyeloablative stem cell transplantation and long-term administration of voriconazole.
Acute myeloid leukemia (AML) associated with central diabetes insipidus (DI) and chromosomal aberrations is characterised by a very poor prognosis. We present a 28-year-old female with AML FAB M0, preceding DI and cytogenetic abnormalities (monosomy 7 and inversion of chromosome 9). Complete remission was achieved with FLAG after she was refractory to two different induction regimens. Prolonged neutropenia resulted in invasive pulmonary aspergillosis. Allogeneic stem cell transplantation from a matched unrelated donor was performed using a reduced-intensity conditioning regimen. Desmopressin substitution for DI was withdrawn after transplant without recurrence of symptoms. Initial antifungal treatment, including liposomal amphotericin B, caspofungin and itraconazole, was replaced by voriconazole after deterioration of pulmonary aspergillosis, resulting in improvement, stabilisation and finally, also as the combined effect of discontinuation of the immunosuppressive therapy, in disappearance of signs and symptoms. Thirteen months after transplant, the patient is in continuous complete remission. The presented case study thus demonstrates that high-risk AML with concomitant invasive fungal infection may be safely and effectively treated by nonmyeloablative stem cell transplantation and long-term administration of voriconazole.


Long-term effect of combination therapy with mitiglinide and once daily insulin glargine in patients who were successfully switched from intensive insulin therapy in short-term study.
We have previously reported the therapeutic efficacy of mitiglinide combined with once daily insulin glargine (mitiglinide regimen) after switching from multiple daily insulin regimen of aspart insulin and glargine (intensive insulin regimen) in inpatients with type 2 diabetes mellitus in two consecutive days. In the present study, we followed up 9 of the 15 responsive patients with these novel regimens for 6 months after discharge. The data collected from these patients were compared to those of 15 randomly chosen patients who had well matched background and received intensive insulin regimen during hospitalization which was continued after discharge. The average HbA1c level of these 9 patients with mitiglinide regimen at 6 months was 6.7 +/- 0.8% and was comparable to that of the patients with intensive insulin regimen (HbA1c = 7.0 +/- 1.0%). In conclusion, mitiglinide and insulin glargine combination therapy maintained fair glycemic control for as long as 6 months in subpopulation of Japanese patients with type 2 diabetes.


MicroRNA-155-3p Mediates TNF-α-Inhibited Cementoblast Differentiation.
Periodontitis is a prevalent and chronic inflammatory disease that is interrelated with systemic health. Periodontitis can be promoted by tumor necrosis factor α (TNF-α). Cementum, a vital part of the periodontium, is a bone-like mineralized tissue that is produced by cementoblasts. Our laboratory previously revealed that TNF-α inhibits cementoblast differentiation and mineralization. However, how TNF-α modulates cementoblast differentiation and mineralization remains largely unknown. MicroRNA-155 (miR-155) is induced and regulates TNF-α-inhibited osteogenic differentiation. In this study, we found that miR-155-3p was increased during TNF-α-stimulated OCCM-30 cells and involved in cementoblast differentiation and mineralization. Overexpression of miR-155-3p suppressed cementoblast mineralization. Bioinformatics analysis revealed that potassium channel tetramerization domain containing 1 ( Kctd1) is a candidate target gene of miR-155-3p. Moreover, miR-155-3p overexpression suppressed KCTD1 levels. Meanwhile, its knockdown increased KCTD1 expression. Transfection with miR-155-3p also inhibited the luciferase activity of 3'-untranslated regions in the Kctd1 wild type but not the mutant. These data indicated that Kctd1 is a direct and novel target of miR-155-3p. The Wnt signaling pathway inhibits cementoblast differentiation, and we further demonstrated that miR-155-3p partially modulates cementoblast differentiation through the canonical Wnt signaling pathway. In addition to the gain/loss function assay of miR-155-3p, the luciferase activity assay of canonical Wnt signaling was performed. The assays revealed that miR-155-3p increased β-catenin-mediated transcriptional activation. Overall, our data clarified that miR-155-3p mediated TNF-α-inhibited cementoblast differentiation by targeting Kctd1, at least partially through canonical Wnt signaling pathway. These findings reveal the expanded function of miRNAs in cementoblast differentiation and mineralization.


