Strain softening behaviour in nonviable rat right-ventricular trabeculae, in the presence and the absence of butanedione monoxime.
Strain softening is commonly reported during mechanical testing of passive whole hearts. It is typically manifested as a stiffer force-extension relationship in the first deformation cycle relative to subsequent cycles and is distinguished from viscoelasticity by a lack of recovery of stiffness, even after several hours of rest. The cause of this behaviour is presently unknown. In order to investigate its origins, we have subjected trabeculae to physiologically realistic extensions (5-15% of muscle length at 26 degrees C and 0.5 mm Ca(2+)), while measuring passive force and dynamic stiffness. While we did not observe strain softening in viable trabeculae, we found that it was readily apparent in nonviable (electrically inexcitable) trabeculae undergoing the same extensions. This result was obtained in both the presence and absence of 2,3-butanedione monoxime (BDM). Furthermore, BDM had no effect on the passive compliance of viable specimens, while its presence partly inhibited, but could not prevent, stiffening of nonviable specimens. Loss of viability was accompanied by a uniform increase of dynamic stiffness over all frequencies examined (0.2-100 Hz). The presence of strain softening during length extensions of nonviable tissue resulted in a comparable uniform decrease of dynamic stiffness. It is therefore concluded that strain softening is neither intrinsic to viable rat right ventricular trabeculae nor influenced by BDM but, rather, reflects irreversible damage of tissue in partial, or full, rigor.


Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer's disease.
Alzheimer's disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metal-free and metal-bound Aβ (metal-Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8-aminoquinolin-2-yl)methanol (1)) for reactivity with Aβ and metal-Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.


Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer.
Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.


Effect of malting conditions and quality characteristics of malt and roasted malt extract from 'acha' grains (Digitaria exilis Stapf).
Considering the importance of malting and roasting on the quality of 'acha' beverages, a study was conducted to find optimum conditions for malting and the production of a high-quality roasted extract that could be used for an 'acha' beverage. The data obtained were analysed using response surface methodology. The results revealed that the most significant (P < 0.05) malting factors that affect the response variables were the linear terms of germination time and drying temperature. However, for the extract production, the linear term of roasting temperature was the most significant (P < 0.05) factor. The quadratic and interaction terms exhibited significant (P < 0.05) effect in all cases apart from the flavour. The overall optimum regions were established at 28 h of germination time, 55 degrees C drying temperature and 5.0% moisture content for the malting conditions while for the extract production, a roasting temperature of 210 degrees C, extraction temperature of 70 degrees C and extraction duration of 20 min were established.


Impact of the combined loss of BOK, BAX and BAK on the hematopoietic system is slightly more severe than compound loss of BAX and BAK.
It is well established that BAX and BAK play crucial, overlapping roles in the intrinsic pathway of apoptosis. Gene targeted mice lacking both BAX and BAK have previously been generated, but the majority of these animals died perinatally. BOK is a poorly studied relative of BAX and BAK that shares extensive amino acid sequence homology to both proteins, but its function remains largely unclear to date. To determine whether BOK plays an overlapping role with BAX and BAK, we utilized a hematopoietic reconstitution model where lethally irradiated wild type mice were transplanted with Bok(-/-)Bax(-/-)Bak(-/-) triple knockout (TKO) fetal liver cells, and compared alongside mice reconstituted with a Bax(-/-)Bak(-/-) double knockout (DKO) hematopoietic compartment. We report here that mice with a TKO and DKO hematopoietic system died at a similar rate and much earlier than control animals, mostly due to severe autoimmune pathology. Both TKO and DKO reconstituted mice also had altered frequencies of various leukocyte subsets in the thymus, bone marrow and spleen, displayed leukocyte infiltrates and autoimmune pathology in multiple tissues, as well as elevated levels of anti-nuclear autoantibodies. Interestingly, the additional deletion of BOK (on top of BAX and BAK loss) led to a further increase in peripheral blood lymphocytes, as well as enhanced lymphoid infiltration in some organs. These findings suggest that BOK may have some functions that are redundant with BAX and BAK in the hematopoietic system.


Antifungal activity of thionated analogues of Nva-FMDP and Lys-Nva-FMDP.
The antifungal activity of synthetic endothiopeptdides, i.e. Nva(psi)[CSNH]-FMDP and Lys(psi)[CSNH]-Nva(psi)[CSNH]-FMDP was studied in medium containing blood serum, against selected Candida strains; Candida albicans Gu4 (fluconazole sensitive), C. albicans Gu5 (fluconazole resistant), C. albicans ATCC 10231, Candida krusei DSM 6128 and Candida parapsilosis DSM 5784. Although thiopeptide bonds in the tested peptides increased their stability in blood serum, their antifungal activity, however, drastically decreased in comparison with the peptides containing non-modified peptide bonds. Moreover, the inhibitory activity towards glucosamine-6-phosphate synthase of thionated synthetic analogue of FMDP was performed. The thiopeptdide bond also influenced its inhibitory properties against enzyme from C. albicans.


The effect of placebo conditioning on capsaicin-evoked urge to cough.
The urge to cough is a clinical symptom of respiratory disease that precedes the motor act of coughing. Although previous studies have shown that cough is particularly susceptible to placebo suppression, it is unclear whether the perception of an urge to cough is also modifiable by placebo. Therefore, we tested the hypothesis that capsaicin-evoked urge to cough could be suppressed by placebo conditioning. Eleven healthy participants were unknowingly conditioned to believe that an inert inhaler temporarily suppressed capsaicin-induced urge to cough by deceptively modifying the challenge concentration of capsaicin. In subsequent testing, capsaicin-evoked urge-to-cough subjective ratings were assessed in four challenges with a single dose of inhaled capsaicin following no treatment or the placebo metered-dose inhaler. An additional 10 participants were informed that the inhaler therapy was inert prior to receiving capsaicin challenges with and without inhaler treatment. There was a significant decrease in mean urge-to-cough ratings to capsaicin challenge following placebo compared with no treatment followed by capsaicin challenge (P < .001), with a peak decrease of 45%. The placebo inhaler alone had no effect on urge-to-cough subjective ratings when participants were aware that it contained no active medication. These data confirm that the urge to cough is susceptible to placebo inhibition. This provides further evidence that higher brain networks are involved in the processing of respiratory sensations related to airway irritation.


Comparison of the inotropic action of morphine and ketamine studied in canine cardiac muscle.
This study compares the inotropic action of morphine sulfate and ketamine hydrochloride on isolated canine right ventricular trabeculae. The heart was removed from 19 mongrel puppies weighing 5 to 9 kilograms and placed in Krebs-Ringer bicarbonate solution. The bathing solution contained 1.3 mM. of Ca2+ and was bubbled with a gas mixture of 95 per cent oxygen and 5 per cent carbon dioxide. At Lmax (i.e., the peak of isometric force-length curve) morphine even in large concentrations (up to 1 mg. per milliter) produced no significant direct inotropic effect. At the lower concentrations tested there was a minor but not significant increase in contractile performance, whereas at the highest concentration used there was a minor but not significant depression in contractility. In these same muscles lower concentrations of ketamine had a significant positive inotropic action, but a concentration of 200 mug per milliliter, which is approximately equimolecular to 1 mg. per milliliter of morphine sulfate, caused a profound depression in contractile performance. In the presence of a beta-blocking agent and in reserpine-pretreated muscles, low concentrations of ketamine, which had only a positive inotropic action in the normal muscles, now caused depression of contractile performance. The positive inotropic action of ketamine is thus indirect and mediated via adrenergic influences. At each concentration studied the direct inotropic action of ketamine was exclusively negative. Because of this bimodal inotropic action seen when adrenergic mechanisms are intact, we conclude that caution must be exercised when ketamine is given to patients previously treated or still under the influence of drugs having adrenolytic properties. Caution is also necessary when ketamine is used in patients having diminished cardiac adrenergic reserves as in congestive heart failure.


Radical cystectomy in the elderly patient.
A total of 77 patients 65 or more years old underwent radical cystectomy with urinary diversion for invasive bladder cancer during a 10-year interval. The preoperative medical condition of the patients, operative mortality and morbidity, and preliminary survival data are reviewed by age group. Two-thirds of the patients had previous medical or surgical problems that increased the surgical risk. The over-all mortality rate was 3.9 per cent. Early complications occurred in 31 per cent of the patients, with an increased risk of complication associated with previous illness and major pelvic surgery, and preoperative radiation therapy. The complication rate was not related directly to age, with patients 65 to 69 and more than 75 years old having lower rates than those 70 to 74 years old. The 3-year survival rate free of disease ranged from 58 per cent in the youngest group to 39 per cent in the oldest group, which is comparable to survival statistics for younger patients undergoing cystectomy. Only 5 patients have died of intercurrent illness, while 20 have died of metastatic disease.


Development and Validation of a New Lymph Node Ratio-Based Staging System for Ampullary Carcinoma After Curative Pancreaticoduodenectomy.
Lymph node metastasis (LNM) is closely associated with the prognosis of ampullary carcinoma (AC). The purpose of this study is to explore the relationship between lymph node ratio (LNR) and the prognosis of patients with AC after curative pancreaticoduodenectomy and to establish a new LNR-based staging system. AC patients in the Cancer Hospital, Chinese Academy of Medical Sciences, between 1998 and 2020 were retrospectively reviewed as the training cohort; and AC patients in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2018 were obtained as the validation cohort. Within the training group, Kaplan-Meier survival analyses and Cox proportional hazards regression were conducted to assess the prognostic value of LNR and establish a new LNR-based staging system. Then, the new staging system was compared with the 8th American Joint Committee on Cancer (AJCC) TNM staging system in both the training and validation cohorts. A total of 264 patients in the training cohort and 199 patients in the validation cohort were enrolled. Significant overall survival (OS) difference was observed between LNR-low stage and LNR-high stage in both training (p = 0.001) and validation cohorts (p < 0.001). Then a new LNR-based staging system was developed. Under the new system, the number of patients in the training cohort and validation cohort of stage I, stage II, and stage III was 30 (11%) vs. 18 (9%), 190 (72%) vs. 96 (48%), and 44 (17%) vs. 85 (43%), respectively. The new staging system classified patients with respect to survival better than did the 8th AJCC TNM staging system. The new LNR-based staging system had better discriminability for predicting survival in AC patients after curative pancreaticoduodenectomy. More data are needed for further validation.


