Osteocyte lacunae in transiliac bone biopsy samples across life span.
Osteocytes act as bone mechanosensors, regulators of osteoblast/osteoclast activity and mineral homeostasis, however, knowledge about their functional/morphological changes throughout life is limited. We used quantitative backscattered electron imaging (qBEI) to investigate osteocyte lacunae sections (OLS) as a 2D-surrogate characterizing the osteocytes. OLS characteristics, the density of mineralized osteocyte lacunae (i.e., micropetrotic osteocytes, md.OLS-Density in nb/mm2) and the average degree of mineralization (CaMean in weight% calcium) of cortex and spongiosa were analyzed in transiliac biopsy samples from healthy individuals under 30 (n=59) and over 30 years (n=50) (i.e., before and after the age of peak bone mass, respectively). We found several differences in OLS-characteristics: 1). Inter-individually between the age groups: OLS-Density and OLS-Porosity were reduced by about 20% in older individuals in spongiosa and in cortex versus younger probands (both, p < 0.001). 2). Intra-individually between bone compartments: OLS-Density was higher in the cortex, +18.4%, p < 0.001 for younger and +7.6%, p < 0.05 for older individuals. Strikingly, the most frequent OLS nearest-neighbor distance was about 30 µm in both age groups and at both bone sites revealing a preferential organization of osteocytes in clusters. OLS-Density was negatively correlated with CaMean in both spongiosa and cortex (both, p < 0.001). Few mineralized OLS were found in young individuals along with an increase of md.OLS-Density with age. In summary, this transiliac bone sample analysis of 200000 OLS from 109 healthy individuals throughout lifespan reveals several age-related differences in OLS characteristics. Moreover, our study provides reference data from healthy individuals for different ages to be used for diagnosis of bone abnormalities in diseases. STATEMENT OF SIGNIFICANCE: Osteocytes are bone cells embedded in lacunae within the mineralized bone matrix and have a key role in the bone metabolism and the mineral homeostasis. Not easily accessible, we used quantitative backscattered electron imaging to determine precisely number and shape descriptors of the osteocyte lacunae in 2D. We analyzed transiliac biopsy samples from 109 individuals with age distributed from 2 to 95 years. Compact cortical bone showed constantly higher lacunar density than cancellous bone but the lacunar density in both bone tissue decreased with age before the peak bone mass age at 30 years and stabilized or even increased after this age. This extensive study provides osteocyte lacunae reference data from healthy individuals usable for bone pathology diagnosis.


How Cognitive Models of Human Body Experience Might Push Robotics.
In the last decades, cognitive models of multisensory integration in human beings have been developed and applied to model human body experience. Recent research indicates that Bayesian and connectionist models might push developments in various branches of robotics: assistive robotic devices might adapt to their human users aiming at increased device embodiment, e.g., in prosthetics, and humanoid robots could be endowed with human-like capabilities regarding their surrounding space, e.g., by keeping safe or socially appropriate distances to other agents. In this perspective paper, we review cognitive models that aim to approximate the process of human sensorimotor behavior generation, discuss their challenges and potentials in robotics, and give an overview of existing approaches. While model accuracy is still subject to improvement, human-inspired cognitive models support the understanding of how the modulating factors of human body experience are blended. Implementing the resulting insights in adaptive and learning control algorithms could help to taylor assistive devices to their user's individual body experience. Humanoid robots who develop their own body schema could consider this body knowledge in control and learn to optimize their physical interaction with humans and their environment. Cognitive body experience models should be improved in accuracy and online capabilities to achieve these ambitious goals, which would foster human-centered directions in various fields of robotics.


[Relation of intra-acinar arteries and their regression with changes of pulmonary artery pressure and blood gas values].
Pulmonary hypertension (PAH) induced by monocrotaline in thirteen rhesus monkeys, seven of them treated by hydralazine to reduce PAH. In hypertensive animals the PAP and PaCO2 increased, the PaO2 decreased. The structural changes in intra-acinar artery manifested mainly by an increase in number of muscular artery resulting from muscularization of precursor cells (pericytes and intermediate cells) located within partially muscular and nonmuscular arterial wall to smooth muscle cell, and by the medial wall thickened due to hypertrophy and hyperplasia of smooth muscle cells as well as accumulation of a large amount of collagen, especially the type 1 collagen. In treated animals the PAPm dropped concomitantly with blood gas values reversing to normal level. The remodelled arteries showed clearly structural regressions: The medial wall thickness was decreased in which the hypertrophied smooth muscles became slender or disappeared, the amount of extracellular matrix, especially the volume density of collagen, decreased. Most of muscularized arteries reversed to nonmuscular arteries leading to an increase in number of nonmuscular artery and a decrease in number of muscular artery. It is concluded that the intra-acinar artery remodelling and their regression closely correlated with the changes of PAP and blood gas values.


Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease.
Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike (S) protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ∼5- to 10-fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2. The substantial ∼5-fold or higher decrease of the half-maximal effective concentrations (EC50s) suggests a plausible treatment strategy based on the combined use of these inhibitors. IMPORTANCE Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the coronavirus disease 2019 (COVID-2019) global pandemic. There are ongoing efforts to uncover effective antiviral agents that could mitigate the severity of the disease by controlling the ensuing viral replication. Promising candidates include small molecules that inhibit the enzymatic activities of host proteins, thus preventing SARS-CoV-2 entry and infection. They include apilimod, an inhibitor of PIKfyve kinase, and camostat mesylate and nafamostat mesylate, inhibitors of TMPRSS2 protease. Our research is significant for having uncovered an unexpected synergism in the effective inhibitory activity of apilimod used together with camostat mesylate or nafamostat mesylate.


Neural Imaging Using Single-Photon Avalanche Diodes.
This paper analyses the ability of single-photon avalanche diodes (SPADs) for neural imaging. The current trend in the production of SPADs moves toward the minimum dark count rate (DCR) and maximum photon detection probability (PDP). Moreover, the jitter response which is the main measurement characteristic for the timing uncertainty is progressing. The neural imaging process using SPADs can be performed by means of florescence lifetime imaging (FLIM), time correlated single-photon counting (TCSPC), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). This trend will result in more precise neural imaging cameras. While achieving low DCR SPADs is difficult in deep submicron technologies because of using higher doping profiles, higher PDPs are reported in green and blue part of light. Furthermore, the number of pixels integrated in the same chip is increasing with the technology progress which can result in the higher resolution of imaging. This study proposes implemented SPADs in Deep-submicron technologies to be used in neural imaging cameras, due to the small size pixels and higher timing accuracies.


A comparison of the Truview blade with the Macintosh blade in adult patients.
The Truview blade facilitates a view of the vocal cords by indirect laryngoscopy. We prospectively compared the view obtained at laryngoscopy and intubating conditions of Truview (Group 1) or Macintosh (Group 2) blades in 170 patients who were scheduled to undergo general anaesthesia. We studied pre-operative airway evaluation, laryngoscopic view, duration of intubation, maximal force applied during intubation, anaesthetist's estimation of intubation effort on a 1-3 scale, bleeding, teeth and soft tissue damage, and postoperative stridor and hoarseness. The results demonstrated that, whilst the Truview produced a better laryngoscopic view and less maximal force applied during intubation, the duration of intubation was longer. No significant difference was found in the anaesthetist's estimation of intubation effort, tooth damage or postoperative stridor and hoarseness. Significantly fewer patients suffered bleeding and soft tissue damage following intubation with the Truview than with the Macintosh blade. The Truview blade is a useful option for tracheal intubation in patients with normal and anticipated difficult airways.


The mental health of immigrants and refugees: Canadian evidence from a nationally linked database.
Few studies of the healthy immigrant effect (HIE) have examined the mental health outcomes of Canadian-born individuals on a national scale compared with immigrants by admission category. This study fills this gap by examining the self-reported mental health (SRMH) of immigrants by admission category and other immigration dimensions (e.g., source world region and duration since landing) and making comparisons with Canadian-born respondents to a population-based survey. Based on four cycles (2011 to 2014) of the Canadian Community Health Survey (CCHS) linked to the Longitudinal Immigration Database (IMDB), odds ratios of high (i.e., excellent or very good) SRMH among Canadian-born respondents and IMDB-linked immigrants are compared using logistic regression. Among the IMDB immigrant population, high SRMH was also examined according to the above-mentioned immigration dimensions. Adjusted results were hierarchically controlled for age, sex, social and economic factors, and sense of belonging. Age-sex adjusted results show that immigrants, especially refugees, are less likely than the Canadian-born population to report high mental health levels, but these differences disappeared after full adjustment. The odds of immigrants having high SRMH differed more by source world region and duration since landing. For example, fully adjusted results show support for the HIE, with recent immigrants (interviewed within 10 years of landing) more likely to report high SRMH than either the Canadian-born population or established immigrants. Greater odds of high SRMH among recent immigrants also holds across admission classes and for selected world regions. This study provides new evidence on differences in mental health between Canadian-born individuals and immigrants by various characteristics. Results support a deterioration of the HIE in SRMH and identify factors significantly associated with SRMH. This study can also serve as a baseline for further studies on the impact of COVID-19 on immigrants' mental health by immigrant category.