Prevalence of the catatonic syndrome in an acute inpatient sample.
In this exploratory open label study, we investigated the prevalence of catatonia in an acute psychiatric inpatient population. In addition, differences in symptom presentation of catatonia depending on the underlying psychiatric illness were investigated. One hundred thirty patients were assessed with the Bush-Francis Catatonia Rating Scale (BFCRS), the Positive and Negative Syndrome Scale, the Young Mania Rating Scale, and the Simpson-Angus Scale. A factor analysis was conducted in order to generate six catatonic symptom clusters. Composite scores based on this principal component analysis were calculated. When focusing on the first 14 items of the BFCRS, 101 patients (77.7%) had at least 1 symptom scoring 1 or higher, whereas, 66 patients (50.8%) had at least 2 symptoms. Interestingly, when focusing on the DSM-5 criteria of catatonia, 22 patients (16.9%) could be considered for this diagnosis. Furthermore, different symptom profiles were found, depending on the underlying psychopathology. Psychotic symptomatology correlated strongly with excitement symptomatology (r = 0.528, p < 0.001) and to a lesser degree with the stereotypy/mannerisms symptom cluster (r = 0.289; p = 0.001) and the echo/perseveration symptom cluster (r = 0.185; p = 0.035). Similarly, manic symptomatology correlated strongly with the excitement symptom cluster (r = 0.596; p < 0.001) and to a lesser extent with the stereotypy/mannerisms symptom cluster (r = 0.277; p = 0.001). There was a high prevalence of catatonic symptomatology. Depending on the criteria being used, we noticed an important difference in exact prevalence, which makes it clear that we need clear-cut criteria. Another important finding is the fact that the catatonic presentation may vary depending on the underlying pathology, although an unambiguous delineation between these catatonic presentations cannot be made. Future research is needed to determine diagnostical criteria of catatonia, which are clinically relevant.


Clinical issues associated with urine testing of substances of abuse.
Several factors may affect the validity and outcome of urine testing for abused drugs such as amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ethanol, opiates, and phencyclidine. Urine is used for large-scale testing because acquisition of the sample is noninvasive and because most abused drugs can be detected in urine for a reasonable duration after ingestion. Urine testing for drugs of abuse is a two-step process. In the first step, screening assays are used to identify presumably positive specimens. Common screening tests are radioimmunoassays, enzyme immunoassays, fluorescence polarization immunoassay, and thin layer chromatography. Since they may be subject to cross-reactivity, once a possible positive sample has been identified by a preliminary test, a second more specific methodology, gas chromatography with mass spectrometry, is done to confirm the results. Knowledge of the pharmacology and pharmacokinetics of abused drugs affects selection and interpretation of test results.


A comprehensive review of protein misfolding disorders, underlying mechanism, clinical diagnosis, and therapeutic strategies.
Proteins are the most common biological macromolecules in living system and are building blocks of life. They are extremely dynamic in structure and functions. Due to several modifications, proteins undergo misfolding, leading to aggregation and thereby developing neurodegenerative and systemic diseases. Understanding the pathology of these diseases and the techniques used to diagnose them is therefore crucial for their effective management . There are several techniques, currently being in use to diagnose them and those will be discussed in this review. Current review aims to discuss an overview of protein aggregation and the underlying mechanisms linked to neurodegeneration and systemic diseases. Also, the review highlights protein misfolding disorders, their clinical diagnosis, and treatment strategies. Literature related to neurodegenerative and systemic diseases was explored through PubMed, Google Scholar, Scopus, and Medline databases. The keywords used for literature survey and analysis are protein aggregation, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, systemic diseases, protein aggregation mechanisms, etc. DISCUSSION /CONCLUSION: This review summarises the pathogenesis of neurodegenerative and systemic disorders caused by protein misfolding and aggregation. The clinical diagnosis and therapeutic strategies adopted for the management of these diseases are also discussed to aid in a better understanding of protein misfolding disorders. Many significant concerns about the role, characteristics, and consequences of protein aggregates in neurodegenerative and systemic diseases are not clearly understood to date. Regardless of technological advancements, there are still great difficulties in the management and cure of these diseases. Therefore, for better understanding, diagnosis, and treatment of neurodegenerative and systemic diseases, more studies to identify novel drugs that may aid in their treatment and management are required.