Botulinum toxin treatment for slipping rib syndrome: a case report.
Slipping rib syndrome (SRS) is a musculoskeletal cause of severe and recurrent thoracic or abdominal pain. The etiology of SRS is unknown, it seems to arise from costal hypermobility with a tendency of one of the ribs (usually from 8th to 10th but also 11th and 12th have been described) to slip under the superior adjacent rib. Its prevalence is underestimated because SRS is mainly a clinical diagnosis, frequently missed. The critical aspect of the diagnosis is knowledge of the condition itself, which, when lacking, often results in the patient being referred to many different specialists and exposed to unnecessary and costly investigations. The management of the condition includes conservative techniques such as manipulation, localized anesthetic, and steroid or anesthetic nerve block. However, where conservative therapy fails, surgical treatment, with excision of the rib, may be performed. In this paper we describe the case of a patient with persistent and debilitating flank pain who, after many investigations, was diagnosed with SRS. The usual conservative treatment failed, after which we treated the patient with injections of incobotulinumtoxin A into muscles inserting on the inferior side of the rib cage (quadratus lumborum muscle, muscle transversus abdomini, abdominal external oblique muscle, and recto abdomini) achieving a complete relief from pain. To our knowledge botulinum toxin has never been proposed before for the treatment of SRS. We believe that it should be considered as a therapeutic option, especially where other medical treatments have failed or as an intermediate step before surgical intervention.


Conjugal transfer of polychlorinated biphenyl/biphenyl degradation genes in Acidovorax sp. strain KKS102, which are located on an integrative and conjugative element.
A polychlorinated biphenyl (PCB)/biphenyl degradation gene cluster in Acidovorax sp. strain KKS102, which is very similar to that in Tn4371 from Cupriavidus oxalaticus A5, was transferred to several proteobacterial strains by conjugation. The mobilized DNA fragment consisted of 61,807 bp and carried genes for mating-pair formation (mpf), DNA transfer (dtr), integrase (int), and replication-partition proteins (rep-parAB). In the transconjugants, transferred DNA was integrated at ATTGCATCAG or similar sequences. The circular-form integrative and conjugative element (ICE) was detected by PCR, and quantitative PCR analyses revealed that, in KKS102 cells, the ratio of the circular form to the integrated form was very low (approximately 10(-5)). The circular form was not detected in a mutant of the int gene, which was located at the extreme left and transcribed in the inward direction, and the level of int transcriptional activity was much higher in the circular form than in the integrated form. These findings clearly demonstrated that the genes for PCB/biphenyl degradation in KKS102 cells are located on an ICE, which was named ICE(KKS102)4677. Comparisons of similar ICE-like elements collected from the public database suggested that those of beta- and gammaproteobacteria were distinguishable from other ICE-like elements, including those in alphaproteobacteria, with respect to the gene composition and gene organization.


Novel Carrier Doping Mechanism for Transparent Conductor: Electron Donation from Embedded Ag Nanoparticles to the Oxide Matrix.
A trade-off between the carrier concentration and carrier mobility is an inherent problem of traditional transparent conducting oxide (TCO) films. In this study, we demonstrate that the electron concentration of TCO films can be increased without deteriorating the carrier mobility by embedding Ag nanoparticles (NPs) into Al-doped ZnO (AZO) films. An increment of Ag NP content up to 0.7 vol % in the AZO causes the electron concentration rising to 4 × 1020 cm-3. A dependence of the conductivity on temperature suggests that the energy barrier for the electron donation from Ag NPs at room temperature is similar to the Schottky barrier height at the Ag-AZO interface. In spite of an increase in the electron concentration, embedded Ag NPs do not compromise the carrier mobility at room temperature. This is evidence showing that this electron donation mechanism by Ag NPs is different from impurity doping, which produces both electrons and ionized scattering centers. Instead, an increase in the Fermi energy level of the AZO matrix partially neutralizes Al impurities, and the carrier mobility of Ag NP embedded AZO film is slightly increased. The optical transmittance of mixture films with resistivity less than 1 × 10-3 Ω·cm still maintains above 85% in visible wavelengths. This opens a new paradigm to the design of alternative TCO composite materials which circumvent an inherent problem of the impurity doping.


Prostaglandin F2α-PTGFR signalling activation, growth factor expression and cell proliferation in bovine endometrial explants.
The endometrium of domestic animals undergoes regular periods of regeneration and degeneration and exhibits a remarkable capacity for self-repair during the oestrous cycle. The endometrial growth pattern is also observed during in the implantation period and early pregnancy, but the mechanism underlying endometrial growth in these processes remains unclear. A positive correlation between endometrial growth in these processes and prostaglandin (PG) F2α secretion has been reported, but the roles that PGF2α plays in endometrial growth is less studied. In the present study, cell proliferation and the responses of a series of growth factors essential for endometrial growth to PGF2α receptor (PTGFR) activation were investigated in bovine endometrial explants in vitro. Using real-time reverse transcription-polymerase chain reaction and western blotting, mRNA and protein expression of connective tissue growth factor, fibroblast growth factor2, interleukin8, matrix metalloproteinase2, transforming growth factor β1 and vascular endothelial growth factor A was increased (P<0.05) and cell proliferation, including epithelial and fibroblast proliferation, was induced in response to increased levels of proliferating cell nuclear antigen, cytokeratin-18 and fibroblast-specific protein-1 (P<0.05) following PTGFR activation by adding fluprostenol (10-9-10-5 M) into culture medium of bovine endometrial explants. However, caspase-3 protein expression was reduced following treatment of explants with fluprostenol (10-9-10-5 M, P<0.05). These results may help define the possible roles the PGF2α-PTGFR signalling pathway plays in endometrial growth.


[Callus cultivation and determination of flavonoids from Tetrastigma hemsleyanum].
The feasibility of producting flavonoids from callus of Tetrastigma hemsleyanum was investigated through callus induction, proliferation, differentiation and determination of flavonoids. The leaves of sterile plantlet, leaves and stems of wild plants were used as explants to induce calluses; The root tuber, the leaves and calluses were selected for the determination of flavonoids. With ethanol as the solvent, the total flavonoids were extracted by ultrasonic and determined by spectrophotometry at 500 nm after stained with NaNO2-Al(NO3) 3. The optimum medium where the calluses were induced was 2/3MS +2.0 mg/L 6-BA +2.0 mg/L NAA; MS +2.0 mg/L 6-BA +2.0 mg/L NAA was the optimum for callus proliferation; for callus root differentiation, the optimum medium was 1/2MS +1.0 mg/L 6-BA +1.0 mg/L NAA. The content of total flavonoids was 31.121 mg/g in root tuber, 12.830 mg/g in leaves while it was up to 18.088 mg/g in calluses. The calluses had a high level of total flavonoids, it could produce flavonoids through the calluses induced by Tetrastigma hemsleyanum in a large scale. In that case, the pressing requirement in medical market will be solved.


Morphine inhibition of ovulation: reversal by naloxone.
The effect of naloxone (N-allylnoroxymorphone), a narcotic antagonist, on the morphine blockade of ovulation was studied. Female rats were treated with morphine (50 mg/kg) at the critical period, resulting in ovulatory blockade. The administration of naloxone (0.5 mg/kg) effectively reversed the anti-ovulatory effect of morphine. The antagonist reversed the morphine effect when given 1 hour before (75% reversla), simultaneously (75% reversal), and up to 3 hours after morphine treatment (63% reversal). The number of ova shed per animal was not affected by naloxone treatment with or without morphine. When the blockade of ovulation occurred in animals treated with both naloxone and morphine, uterine distension was present in 85% of the animals on the day of estrus.


Unexpected finding of T-cell lymphoma in a previously healthy 16-year-old patient after a thorax trauma: a case report.
We describe the clinical course and emphasize the difficulties in diagnosing T-cell lymphoblastic lymphoma. The differential diagnostic difficulties have previously been described in regard to pneumonia, but to the best of the authors' knowledge this is the first case report to describe lymphoma in relation to trauma. A previously healthy 16-year-old Danish boy presented to our hospital with chest pain and accentuated protruding thoracic veins. Ten days prior to hospitalization he had suffered a blunt thoracic trauma while playing soccer. After drainage of an excessive amount of pleural fluid, he developed severe respiratory distress. A chest tube was inserted and he was transferred to a level 1 trauma centre. Here, a computed tomography scan unexpectedly revealed significantly swollen mediastinal and retroperitoneal lymph nodes, and he was later diagnosed with T-cell lymphoblastic lymphoma. This case emphasizes the importance of reacting to an unexplained large amount of pleural fluid after a patient suffers thoracic trauma and to consider possible underlying causes. This report is mainly addressed to emergency personnel, but it is also relevant to pediatricians, surgeons, anesthesiologists, and general practitioners.