Chronic hyperosmotic stress inhibits renal Toll-Like Receptors expression in striped catfish (Pangasianodon hypophthalmus, Sauvage) exposed or not to bacterial infection.
Toll-like Receptors (TLRs) are the first innate receptors in recognizing pathogen-associated molecular patterns. In fish, upregulation of toll-like receptors during infection has been largely demonstrated while the effects of abiotic stressors on their expression remain poorly investigated. In this study, striped catfish were submitted during 20 days to three salinity profiles (freshwater, low saline water, saline water), followed by injection of a bacterial strain of Edwardsiella ictaluri. The expression of TLRs 1, 3, 4, 5, 7, 9, 19, 21, and 22 was measured in kidney at different time points in non infected and infected striped catfish. Infection induced overexpression of TLRs 1, 3, 4, 5, 7, 21 and 22. With elevated salinity, the expression of all TLRs, except TLR5, was severely decreased, particularly after bacterial infection. The TLRs responsiveness of striped catfish facing bacterial disease and salinity stress and possible consequences on striped catfish immune response's efficiency are discussed.


Intestinal transit of a glucose bolus and incretin kinetics: a mathematical model with application to the oral glucose tolerance test.
The rate of appearance (R(a)) of exogenous glucose in plasma after glucose ingestion is presently measured by tracer techniques that cannot be used in standard clinical testing such as the oral glucose tolerance test (OGTT). We propose a mathematical model that represents in a simple way the gastric emptying, the transport of glucose along the intestinal tract, and its absorption from gut lumen into portal blood. The model gives the R(a) time course in terms of parameters with a physiological counterpart and provides an expression for the release of incretin hormones as related to glucose transit into gut lumen. Glucose absorption was represented by assuming two components related to a proximal and a distal transporter. Model performance was evaluated by numerical simulations. The model was then validated by fitting OGTT glucose and GLP-1 data in healthy controls and type 2 diabetic patients, and useful information was obtained for the rate of gastric emptying, the rate of glucose absorption, the R(a) profile, the insulin sensitivity, and the glucose effectiveness. Model-derived estimates of insulin sensitivity were well correlated (r = 0.929 in controls and 0.886 in diabetic patients) to data obtained from the euglycemic hyperinsulinemic clamp. Although the proposed OGTT analysis requires the measurement of an additional hormone concentration (GLP-1), it appears to be a reasonable choice since it avoids complex and expensive techniques, such as isotopes for glucose R(a) measurement and direct assessment of gastric emptying and intestinal transit, and gives additional correlated information, thus largely compensating for the extra expense.


Selective excision of chain-terminating nucleotides by HIV-1 reverse transcriptase with phosphonoformate as substrate.
A major mechanism for human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) resistance to nucleoside analogs involves the phosphorolytical removal of the chain-terminating nucleotide from the 3'-end of the primer. In this work, we analyzed the effect of phosphonoformate (PFA) and other pyrophosphate (PP(i)) analogs on PP(i)- and ATP-dependent phosphorolysis catalyzed by HIV-1 RT. Our experimental data demonstrated that PFA did not behave as a linear inhibitor but as an alternative substrate, allowing RT to remove AZT from a terminated primer through a PFA-dependent mechanism. Interestingly, in non-terminated primers, PFA was not a substrate for this reaction and competitively inhibited PP(i)- and ATP-dependent phosphorolysis. In fact, binding of PFA to the RT.template/primer complex was hindered by the presence of a chain terminator at the 3'-end of the primer. Other pyrophosphate analogs, such as phosphonoacetate, were substrates for the excision reaction with both terminated and nonterminated primers, whereas pamidronate, a bisphosphonate that prevents bone resorption, was not a substrate for these reactions and competitively inhibited the phosphorolytic activity of RT. As expected from their mechanisms of action, pamidronate (but not PFA) synergistically inhibits HIV-1 RT in combination with AZT-triphosphate in the presence of PP(i) or ATP. These results provide new clues about the mechanism of action of PFA and demonstrate that only certain pyrophosphate analogs can enhance the effect of nucleosidic inhibitors by blocking the excision of chain-terminating nucleotides catalyzed by HIV-1 RT. The relevance of these findings in combined chemotherapy is discussed.


The effect of combined therapy according to the guidelines for the treatment of Mycobacterium avium complex pulmonary disease.
To investigate whether the combined therapy according to the guideline proposed by American Thoracic Society (ATS) and Japanese Society for Tuberculosis (JST) is clinically appropriate for Mycobacterium avium complex (MAC) pulmonary disease. Seventy-one patients in whom MAC pulmonary disease was diagnosed at Kawasaki Medical School and our associated ten hospitals were prospectively studied. Seventy-one patients with Mycobacterium avium complex (MAC) pulmonary disease were 27 males and 44 females with a mean age of 64.4 +/- 10.2 years old. Patients received 400 mg/day or 600 mg/day of clarithromycin plus ethambutol, rifampicin, and initial streptomycin for 12 months. Among 71 patients who received more than 12 months of therapy, 41 patients (57.7%) converted their sputum to negative within six months after the initiation of this regimen, 16 of 41 patients (39.0%) relapsed, and 23 of 71 patients (32.4%) obtained clinical improvement on chest X-ray and/or clinical symptoms. The mortality rate had a comparatively good prognosis with a low incidence of 2.8%. Although the species of pathogen (M. avium or M. intracellulare) did not significantly affect the conversion rate or clinical improvement, the infectious form with or without respiratory underlying disease, the characteristics and extent of lesion on chest X-ray, and the dose of clarithromycin significantly influenced the conversion rate or clinical improvement. There were no problems concerning adverse reactions for this regimen. This combined therapy, according to the guideline proposed by ATS and JST, was one of the effective treatments compared to the clinical effect of only antituberculous drugs through this study. However, this combined therapy was unsatisfactory compared to the clinical effect for pulmonary tuberculosis. The development of new companion drugs for MAC pulmonary diseases is needed.


Prevalence of Fungal and Bacterial Co-Infection in Pulmonary Fungal Infections: A Metagenomic Next Generation Sequencing-Based Study.
With the widespread use of antibacterial drugs and increasing number of immunocompromised patients, pulmonary fungal infections are becoming more common. However, the incidence of pulmonary fungal and bacterial co-infection is rarely reported. In this study, 119 patients definitively diagnosed with pulmonary fungal infections between July 2018 and March 2020 were assessed using metagenomic next-generation sequencing (mNGS) as well as traditional pathogen detection to gauge the incidence of fungal and bacterial co-infection and evaluate the associated risk factors. We found that of the 119 patients with fungal infections, 48 (40.3%) had pulmonary fungal and bacterial co-infection. We identified immunocompromised status and the presence of one or more pulmonary cavities as risk factors associated with fungal and bacterial co-infection. The most commonly isolated fungi species were Aspergillus, Pneumocystis, and Rhizopus. The most commonly isolated bacterial species were Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. Seventy-nine (66.4%) patients had received empirical antibiotic treatment before their pathogenic test results became available, and 41.7% (fungal infection group) and 38.7% (fungal and bacterial co-infection group) of the patients had their antibacterial drug dosage changed accordingly. This mNGS-based study showed that the incidence of fungal and bacterial co-infection is significant. Our research outcomes can, thus, guide the use of antibacterial drugs in the treatment of clinical fungal infections.


The potential of aquatic bloodfeeding and nonbloodfeeding leeches as a tool for iDNA characterisation.
Leeches play important roles in food webs due to their abundance, diversity and feeding habits. Studies using invertebrate-derived DNA (iDNA) extracted from leech gut contents to target vertebrate DNA have focused on the Indo-Pacific region and mainly leveraged the leech family Haemadipsidae, composed of bloodfeeding terrestrial leeches, while predatory, fluid/tissue-feeding and aquatic bloodfeeding species have been largely disregarded. While there is some general knowledge regarding the taxonomic groups that leeches prefer to feed on, detailed taxonomic resolution is missing and, therefore, their potential use for monitoring animals is unknown. In this study, 116 leeches from 12 species (six families) and spanning the three feeding habits were collected in Mexico and Canada. We used DNA metabarcoding to investigate their diet and assess their potential use for biodiversity monitoring. We detected vertebrates from five orders including fish, turtles and birds in the diet of aquatic bloodfeeding leeches; eight invertebrate orders of annelids, arthropods and molluscs in leeches that feed on body fluids and tissues; and 10 orders of invertebrates belonging to Arthropoda and Annelida, as well as one vertebrate and one parasitic nematode, in predatory leeches. These results show the potential use of iDNA from aquatic bloodfeeding leeches for retrieving vertebrate taxa, and from predatory and fluid-feeding leeches for invertebrates. Our study provides information about the dietary range of freshwater leeches and one terrestrial leech and contributes proof-of-concept for the use of these leeches for animal monitoring, expanding our knowledge of the use of iDNA from leech gut contents to North America.


[Combined deficiency of thyroid stimulating hormone and growth hormone in a diabetic patient with Hashimoto thyroiditis].
We report the case of a 36-year-old female patient with insulin dependent diabetes who developed hypothyroidism of pituitary origin after giving birth. She had low levels of free T4 and TSH with no response to i.v. TRH. Antimicrosome antibodies were increased (1/25000), suggesting Hashimoto's thyroiditis. The other hormones were normal except for a low level of growth hormone and insulin growth factor 1. There were no antibodies against the pituitary. MRI of the pituitary was normal. We suspect a vascular origin for this partial pituitary deficiency.