Radiation-induced changes in flavin fluorescence of dihydroorotate dehydrogenase.
The effect of gamma-radiation on the flavin moiety of dihydroorotate dehydrogenase was studied by fluorescence spectroscopy. Irradiation of aerated solutions (0-7 Gy) led to a small increase in fluorescence intensity, but with higher doses a decrease in intensity was observed. The increase in fluorescence intensity after irradiation at low doses may be attributed to protein unfolding, leading to greater exposure of flavin groups and a concomitant increase in separation between the flavin moiety and the iron-sulphur centre. This was confirmed by fluorescence quenching studies using potassium iodide as quencher. The Stern-Volmer constant calculated for iodide quenching indicates a two-fold increase in the fraction of flavin moiety being accessible to the quencher after 6.6 Gy. No spectral change was observed when unirradiated or irradiated enzyme was denatured with guanidine hydrochloride. However, a decrease in fluorescence intensity in the case of irradiated samples indicated a radiation-induced decrease in the flavin fluorophore. The flavin fluorophore loss in dihydroorotate dehydrogenase was also determined using aerated, argon-saturated or nitrous oxide-saturated solutions. H and OH radicals were found to have nearly equal contributions in damaging the flavin moiety of dihydroorotate dehydrogenase.


Necrotrophic Mycoparasites and Their Genomes.
Mycoparasitism is a lifestyle where one fungus establishes parasitic interactions with other fungi. Species of the genus Trichoderma together with Clonostachys rosea are among the most studied fungal mycoparasites. They have wide host ranges comprising several plant pathogens and are used for biological control of plant diseases. Trichoderma as well as C. rosea mycoparasites efficiently overgrow and kill their fungal prey by using infection structures and by applying lytic enzymes and toxic metabolites. Most of our knowledge on the putative signals and signaling pathways involved in prey recognition and activation of the mycoparasitic response is derived from studies with Trichoderma. These fungi rely on G-protein signaling, the cAMP pathway, and mitogen-activated protein kinase cascades during growth and development as well as during mycoparasitism. The signals being recognized by the mycoparasite may include surface molecules and surface properties as well as secondary metabolites and other small molecules released from the prey. Their exact nature, however, remains elusive so far. Recent genomics-based studies of mycoparasitic fungi of the order Hypocreales, i.e., Trichoderma species, C. rosea, Tolypocladium ophioglossoides, and Escovopsis weberi, revealed not only several gene families with a mycoparasitism-related expansion of gene paralogue numbers, but also distinct differences between the different mycoparasites. We use this information to illustrate the biological principles and molecular basis of necrotrophic mycoparasitism and compare the mycoparasitic strategies of Trichoderma as a "model" mycoparasite with the behavior and special features of C. rosea, T. ophioglossoides, and E. weberi.


Acute mesenteric ischemia: updated guidelines of the World Society of Emergency Surgery.
Acute mesenteric ischemia (AMI) is a group of diseases characterized by an interruption of the blood supply to varying portions of the intestine, leading to ischemia and secondary inflammatory changes. If untreated, this process may progress to life-threatening intestinal necrosis. The incidence is low, estimated at 0.09-0.2% of all acute surgical admissions, but increases with age. Although the entity is an uncommon cause of abdominal pain, diligence is required because if untreated, mortality remains in the range of 50%. Early diagnosis and timely surgical intervention are the cornerstones of modern treatment to reduce the high mortality associated with this entity. The advent of endovascular approaches in parallel with modern imaging techniques is evolving and provides new treatment options. Lastly, a focused multidisciplinary approach based on early diagnosis and individualized treatment is essential. Thus, we believe that updated guidelines from World Society of Emergency Surgery are warranted, in order to provide the most recent and practical recommendations for diagnosis and treatment of AMI.