Robust GICP-Based 3D LiDAR SLAM for Underground Mining Environment.
Unmanned mining is one of the most effective methods to solve mine safety and low efficiency. However, it is the key to accurate localization and mapping for underground mining environment. A novel graph simultaneous localization and mapping (SLAM) optimization method is proposed, which is based on Generalized Iterative Closest Point (GICP) three-dimensional (3D) point cloud registration between consecutive frames, between consecutive key frames and between loop frames, and is constrained by roadway plane and loop. GICP-based 3D point cloud registration between consecutive frames and consecutive key frames is first combined to optimize laser odometer constraints without other sensors such as inertial measurement unit (IMU). According to the characteristics of the roadway, the innovative extraction of the roadway plane as the node constraint of pose graph SLAM, in addition to automatic removing the noise point cloud to further improve the consistency of the underground roadway map. A lightweight and efficient loop detection and optimization based on rules and GICP is designed. Finally, the proposed method was evaluated in four scenes (such as the underground mine laboratory), and compared with the existing 3D laser SLAM method (such as Lidar Odometry and Mapping (LOAM)). The results show that the algorithm could realize low drift localization and point cloud map construction. This method provides technical support for localization and navigation of underground mining environment.


The Symmetrical Wave Pattern of Base-Pair Substitution Rates across the Escherichia coli Chromosome Has Multiple Causes.
Mutation accumulation experiments followed by whole-genome sequencing have revealed that, for several bacterial species, the rate of base-pair substitutions (BPSs) is not constant across the chromosome but varies in a wave-like pattern that is symmetrical about the origin of replication. The experiments reported here demonstrated that, in Escherichia coli, several interacting factors determine the wave. The origin is a major driver of BPS rates. When it is relocated, the BPS rates in a 1,000-kb region surrounding the new origin reproduce the pattern that surrounds the normal origin. However, the pattern across distant regions of the chromosome is unaltered and thus must be determined by other factors. Increasing the deoxynucleoside triphosphate (dNTP) concentration shifts the wave pattern away from the origin, supporting the hypothesis that fluctuations in dNTP pools coincident with replication firing contribute to the variations in the mutation rate. The nucleoid binding proteins (HU and Fis) and the terminus organizing protein (MatP) are also major factors. These proteins alter the three-dimensional structure of the DNA, and results suggest that mutation rates increase when highly structured DNA is replicated. Biases in error correction by proofreading and mismatch repair, both of which may be responsive to dNTP concentrations and DNA structure, also are major determinants of the wave pattern. These factors should apply to most bacterial and, possibly, eukaryotic genomes and suggest that different areas of the genome evolve at different rates.IMPORTANCE It has been found in several species of bacteria that the rate at which single base pairs are mutated is not constant across the genome but varies in a wave-like pattern that is symmetrical about the origin of replication. Using Escherichia coli as our model system, we show that this pattern is the result of several interconnected factors. First, the timing and progression of replication are important in determining the wave pattern. Second, the three-dimensional structure of the DNA is also a factor, and the results suggest that mutation rates increase when highly structured DNA is replicated. Finally, biases in error correction, which may be responsive both to the progression of DNA synthesis and to DNA structure, are major determinants of the wave pattern. These factors should apply to most bacterial and, possibly, eukaryotic genomes and suggest that different areas of the genome evolve at different rates.


Wernicke Encephalopathy Secondary to Hyperemesis Gravidarum in a 22-Year-Old Female Patient: A Case Report.
Wernicke encephalopathy is an acute, reversible neurological disorder, which, if untreated, can develop into Korsakoff syndrome. Commonly associated with alcohol use disorder, Wernicke encephalopathy is a metabolic disorder caused by a deficiency of thiamine, vitamin B1. This case report presents a clinical manifestation of Wernicke encephalopathy, in which a 22-year-old pregnant female with hyperemesis gravidarum and significant weight loss developed acute metabolic encephalopathy. Diagnostic imaging played an important role both in diagnosing the patient acutely in the hospital and during a follow-up visit one year after treatment.


Enfuvirtide: first fusion inhibitor for treatment of HIV infection.
The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and availability of enfuvirtide are discussed. To date, 20 antiretrovirals have been approved by FDA for the treatment of HIV infection. The recent approval of enfuvirtide offers a new and fourth class of antiretroviral agents called fusion inhibitors. Enfuvirtide is indicated for use in treatment-experienced patients who have evidence of viral replication despite receiving current therapy. The drug is a 36-amino-acid synthetic peptide that prevents completion of the HIV fusion sequence. Absolute bioavailability after subcutaneous injection is 84%. Clinical trials indicate that adding enfuvirtide to a salvage regimen in heavily treated patients may lead to an improved virologic response. Up to a 1.48 log decrease in the viral load was seen at 48 weeks when enfuvirtide was combined with an optimized background regimen. Patients who have at least two or more active drugs in the regimen, a CD4+ cell count of >100 cells/mm3, and previous exposure to two or more antiretrovirals prior to starting enfuvirtide appear to respond best. The most common adverse effect, occurring in 98% of all enfuvirtide recipients, is an injection-site reaction that generally can be managed nonpharmacologically. A much less common but more significant concern is an increased risk of bacterial pneumonia. Enfuvirtide is available through the Fuzeon Progressive Distribution Program. The annual cost of therapy is about 24,000 dollars. Enfuvirtide is the first fusion inhibitor available for the treatment of HIV infection. The drug is indicated for use with other antiretroviral agents in treatment-experienced patients who have evidence of HIV replication despite ongoing antiretroviral treatment.


Early Palliative Care and Its Impact on End-of-Life Care for Cancer Patients in Brazil.
Integrating palliative care into standard oncology care has been recommended for cancer patients. Early palliative care is associated with less aggressive treatment at the end of life. To describe cancer patients receiving palliative care in Brazil, determining the time from entry into palliative care to death, and investigating whether late referral to palliative care is associated with aggressive end-of-life treatment. This was a cross-sectional study of cancer patients receiving palliative care in Brazil. Subjects were 2985 cancer patients ≥18 years of age who received at least two palliative care visits at the São Paulo State Cancer Institute, in the city of São Paulo, Brazil, and died between 2010 and 2013. We evaluated the time from the first palliative care consult to death, stratifying cases by the timing of entry into palliative care (≥3 or <3 months before death). The associations between early palliative care and indicators of aggressive treatment were assessed by Pearson's chi-square test and Fisher's exact test. The overall median time between entry into palliative care and death was 34 days (mean, 72 days) and was significantly shorter in 2013 than in 2010 (p < 0.001). The number of emergency department visits was significantly lower among the patients who entered palliative care earlier (p < 0.001). Among cancer patients in Brazil, late referral to palliative care is common. Patients who enter palliative care earlier appear to receive less aggressive end-of-life treatment.


Brown Adipose Tissue and BMP3b Decrease Injury in Cardiac Ischemia-Reperfusion.
Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing cardiac injury. A previous study using a mouse model of nonreperfused MI showed activation of brown adipose tissue (BAT). Recent studies showed that molecules secreted by BAT target the heart. We investigated whether BAT attenuates cardiac injury in I/R and sought to identify potential cardioprotective proteins secreted by BAT. Myocardial I/R surgery with or without BAT transplantation was performed in wild-type (WT) mice and in mice with impaired BAT function (uncoupling protein 1 [Ucp1]-deficient mice). To identify potential cardioprotective factors produced by BAT, RNA-seq (RNA sequencing) was performed in BAT from WT and Ucp1-/- mice. Subsequently, myocardial I/R surgery with or without BAT transplantation was performed in Bmp3b (bone morphogenetic protein 3b)-deficient mice, and WT mice subjected to myocardial I/R were treated using BMP3b. Dysfunction of BAT in mice was associated with larger MI size after I/R; conversely, augmenting BAT by transplantation decreased MI size. We identified Bmp3b as a protein secreted by BAT after I/R. Compared with WT mice, Bmp3b-deficient mice developed larger MIs. Increasing functional BAT by transplanting BAT from WT mice to Bmp3b-deficient mice reduced I/R injury whereas transplanting BAT from Bmp3b-deficient mice did not. Treatment of WT mice with BMP3b before reperfusion decreased MI size. The cardioprotective effect of BMP3b was mediated through SMAD1/5/8. In humans, the plasma level of BMP3b increased after MI and was positively correlated with the extent of cardiac injury. The results of this study suggest a cardioprotective role of BAT and BMP3b, a protein secreted by BAT, in a model of I/R injury. Interventions increasing BMP3b levels or targeting Smad 1/5 may represent novel therapeutic approaches to decrease myocardial damage in I/R injury.


Assessing and Optimizing Socio-Moral Reasoning Skills: Findings From the MorALERT Serious Video Game.
Social cognition and competence are a key part of daily interactions and essential for satisfying relationships and well-being. Pediatric neurological and psychological conditions can affect social cognition and require assessment and remediation of social skills. To adequately approximate the complex and dynamic nature of real-world social interactions, innovative tools are needed. The aim of this study was to document the performance of adolescents on two versions of a serious video game presenting realistic, everyday, socio-moral conflicts, and to explore whether their performance is associated with empathy or sense of presence, factors known to influence social cognition. Participants (12-17 years, M = 14.39; SD = 1.35) first completed a pre-test measure of socio-moral reasoning based on three dilemmas from a previously validated computer task. Then, they either played an evaluative version (n = 24) or an adaptive (n = 33) version of a video game presenting nine social situations in which they made socio-moral decisions and provided justifications. In the evaluative version, participants' audio justifications were recorded verbatim and coded manually to obtain a socio-moral reasoning maturity score. In the adaptive version (AV), tailored feedback and social reinforcements were provided based on participant responses. An automatic coding algorithm developed using artificial intelligence was used to determine socio-moral maturity level in real-time and to provide a basis for the feedback and reinforcements in the game. All participants then completed a three-dilemma post-test assessment. Those who played the adaptive version showed improved SMR across the pre-test, in-game and post-test moral maturity scores, F(1.97,63.00) = 9.81, pHF < 0.001, ϵ2 = 0.21, but those who played the Evaluative version did not. Socio-moral reasoning scores from both versions combined did not correlate with empathy or sense of presence during the game, though results neared significance. The study findings support preliminary validation of the game as a promising method for assessing and remediating social skills during adolescence.