Replication signals in the genome of vesicular stomatitis virus and its defective interfering particles: identification of a sequence element that enhances DI RNA replication.
We have analyzed the role of terminal sequences of a defective interfering (DI) particle RNA of vesicular stomatitis virus (VSV) in replication. A series of internal deletion mutants of DI cDNA was generated to obtain DI genomic RNAs that differed from one another by the presence of different lengths of 3'-terminal and/or 5'-terminal sequences. Analyses of the mutant. RNAs for their ability to replicate in cells transfected with the corresponding plasmids suggested that distinct regions at the termini of DI RNA are important for RNA replication. Region I, encompassing nucleotides 1-24, is absolutely required for replication since DI RNA genomes lacking any part of this region failed to replicate. Region II, spanning nucleotides 25-45, is not essential for replication but it functions as an enhancer of replication in that the presence of these specific sequences confers high efficiency of replication to the template. Deleting these specific sequences from both termini of DI RNA but maintaining the length of terminal complementarity as seen in wild-type DI RNA resulted in a template that replicated poorly (about 20-fold less efficiently). Furthermore, insertion or substitution of these sequences into the 3'-terminus of a VSV minigenome resulted in a template that replicated more efficiently (at least 4-fold to as high as 15-fold) than the parental minigenome. These results strongly support the conclusion that the presence of specific sequences rather than the extent of complementarity at the termini of DI RNA is a major determinant of the efficiency of replication. The presence of the specific sequences at the 3'-terminus of both genomic and antigenomic DI RNAs may explain in part the replicative dominance of DI RNA over the full-length VSV genome which contains these sequences only at the 3'-terminus of the antigenome.


Transport properties of cultured branchial epithelia from freshwater rainbow trout: a novel preparation with mitochondria-rich cells.
A new double-seeded insert (DSI) technique is described for culture of branchial epithelial preparations from freshwater rainbow trout on filter supports. DSI epithelia contain both pavement cells and mitochondria-rich (MR) cells (15.7+/-2.5 % of total cell numbers). MR cells occur singly or in clusters, are voluminous, open apically to the 'external environment' and exhibit ultrastructural characteristics similar to those found in the 'chloride cells' of freshwater fish gills. After 6-9 days in culture with Leibovitz's L-15 medium on both surfaces (symmetrical conditions), transepithelial resistance (TER) stabilized at values as high as 34 k capomega cm(2), indicative of electrically 'tight' epithelia. The density of MR cells, the surface area of their clusters and transepithelial potential (TEP; up to +8 mV basolateral positive, mean +1.9+/-0.2 mV) were all positively correlated with TER. In contrast, preparations cultured using an earlier single-seeded insert (SSI) technique contained only pavement cells and exhibited a negligible TEP under symmetrical conditions. Na(+)/K(+)-ATPase activities of DSI preparations were comparable with those in gill filaments, but did not differ from those of SSI epithelia. Replacement of the apical medium with fresh water to mimic the in vivo situation (asymmetrical conditions) induced a negative TEP (-6 to -15 mV) and increased permeability to the paracellular marker PEG-4000. Under symmetrical conditions, unidirectional Na(+) and Cl(-) fluxes were in balance, and there was no active transport by the Ussing flux ratio criterion. Under asymmetrical conditions, there were large effluxes, small influxes and evidence for active Cl(-) uptake and Na(+) extrusion. Unidirectional Ca(2+) fluxes were only 0.5-1.0 % of Na(+) and Cl(-) fluxes; active net Ca(2+) uptake occurred under symmetrical conditions and active net extrusion under asymmetrical conditions. Thus, DSI epithelia exhibit some of the features of the intact gill, but improvements in culture conditions are needed before the MR cells will function as true freshwater 'chloride cells'.


Anthropometric and Cephalometric Facial Characteristics of Adult Saudi Patients with Skeletal Class III Malocclusions.
We aimed to assess adult Saudi patients' facial anthropometry and cephalometric characteristics with skeletal Class III malocclusions compared to Class I malocclusion patients. Our cross-sectional study included a review of the orthodontic records of 108 patients: 54 patients with skeletal Class III malocclusions and 54 patients with skeletal Class I malocclusions, equally distributed between males and females. Using anthropometric landmarks, seven angular and eight linear measurements were recorded and compared between Class III and Class I patients. In addition, we compared three horizontal facial proportions and three horizontal neoclassical canons between the two groups. Finally, we used Student's t-tests to compare continuous variables and Chi-square tests for categorical variables. Class III patients had significantly larger mandibular length, mandibular plane angle, mid- and lower-anterior face height, and posterior face height (P < 0.05) compared to Class I patients. Class III patients had significantly proclined upper incisors, retroclined lower incisors, and an obtuse interincisal angle (P < 0.05). The mouth: nose ratio differed significantly between skeletal Class III and I patients (P = 0.008). The orbital canon was valid in 14.8% of Class I and 9.3% of Class III patients, respectively. The orbitonasal proportion applied only to 31.5% and 20.4% of Class I and III patients, respectively. The naso-oral canon occurred in 18.5% and 1.9% of Class I and III patients, respectively. Saudis with Class III skeletal profiles have some distinctive Class III characteristics not observed in most other ethnic groups. The established horizontal facial proportions, neoclassical facial canons, and Class III skeletal profile did not apply to Saudis with skeletal Class I malocclusions, indicating that these proportions and characteristics may not be suitable as references when planning the surgical treatment for these patients.


Prolactin induces ERalpha-positive and ERalpha-negative mammary cancer in transgenic mice.
The role of prolactin in human breast cancer has been controversial. However, it is now apparent that human mammary epithelial cells can synthesize prolactin endogenously, permitting autocrine/paracrine actions within the mammary gland that are independent of pituitary prolactin. To model this local mammary production of prolactin (PRL), we have generated mice that overexpress prolactin within mammary epithelial cells under the control of a hormonally nonresponsive promoter, neu-related lipocalin (NRL). In each of the two examined NRL-PRL transgenic mouse lineages, female virgin mice display mammary developmental abnormalities, mammary intraepithelial neoplasias, and invasive neoplasms. Prolactin increases proliferation in morphologically normal alveoli and ducts, as well as in lesions. The tumors are of varied histotype, but papillary adenocarcinomas and adenosquamous neoplasms predominate. Neoplasms can be separated into two populations: one is estrogen receptor alpha (ERalpha) positive (greater than 15% of the cells stain for ERalpha), and the other is ERalpha- (<3%). ERalpha expression does not correlate with tumor histotype, or proliferative or apoptotic indices. These studies provide a mouse model of hormonally dependent breast cancer, and, perhaps most strikingly, a model in which some neoplasms retain ERalpha, as occurs in the human disease.


Site-specific postural and locomotor changes evoked in awake, freely moving intact cats by stimulating the brainstem.
Locomotor behaviors evoked by stimulating the hypothalamus and the brainstem were studied in freely moving, awake cats. To do this, stimulating microelectrodes were chronically implanted into the subthalamic locomotor region (SLR) in the lateral hypothalamic area (LHA), the mesencephalic locomotor region (MLR) corresponding to the nucleus cuneiformis, the dorsal tegmental field (DTF) and the ventral tegmental field (VTF) of caudal pons along its midline. After recovery from surgery (2-3 days), open field tests were performed to study stimulus effects upon posture and locomotor movements. The stimuli consisted of pulses of 0.2 ms duration of less than 80 microA delivered at 50 pulses/s for 5-20 s. DTF stimulation resulted in suppression of postural support by the hindlimbs. When the cat was in a standing posture, DTF stimulation simply resulted in a sequential alteration of posture to a squatting and then to a final lying posture. In contrast, VTF stimulation evoked an almost opposite series of postural changes to those induced by DTF stimulation. With VTF stimulation, the cat changed from a lying or a squatting position, and then started to walk during continuation of the stimulation. With MLR stimulation, the cat invariably exhibited fast walking and then running movements. It ran straight forward, avoiding collision with walls or other obstacles, and even tried to jump over a fence placed in front of it. With LHA stimulation, the cat started to walk slowly extending its head forward and looking around repeatedly. It tended to walk with a stoop and stealthy steps along the corners of the room. Induced postural and locomotor changes were always accompanied by behavioral arousal reactions.(ABSTRACT TRUNCATED AT 250 WORDS)


Sudden Death Secondary to an Undiagnosed B-Cell Lymphoma of the Hypopharynx and Infiltration of the Inferior Constrictor Muscle.
The aim of this presentation was to share an uncommon form of sudden death, suffered by a 64-year-old woman, due to a mechanical obstruction of hypopharynx by an undiagnosed B-cell lymphoma, infiltrating the inferior pharyngeal constrictor muscle. A forensic approach by means of scene investigation, circumstantial data collection, autopsy, and histological and toxicological investigations led to conclude that the cause of death was asphyxia, correlated with B-cell lymphoma of the hypopharynx. The autopsy examination highlighted the presence of a wall thickening, infiltrating, and projecting into the hypopharynx lumen. The histological analysis showed the essential finding of a B-cell lymphoma of the hypopharynx, diffusely infiltrating the inferior pharyngeal constrictor muscle. To conclude, this case demonstrates once more that in the absence of specific data, a thorough forensic investigation including autopsy, histological examination, and circumstantial data collection is mandatory to reach a correct cause of death.


[Little known forms of compression neuropathies of the lower extremities].
Neuropathies of the sural nerve, deep peroneal nerve and tibial nerve at the level of the tendinous arch of the musculus soleus pertain to the little-known forms of compression neuropathies. Examinations of 36 patients with 57 cases of such compression neuropathies have demonstrated that the main etiological moments of the disease are orthopedic diseases, illnesses of the joints and veins of the lower limbs and loading factor. The major clinical symptoms of the disease are spontaneous pains at the site of nerve compression, paresthesias, disorders of sensitivity in the area of innervation of the damaged nerve as well as pains on palpation at the level of nerve compression. Diagnosis is verified by the positive tests inducing pains and paresthesias and by stimulation electromyography. The principal treatment method lies in paraneural injection of glucocorticoids.