Shoulder arthroplasty for proximal humeral malunions: long-term results.
Between 1976 and 1997, 50 shoulders with proximal humeral malunions in 50 patients were treated with hemiarthroplasty or total shoulder arthroplasty and followed up for a mean of 9 years (range, 2-21 years) or until the time of revision surgery. Of these, 13 had a 4-part malunion, 24 had a 3-part greater tuberosity malunion, 6 had a 2-part greater tuberosity malunion, and 7 had a 2-part head segment malunion. Articular incongruity resulted from an articular surface step-off in 5 shoulders, from osteonecrosis in 19, and from secondary degenerative arthritis in 26. Shoulder arthroplasty resulted in significant pain relief (P <.005). At most recent follow-up, shoulder pain was more intense in patients who had initial operative treatment of their fracture, in those with osteonecrosis, and in those who had arthroplasty less than 2 years after their fracture. Active elevation improved from 65 degrees to 102 degrees on average, and external rotation improved from 12 degrees to 35 degrees on average. There was significantly less postoperative motion in those who had initial operative treatment of their fracture or who underwent tuberosity osteotomy. Of the 24 shoulders undergoing tuberosity osteotomy, 14 healed in good position, 4 had a nonunion develop, 3 had some degree of malunion develop, and in 3 the tuberosity resorbed. On the basis of the Neer result rating, 12 shoulders had an excellent result, 13a satisfactory result, and 25 an unsatisfactory result. Unsatisfactory results occurred in 8 who underwent reoperation with component revision or removal and because of lack of postoperative motion in 14, moderate pain in 2, and patient dissatisfaction in 1. All shoulders with tuberosity nonunion or resorption had an unsatisfactory result.


Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling.
Thiazolidinediones (TZDs) are insulin-sensitizing agents that also decrease systemic blood pressure, attenuate the formation of atherosclerotic lesions, and block remodeling of injured arterial walls. Recently, TZDs were shown to prevent pulmonary arterial (PA) remodeling in rats treated with monocrotaline. Presently we report studies testing the ability of the TZD rosiglitazone (ROSI) to attenuate pathological arterial remodeling in the lung and prevent the development of pulmonary hypertension (PH) in rats subjected to chronic hypoxia. PA remodeling was reduced in ROSI-treated animals exposed to hypoxia compared with animals exposed to hypoxia alone. ROSI treatment blocked muscularization of distal pulmonary arterioles and reversed remodeling and neomuscularization in lungs of animals previously exposed to chronic hypoxia. Decreased PA remodeling in ROSI-treated animals was associated with decreased smooth muscle cell proliferation, decreased collagen and elastin deposition, and increased matrix metalloproteinase-2 activity in the PA wall. Cells expressing the c-Kit cell surface marker were observed in the PA adventitia of untreated animals exposed to hypoxia but not in ROSI-treated hypoxic rats. Right ventricular hypertrophy and cardiomyocyte hypertrophy were also blunted in ROSI-treated hypoxic animals. Interestingly, mean PA pressures were elevated equally in the untreated and ROSI-treated groups, indicating that ROSI had no effect on the development of PH. However, mean PA pressure was normalized acutely in both groups of hypoxia-exposed animals by Fasudil, an agent that inhibits RhoA/Rho kinase-mediated vasoconstriction. We conclude that ROSI can attenuate and reverse PA remodeling and neomuscularization associated with hypoxic PH. However, this agent fails to block the development of PH, apparently because of its inability to repress sustained Rho kinase-mediated arterial vasoconstriction.


[Clinical implication of bone regeneration in oral surgery].
Bone augmentation or the alveolar ridge augmentation procedure is inevitable for functional and esthetic prosthetic oral rehabilitation. In this article, conventional alveolar ridge augmentation methods are clinically demonstrated and are reviewed with reference to literature. In addition, distraction osteogenesis (DO), which has drawn considerable attention as a regenerative medicine, was clinically demonstrated. Then, the conventional augmentation methods and distraction are compared. Indications, advantages, and disadvantages of conventional augmentation methods including bone grafts, guided bone regeneration (GBR) and GBR with titanium micromesh (TIME technique) are demonstrated. Next, the mechanisms, indications, and advantages of DO are demonstrated and compared with conventional methods. Although conventional augmentation methods are well established, there are some problems including donor site morbidity and risks of wound dehiscence and infection. DO seems to have advantages compared to conventional augmentation methods. However, there still have some clinical problems such as difficulty in vector control and technique sensitivity. For less morbidity and better efficacy in alveolar ridge bone augmentation, tissue engineering offers potential in the future. However, further basic and clinical study will be necessary for clinical application.