Depressive status explains a significant amount of the variance in COPD assessment test (CAT) scores.
COPD assessment test (CAT) is a short, easy-to-complete health status tool that has been incorporated into the multidimensional assessment of COPD in order to guide therapy; therefore, it is important to understand the factors determining CAT scores. This is a post hoc analysis of a cross-sectional, observational study conducted in respiratory medicine departments and primary care centers in Spain with the aim of identifying the factors determining CAT scores, focusing particularly on the cognitive status measured by the Mini-Mental State Examination (MMSE) and levels of depression measured by the short Beck Depression Inventory (BDI). A total of 684 COPD patients were analyzed; 84.1% were men, the mean age of patients was 68.7 years, and the mean forced expiratory volume in 1 second (%) was 55.1%. Mean CAT score was 21.8. CAT scores correlated with the MMSE score (Pearson's coefficient r=-0.371) and the BDI (r=0.620), both p<0.001. In the multivariate analysis, the usual COPD severity variables (age, dyspnea, lung function, and comorbidity) together with MMSE and BDI scores were significantly associated with CAT scores and explained 45% of the variability. However, a model including only MMSE and BDI scores explained up to 40% and BDI alone explained 38% of the CAT variance. CAT scores are associated with clinical variables of severity of COPD. However, cognitive status and, in particular, the level of depression explain a larger percentage of the variance in the CAT scores than the usual COPD clinical severity variables.


A conceptual investigation of variables affecting the success and acceptance of SMS Marketing in Iran.
This paper's aim was to develop a conceptual overview of SMS marketing and delineate factors of new communications technologies on business practice. This study, which was a descriptive survey, was built on primary and secondary data source including a literature review of SMS marketing and a Questionnaire were used as the primary means of collecting secondary data. The sample size of 300 patients was determined according to the Cochran formula. Moreover, data analysis was done in SPSS by using linear regression, chi-square, t-test and Binomial test. According to the research, sex, age, education, relevance, timeliness, reliability to sender, sense of control were variables affecting the SMS marketing acceptance. This paper was qualitative and provided a solid conceptual foundation for the future empirical research on e- marketing. The potential limitation was related to the broad user of computer and mobile. In this research, we considered SMS marketing, Mobile marketing, SMS advertising as the same subject. This research will be a useful resource with important insight into the factors that may encourage or determine consumer acceptance of this new form of direct marketing. This paper addressed an important timely issue, and added to the body of literature and knowledge focusing on e-marketing.


Case of granulomatosis with polyangiitis (Wegener's granulomatosis) manifested with asymptomatic intracerebral hemorrhage.
A 46-year-old man, who had had sinusitis, developed bilateral omalgia, petechiae on his lower extremities and a congested right eye. A blood test detected elevated serum C-reactive protein level. Computed tomography incidentally found an acute lesion of thalamic hemorrhage without neurological symptoms and no specific therapy was given at the time. Thereafter, he developed vertigo, vomiting and pneumonia for which antibiotics were ineffective. He was referred and admitted to our hospital. Further, aural and renal lesions, and presence of serum proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) confirmed his diagnosis of granulomatosis with polyangiitis (Wegener's) (GPA). With corticosteroid and cyclophosphamide therapy, his symptoms disappeared in two months along with faded PR3-ANCA. Afterward he showed neither new cerebral lesion nor symptom. This is a rare case of GPA manifested with asymptomatic intracerebral hemorrhage. It should be noted that GPA could cause various manifestations in central nervous system such as a fatal or an asymptomatic hemorrhagic lesion, which might respond to immunosuppressive therapy.


[Surgical treatment of urinary incontinence in geriatric patients].
Recently, there has been a steady upward trend in life expectancy, so it is extremely important to remember some of the features of the body associated specifically with aging. Thus, an important topic for discussion is the issue of ensuring the quality of life of an elderly woman. The prevalence of urinary incontinence in patients of the older age group leads to significant restrictions in their social life. Surgical treatment using general and regional anesthesia has significant contraindications due to age and comorbidities. In this regard, in some cases, local anesthesia is the method of choice of anesthesia in this category of patients. Evaluation of the possibility of using local anesthesia in the surgical treatment of stress urinary incontinence in geriatric patients. We analyzed the results of surgical treatment of stress urinary incontinence in 42 patients. The mean age of the patients was 78+/-4 years. All patients were treated for urinary incontinence using mini loops under local anesthesia. Pre- and postoperative examination included vaginal examination in mirrors, cough test, cystoscopy (if indicated), uroflowmetry, ultrasound examination of the pelvic organs and bladder, bacterial culture of urine with determination of sensitivity to antibiotics. Taking into account the advanced age of the patients, the protocol of the preoperative examination included the obligatory performance of ultrasound Doppler examination of the veins of the lower extremities and echocardiography. The duration of the operation averaged 22+/-5 minutes. Complications requiring a change in the course of the operation were not registered during the operation. 1 month after the operation, at the control examination, the cough test was negative in 40 (95,2%) patients. 2 (4,8%) had a positive cough test. After 6 months, out of 40 (100%) successfully operated patients, 4 (9,52%) had urine leakage during the cough test. The maximum follow-up period for patients was 12 months. Out of 40 (100%) patients with a negative cough test after surgery, it was possible to track the long-term results of treatment only in 33 (82,5%) patients. After evaluating the results of 33 (100%) operated patients after 12 months, it was found that in 30 (90,9%) patients the symptoms of urinary incontinence were completely absent, in 3 (9,09%) there was a recurrence of urinary incontinence. Surgical treatment of stress urinary incontinence using a synthetic loop under local anesthesia is effective and safe in geriatric patients.


An update on the current management of adult obstructive sleep apnoea.
Obstructive sleep apnoea (OSA) is common in adults. Various contributing factors to this condition have resulted in the development of a number of potential treatment modalities, some of which are in evolution. A multidisciplinary team involving the general practitioner is an important aspect in providing personalised care. The aim of this review is to provide a clinical update on the recent developments and future directions in adult OSA management. In-lab polysomnography remains important in the diagnosis of OSA, although home sleep studies have good specificity and sensitivity in particular subgroups of patients. First-line therapy in adult OSA is continuous positive airway pressure, with mandibular advancement splints and surgical intervention considered second-line. Adjunctive therapies include weight loss, avoidance of supine sleep, management of nasal obstruction, alcohol intake limitation and exercise. Advancements in medications targeting multiple neurophysiological pathways, and surgical insertion of hypoglossal nerve stimulator devices represent possible future treatment pathways in Australia.


Using combined computational techniques to predict the glass transition temperatures of aromatic polybenzoxazines.
The Molecular Operating Environment software (MOE) is used to construct a series of benzoxazine monomers for which a variety of parameters relating to the structures (e.g. water accessible surface area, negative van der Waals surface area, hydrophobic volume and the sum of atomic polarizabilities, etc.) are obtained and quantitative structure property relationships (QSPR) models are formulated. Three QSPR models (formulated using up to 5 descriptors) are first used to make predictions for the initiator data set (n = 9) and compared to published thermal data; in all of the QSPR models there is a high level of agreement between the actual data and the predicted data (within 0.63-1.86 K of the entire dataset). The water accessible surface area is found to be the most important descriptor in the prediction of T(g). Molecular modelling simulations of the benzoxazine polymer (minus initiator) carried out at the same time using the Materials Studio software suite provide an independent prediction of T(g). Predicted T(g) values from molecular modelling fall in the middle of the range of the experimentally determined T(g) values, indicating that the structure of the network is influenced by the nature of the initiator used. Hence both techniques can provide predictions of glass transition temperatures and provide complementary data for polymer design.


Case Analysis of Factors Contributing to Patient Falls.
Falls are a constant risk for patients in acute-care hospitals, which can lead to serious consequences. The purpose of this study was to examine hospital fall case studies and to learn the contributing factors for patient falls. This was achieved by conducting a secondary analysis of 11 fall case studies obtained from two previous studies. The fall cases used the Senior Falls Investigative Methodology (SFIM) approach, which provided detailed analysis of the circumstances surrounding the falls. A total of 549 contributing factors were identified in the 11 case studies, where major categories were classified according to the four different layers of defenses using Reason's Swiss Cheese Model of Accident Causation (organizational factors, supervision, preconditions, and unsafe acts). Hospital policies, reduced supervision, disease processes, the environment, and patients transferring without assistance dominated the reasons for increased risk. Additional strategies were recommended for all layers of defense to reduce patient falls.


Preliminary findings of long-term neurodevelopmental outcomes of infants treated with intravenous fat emulsion reduction for the management of parenteral nutrition-associated cholestasis.
Parenteral nutrition-associated cholestasis (PNAC) is linked with the administration of soybean-based intravenous fat emulsion (IVFE). IVFE reduction (IFER) may be an effective management strategy for PNAC; however, long-term associated neurodevelopmental outcomes (NDOs) for infants undergoing IFER have not been measured previously. This single-institution, prospective study examined the risk for negative NDOs and key predictors of NDOs associated with IFER. Patients (2-5 years) treated with soybean-based IFER as neonates underwent NDO measurements, including Ages and Stages Questionnaires-3 (ASQ-3), Parents' Evaluations of Developmental Status (PEDS), and Behavior Assessment System for Children, Second Edition Preschool, Parent (BASC-2 PRS-P). The relationship between NDOs and predictive variables was evaluated. A total of 25 children had a complete PEDS survey, and 17 were found to be "not at risk." The BASC-2 PRS-P evaluation (n = 18 patients) showed that all 4 composite domains fell within the normative developmental range, and 67%-89% of patients were observed to be "typically developing." For the primary outcome measure, ASQ-3, 82.4%-94.4% of patients were "not at risk." Logistical regression analyses were performed to examine risk factors contributing to negative NDOs. Of children completing all NDO studies, IFER-related variables (eg, development of essential fatty acid deficiency, duration of IFER, and mean IVFE dose) were not found to be predictors of adverse NDOs. This study represents the first report of NDOs in pediatric patients treated with IFER. IFER-treated patients score within the normative range most of the time. IFER-related variables were not found to be associated with negative NDOs. The results set the stage for a larger, multicenter, prospective study.