Predictors of left ventricular remodeling after ST-elevation myocardial infarction.
Adverse left ventricular (LV) remodeling after acute ST-elevation myocardial infarction (STEMI) is associated with morbidity and mortality. We studied clinical, biochemical and angiographic determinants of LV end diastolic volume index (LVEDVi), end systolic volume index (LVESVi) and mass index (LVMi) as global LV remodeling parameters 4 months after STEMI, as well as end diastolic wall thickness (EDWT) and end systolic wall thickness (ESWT) of the non-infarcted myocardium, as compensatory remote LV remodeling parameters. Data was collected in 271 patients participating in the GIPS-III trial, presenting with a first STEMI. Laboratory measures were collected at baseline, 2 weeks, and 6-8 weeks. Cardiovascular magnetic resonance imaging (CMR) was performed 4 months after STEMI. Linear regression analyses were performed to determine predictors. At baseline, patients were 21% female, median age was 58 years. At 4 months, mean LV ejection fraction (LVEF) was 54 ± 9%, mean infarct size was 9.0 ± 7.9% of LVM. Strongest univariate predictors (all p < 0.001) were peak Troponin T for LVEDVi (R2 = 0.26), peak CK-MB for LVESVi (R2 = 0.41), NT-proBNP at 2 weeks for LVMi (R2 = 0.24), body surface area for EDWT (R2 = 0.32), and weight for ESWT (R2 = 0.29). After multivariable analysis, cardiac biomarkers remained the strongest predictors of LVMi, LVEDVi and LVESVi. NT-proBNP but none of the acute cardiac injury biomarkers were associated with remote LV wall thickness. Our analyses illustrate the value of cardiac specific biochemical biomarkers in predicting global LV remodeling after STEMI. We found no evidence for a hypertrophic response of the non-infarcted myocardium.


Male-Male Competition Causes Parasite-Mediated Sexual Selection for Local Adaptation.
AbstractSexual selection has been suggested to accelerate local adaptation and promote evolutionary rescue through several ecological and genetic mechanisms. Condition-dependent sexual selection has mainly been studied in laboratory settings, while data from natural populations are lacking. One ecological factor that can cause condition-dependent sexual selection is parasitism. Here, we quantified ectoparasite load (Arrenurus water mites) in a natural population of the common bluetail damselfly (Ischnura elegans) over 15 years. We quantified the strength of sexual selection against parasite load in both sexes and experimentally investigated the mechanisms behind such selection. Then we investigated how parasite resistance and tolerance changed over time to understand how they might influence population density. Parasites reduced mating success in both sexes, and sexual selection was stronger in males than in females. Experiments show that male-male competition is a strong force causing precopulatory sexual selection against parasite load. Although parasite resistance and male parasite tolerance increased over time, suggestive of increasing local adaptation against parasites, no signal of evolutionary rescue could be found. We suggest that condition-dependent sexual selection facilitates local adaptation against parasites and discuss its effects in evolutionary rescue.


Healthy communities. Our focus for the future.
The autumn of 1994 has arrived. At this same time last year, most political pundits and policy wonks proclaimed that the Congress would surely take action to overhaul the American health care system before this year's November elections. But as 1994 draws to a close, it has become apparent that Washington is unlikely to produce comprehensive reform legislation at any time in the near future. However, while our political system has failed to act in any meaningful way, its inability to chart a course for change has not quelled the movement to reshape our nation's health care system. Despite Congressional inertia, substantial health care reform is taking place both in Michigan and throughout the nation. These reforms are characterized by a central theme: rapid movement away from our historic focus on illness, and toward a more rational focus on health. Our commitment to healthy communities stands as a firm testament to our mission of service and our role as the central core of the health care delivery system. This article will address the various components of that paradigm shift, and highlight some of the outstanding efforts of Michigan hospitals as they partner with their communities to reshape the delivery of health care services.


Employment of the Triple Helix concept for development of regenerative medicine applications based on human pluripotent stem cells.
Using human pluripotent stem cells as a source to generate differentiated progenies for regenerative medicine applications has attracted substantial interest during recent years. Having the capability to produce large quantities of human cells that can replace damaged tissue due to disease or injury opens novel avenues for relieving symptoms and also potentially offers cures for many severe human diseases. Although tremendous advancements have been made, there is still much research and development left before human pluripotent stem cell derived products can be made available for cell therapy applications. In order to speed up the development processes, we argue strongly in favor of cross-disciplinary collaborative efforts which have many advantages, especially in a relatively new field such as regenerative medicine based on human pluripotent stem cells. In this review, we aim to illustrate how some of the hurdles for bringing human pluripotent stem cell derivatives from bench-to-bed can be effectively addressed through the establishment of collaborative programs involving academic institutions, biotech industries, and pharmaceutical companies. By taking advantage of the strengths from each organization, innovation and productivity can be maximized from a resource perspective and thus, the chances of successfully bringing novel regenerative medicine treatment options to patients increase.


Traditional Chinese Medicine Formula Kang Shuai Lao Pian Improves Obesity, Gut Dysbiosis, and Fecal Metabolic Disorders in High-Fat Diet-Fed Mice.
High-fat diet (HFD)-induced obesity is a risk factor for many metabolic disorders including cardiovascular diseases, diabetes, and fatty liver disease. Although there are accumulating evidences supporting the assumption that regulating gut microbiota as well as its metabolic status is able to mitigate obesity, the inner relationship between the obesity-related gut microbiota and the relevant metabolites are not well defined. In current study, we applied a traditional herbal formula Kang Shuai Lao Pian (KSLP) to HFD-fed mice and evaluated its effect against obesity. Emphases were addressed on identifying profiles of gut microbiota and fecal metabolites with the aid of 16S rRNA gene sequencing and non-target fecal metabolomics techniques. We showed that KSLP could improve HFD-induced obesity, glucose tolerance disorder, as well as gut dysbiosis. In the gut, KSLP corrected the increased abundance of Firmicutes and Proteobacteria, increased ratio of Firmicutes/Bacteroidetes, and decreased abundance of Bacteroidetes caused by HFD. KSLP also reversed HFD-induced significant changes in the abundance of certain genus including Intestinimonas, Oscillibacter, Christensenellaceae_R-7_group, Ruminococcaceae_UCG-010, and Aliihoeflea. Pearson correlation analysis indicated that except for Ruminococcaceae_UCG-010, other four genera had positive correlations with obesity. In addition, 22 key fecal metabolites responding to KSLP treatment were identified. Pearson correlation analysis showed that those metabolites are intimately related to KSLP effective genera of Intestinimonas, Oscillibacter, and Christensenellaceae_R-7_group. Our results indicate that KSLP is a promising traditional Chinese medicine (TCM) applicable for individuals with HFD habit. Intestinimonas, Oscillibacter, and Christensenellaceae_R-7_group might be responsible for the regulatory effect of KSLP. Linking of obesity phenotypes with gut microbiota as well as fecal metabolites is therefore a powerful research strategy to reveal the mechanism of obesity and the targets of intervention.


Brain Endothelial Erythrophagocytosis and Hemoglobin Transmigration Across Brain Endothelium: Implications for Pathogenesis of Cerebral Microbleeds.
Peripheral endothelial cells are capable of erythrophagocytosis, but data on brain endothelial erythrophagocytosis are limited. We studied the relationship between brain endothelial erythrophagocytosis and cerebral microhemorrhage, the pathological substrate of MRI-demonstrable cerebral microbleeds. To demonstrate the erythrophagocytic capability of the brain endothelium, we studied the interactions between brain endothelial cells and red blood cells exposed to oxidative stress in vitro, and developed a new in vitro cerebral microbleeds model to study the subsequent passage of hemoglobin across the brain endothelial monolayer. Using multiple approaches, our results show marked brain endothelial erythrophagocytosis of red blood cells exposed to oxidative stress compared with control red blood cells in vitro. This brain endothelial erythrophagocytosis was accompanied by passage of hemoglobin across the brain endothelial monolayer with unaltered monolayer integrity. In vivo and confocal fluorescence microscopy studies confirmed the extravasation of RBC exposed to oxidative stress across brain endothelium. These findings, demonstrating erythrophagocytosis mediated by the brain endothelial monolayer and the subsequent passage of iron-rich hemoglobin in vitro and RBC in vivo, may have implications for elucidating mechanisms involved in the development of cerebral microbleeds that are not dependent on disruption of the microvasculature.


Methamphetamine enhances Cryptococcus neoformans pulmonary infection and dissemination to the brain.
Methamphetamine (METH) is a major addictive drug of abuse in the United States and worldwide, and its use is linked to HIV acquisition. The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis in patients with AIDS. In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity. Using a systemic mouse model of infection and in vitro assays in order to critically assess the impact of METH on C. neoformans pathogenesis, we demonstrate that METH stimulates fungal adhesion, glucuronoxylomannan (GXM) release, and biofilm formation in the lungs. Interestingly, structural analysis of the capsular polysaccharide of METH-exposed cryptococci revealed that METH alters the carbohydrate composition of this virulence factor, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Additionally, we show that METH promotes C. neoformans dissemination from the respiratory tract into the brain parenchyma. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms. Methamphetamine (METH) is a major health threat to our society, as it adversely changes people's behavior, as well as increases the risk for the acquisition of diverse infectious diseases, particularly those that enter through the respiratory tract or skin. This report investigates the effects of METH use on pulmonary infection by the AIDS-related fungus Cryptococcus neoformans. This drug of abuse stimulates colonization and biofilm formation in the lungs, followed by dissemination of the fungus to the central nervous system. Notably, C. neoformans modifies its capsular polysaccharide after METH exposure, highlighting the fungus's ability to adapt to environmental stimuli, a possible explanation for its pathogenesis. The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse.