Postoperative complications in the treatment of chagasic megaesophagus.
The postoperative complications of Chagasic megaesophagus were studied in 250 Chagasic patients referred to the Gastroenterology Clinic of Hospital das Clinicas, Federal University of Minas Gerais, Belo Horizonte, Brazil. The treatment was balloon dilatation in 45 (18.0%), myotomy and cardioplasty in 63 (25.2%), Merendino's surgery in 139 (55.6%), esophagogastroplasty in 2 (0.8%) and esophagocoloplasty in 1 (0.4%). There were 125 (50%) early and 30 (12%) late postoperative complications, and in 65 patients (26%) recurrent dysphagia was noted: nineteen (7.6%) after myotomy and cardioplasty, 9 (3.6%) after Merendino's operation and 37 (14.8%) after balloon dilatation. Eighty-five patients (34%) needed reoperations either to correct recurrent dysphagia (56 patients, 22.4%) or to treat other complications (29 patients, 11.6%). The reoperations to correct the 19 recurrences after myotomy and cardioplasty were Merendino's operation (12 patients, 4.8%), forceful dilatation (1 patient, 0.4%), forceful dilatation followed by Merendino's (2 patients, 0.8%), another myotomy (2 patients, 0.8%), myotomy followed by Merendino and balloon dilatation (1 patient, 0.4%) or esophagogastroplasty (1 patient, 0.4%). The recurrences after dilatation were treated by myotomy (15 cases, 6%), Merendino's operation (12 cases, 4.8%) and myotomy followed by Merendino's (3 cases, 1.2%). After Merendino seven reoperations (2.8%) were done: reduction of interposed loop (6 cases, 2.4%) and esophagocoloplasty (1 case, 0.4%). The time elapsed between the first operation and reoperation or dilatation varied from a few weeks to 18 years.(ABSTRACT TRUNCATED AT 250 WORDS)


Why has postal prescriber feedback no substantial impact on general practitioners' prescribing practice? A qualitative study.
To better understand the reasons for lack of impact of sending feedback on prescribing pattern to general practitioners (GPs). Semi-structured interviews with GPs who had all participated in intervention studies addressing effects of prescriber feedback. Interviews were audiotaped and fully transcribed. Transcripts were studied repeatedly and coded into categories in order to produce meaningful patterns. None of the GPs believed they altered prescribing practice after they received prescriber feedback. Unsolicited prescriber feedback was perceived as violating the GPs' autonomy. The GPs wanted to decide for themselves what data should be sent to them. Aggregated data were difficult to interpret, and GPs did not regard it as a problem that their practice pattern deviated from that of other practices. There was a mistrust of the validity of data, and the GPs wanted to be able to identify the patients with a need for optimised therapy directly from the information provided in the prescriber feedback. In addition they wanted advice on how to optimise therapy. Postal prescriber feedback (not revealing the patients' identities) is not effective because it does not motivate GPs to change nor does it address the barriers to change. Prescriber feedback requested by the GPs may be more effective, however, if it includes identities of inappropriately treated patients combined with relevant advice on how to optimise prescribing.


Helicobacter pylori: clarifying the issues and curing the disease.
This paper summarizes the presentations and discussions at a recent meeting on H. pylori infection attended by gastroenterologists from around Europe and North America. The meeting was sponsored by Abbott Laboratories International Division.


Dorsal horn neurons firing at high frequency, but not primary afferents, release opioid peptides that produce micro-opioid receptor internalization in the rat spinal cord.
To determine what neural pathways trigger opioid release in the dorsal horn, we stimulated the dorsal root, the dorsal horn, or the dorsolateral funiculus (DLF) in spinal cord slices while superfusing them with peptidase inhibitors to prevent opioid degradation. Internalization of mu-opioid receptors (MOR) and neurokinin 1 receptors (NK1R) was measured to assess opioid and neurokinin release, respectively. Dorsal root stimulation at low, high, or mixed frequencies produced abundant NK1R internalization but no MOR internalization, indicating that primary afferents do not release opioids. Moreover, capsaicin and NMDA also failed to produce MOR internalization. In contrast, dorsal horn stimulation elicited MOR internalization that increased with the frequency, being negligible at <10 Hz and maximal at 500 Hz. The internalization was abolished by the MOR antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), in the presence of low Ca2+ and by the Na+ channel blocker lidocaine, confirming that it was caused by opioid release and neuronal firing. DLF stimulation in "oblique" slices (encompassing the DLF and the dorsal horn of T11-L4) produced MOR internalization, but only in areas near the stimulation site. Moreover, cutting oblique slices across the dorsal horn (but not across the DLF) eliminated MOR internalization in areas distal to the cut, indicating that it was produced by signals traveling in the dorsal horn and not via the DLF. These findings demonstrate that some dorsal horn neurons release opioids when they fire at high frequencies, perhaps by integrating signals from the rostral ventromedial medulla, primary afferents, and other areas of the spinal cord.