Injury risk functions for the four primary knee ligaments.
The purpose of this study was to develop injury risk functions (IRFs) for the anterior and posterior cruciate ligaments (ACL and PCL, respectively) and the medial and lateral collateral ligaments (MCL and LCL, respectively) in the knee joint. The IRFs were based on post-mortem human subjects (PMHSs). Available specimen-specific failure strains were supplemented with statistically generated failure strains (virtual values) to accommodate for unprovided detailed experimental data in the literature. The virtual values were derived from the reported mean and standard deviation in the experimental studies. All virtual and specimen-specific values were thereafter categorized into groups of static and dynamic rates, respectively, and tested for the best fitting theoretical distribution to derive a ligament-specific IRF. A total of 10 IRFs were derived (three for ACL, two for PCL, two for MCL, and three for LCL). ACL, MCL, and LCL received IRFs in both dynamic and static tensile rates, while a sufficient dataset was achieved only for dynamic rates of the PCL. The log-logistic and Weibull distributions had the best fit (p-values: >0.9, RMSE: 2.3%-4.7%) to the empirical datasets for all the ligaments. These IRFs are, to the best of the authors' knowledge, the first attempt to generate injury prediction tools based on PMHS data for the four knee ligaments. The study has summarized all the relevant literature on PHMS experimental tensile tests on the knee ligaments and utilized the available empirical data to create the IRFs. Future improvements require upcoming experiments to provide comparable testing and strain measurements. Furthermore, emphasis on a clear definition of failure and transparent reporting of each specimen-specific result is necessary.


Bladder neck suspension using bone anchors for the treatment of female stress incontinence.
A new technique and related devices for the treatment of urinary incontinence in women was developed and tested. The technique involves soft tissue to bone fixation by means of miniature bone anchors and a bone anchor inserter. The novel bone anchors are made of a shape-memory nickel titanium alloy (Nitinol) attached to Polypropylene or Gortex suture. A spring-loaded bone anchor inserter drives the anchors through the vaginal wall to a predetermined depth into the pubic bone medulla regardless of the bone's hardness, with no incision or drilling required. The device allows for the performance of a minimally invasive transvaginal bladder neck suspension. The procedure has minimal morbidity and a short learning curve. This technique was evaluated clinically in 15 women with incontinence, with a mean follow-up of 6 months. Good urinary continence was achieved in all patients, with no mechanical failures.


Hepatic angiomyolipoma, misdiagnosed as hepatocellular carcinoma.
Perivascular epithelioid cell neoplasm (PEComa) is a rare type of tumor, and hepatic PEComa is even rarer. Its preoperative diagnosis is difficult, given the absence of specific clinical manifestations, often constituting an accidental finding, and the lack of a gold standard for identification using imaging studies. Instead, the diagnosis of hepatic PEComa is based on morphological and immunohistochemical features. We describe a case of an asymptomatic hepatic PEComa, angiomyolipoma type, which appeared in a middle-aged woman with chronic liver disease, during her follow-up and screening. Given the patient's context, human immunodeficiency virus-positive with chronic hepatitis C, and the similarities between the two tumors, the hepatic lesion was interpreted as hepatocellular carcinoma. The patient underwent surgical excision of the tumor, and the positive immunohistochemical staining for human melanoma black 45 and Melan A made the definitive diagnosis. In the absence of aggressiveness tumor markers, surveillance was decided. We also provide a literature review of these tumors.


Multiclass Sparse Bayesian Regression for fMRI-Based Prediction.
Inverse inference has recently become a popular approach for analyzing neuroimaging data, by quantifying the amount of information contained in brain images on perceptual, cognitive, and behavioral parameters. As it outlines brain regions that convey information for an accurate prediction of the parameter of interest, it allows to understand how the corresponding information is encoded in the brain. However, it relies on a prediction function that is plagued by the curse of dimensionality, as there are far more features (voxels) than samples (images), and dimension reduction is thus a mandatory step. We introduce in this paper a new model, called Multiclass Sparse Bayesian Regression (MCBR), that, unlike classical alternatives, automatically adapts the amount of regularization to the available data. MCBR consists in grouping features into several classes and then regularizing each class differently in order to apply an adaptive and efficient regularization. We detail these framework and validate our algorithm on simulated and real neuroimaging data sets, showing that it performs better than reference methods while yielding interpretable clusters of features.


Genome-wide identification and comparative analysis of lipocalin families in Lepidoptera with an emphasis on Bombyx mori.
Lipocalins exhibit functional diversity, including roles in retinol transport, invertebrate cryptic coloration, and stress response. However, genome-wide identification and characterization of lipocalin in the insect lineage have not been thoroughly explored. Here, we found that a lineage-specific expansion of the lipocalin genes in Lepidoptera occurred in large part due to tandem duplication events and several lipocalin genes involving insect coloration were expanded more via tandem duplication in butterflies. A comparative analysis of conserved motifs showed both conservation and divergence of lepidopteran lipocalin family protein structures during evolution. We observe dynamic changes in tissue expression preference of paralogs in Bombyx mori, suggesting differential contribution of paralogs to specific organ functions during evolution. Subcellular localization experiments revealed that lipocalins localize to the cytoplasm, nuclear membrane, or nucleus in BmN cells. Moreover, several lipocalin genes exhibited divergent responses to abiotic and biotic stresses, and 1 lipocalin gene was upregulated by 300 fold in B. mori. These results suggest that lipocalins act as signaling components in defense responses by mediating crosstalk between abiotic and biotic stress responses. This study deepens our understanding of the comprehensive characteristics of lipocalins in insects.


Side effects and potential risk factors of botulinum toxin type A intramuscular injections in knee flexion contractures of hemophiliacs.
Knee flexion contracture (KFC) is a common complication of recurrent hemarthrosis in children and young adults with hemophilia. If the KFC is not prevented (by means of primary prophylaxis) and treated properly and early (be means of physical medicine and rehabilitation), it will become fixed. Areas covered: The aim of this article is to review the potential role of botulinum toxin type A (BTX-A) intramuscular injections for the treatment of KFC in people with hemophilia (PWH). Expert commentary: Although two recent reports have mentioned the benefits of intramuscular injections of BTX-A in PWH with KFC, the data are still scant and too preliminary. The use of intramuscular injections of BTX-A in PWH today should not be recommended until more case studies/small series (ideally well-designed clinical trials) fully demonstrate that this is safe and effective. The risks of intramuscular injections to a hemophilia patient cannot be underestimated (iatrogenic muscle hematomas and pseudotumors). This paper calls the attention of hemophilia treaters on the potential risks of this apparently interesting technique. The current use of BTX-A intramuscular injections in KFC of PWH could make no sense. Raising false expectations in these patients should be avoided.


An examination of the expectation value profiles for average stretch and momentum in O-H and O-D bonds of the HOD molecule to determine their role in selective photodissociation.
The expectation values for stretch and momentum in O-H and O-D bonds of the H-O-D molecule subjected to UV pulses effecting selective cleavage of these bonds have been analyzed to decipher the mechanistic basis of selective dissociation. Fully quantum dynamical calculations using both the ground and excited potential energy surfaces with different initial states and UV pulses reveal that prior stretch in a bond before transferring it to the repulsive first excited-state ensures preferential dissociation of this bond. The sampling of large stretch values and a quick downhill motion in the channel corresponding to dissociation of the prestretched bond on the upper surface are seen to underlie this preferential dissociation.


Current and emerging pharmacotherapies for opioid dependence treatments in adults: a comprehensive update.
Opioid use disorder (OUD) is characterized by compulsive opioid seeking and taking, intense drug craving, and intake of opioids despite negative consequences. The prevalence of OUDs has now reached an all-time high, in parallel with peak rates of fatal opioid-related overdoses, where 15 million individuals worldwide meet the criteria for OUD. Further, in 2020, 120,000 opioid-related deaths were reported worldwide with over 75,000 of those deaths occurring within the United States. In this review, we highlight pharmacotherapies utilized in patients with OUDs, including opioid replacement therapies, and opioid antagonists utilized for opioid overdoses and deterrent of opioid use. We also highlight newer treatments, such as those targeting the neuroimmune system, which are potential new directions for research given the recently established role of opioids in activating neuroinflammatory pathways, as well as over the counter remedies, including kratom, that may mitigate withdrawal. To effectively treat OUDs, a deeper understanding of the current therapeutics being utilized, their additive effects, and the added involvement of the neuroimmune system are essential. Additionally, a complete understanding of opioid-induced neuronal alterations and therapeutics that target these abnormalities - including the neuroimmune system - is required to develop effective treatments for OUDs.