Social factors in frequent callers: a description of isolation, poverty and quality of life in those calling emergency medical services frequently.
Frequent users of emergency medical services (EMS) comprise a disproportionate percentage of emergency department (ED) visits. EDs are becoming increasingly overwhelmed and a portion of use by frequent callers of EMS is potentially avoidable. Social factors contribute to frequent use however few studies have examined their prevalence. This study aims to describe social isolation/loneliness, poverty, and quality of life in a sample of frequent callers of EMS in the Hamilton region, a southern Ontario mid-sized Canadian city. Cross-sectional quantitative study. We surveyed people who called EMS five or more times within 12 months. A mailed self-administered survey with validated tools, and focused on four major measures: demographic information, social isolation, poverty, and quality of life. Sixty-seven frequent EMS callers revealed that 37-49% were lonely, 14% had gone hungry in the preceding month, and 43% had difficulties making ends meet at the end of the month. For quality of life, 78% had mobility problems, 55% had difficulty with self-care, 78% had difficulty with usual activities, 87% experienced pain/discomfort, and 67% had anxiety/depression. Overall quality adjusted life years value was 0.53 on a scale of 0 to 1. The response rate was 41.1%. Loneliness in our participants was more common than Hamilton and Canadian rates. Frequent EMS callers had higher rates of poverty and food insecurity than average Ontario citizens, which may also act as a barrier to accessing preventative health services. Lower quality of life may indicate chronic illness, and users who cannot access ambulatory care services consistently may call EMS more frequently. Frequent callers of EMS had high rates of social loneliness and poverty, and low quality of life, indicating a need for health service optimization for this vulnerable population.


[Periarteritis nodosa in children. Diagnostic difficulties in 2 cases].
Periarteritis nodosa is a rare multisystemic disease whose diagnosis is difficult: diagnostic approach by biopsies in various involved organs is of poor efficacy; abdominal selective angiography yields a precise diagnosis in 50 to 60 of the studied cases as far as the celiac, mesenteric and renal circulations are investigated selectively. Digitalized intravenous angiography (DIVA) carried out in two patients of 9 and 13 years of age allowed to demonstrate aneurysm formations in hepatic, renal and cerebral circulations. Its true efficacy in the diagnosis of periarteritis nodosa of children remains to be determined.


Detection and reporting of drug-induced proarrhythmias: room for improvement.
Recently adopted guidelines mandate the inclusion of detailed non-clinical and clinical QT data in future drug labels. As a result of increasing recognition of drug-induced proarrhythmias, and the bias introduced by the prescribing physician's awareness of these events, it is likely that the number of adverse drug reaction (ADR) reports of life-threatening ventricular arrhythmias and sudden death, allegedly caused by the drug, will increase. To illustrate how different approaches have been used to assess proarrhythmic liability and validate ADR reports on serious ventricular arrhythmias, this overview assesses pharmacoepidemiology studies on terfenadine and cisapride, the quality of ADR reports and the effect of label changes on prescribing patterns and other information to prescribing physicians. Clinical and pharmacoepidemiology studies, which in most cases did not demonstrate an increased risk for proarrhythmias with these two drugs, are discussed with emphasis on limitations, studied endpoints, and populations. Recommendations are made on how to improve the effectiveness of labelled precautions and contraindications, which may include the implementation of more effective alert systems. Given the low incidence of drug-induced proarrhythmias, 'signal' generation through ADR reports will continue to have a key role for early identification of proarrhythmic liability of newly marketed drugs. The quality of these reports varies widely, and can be improved through implementation of procedures by which complementary information is captured and events are adjudicated and classified into confidence categories using a consistent scheme across different classes of drugs.


Inflammatory low back pain with radiculopathy revealing epidural disintegration of a bullet complicated by lead poisoning.
Inflammatory low back pain with radiculopathy is suggestive of cancer, infection or inflammatory diseases. We report a unique case of a 42-year-old patient with an acute inflammatory low back pain with bilateral radiculopathy associated with weight loss and abdominal pain, revealing the disintegration of a lead bullet along the epidural space and the S1 nerve root complicated by lead poisoning. Because of the high blood lead level of intoxication (>10 times over the usual lead levels) and the failure of repeated lead chelator cycles, a surgical treatment to remove bullet fragments was performed. It resulted in a significant decrease of pain and lead intoxication.


Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Investigating microscopic haematuria in blunt abdominal trauma.
A short cut review was carried out to establish whether it is necessary to carry out further imaging in order to identify clinically significant renal injury in patients with microscopic haematuria after blunt abdominal trauma. Altogether 57 papers were found using the reported search, of which 10 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.


B-type natriuretic peptide levels in patients with COPD and normal right ventricular function.
Evidence suggests that elevated plasma levels of B-type natriuretic peptide (BNP) are found in patients with chronic obstructive pulmonary disease (COPD) and right ventricular dysfunction. We examined the effects of exercise on plasma BNP levels in patients with COPD who have normal right ventricular function Seventeen patients with a diagnosis of COPD and normal right ventricular function demonstrated by radionuclide ventriculography, and 17 age-and sex-matched healthy subjects underwent a treadmill exercise test. Plasma BNP levels were measured sequentially before, immediately after, and 1 hour after the exercise test The mean plasma BNP+/-standard deviation levels of the COPD and control groups before exercise were 21.3+/-16 pg/ml and 13.4+/-11 pg/ml, respectively (P>0.05). Mean plasma BNP level measured immediately after exercise was 37.9+/-31 pg/ml in the COPD group, reflecting a statistically significant increase when compared with the initial value (P<0.05). The control group did not show any significant change in plasma BNP levels after the exercise test Exercise induces an increase in plasma BNP levels in patients with COPD who do not have right ventricular dysfunction at rest. Measurement of exercise-induced BNP levels may be a useful alternative to pulmonary artery catheterisation in identifying the patients who are likely to benefit from long-term oxygen therapy.


Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia.
Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 × 10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2) and 17 mg/m(2)) were explored dosing on a weekly schedule × 3 with 1 week off (4-week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.


Dietary pea fibre alters the microbial community and fermentation with increase in fibre degradation-associated bacterial groups in the colon of pigs.
This study was attempted to investigate the influence of dietary pea fibre (PF) on the community and quantity of colonic bacteria of piglets and finisher pigs using pyrosequencing data and real-time PCR. The concentration of acetate in colonic digesta from PF-fed piglets was significantly higher than that from control (p < .05). Feeding PF diet to finisher pigs increased the ratio of acetate to total volatile fatty acids (VFAs) but decreased the ratio of butyrate, as compared with the control pigs (p < .05 in both cases). The lower ratio of butyrate in samples from finisher pigs receiving PF suggested that this dietary fibre did not favour butyrate production in the hindgut. Supplementation of PF to piglets reduced abundance of Bacteroidetes, as compared with control animals. However, PF had opposite effects in finisher pigs, higher abundance of Bacteroidetes but lower of Firmicutes. Lactobacillus and Prevotella were found as the predominant genera in PF piglets. Prevotella accounted for nearly half of the total bacteria in the colon of finisher pigs in the PF group, but only one-third in the control animals. Quantitative PCR showed that Firmicutes/Bacteroidetes were significantly increased in the colon of PF piglets (p < .05) as compared with control animals, but decreased in PF finisher pigs. Bacteroidetes-Prevotella-Porphyromonas and Desulfovibrio desulfuricans which are involved in degradation of dietary fibres were more abundant in the PF finisher pigs than in the controls (p < .05), suggesting mutualism between host and its gut microbes.


Analysis of Reports on Observational Studies Published in the Korean Journal of Women Health Nursing based on the STROBE Guideline.
The purpose of this study was to analyze the quality of reports on observational studies published in the Korean Journal of Women Health Nursing (KJWHN). Forty-six studies using cross-sectional designs published in KJWHN from January 2011 to June 2013 were selected for analysis. Selected articles were reviewed and evaluated by three reviewers using the 22 items of the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement. As some of 22 items had more than one check point, further broken down, 34 checklist items were used for analysis. Overall, the reviewed studies provided sufficient descriptions for many STROBE items. Seven of the 34 items were found to be not applicable, and 15 of the remaining 27 items (55.5%) were evaluated as 'sufficient' in reporting. Only one study included a flow diagram illustrating participation and this lack of flow diagram was the weakest area of reporting in this review. Clearer reporting of cross-sectional studies can be attained by attention to vulnerable areas of reporting, such as including a flow diagram of participants, descriptions of sources of bias and reason for non-participation, and describing limitations of the study. Issues regarding the application of STROBE statement items should be actively discussed in order to aid future revision and clarification of items included in STROBE statement.


UVEAL MELANOMA IN A 15-YEAR-OLD GIRL. CASE REPORT.
Uveal melanoma is the most common intraocular tumour in adults, it is a form of cancer that affects mostly older adults, as the average age at detection of this tumour is 60 years, but it can occur in any age group with no significant gender difference. However, uveal melanoma is very rare in children compared to the adult population, accounting for 1 % of all cases. In pediatric patients, malignant uveal melanoma is more frequently manifested during puberty, leading to speculation of an association between uveal melanoma and growth hormone levels. Prognostic factors for uveal melanoma include tumour histology, chromosomal abnormalities, tumour size, extrascleral spread and tumour location. Risk factors for uveal melanoma include melanocytosis, neurofibromatosis type 1 and dysplastic naevus syndrome. Some studies point to a significantly lower risk of developing metastases in younger patients, but the prognosis of uveal melanoma in children is not yet fully known. Clinical signs and treatment options for malignant uveal melanoma in children are still under discussion. Differential diagnosis of uveal lesions in children can sometimes be very difficult, as evidenced by following case report in which authors describe a case of choroidal melanoma in a 15-year-old girl.


A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer.
Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution-the selection of mutant clones in response to drug treatment-non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.


Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese.
The metabolic syndrome is characterized by a clustering of cardiovascular risk factors including type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity. Elevated plasma insulin and urinary norepinephrine (noradrenaline) and reduced urinary epinephrine (adrenaline) excretion are associated with obesity in Caucasian populations. We examined the interrelationships between obesity, plasma insulin, and urinary catecholamine excretion in Chinese subjects with various components of the metabolic syndrome. A total of 577 Chinese subjects (aged 38 +/- 10 years; 68% with type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria and 32% healthy subjects) were studied, all of whom had a plasma creatinine less than 150 micromol/L. The blood pressure, height, weight, waist and hip circumference, and fasting plasma glucose, insulin, lipid, and creatinine levels were measured. A 24-hour urine sample was collected for measurement of albumin and catecholamine excretion. The body mass index (BMI) and waist circumference were used as measures of general and central obesity, respectively. The insulin resistance index was estimated by the calculated product of fasting plasma insulin and glucose concentrations. Patients with an increasing number of components of the metabolic syndrome (type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria) were more obese, hyperglycemic, dyslipidemic, and albuminuric and had higher blood pressure, plasma insulin, insulin resistance indices, and 24-hour urinary norepinephrine excretion but lower urinary epinephrine output (all P < .005). Increasing quintiles of BMI in the whole population or waist circumference in both sexes were associated with increasing trends for adverse lipid profiles, plasma insulin, insulin resistance indices, and urinary norepinephrine excretion but a decreasing trend for urinary epinephrine output (all P < .001). There were close associations between age, obesity, blood pressure, fasting plasma glucose, lipid, insulin, insulin resistance indices, and urinary catecholamine excretion. Using stepwise multiple regression analysis (all P < .001), 34% of the variability of the BMI and 45% of that of the waist circumference were independently related to gender (waist higher in males and BMI higher in females), increased plasma insulin, triglyceride, and urinary norepinephrine excretion, and decreased high-density lipoprotein (HDL) cholesterol and urinary epinephrine output. In Chinese subjects with different manifestations of the metabolic syndrome, hyperinsulinemia, insulin resistance, elevated norepinephrine, and reduced epinephrine excretion were closely associated with general and central obesity. Based on these findings, we postulate that complex interactions between the insulin and sympathoadrenal systems may lead to the development of obesity and the metabolic syndrome.


Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer.
Selective estrogen receptor downregulators (SERDs) are a novel class of compounds capable of reducing the ERα protein level and blocking ER activity. Therefore, SERDs are considered as a significant therapeutic approach to treat ER+ breast cancer in both early stage and more advanced drug-resistant cases. After the FDA approval of a steroidal drug, fulvestrant, as a SERD for the treatment of breast cancer in patients who have progressed on antihormonal agents, several molecules with diverse chemical structures have been rapidly developed, studied and evaluated for selective estrogen receptor downregulation activity. Here we compile the promising SERDs reported in recent years and discuss the chemical structure and pharmacological profile of the most potent compound of the considered series. Because of the availability of only a limited number of effective drugs for the treatment of breast cancer, the quest for a potent SERD with respectable activity and bioavailability is still ongoing. The goal of this article is to make available to the reader an overview of the current progress in SERDs and provide clues for the future discovery and development of novel pharmacological potent SERDs for the treatment of breast cancer.


Reducing Risk for Adolescent Substance Misuse with Text-Delivered Counseling to Adolescents and Parents.
Background: Text-delivered prevention programs provide unique opportunities to deliver substance use prevention interventions to at-risk populations. Methods: A pilot randomized controlled trial was conducted to test the feasibility, acceptability, and preliminary efficacy of a 4-week, automated personalized text-messaging prevention program, designed to reduce risk factors and increase protective factors associated with adolescent substance use and misuse. Sixty-nine adolescents were recruited from a Federally Qualified Health Care clinic and randomized to a text-delivered intervention, or a wait-list control condition. Simultaneously, fifty-two parents of adolescent participants were enrolled into a parenting skills text-delivered intervention. Participants completed a baseline assessment and three follow-up surveys over three-months. Adolescent saliva specimens for drug testing were collected. Results: All intervention-allocated adolescents implemented at least one of the text-based counseling recommendations and 79% indicated that they found the texts helpful. Significant intervention effects were found on risk and protective factors for substance misuse. Adolescents in the intervention group reported reduced depression symptoms (d = -.63) and anxiety symptoms (d = -.57). Relative to controls, adolescents in the intervention group maintained a higher quality of parental relationship (d = .41) and parenting skills (d = .51), suggesting a prophylactic effect. Marginal decrease in the odds of positive drug tests were found for youth in intervention group (77.1% decrease, p = 0.07) but not with controls (54.3% decrease, p = 0.42,). Conclusions: Results provide preliminary evidence in the feasibility, acceptability, and efficacy of targeting risk and protective factors that are implicated in substance use via text-delivered interventions for high-risk populations.


CD10 and calretinin staining of endocervical glandular lesions, endocervical stroma and endometrioid adenocarcinomas of the uterine corpus: CD10 positivity is characteristic of, but not specific for, mesonephric lesions and is not specific for endometrial stroma.
In the female genital tract CD10 has been used to assist in the evaluation of mesenchymal tumours of the uterus and in determining whether endometrial stroma is present. CD10 positivity has also been shown in cervical mesonephric remnants and this antibody has been suggested as a useful immunohistochemical marker of mesonephric lesions in the female genital tract. Calretinin has also been shown to be positive in mesonephric lesions. In this study the specificity of these two antibodies in evaluating cervical and uterine glandular lesions and the value of CD10 in determining whether stroma is endometriotic or not were investigated. Cases of cervical tubo-endometrial metaplasia (TEM) (n = 11), microglandular hyperplasia (MGH) (n = 10), endometriosis (n = 8), mesonephric remnants/hyperplasia (n = 12), endocervical adenocarcinoma, usual type (n = 15), mucinous variant of minimal deviation adenocarcinoma (MDA) (n = 7) and mesonephric adenocarcinoma (n = 3) were stained with antibodies against CD10 and calretinin. Nine cases of endometrial adenocarcinoma of endometrioid type were also stained. In all the cervical cases normal endocervical glands were negative with both antibodies except for one case with strong positive luminal staining with CD10. All cases of TEM, MGH and endometriosis were negative with CD10 and calretinin except for focal staining with CD10 in one case each of MGH (cytoplasmic staining) and endometriosis (luminal staining). Most usual endocervical adenocarcinomas were negative with both antibodies, although one exhibited focal cytoplasmic staining with calretinin and five exhibited limited luminal positivity with CD10. All MDAs were negative with both antibodies. Ten of 12 mesonephric remnants/hyperplasia showed luminal positivity with CD10 and one exhibited cytoplasmic and nuclear staining with calretinin. Two of three mesonephric adenocarcinomas showed luminal positivity with CD10 and nuclear and cytoplasmic positivity with calretinin. Seven of nine endometrial adenocarcinomas were positive with CD10 (four cytoplasmic, two membranous and cytoplasmic, one luminal and cytoplasmic) and three with calretinin (two cytoplasmic, one nuclear and cytoplasmic). Positive staining of endometriotic stroma with CD10 was present in all endometriosis cases but normal cervical stroma was also strongly positive, especially around glands. Endometriotic stroma and cervical stroma were negative with calretinin. We conclude that most endocervical glandular lesions, including mesonephric remnants/ hyperplasia, are negative with calretinin. However, the focal nuclear and cytoplasmic positivity with calretinin in two of three mesonephric adenocarcinomas suggests that this may be a useful indicator of a mesonephric origin of a cervical adenocarcinoma. Most mesonephric remnants/hyperplasias exhibit luminal positivity with CD10, although this is not invariable and staining is usually focal. Positive luminal staining of a benign endocervical glandular lesion with CD10 may help confirm mesonephric remnants. Although positive staining with CD10 was found in two of three mesonephric adenocarcinomas, the observed immunoreactivity of several conventional cervical adenocarcinomas limits the diagnostic value of CD10 in confirming a mesonephric origin for an adenocarcinoma. Since all cervical MDAs were negative with CD10, positivity with this antibody may be of value in distinguishing mesonephric hyperplasia from MDA, although this distinction rarely necessitates immunohistochemistry. Most endometrial adenocarcinomas of endometrioid type stain with CD10 and thus positivity with this antibody is not specific for a mesonephric origin of an endometrial adenocarcinoma. Positivity of normal cervical stroma limits the value of CD10 staining in confirming a diagnosis of cervical endometriosis.


[Mini Mental State Examination (MMSE): determination of cutoff scores according to age and educational level].
For the last 38 years, Mini Mental State Examination (MMSE) has been widely used as a dementia screening measure in everyday clinical practice as well as in both cohort and cross-sectional studies. Its validity and reliability for the Greek population has explicitly been documented. However, the effect of age and education on the subject's performance makes it necessary to reckon them in the estimation of the "cutoff score". The purpose of this study is to estimate the prevalence of dementia in Greek population and determine the "cutoff score" by age and education-corrected norms. Cross sectional study of 630 patients older than 55 years, who live independently in Ilion and Helioupolis Municipalities was conducted, 27.3% of the subjects tested in the study were diagnosed with memory disorder according to their MMSE scores and the validation for the Greek population. The effect of age and education to the subjects' performance was statistically significant (p=.000). The use of standard "cutoff score" was not proved to be useful for the personalized interpretation of the results, as documented by the fact that older individuals with lower education had a poorer performance relatively to younger, highly educated subjects. Comparatively to the group age of 55-60 years, the odds ratio after the age of 75 years varies from 2.58 to 4.91. Regarding the variable factor of education, the odds ratio for the first degree education graduates decreases from 1.43 to 3.19 for the third degree education graduates in comparison with the group of illiterates. In conclusion, the use of the "cutoff score" algorithm and the simultaneous estimation of age and education effect on MMSE score may prove useful for the proper evaluation of MMSE performance. According to the age and education of examine candidates in the community and the primary care, we propose the use of the 25th percentile as a more useful cutoff score in order to decrease the false positive results.