Voltage-stepping schemes for the simulation of spiking neural networks.
The numerical simulation of spiking neural networks requires particular attention. On the one hand, time-stepping methods are generic but they are prone to numerical errors and need specific treatments to deal with the discontinuities of integrate-and-fire models. On the other hand, event-driven methods are more precise but they are restricted to a limited class of neuron models. We present here a voltage-stepping scheme that combines the advantages of these two approaches and consists of a discretization of the voltage state-space. The numerical simulation is reduced to a local event-driven method that induces an implicit activity-dependent time discretization (time-steps automatically increase when the neuron is slowly varying). We show analytically that such a scheme leads to a high-order algorithm so that it accurately approximates the neuronal dynamics. The voltage-stepping method is generic and can be used to simulate any kind of neuron models. We illustrate it on nonlinear integrate-and-fire models and show that it outperforms time-stepping schemes of Runge-Kutta type in terms of simulation time and accuracy.


Projecting kelp (Ecklonia radiata) gametophyte thermal adaptation and persistence under climate change.
Kelp forests underpin temperate marine ecosystems but are declining due to ocean warming, causing loss of associated ecosystem services. Projections suggest significant future decline but often only consider the persistence of adult sporophytes. Kelps have a biphasic life cycle, and the haploid gametophyte can be more thermally tolerant than the sporophyte. Therefore, projections may be altered when considering thermal tolerance of gametophytes. We undertook thermal tolerance experiments to quantify the effect of temperature on gametophyte survival, relative growth rates (RGR) and sex ratio for three genetically distinct populations of Ecklonia radiata gametophytes from comparatively high, mid and low latitudes (43°, 33° and 30°S). We then used this data to project the likely consequences of climate induced thermal change on gametophyte persistence and performance across its eastern Australian range, using generalised additive and linear models.Key results All populations were adapted to local temperatures and their thermal maximum was 2-3°C above current maximum in situ temperatures. The lowest latitude population was most thermally tolerant (~70% survival up to 27°C), while survival and RGR decreased beyond 25.5°C and 20.5°C for the mid- and low latitude populations, respectively. Sex ratios were skewed towards females with increased temperature in the low- and high latitude populations. Spatially explicit model projections under future ocean warming (2050-centred) revealed a minimal decline in survival (0-30%) across populations, relative to present-day predictions. RGRs were also projected to decline minimally (0-2% d -1).Conclusions: Our results contrast with projections for the sporophyte stage of E. radiata, which suggest a 257 km range contraction concurrent with loss of the low latitude population by 2100. Thermal adaptation in E. radiata gametophytes suggests this life stage is likely resilient to future ocean warming and is unlikely a bottleneck for the future persistence of kelp.


A prevention and management aid. Evaluation of the Nimbus II mattress.
1. Pressure relief is an important aspect of pressure sore prevention. 2. There are insufficient controlled clinical trials of the many pressure-relieving products available for use. 3. Clinical evaluations of new products can elicit useful information. 4. Evaluation of the Nimbus II Dynamic Flotation System found it to be useful in pressure sore prevention and management.