Long-term mortality and causes of death in endoscopically verified upper gastrointestinal bleeding: comparison of bleeding patients and population controls.
Upper gastrointestinal bleeding (UGIB) is a common emergency, with in-hospital mortality between 3 and 14%. However, the long-term mortality and causes of death are unknown. We investigated the long-term mortality and causes of death in UGIB patients in a retrospective single-centre case-control study design. A total of 569 consecutive patients, aged ≥18 years, admitted to Kuopio University Hospital for their first endoscopically verified UGIB during the years 2009-2011 were identified from hospital records. For each UGIB patient, an age, sex and hospital district matched control patient was identified from the Statistics Finland database. Data on endoscopy procedures, laboratory values, comorbidities and medication were obtained from patient records. Data on deaths and causes of death were obtained from Statistics Finland. In-hospital mortality of UGIB patients was low at 3.3%. The long-term (mean follow-up 32 months) mortality of UGIB patients was significantly higher than controls (34.1 versus 12.1%, p < .001). During the 6 months following UGIB, the risk of death compared to controls was highest (HR 19.2, 95% CI 7.0-52.4, p < .001) and remained higher up to 3 years after the bleeding. Beyond 3 years' follow-up, there was no difference in mortality between the groups (HR 0.7, 95% CI 0.4-1.6, p = .436). During the first 3 months after the UGIB episode, mortality was related to gastrointestinal diseases; after 3 months, the causes of death were related to comorbidities and did not differ from causes of death in controls. UGIB patients have three times higher long-term mortality than population controls.


Temporal trends in multiple sclerosis prevalence and incidence in a large population.
We sought to better understand the reasons for increasing prevalence of multiple sclerosis (MS) by studying prevalence in relation to incidence, mortality rates, sex ratio, and geographic distribution of cases. We identified MS cases from 1996 to 2013 in Ontario, Canada, by applying a validated algorithm to health administrative data. We calculated age- and sex-standardized prevalence and incidence rates for the province and by census division. Incidence and prevalence sex ratios for women to men were computed. The prevalence of MS increased by 69% from 1.57 (95% confidence interval [CI]: 1.54-1.59) per 1,000 in 1996 (n = 12,155) to 2.65 (95% CI: 2.62-2.68) in 2013 (n = 28,192). Incidence remained relatively stable except for a spike in 2010, followed by a subsequent decline in 2011-2013, particularly among young people and men. Mortality decreased by 33% from 26.7 (95% CI: 23.5-30.3) per 1,000 to 18.0 (95% CI: 16.4-19.8) per 1,000. The incidence sex ratio was stable from 1996 to 2009, then declined in 2010, with partial rebound by 2013. MS prevalence and incidence showed no consistent association with latitude. In this large, population-based MS cohort, we found stable incidence and increasing prevalence of MS; the latter largely reflected declining mortality. A spike in incidence in 2010 among younger patients and men at a time of widespread media coverage of MS suggests that these groups may be vulnerable to delayed diagnosis. We did not find a latitudinal gradient; however, most Ontarians live between the 42nd and 46th parallels, reducing our ability to detect an effect of latitude.


Dependence of Membrane Tether Strength on Substrate Rigidity Probed by Single-Cell Force Spectroscopy.
Substrate rigidity modulates cell mechanics, which affect cell migration and proliferation. Quantifying the effects of substrate rigidity on cancer cell mechanics requires a quantifiable parameter that can be measured for individual cells, as well as a substrate platform with rigidity being the only variable. Here we used single-cell force spectroscopy to pull cancer cells on substrates varying only in rigidity, and extracted a parameter from the force-distance curves to be used to quantify the properties of membrane tethers. Our results showed that tether force increases with substrate rigidity until it reaches its asymptotic limit. The variations are similar for all three cancer cell lines studied, and the largest change occurs in the rigidity regions of softer tissues, indicating a universal response of cancer cell elasticity to substrate rigidity.


Scaling of sensitivity and efficiency in planar microresonators for electron spin resonance.
Electron spin resonance (ESR) of volume-limited samples or nanostructured materials can be made significantly more efficient by using microresonators whose size matches that of the structures under investigation. We describe a series of planar microresonators that show large improvements over conventional ESR resonators in terms of microwave conversion efficiency (microwave field strength for a given input power) and sensitivity (minimum number of detectable spins). We explore the dependence of these parameters on the size of the resonator and find that both scale almost linearly with the inverse of the resonator size. Scaling down the loops of the planar microresonators from 500 down to 20 mum improves the microwave efficiency and the sensitivity of these structures by more than an order of magnitude and reduces the microwave power requirements by more than two orders of magnitude.


Molecular and epidemiological review of toxigenic diphtheria infections in England between 2007 and 2013.
Human infections caused by toxigenic corynebacteria occur sporadically across Europe. In this report, we undertook the epidemiological and molecular characterization of all toxigenic corynebacterium strains isolated in England between January 2007 and December 2013. Epidemiological aspects include case demographics, risk factors, clinical presentation, treatment, and outcome. Molecular characterization was performed using multilocus sequence typing (MLST) alongside traditional phenotypic methods. In total, there were 20 cases of toxigenic corynebacteria; 12 (60.0%) were caused by Corynebacterium ulcerans, where animal contact was the predominant risk factor. The remaining eight (40.0%) were caused by Corynebacterium diphtheriae strains; six were biovar mitis, which were associated with recent travel abroad. Adults 45 years and older were particularly affected (55.0%; 11/20), and typical symptoms included sore throat and fever. Respiratory diphtheria with the absence of a pharyngeal membrane was the most common presentation (50.0%; 10/20). None of the eight C. diphtheriae cases were fully immunized. Diphtheria antitoxin was issued in two (9.5%) cases; both survived. Two (9.5%) cases died, one due to a C. diphtheriae infection and one due to C. ulcerans. MLST demonstrated that the majority (87.5%; 7/8) of C. diphtheriae strains represented new sequence types (STs). By adapting several primer sequences, the MLST genes in C. ulcerans were also amplified, thereby providing the basis for extension of the MLST scheme, which is currently restricted to C. diphtheriae. Despite high population immunity, occasional toxigenic corynebacterium strains are identified in England and continued surveillance is required.


Fine and bidirectional regulation of toehold-mediated DNA strand displacement by a wedge-like DNA tool.
A wedge-like tool was established to finely and bidirectionally regulate the displacement rate of toehold-mediated strand displacement. This novel tool is very robust in terms of sequence generality and is compatible with most of the current DNA nanodevices based on traditional toehold reactions.


Why do general practitioners apply to do an MSc in primary healthcare? A retrospective study.
The aim of this study was to examine the characteristics of general practitioners (GPs) applying to the MSc in Primary Health Care at King's College London and their reasons for doing so, and to see whether these have changed during the last 20 years. Demographic data came from 157 applications submitted between 1986 and 2006. GPs' answers to an open-ended question on the reasons for applying were analysed, using both qualitative and quantitative methods. Male sex (66%) and experience of 11.1 (+/-7.1) years in primary care characterised the GPs. Six reasons for applying were identified: (a) career development; (b) personal development; (c) understanding the context of general practice; (d) to improve job satisfaction; (e) to improve clinical practice; and (f) to be a member of an educational group. Understanding the context of general practice was stated more frequently by GPs in the later cohorts (P < 0.05), who also tended to have had less experience of general practice (8.3 versus 11.1 years, P < 0.05). Understanding the developing discipline of general practice is an increasingly important motivation in applying for an MSc, and one that is identified earlier in GPs' careers. The requirement of appraisals and the advent of revalidation may motivate many more GPs to pursue Master's study. Postgraduate educators need to continue to ensure that their programmes reflect the changing landscape of primary care.


Patients With Severe Multiple Sclerosis Exhibit Functionally Altered CD8+ Regulatory T Cells.
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Studies of immune dysfunction in MS have mostly focused on CD4+ Tregs, but the role of CD8+ Tregs remains largely unexplored. We previously evidenced the suppressive properties of rat and human CD8+CD45RClow/neg Tregs from healthy individuals, expressing Forkhead box P3 (FOXP3) and acting through interferon-gamma (IFN-γ), transforming growth factor beta (TGFβ), and interleukin-34 (IL-34). secretions to regulate immune responses and control diseases such as transplant rejection. To better understand CD8+CD45RClow/neg Tregs contribution to MS pathology, we further investigated their phenotype, function, and transcriptome in patients with MS. We enrolled adults with relapsing-remitting MS and age-matched and sex-matched healthy volunteers (HVs). CD8+ T cells were segregated based on low or lack of expression of CD45RC. First, the frequency in CSF and blood, phenotype, transcriptome, and function of CD8+CD45RClow and neg were investigated according to exacerbation status and secondarily, according to clinical severity based on the MS severity score (MSSS) in patients with nonexacerbating MS. We then induced active MOG35-55 EAE in C57Bl/6 mice and performed adoptive transfer of fresh and expanded CD8+CD45RCneg Tregs to assess their ability to mitigate neuroinflammation in vivo. Thirty-one untreated patients with relapsing-remitting MS were compared with 40 age-matched and sex-matched HVs. We demonstrated no difference of CSF CD8+CD45RClow and CD8+CD45RCneg proportions, but blood CD8+CD45RClow frequency was lower in patients with MS exacerbation when compared with that in HVs. CD8+CD45RCneg Tregs but not CD8+CD45RClow showed higher suppressive capacities in vitro in MS patients with exacerbation than in patients without acute inflammatory attack. In vitro functional assays showed a compromised suppression capacity of CD8+CD45RClow Tregs in patients with nonexacerbating severe MS, defined by the MSSS. We then characterized murine CD8+CD45RCneg Tregs and demonstrated the potential of CD45RCneg cells to migrate to the CNS and mitigate experimental autoimmune encephalomyelitis in vivo. Altogether, these results suggest a defect in the number and function of CD8+CD45RClow Tregs during MS relapse and an association of CD8+CD45RClow Tregs dysfunction with MS severity. Thus, CD8+CD45RClow/neg T cells might bring new insights into the pathophysiology and new therapeutic approaches of MS.