Vitro culture of axe-head glochidia in pink heelsplitter Potamilus alatus and mechanism of its high host specialists.
The basal media M199 or MEM was utilized in the classical method of vitro culture of glochidia where 1-5% CO2 was required to maintain stable physiological pH for completion of non-parasitic metamorphosis. The classical method encounters a great challenge to those glochidia which undergo development of visceral tissue but significantly increase in size during metamorphosis. The improved in vitro culture techniques and classical methods were firstly compared for non-parasitic metamorphosis and development of glochidia in pink heelsplitter. Based on the improved method, the optimal vitro culture media was further selected from 14 plasmas or sera, realizing the non-parasitic metamorphosis of axe-head glochidia for the first time. The results showed that addition of different plasma (serum) had significant effect on glochidial metamorphosis in pink heelsplitter. Only glochidia in the skewband grunt and red drum groups could complete metamorphosis, the metamorphosis rate in skewband grunt was 93.3±3.1% at 24±0.5°C, significantly higher than in marine and desalinated red drum. Heat-inactivated treatment on the plasma of yellow catfish and Barbus capito had significant effect on glochidia survival and shell growth. The metamorphosis rate also varied among different gravid period, and generally decreased with gravid time. Further comparison of free amino acid and fatty acid indicated that the taurine of high concentration was the only amino acid that might promote the rapid growth of glochidial shell, and the lack of adequate DPA and DHA might be an important reason leading to the abnormal foot and visceral development. Combined with our results of artificial selection of host fish, we tentatively established the mechanism of its host specialists in pink heelsplitter for the first time. This is the first report on non-parasite metamorphosis of axe-head glochidia based on our improved vitro culture method, which should provide important reference to fundamental theory research of glochidia metamorphosis and also benefit for better understand of mechanism of host specialists and generalists of Unionidae species.


[New method of plastic in surgery for skin melanoma localized near body's midline].
With a wide excision of skin melanoma localized in areas of the sternum, the sacrum or on the back near body's midline there is often occurred a problem of closing appeared defect. Local tissues are insufficient and performing of free plastic is undesirable because of the unfavorable conditions of the free flap engraftment due to the peculiarities of transplant bed and difficulties of immobilization and fixation of the flap. For exactly such surgical situations we have developed a method of reliable replacement of appeared defects by two adjacent symmetrical rotary flaps.


The use and clinical outcomes of rotablation in challenging cases in the drug-eluting stent era.
Rotational atherectomy (RA) has been advocated in the bare metal stent (BMS) era but is underused now due to technique demands and nonsuperior outcomes. The aim of this study was to evaluate the procedural and clinical outcomes of patients with very complex, severely calcified coronary lesions treated by RA and drug-eluting stents (DESs) in our current percutaneous coronary intervention (PCI) practice in a region where RA use has been limited by lack of insurance reimbursement. From March 2004 to November 2010, all consecutive patients who required RA treatment for severely calcified de novo lesions of native coronary arteries followed by DES implantation were queried from the cath lab database and recruited. Their clinical and angiographic characteristics at the index PCI were analyzed and completed by a thorough review of the medical charts. A total of 67 consecutive patients with 71 very complex, heavily calcified coronary lesions treated with RA plus DES were recruited. Of these patients, 64% presented with acute coronary syndrome, 9.0% with cardiogenic shock, 43.3% with chronic renal failure, and 50.7% with diabetes. Multiple-vessel diseases were found in 92.5% of our patients, and the average coronary artery calcification (CAC) score was 3.6±1.4. Of the coronary lesions, 26.7% were either balloon-uncrossable or balloon-undilatable. The angiographic success rate was 100% with one non-Q myocardial infarction. Five patients (7.5%) died in hospital, all initially presenting with extensive myocardial infarction and/or cardiogenic shock. The out-of-hospital major adverse cardiac event was 17.9% at the mean follow-up of 23.2 months (range: 5-86), primarily due to high target-lesion revascularization and target-vessel revascularization rates of 10.4% and 10.4%, respectively. Only one (1.5%) probable subacute stent thrombosis was observed in the follow-up. RA with DES implantation in very complex, heavily calcified coronary lesions can achieve very low complication and low out-of-hospital major adverse cardiac event rates even in high-risk patients despite use limited by lack of insurance reimbursement. The study results convince us to sustain and even broaden the use of this novel, but underused, device in the DES era.


Energy balance affects pulsatile secretion of luteinizing hormone from the adenohypophesis and expression of neurokinin B in the hypothalamus of ovariectomized gilts.
The pubertal transition of gonadotropin secretion in pigs is metabolically gated. Kisspeptin (KISS1) and neurokinin B (NKB) are coexpressed in neurons within the arcuate nucleus of the hypothalamus (ARC) and are thought to play an important role in the integration of nutrition and metabolic state with the reproductive neuroendocrine axis. The hypothesis that circulating concentrations of luteinizing hormone (LH) and expression of KISS1 and tachykinin 3(TAC3, encodes NKB) in the ARC of female pigs are reduced with negative energy balance was tested using ovariectomized, prepubertal gilts fed to either gain or lose body weight. Restricted feeding of ovariectomized gilts caused a rapid and sustained metabolic response characterized by reduced concentrations of plasma urea nitrogen, insulin, leptin, and insulin-like growth factor-1 and elevated concentrations of free fatty acids. The secretory pattern of LH shifted from one of low amplitude to one of high amplitude, which caused overall circulating concentrations of LH to be greater in restricted gilts. Nutrient-restricted gilts had greater expression of follicle-stimulating hormone and gonadotropin-releasing hormone receptor, but not LH in the anterior pituitary gland. Expression of KISS1 in the ARC was not affected by dietary treatment, but expression of TAC3 was greater in restricted gilts. These data are consistent with the idea that hypothalamic expression of KISS1 is correlated with the number of LH pulse in pig, and further indicate that amplitude of LH pulses may be regulated by NKB in the gilt.


Radical pancreatectomy for pancreatic cancer in the elderly. Is it safe and justified?
Surgical resection provides the only potential cure for pancreatic cancer, yet resection in patients 70 years of age and older remains controversial because of presumed increased morbidity and mortality. Our aim was to determine the operative results in patients 70 years of age or older undergoing potentially curative radical pancreatic resection for pancreatic cancer from 1982 through 1987. Of 206 consecutive patients explored for potential resection, 42 patients (mean age, 75 years) had potentially curative procedures, including radical pancreaticoduodenectomy in 23 patients, total pancreatectomy in 8 patients, and distal pancreatectomy in 11 patients. Ductal adenocarcinoma was the most frequently encountered neoplasm (69%), but cystadenocarcinoma and islet cell carcinoma accounted for 12% and 7%, respectively. The overall operative mortality rate was 9%, while surgical morbidity was 28%, and medical morbidity was 12%. Overall median survival was 19 months, and 5-year survival was 4%. Despite the low overall incidence of resectability and postoperative cure rate for pancreatic carcinoma, exploration for potential curative resection should not necessarily be withheld for healthy, selected patients who are older than 70 years. Morbidity and mortality rates, although slightly greater than for patients who are older than 70 years, are acceptable.


Development of an acid ceramidase activity-based probe.
Acid ceramidase is responsible for the ultimate step in the catabolism of (glyco)sphingolipids by hydrolysis of ceramide into sphingosine and free fatty acid. Deficiency in acid ceramidase is the molecular basis of Farber disease. Here we report the synthesis and characterization of an activity-based acid ceramidase probe.


Effective treatment of cervical incompetence in a monochorionic monoamniotic twin pregnancy with a rescue cervical cerclage and pessary--a case report and review of literature.
A monochorionic monoamniotic (MCMA) twin pregnancy is the rarest form of twin gestation, accounting for around 1:10000 to 1:20000 of all deliveries regardless of the region of the world. All multiple gestations have a higher risk of preterm delivery due to either preterm uterine contractions or asymptomatic cervical shortening (cervical incompetence). A case of a 28-year-old primigravida in MCMA twin pregnancy with cervical incompetence diagnosed at 22 weeks of gestation is presented. After obtaining cervical swabs, negative laboratory infection parameters and confirming concordant gestational age on ultrasound scan with no structural abnormalities of both fetuses, the patient was qualified for an emergency cervical cerclage according to Wurm-Hefner method. Five days after the procedure, a cervical pessary was additionally inserted. She was administered antibiotics and steroids. The wellbeing of both fetuses was strictly monitored by means of cardiotocography tracing and ultrasound examinations, on which they were both eutrophic, with no abnormalities in Doppler blood flow patterns. Spontaneous premature rupture of membranes took place at 32 weeks of gestation, a cesarean section was performed and two female fetuses of 1740 g and 1760 g were delivered. They both required antibiotics because of congenital pneumonia, but no respiratory support was necessary The twins were discharged from the hospital 22 days after birth in good general condition. This case of a rescue cervical cerclage and pessary used simultaneously can be an example of an effective method of cervical incompetence treatment in twin pregnancies.