Overexpression of the miR-141/200c cluster promotes the migratory and invasive ability of triple-negative breast cancer cells through the activation of the FAK and PI3K/AKT signaling pathways by secreting VEGF-A.
The role of microRNA-200 (miR-200) family members in the migration and invasion of breast cancer is controversial. This study investigated the mechanisms by which the miR-200 family members modulated the migratory and invasive abilities of an aggressive triple-negative breast cancer (TNBC) cell line, MDA-MB-231. The miR-200 family (miR-200b/200a/429 and miR-141/200c clusters) and green fluorescence protein (GFP) were transduced into MDA-MB-231 cells using a lentiviral system. Stable cells highly expressing the miR-200 family and GFP were isolated by puromycin selection and fluorescence-activated cell sorting. Gene expression was evaluated using real-time polymerase chain reaction (PCR) and reverse transcriptase-PCR (RT-PCR). The migratory and invasive abilities were assessed using trans-well and wound-healing assays. The secreted cytokines and growth factors in cultured media were quantified using a Bio-Plex200 multiplex array system. Western blot assays and immunofluorescence staining were conducted to investigate miR-200 family-regulated signaling pathways. The entire dataset obtained in this study was statistically evaluated using a one-way ANOVA followed by a t-test. The stable overexpression of the miR-200b/200a/429 or miR-141/200c cluster suppressed cell growth and significantly increased migration and invasion of MDA-MB-231 cells. miR-141/200c overexpression was more effective in decreasing cell growth and promoting migration and invasion of MDA-MB-231 cells than was miR-200b/200a/429 overexpression. In addition, the overexpression of the miR-200b/200a/429 or miR-141/200c cluster led to an increase in the phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT). Chemical inhibitors of FAK and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT suppressed the migration and invasion of MDA-MB-231 cells that was enhanced by the overexpression of the miR-200b/200a/429 or miR-141/200c cluster. Compared to the miR-200b/200a/429 cluster-transduced MDA-MB-231 cells, the miR-141/200c cluster-transduced MDA-MB-231 cells exhibited a significant increase in vascular endothelial growth factor (VEGF)-A secretion and integrin-alphaV (integrin-αV) expression. Treatment with an anti-VEGF-A-neutralizing antibody inhibited the increase in migration and invasion in both the miR-200b/200a/429- and miR-141/200c-transduced MDA-MB-231 cells but significantly reduced the phosphorylation of FAK and AKT in only the miR-141/200c cluster-transduced MDA-MB-231 cells. Taken together, our data demonstrate a mechanism in which the miR-141/200c cluster, through FAK- and PI3K/AKT-mediated signaling by means of increased VEGF-A secretion, promotes the migratory and invasive abilities of MDA-MB-231 cells.


Cytologic follow up of Low-grade Squamous Intraepithelial Lesions in Pap smears after integrated treatment with antimicrobials followed by oral turmeric oil extract.
Cervical cancer is preventable because the carcinogenesis is slow and there are opportunities to detect precancerous lesions by Papanicolaou (Pap) smears, colposcopy, or HPV DNA tests and to treat them by antimicrobials, surgery or cold CO2 vapourization. We have earlier reported on the chemopreventive potential of integrated treatment with antimicrobials therapy followed by a standardized oral Turmeric Oil (TO) extract upto 12 weeks in women who had persistent Low-grade Squamous Intra-epithelial Lesion (LSIL) in their Pap smears. In this communication we report their post-therapy follow up for 36 months (N = 18) with Pap smears. We were also able to follow up for 36 months control cases (N = 10) who had only standard therapy with antimicrobials. During 36 months of follow up none of the cases with integrated treatment, progressed to HSIL or cancer. Out of 15/18 cases which had a regression of Pap smear, all 15 remained free of LSIL from 6 to 36 months post-therapy showing persistent therapeutic effect of integrated therapy. In one case there was recurrence of LSIL in Pap smear, ten months post-therapy, which regressed to mild atypia after a second course of oral TO for 8 weeks. In the control group, persistence of LSIL after antimicrobials was observed in Pap smears in 5/10 cases when followed up by Pap smears up to 36 months. This preliminary report indicates some post-therapeutic benefit with integrative treatment as compared to the use of antimicrobials alone. A large scale controlled study is warranted.