The effect of audio and video modeling on beginning guitar students' ability to accurately sing and accompany a familiar melody on guitar by ear.
The purpose of this research was to determine the effect of audio and visual modeling on music and nonmusic majors' ability to accurately sing and accompany a familiar melody on guitar by ear. Two studies were run to investigate the impact of musical training on the ability to play by ear. All participants were student volunteers enrolled in sections of a beginning class guitar course and were randomly assigned to one of three groups: control, audio modeling only, or audio and visual modeling. All participants were asked to sing the same familiar song in the same key and accompany on guitar. Study 1 compared music majors with nonmusic majors and showed no significant difference between treatment conditions, however, there was a significant difference between music majors and nonmusic majors across all conditions. There was no significant interaction between groups and treatment conditions. Study 2 investigated the operational definition of "musically trained" and compared musically trained with nonmusically trained participants across the same three conditions. Results of Study 2 showed no significant difference between musically trained and nonmusically trained participants; however, there was a significant difference between treatment conditions with the audio-visual group completing the task in the shortest amount of time. There was no significant interaction between groups and treatment conditions. Results of these analyses support the use of instructor modeling for beginning guitar students and suggest that previous musical knowledge does not play a role in guitar skills acquisition at the beginning level.


Lung cancer nanomedicine: potentials and pitfalls.
Lung cancer is by far the most common cause of cancer-related deaths in the world. Nanoparticle-based therapies enable targeted drug delivery for lung cancer treatment with increased therapeutic efficiency and reduced systemic toxicity. At the same time, nanomedicine has the potential for multimodal treatment of lung cancer that may involve 'all-in-one' targeting of several tumor-associated cell types in a timely and spatially controlled manner. Therapeutic approaches, however, are hampered by a translational gap between basic scientists, clinicians and pharma industry due to suboptimal animal models and difficulties in scale-up production of nanoagents. This calls for a disease-centered approach with interdisciplinary basic and clinical research teams with the support of pharma industries.


Two-Pore Channels and Parkinson's Disease: Where's the Link?
Two-pore channels are endolysosomal Ca2+ release channels involved in proper trafficking to and from those organelles. They are the likely targets for the Ca2+-mobilizing messenger NAADP, and are further regulated by a variety of mechanisms including phosphoinositide levels and Rab proteins. As discussed here, recent studies highlight a role for these channels in the pathomechanism(s) underlying Parkinson's disease, with important implications for possible alternative treatment strategies.


Women with Subclinical Hypothyroidism Are at Low Risk of Poor Pregnancy Outcome in Japan.
Maternal subclinical hypothyroidism may be associated with adverse pregnancy outcomes, although not consistently across regions. Here, we sought to determine the effect of elevated thyroid-stimulating hormone (TSH) on pregnancy outcomes in Japanese women without known medical complications. TSH was determined by dried blood spots at 8-20 weeks of gestation, and 3.0-10.0 μU/mL of TSH was considered as elevated TSH (eTSH). A retrospective study involving 167 cases of eTSH was conducted. Five hundred and seventy eight of controls with normal TSH and without thyroid antibodies were selected. We compared a composite adverse maternal outcome comprised of spontaneous abortion, premature delivery, gestational diabetes mellitus (GDM), placental abruption, and pregnancy-induced hypertension, as well as composite adverse neonatal outcome including stillbirths, heavy for date, light for date, and a low Apgar score (< 7) at 5 minutes between two groups. The incidence of GDM was significantly higher in eTSH (p < 0.01); however, composite adverse maternal and neonatal outcome did not differ between groups (p = 0.19 and p = 0.50, respectively). Although 27 out of 167 cases in eTSH have antibodies, composite adverse outcome did not differ between eTSH with antibodies and controls (p = 0.64 and p = 0.50, respectively). Additionally, composite adverse maternal and neonatal outcome did not differ between the group larger than the median of TSH in eTSH (n = 81) and controls (p = 0.43 and p = 0.98, respectively). Thus, elevated TSH is not associated with overall adverse pregnancy outcomes in women without known medical complications.


Sarcoidosis: vaginal wall and vulvar involvement.
Sarcoidosis is a non-caseous granulomatous disease which could involve numerous organs including lungs, eyes, skin, nervous system, heart, liver. However, the genitourinary tract involvement was rarely reported in sarcoidosis. We report the case of a 45-year-old married woman who presented with 2 months history of a vulval mass as large as a soybean, and did not reveal any remarkable pulmonary signs. Biopsy results showed non-caseous granulomatous inflammation consistent with sarcoidosis in the vulvar lesion. To our knowledge, this is the first reported case of this entity in the world. Based on the related literature, we highlight the possibility of gynecologic involvement in sarcoidosis.


[Vascular pedicled iliac bone graft in therapy of femur head necrosis in the adult. Clinical and angiographic results].
23 hip joints with hip head necrosis in 22 patients were provided with a pedicle bone-graft perfused by the art. circumflexa ilium profunda. I two cases it was necessary to remove the bone-graft contralaterally because bone had already been removed from the side with the necrosis at an earlier date. In these cases the arterio-venous bundle of vessels of the autologous heterotope transplant was connected through microanastomosis with the arteria and vena circumflexa femoris lateralis. In addition to the usual clinical follow-up the method of superselective angiography was also applied to make possible direct perfusion control of the implanted bone-graft in the operated patients. In 18 of the 23 pedicle autologous heterotope transplants unimpeded perfusion could be shown. By introducing regional stress angiography in 7 cases it became possible to make further well-founded statements about the physiotherapeutical follow-up treatment. Electronic subtraction provides a more accurate assessment of even the minutest arteries possible.


The mechanism of urinary kallikrein excretion in the rat.
1. In male Wistar rats urinary kallikrein excretion was positively correlated with urinary flow and glomerular filtration rate (GFR). 2. Osmotic diuresis produced by a 30% (w/v) glucose solution increased urinary kallikrein, and a positive correlation between this variable and urine flow was observed. No correlation was observed with GFR. 3. The mechanism of urinary kallikrein excretion is interpreted as a wash-out effect of renal kallikrein.


INCIDENCE OF, AND RISK FACTORS FOR, MALNUTRITION AMONG CHILDREN AGED 5-7 YEARS IN SOUTH INDIA.
Protein-energy malnutrition is a major health problem contributing to the burden of disease in developing countries. The aim of this study was to assess the incidence of, and risk factors for, malnutrition among school-going children in south India. A total of 2496 children aged 5-7 years from rural and urban areas of south India were recruited in 1982 and followed up for malnutrition over a period of 9 years. Their body heights and weights were measured every six months and socio-demographic factors such as mother's education and father's education and relevant household characteristics and hygiene practices collected. Body mass index and height-for-age z-scores were used to determine children's levels of underweight and stunting, respectively, classified as normal, mild/moderate or severe. Risk factor analysis was done for pre-pubertal ages only using Generalized Estimating Equations with cumulative odds assumption. There was a significant difference between male and female children in the incidence of severe underweight and stunting (6.4% and 4.2% respectively). Children in households with no separate kitchen had 1.3 (1.0-1.6) times higher odds of being severely underweight (p=0.044) compared with those with a kitchen. Children without a toilet facility had significantly higher odds of severe underweight compared with those who did. Children with illiterate parents had higher odds of severe stunting than those with literate parents. In conclusion, the prevalence of malnutrition among these south Indian children has not changed over the years, and the incidence of severe malnutrition was highest in children when they were at pubertal age. The risk factors for stunting were mostly poverty-related, and those for underweight were mostly hygiene-related. Adolescent children in south India should be screened periodically at school for malnutrition and provided with nutritional intervention if necessary.


Simultaneous 18F choline positron emission tomography/magnetic resonance imaging of the prostate: initial results.
The purposes of this study were to evaluate the feasibility of simultaneous 18F choline positron emission tomography (PET) and magnetic resonance imaging (MRI) of the prostate and to present the first clinical results of the method. From March 2012 to October 2012, a total of 15 consecutive patients were examined with simultaneous 18F choline PET/MRI. At the time of the examination, 8 patients had histologically proven prostate cancer, 2 patients had repeated prostate biopsies with negative results, and 5 patients had suspected prostate cancer with an elevated or rising prostate specific antigene level but did not have a prostate biopsy. Sequence protocol comprised T2-weighted high-resolution images and diffusion-weighted images of the prostate in addition to PET imaging. Image quality was assessed by 2 radiologists, and the PET images were evaluated qualitatively and quantitatively. Simultaneous PET/MRI of the prostate was accomplished successfully in all patients. The method proved to be robust without technical failure, and the image quality was rated to be diagnostic in all examinations except in 1 diffusion-weighted imaging (DWI) data set that was judged to be nondiagnostic because of susceptibility artifacts. High-resolution T2-weighted images allowed exact correlation of elevated focal or diffuse choline uptake to suspicious T2-weighted lesions of the prostate. A high accordance was found between PET and DWI. However, PET-positive lesions were found in 3 patients wherein DWI did not indicate tumor in suspicious T2-weighted lesions. Simultaneous positron emission tomography/magnetic resonance imaging of the prostate has the advantage of combining high-resolution prostate images, functional studies, and metabolic/molecular imaging. The PET component adds diagnostic confidence to the MRI-based parameters in identifying and localizing tumor in the prostate.


The role of short-chain fatty acids in health and disease.
There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.