Effects of cryopreservation on bull spermatozoa distribution in morphometrically distinct subpopulations.
Assisted sperm morphometry analysis (ASMA) was used in this study to determine the effects of cryopreservation on bull spermatozoa distribution in morphometrically distinct subpopulations. Ejaculates were collected from five bulls and were divided. One portion was diluted at 30 degrees C in a skim milk-egg yolk medium, containing glycerol. A microscope slide was prepared from single extended sperm samples prior to freezing. The remainder of each sample was frozen in nitrogen vapours. After thawing, sperm smears were prepared as described above. All slides were air dried and stained with Hemacolor. The sperm-head dimensions for a minimum of 200 sperm heads were analysed from each sample by means of the Sperm-Class Analyser (SCA), and the mean measurements recorded. Our results showed that applying the ASMA technology and multivariate cluster analyses, it was possible to determine that three separate subpopulations of spermatozoa with different morphometric characteristics coexist in bull ejaculates (large, average and small spermatozoa). The mean values of each sperm head dimension among the three subpopulations of spermatozoa were significantly different (p < 0.001). Besides, there were significant (p < 0.001) differences in the distribution of these three sperm subpopulations between fresh and thawed samples. Thus, the percentage of representation of the subpopulation that includes those spermatozoa whose dimensions are the biggest, decreased from 52.06% in extended fresh samples to 15.51% in the thawed ones. Contrarily, the percent of representation of the subpopulation containing the smallest spermatozoa, increased from 8.70% in extended fresh samples to 34.04% in the thawed ones. In conclusion, the present study confirms the heterogeneity of sperm head dimensions in bull semen, heterogeneity that vary through the cryopreservation procedure.


Pleiotropic roles of tankyrase/PARP proteins in the establishment and maintenance of human naïve pluripotency.
Tankyrase 1 (TNKS1; PARP-5a) and Tankyrase 2 (TNKS2; PARP-5b) are poly-ADP-ribosyl-polymerase (PARP)-domain-containing proteins that regulate the activities of a wide repertoire of target proteins via post-translational addition of poly-ADP-ribose polymers (PARylation). Although tankyrases were first identified as regulators of human telomere elongation, important and expansive roles of tankyrase activity have recently emerged in the development and maintenance of stem cell states. Herein, we summarize the current state of knowledge of the various tankyrase-mediated activities that may promote human naïve and 'extended' pluripotency'. We review the putative role of tankyrase and PARP inhibition in trophectoderm specification, telomere elongation, DNA repair and chromosomal segregation, metabolism, and PTEN-mediated apoptosis. Importantly, tankyrases possess PARP-independent activities that include regulation of MDC1-associated DNA repair by homologous recombination (HR) and autophagy/pexophagy, which is an essential mechanism of protein synthesis in the preimplantation embryo. Additionally, tankyrases auto-regulate themselves via auto-PARylation which augments their cellular protein levels and potentiates their non-PARP tankyrase functions. We propose that these non-PARP-related activities of tankyrase proteins may further independently affect both naïve and extended pluripotency via mechanisms that remain undetermined. We broadly outline a hypothetical framework for how inclusion of a tankyrase/PARP inhibitor in small molecule cocktails may stabilize and potentiate naïve and extended pluripotency via pleiotropic routes and mechanisms.


[Laparoscopic procedures at diagnosis and treatment of early postoperative intraabdominal complications in urgent surgery].
Results of diagnosis and treatment of 318 patients with early postoperative intraabdominal complications (EPIAC) after urgent abdominal operations are analyzed. All the patients were divided into two groups depending on method of repeated operation. First group consisted of 212 patients who have undergone traditional relaparotomy, at 106 patients of second group the treatment was started with diagnostic laparoscopy. At 21 (6.5%) patients of 1st group the relaparotomy was diagnostic. At 58 (55%) patients of 2nd group the laparoscopic procedures was the final method of treatment, at 13 (12%) cases the EPIAC were excluded, conversion to open surgery was performed at 35 (33%) cases. Laparoscopy permitted to reduce lethality in 2.5 times and hospital stay in 2 times.


Pristine Graphene Insertion at the Metal/Semiconductor Interface to Minimize Metal-Induced Gap States.
Metal (M) contact with a semiconductor (S) introduces metal-induced gap states (MIGS), which makes it difficult to study the intrinsic electrical properties of S. A bilayer of metal with graphene (Gr), i.e., a M/Gr bilayer, may form a contact with S to minimize MIGS. However, it has been challenging to realize the pristine M/Gr/S junctions without interfacial contaminants, which result in additional interfacial states. Here, we successfully demonstrate the atomically clean M/Gr/n-type silicon (Si) junctions via all-dry transfer of M/Gr bilayers onto Si. The fabricated M/Gr/Si junctions significantly increase the current density J at reverse bias, compared to those of M/Si junctions without a Gr interlayer (e.g., by 105 times for M = Au in Si(111)). The increase of the reverse J by a Gr interlayer is more prominent in Si(111) than in Si(100), whereas in M/Si junctions, J is independent of the type of Si surface. The different transport data between M/Gr/Si(111) and M/Gr/Si(100) are consistent with Fermi-level pinning by different surface states of Si(111) and Si(100). Our findings suggest the effective way to suppress MIGS by an introduction of the clean Gr interlayer, which paves the way to study intrinsic electrical properties of various materials.


The natural history of orbital cavernous hemangiomas.
Orbital cavernous hemangiomas (OCH) often present as incidentally found asymptomatic lesions, and it has been reported that such lesions do not grow. The authors' own experience has been different. They describe the natural history of OCH in a cohort with asymptomatic incidentally found lesions and compare them with patients with symptomatic OCH to identify any characteristics that might predict those which enlarge and produce symptoms. This was a retrospective comparative case series from 3 tertiary referral orbital centers in Australia. There were 104 patients with OCH, 31 of whom presented with incidentally found lesions. For patients with incidental lesions, only those with a minimum follow-up period of 12 months were included. Outcome measures included demographic features, clinical features at presentation and during follow up, anatomical location of the OCH, change in maximal linear dimensions of the OCH over time, follow-up period, and requirement for treatment in the follow-up period. There were 104 patients included in the study. Thirty-one had an asymptomatic, incidental OCH on imaging performed for other indications. Seventy-nine patients had treatment, and 11 of these had presented with an incidental, asymptomatic OCH that enlarged and produced symptoms or new clinical findings. In the 20 other patients with incidentally found OCH, there was no or minimal change in the follow-up period of 1.2 to 20 years (mean 5.8 years, standard deviation [SD] 4.6 years). None of the factors analyzed in the study were able to predict those patients with an incidental OCH that enlarged and required treatment. Patients with incidental lesions that did not grow over several years did not change over much longer periods of time. When considering all patients with OCH, both incidentally diagnosed and symptomatic, there were 4 factors that predicted whether someone with an OCH would require treatment. These were maximal linear dimension, male gender, extraconal location (increased risk of requiring treatment), and being an incidental finding (decreased risk of requiring treatment). OCH may present as an incidental finding. A significant number will grow over time and require treatment. The authors could not identify any factor that would predict those lesions that enlarge over time and require treatment. If an incidental OCH does not change over several years, it is very unlikely to do so in longer periods of follow up.


Mapping the interaction of Snf1 with TORC1 in Saccharomyces cerevisiae.
Nutrient sensing and coordination of metabolic pathways are crucial functions for all living cells, but details of the coordination under different environmental conditions remain elusive. We therefore undertook a systems biology approach to investigate the interactions between the Snf1 and the target of rapamycin complex 1 (TORC1) in Saccharomyces cerevisiae. We show that Snf1 regulates a much broader range of biological processes compared with TORC1 under both glucose- and ammonium-limited conditions. We also find that Snf1 has a role in upregulating the NADP(+)-dependent glutamate dehydrogenase (encoded by GDH3) under derepressing condition, and therefore may also have a role in ammonium assimilation and amino-acid biosynthesis, which can be considered as a convergence of Snf1 and TORC1 pathways. In addition to the accepted role of Snf1 in regulating fatty acid (FA) metabolism, we show that TORC1 also regulates FA metabolism, likely through modulating the peroxisome and β-oxidation. Finally, we conclude that direct interactions between Snf1 and TORC1 pathways are unlikely under nutrient-limited conditions and propose that TORC1 is repressed in a manner that is independent of Snf1.


Determining the sequence of intersecting gel pen and laser printed strokes--a comparative study.
The relative chronological sequence of intersecting gel pen ink lines and laser printed marks has been determined using optical methods. The results were obtained by observing spectral reflection, relative sheen, skipping and gaps of gel pen ink strokes at the point of intersection. The intersections are observed under stereomicroscope and digital microscope. The effectiveness of both the optical instruments for sequence of the strokes has been compared. The sequence of intersecting lines (of same colour, different colours and where one of the strokes is darker) has been established.


Oxidative stress and tryptophan degradation pattern of acute Toxoplasma gondii infection in mice.
Toxoplasma gondii is a very common obligate single-cell protozoan parasite which induces overproduction of interferon (IFN)-gamma and of other proinflammatory cytokines. Although immunomodulatory role of IFN-gamma favors tryptophan (Trp) degradation via indoleamine-2,3-dioxygenase (IDO) activity and is related with nitric oxide (NO) synthesis, the mechanism of antitoxoplasma activity is complex. In order to characterize the Trp degradation pattern during the acute T. gondii infection, serum Trp, kynurenine (Kyn), and urinary biopterin levels of mice were measured. The possible oxidative status was evaluated by the liver, spleen, brain, and serum malondialdehyde (MDA) and NO levels. Increased free radical toxicity may cause elevation in tissue MDA in T. gondii-infected mice, while unchanged serum MDA might indicate the increased oxidative stress due to T. gondii infection restricted to intracellular area. Elevated serum NO most probably might be due to the formation of reactive nitrogen radicals. The Kyn/Trp ratio was higher in T. gondii-infected mice compared to healthy animals (p < 0.05); however, it was not correlated with urinary biopterin. These results suggested that Trp degradation might be promoted by a pathway other than IDO during T. gondii infection and the reduction of Trp concentration favors the local immunosuppression and systemic tolerance.