Synthetic lethality in large-scale integrated metabolic and regulatory network models of human cells.
Synthetic lethality (SL) is a promising concept in cancer research. A wide array of computational tools has been developed to predict and exploit synthetic lethality for the identification of tumour-specific vulnerabilities. Previously, we introduced the concept of genetic Minimal Cut Sets (gMCSs), a theoretical approach to SL developed for genome-scale metabolic networks. The major challenge in our gMCS framework is to go beyond metabolic networks and extend existing algorithms to more complex protein-protein interactions. In this article, we take a step further and incorporate linear regulatory pathways into our gMCS approach. Extensive algorithmic modifications to compute gMCSs in integrated metabolic and regulatory models are presented in detail. Our extended approach is applied to calculate gMCSs in integrated models of human cells. In particular, we integrate the most recent genome-scale metabolic network, Human1, with 3 different regulatory network databases: Omnipath, Dorothea and TRRUST. Based on the computed gMCSs and transcriptomic data, we discovered new essential genes and their associated synthetic lethal for different cancer cell lines. The performance of the different integrated models is assessed with available large-scale in-vitro gene silencing data. Finally, we discuss the most relevant gene essentiality predictions based on published literature in cancer research.


Influenza type A virus: an outstandingly protean pathogen and a potent modular weapon.
A remarkable debate recently arose on a global scale, about bioethics, biohazard, bioweaponry and bioterrorism issues related to scientific research concerning the induced transition of the highly lethal H5N1 avian flu virus from a non-pandemic to a tentatively pandemic strain, which might fall into malevolent hands. Appreciable ecogenetic complexity marks the main attributes of influenza type A viruses, namely infectivity, virulence, antigenicity, transmissibility, host range, endemicity, and epidemicity. They all shape, conjunctively, the outstanding protean nature of this pathogen, hence the modularity of the latter as a potent weapon. The present analysis inquires into those attributes, so as to profile and gauge threat, usability, impact and coping, particularly that the dimension of genetic engineering of this virus largely amplifies its potential. Within that context, various human interventions and misuses, including human experimental infections, undesirable vaccinations, as well as unauthorized and unskillful operations, led to bad corollaries and are also discussed in the present study. Altogether, a variety of interrelated properties underlying the complicatedness of and menaces posed by influenza A virus as a grave medical challenge, a dually explorable pathogen, and a modular biological warfare agent, are thereby illuminated, alongside with their scientific, strategic and practical implications.


Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance.
Activation Induced Cell Death of T helper cells is central to maintaining immune homeostasis and a perturbation often manifests in aberrant T helper cells that is associated with immunopathologies. Significant presence of T cells positive for IL-17A (Th17) and dual positive for IFN-γ/IL-17A (Th1/Th17) in both effector (CD45RA+RO+) and memory (CD45RA-RO+) compartments with differential FasL protein in RA peripheral blood suggested their differential TCR AICD sensitivity. Lowered active caspase-3 in Th17 and Th1/Th17 over Th1 cells confirmed their capability to resist AICD and pointed to early upstream events. Differential MAPK activities, FasL protein and downstream caspase-3 activities in murine Th1 and Th17 cells established distinct TCR mediated signaling pathways and suggested low Erk and p38 activity as pivotal for AICD sensitivity. We extrapolated our mouse and human data and report that Fas-FasL is the preferred death pathway for both Th1 and Th17 and that inherently low Erk2 activity protected Th17 cells from TCR AICD. The presence of significantly higher numbers of aberrant T helper cells in RA also suggest an inflammatory cytokine milieu and AICD insensitive T cell link to sustained inflammation. Re sensitization to apoptosis by targeting MAPK activity especially Erk2 in RA might be of therapeutic value.


Enhanced creatinine and estimated glomerular filtration rate reporting to facilitate detection of acute kidney injury.
While acute kidney injury (AKI) can be diagnosed based on specified increases in a patient's plasma creatinine level, standard creatinine reporting methods typically only flag creatinine results as abnormal when outside the reference range and often fail to identify rising creatinine values indicative of AKI. Here, we evaluate the impact of this limitation in standard creatinine reporting and develop and implement an enhanced creatinine reporting algorithm. We evaluated 59,712 plasma creatinine results collected over approximately 3 months, using computational simulations and statistical analyses. Our analyses demonstrated that 29% of creatinine results substantially increased over the patient's baseline and concerning for AKI remained within the normal reference range. These concerning results would not be flagged as abnormal using standard reporting. Likewise, we found that simple delta checks are also insensitive at AKI detection. To improve creatinine reporting, we developed and implemented an algorithm within our laboratory information system to alert clinicians to rising creatinine results, which we describe in this report. While both creatinine reference limits and simple delta checks are insensitive for AKI identification, a simple algorithm can be implemented within a common laboratory information system to enhance AKI identification.