Correlation between transcriptional expression of survivin isoforms and clinicopathological findings in human colorectal carcinomas.
Survivin, a novel member of the inhibitor of apoptosis protein (IAP) family, has been markedly overexpressed in most types of human carcinoma, and recognized as a potential target in anticancer therapy. In addition, two splice variants of survivin, survivin-2B and survivin-deltaEx3, have recently been identified. However, expression analysis on its splice variants has not been reported in colorectal carcinomas. Therefore, we investigated the transcription levels of survivin and its splice variants in human colorectal carcinomas, and the correlation between transcript expression levels and pathological findings was analyzed. Tumor tissue samples were provided from 52 cases with colorectal adenocarcinoma resected at the Osaka Medical College from 1995 to 1996. Transcription levels were measured by performing quantitative reverse transcription-polymerase chain reaction (RT-PCR) using primer pairs specific for survivin and either of its splice variants, then normalized by the glyceraldehyde 6-phosphate dehydrogenase. The transcription levels of survivin and its splice variants were significantly higher in the tumor tissue samples, and significantly lower in the normal tissue samples. In addition, approximately 40% of the normal tissue samples did not have any survivin expression. The relative expression level of survivin-2B to survivin (survivin-2B/survivin) was significantly higher in the tumor tissue samples than in the normal ones. In contrast, survivin-deltaEx3/survivin revealed no difference between tumor and normal samples. When Comparing the histological disease stages (stage I and II vs. stage III and IV), there were no significant differences in the expression levels of survivin and its splice variants. The expression level of survivin-2B/survivin for stage III and IV was lower than the one for stage I and II. In addition, a higher level of survivin-2B/survivin significantly correlated with a better prognosis in the present series. The present study demonstrates high expression level of survivin and its splice variants, which is relatively specific in tumor tissue and suggests that they have important roles in the progression of human colorectal carcinomas.


Adolescents' experience with scoliosis surgery: a qualitative study.
This article reports a study of adolescents' narrated experiences of undergoing scoliosis surgery. Six adolescents were interviewed. Open and semistructured questions were asked, and a qualitative content analysis of the text was performed. The results are presented in three main categories followed by subcategories. The three main categories of experience were emotional, physical, and social. The emotional aspects that emerged were fear, nightmares, nervousness, and helplessness. These had a great impact on adolescents' well-being before, during, and after the hospital visit. The physical aspects were mobilization, scars, different hip levels, pain, nausea, appetite, and urinary catheter. These aspects caused much discomfort, mostly during the hospital visit. The social aspects were friends, power, coaching and comfort, and sports. Some of the social aspects had a strong negative impact on the adolescents' well-being mostly after the hospital visit. This study suggests that both before and long after the surgery adolescents have strong emotions that they should be better prepared and helped to manage. To optimize perioperative care an interdisciplinary, a holistic approach must be taken that incorporates the complexity and whole of the adolescent's experiences. The findings of this study suggest that perioperative care of adolescents during scoliosis surgery needs to be optimized. To improve patients' psychologic preparation before surgery pediatric nurses should learn more about the individual patient and make care plans from a holistic perspective. Follow-up after discharge should address emotional, social, and physical aspects of the adolescent's health.


Hypoadrenia following adrenal venography in Cushing's disease.
Three patients with Cushing's disease are reported. In two patients the hyperfunction of the adrenal glands ceased following selective adrenal venography, moreover hypoadrenia has developed. In the third case necrosis following venography was proved by surgery and confirmed by histology. Regarding the therapeutic possibilities of Cushing's disease the use of this diagnostic procedure is taken into consideration but not recommended.


Breast cancer underestimation rate of atypical ductal hyperplasia diagnosed by core-needle biopsy under imaging guidance.
To evaluate breast cancer underestimation rate of atypical ductal hyperplasia (ADH) diagnosed by core-needle biopsy (CNB) under imaging guidance in Ramathibodi Hospital and to determine the difference between the malignant and benign groups in terms of clinical and imaging characteristics. The pathological records of 1521 patients who underwent CNB under imaging guidance were reviewed. Thirty-nine patients diagnosed with ADH were enrolled into the present study. Clinical data, imaging features, biopsy technique and result of excisional biopsy as well as follow-up data were retrospectively reviewed. Of 39 ADH cases, eight (20.5%) were found to have malignancy on subsequent excisional biopsy. The majority of these were ductal carcinoma in situ (DCIS) (62.5%). Lesion categorized as category 5 according to BI-RADS (Breast imaging reporting and data system) was the only feature which was statistically different between the benign and malignant groups. No statistically significant difference was found between the benign and malignant groups in terms of age, personal and family history of breast cancer, clinical finding, mammographic lesion type, size of lesion, image-guided technique and percentage of lesion removal. The underestimation rate of ADH in the present study was comparable to other studies. The finding of Bl-RADS category 5 in patients with ADH diagnosed from CNB is a strong indication for subsequent excisional biopsy.


[Study of the androgenic activity of the ovaries in various forms of virilism of ovarian etiology].
The authors present the results of determination of the testosterone level in the blood by the method of competitive fixation by proteins under conditions of a functional test with the depression of the adrenal cortex function with dexamethazone and stimulation of the ovarian function with choriogonin against this background in patients with the virile syndrome of ovarian genesis. Three groups of patients with the ovarian hyperandrogenia were distinguished. Changes in the blood testosterons level under the test conditions confirmed objectively the ununiformity of of this syndrome and permitted one to characterize the hormonal activity of the androgen-producing structures of the ovaries and their sensitivity to choriogonin stimulation in patients of different groups. The functional test with the determination of the blood testosterone level can be applied under clinical conditions for detection of the source and the degree of hyperandrogenia.


Abnormal vascular phosphoinositide hydrolysis in the spontaneously hypertensive rat.
The production of [3H]-inositol phosphates was studied in labelled segments of aorta from spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls at 5 and 19 weeks, either unstimulated or in the presence of noradrenaline. Basal hydrolysis of inositol phospholipids was significantly enhanced in young SHR (P less than 0.05) compared to controls but this difference was no longer detected at 19 weeks. Noradrenaline increased [3H]-inositol phosphate accumulation in both SHR and WKY, but maximal hydrolysis was significantly greater in WKY (P less than 0.01), although the ED50 was similar in both groups of animals. These data demonstrate that phosphatidylinositide hydrolysis is enhanced in the young hypertensive rat at the time blood pressure is rising, but that this activity has declined by the time hypertension has reached an established phase. In addition, alpha 1-agonist induction of inositol phospholipid hydrolysis differs in the two species of animals, being reduced in genetically mature hypertensive rats.


Comparative analysis of the mitochondrial genomes of Callitettixini Spittlebugs (Hemiptera: Cercopidae) confirms the overall high evolutionary speed of the AT-rich region but reveals the presence of short conservative elements at the tribal level.
The present study compares the mitochondrial genomes of five species of the spittlebug tribe Callitettixini (Hemiptera: Cercopoidea: Cercopidae) from eastern Asia. All genomes of the five species sequenced are circular double-stranded DNA molecules and range from 15,222 to 15,637 bp in length. They contain 22 tRNA genes, 13 protein coding genes (PCGs) and 2 rRNA genes and share the putative ancestral gene arrangement of insects. The PCGs show an extreme bias of nucleotide and amino acid composition. Significant differences of the substitution rates among the different genes as well as the different codon position of each PCG are revealed by the comparative evolutionary analyses. The substitution speeds of the first and second codon position of different PCGs are negatively correlated with their GC content. Among the five species, the AT-rich region features great differences in length and pattern and generally shows a 2-5 times higher substitution rate than the fastest PCG in the mitochondrial genome, atp8. Despite the significant variability in length, short conservative segments were identified in the AT-rich region within Callitettixini, although absent from the other groups of the spittlebug superfamily Cercopoidea.


Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer.
Cytochrome P4502E1 (CYP2E1) is involved in the metabolic activation of carcinogenic N-nitrosoamines. We therefore assessed the genotype frequencies of PstI or RsaI CYP2E1 restriction fragment length polymorphisms and another susceptibility marker, mutagen sensitivity, in 137 lung cancer cases (92 African American and 45 Mexican American) and 206 controls (114 African American and 92 Mexican American) identified in a molecular epidemiological study of lung cancer. The CYP2E1 c1/c1 genotype was found in 86.7% of Mexican American cases, 70.6% of Mexican American controls, 89.1% of African American cases and 86.8% of African American controls. By multivariate analysis, this genotype was found to be associated with a 14.0-fold increased risk of lung cancer in Mexican Americans but not in African Americans; a 9.9-fold increased risk of lung cancer in Mexican American former smokers, but not in non-smokers or current smokers; a 15-fold increased risk of lung cancer in Mexican American males, but not in females. Patients with the susceptible genotype appeared to have developed cancer at an earlier age and with lower cigarette pack-year of exposure than did patients with the c1/c2 or c2/c2 genotypes. Stratified analysis suggested a greater than multiplicative interaction between cigarette smoking and CYP2E1 c1/c1 genotype, although not statistically significant. The odds ratios (ORs) for the CYP2E1 c1/c1 genotype, cigarette smoking and both risk factors combined were 1.3, 6.7 and 16.3, respectively. The association between CYP2E1 c1/c1 genotype and pack-years of smoking followed the same pattern. The interaction between mutagen sensitivity and CYP2E1 c1/c1 genotype was especially strong in former smokers (the ORs for the CYP2E1 c1/c1 genotype, mutagen sensitivity and both risk factors combined were 3.9, 5.4 and 23.0, respectively). Therefore, the data suggest that individuals who lack a c2 allele might be at higher risk for developing lung cancer.


Free energy landscape within the hysteresis regime for fluids confined in disordered mesoporous solids.
Adsorption/desorption and melting/freezing in structurally disordered nanoporous solids exhibit strongly non-equilibrium behavior as revealed by the formation of a hysteresis region populated by the multitude of different states. Many questions concerning the free energy spectrum of these states, including the existence of the equilibrium transition, if any, their accessibility in the experiments, and internal relaxation dynamics toward the global energy minimum, still remain poorly addressed. By using a serially connected pore model with the statistical disorder as a minimal model of the pore networks, we explore the system free energies along the solid-liquid and liquid-gas transitions in the pore systems. The rigorous results obtained with this model shed light on the occurrence and nature of the equilibrium transition line in porous solids with arbitrary pore topology. We discuss further the free energies along the experimentally measured boundary and scanning transitions and how close the equilibrium states can be approached in these experiments.