Disseminated cryptococcosis manifested as a single tumor in an immunocompetent patient, similar to the cutaneous primary forms.
Cryptococcosis is a fungal infection caused by Cryptococcus neoformans that tends to affect immunocompromised individuals. The fungi are mostly acquired by inhalation, which leads to an initial pulmonary infection. Later, other organs - such as the central nervous system and the skin - can be affected by hematogenous spread. In addition, cutaneous contamination can occur by primary inoculation after injuries (primary cutaneous cryptococcosis), whose diagnosis is defined based on the absence of systemic involvement. The clinical presentation of cutaneous forms typically vary according to the infection mode. We report an unusual case of disseminated cryptococcosis in an immunocompetent patient with cutaneous lesions similar to those caused by primary inoculation. This clinical picture leads us to question the definition of primary cutaneous cryptococcosis established in the literature.


Long-acting and short-acting diuretics in the treatment of hypertension.
A single-blind trial was carried out in 36 people with mild to moderate hypertension to compare the efficacy and tolerance of long-term treatment with furosemide and chlorthalidone. After a 30-day wash-out period, patients were treated for 6 months with a single daily dose of either 25 mg furosemide or 50 mg chlorthalidone. They were then crossed over to the alternative drug, after a 15-day wash-out period, for a further 6 months. Results from the 25 patients who completed the study period showed that both treatments were successful in reducing systolic and diastolic blood pressure significantly after 1 month and blood pressure was controlled at the lower level for the remainder of the study period. There was no statistically significant difference between the two treatments at the end of the trial in respect of their antihypertensive efficacy. However, patients on chlorthalidone showed a marked, significant decrease in serum potassium levels from 1 month onwards compared to patients treated with furosemide and at the end of 6 months 10 (25%) were considered to be hypokalaemic whereas only 2 (8%) of the furosemide-treated patients had serum potassium levels lower than 3.5 mmol/l. Few side-effects were reported and patient compliance was good in both treatment groups.


Real-world evidence comparing oral anticoagulants in non-valvular atrial fibrillation: a systematic review and network meta-analysis.
Aim: To compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. Materials & methods: A systematic review of electronic databases yielded 7661 citations published from January 2013 to January 2020. Fifty-five studies were included in Bayesian network meta-analyses of hazard ratios. Results & conclusion: In comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.


Supercritical Fluid Chromatography of Drugs: Parallel Factor Analysis for Column Testing in a Wide Range of Operational Conditions.
Retention mechanisms involved in supercritical fluid chromatography (SFC) are influenced by interdependent parameters (temperature, pressure, chemistry of the mobile phase, and nature of the stationary phase), a complexity which makes the selection of a proper stationary phase for a given separation a challenging step. For the first time in SFC studies, Parallel Factor Analysis (PARAFAC) was employed to evaluate the chromatographic behavior of eight different stationary phases in a wide range of chromatographic conditions (temperature, pressure, and gradient elution composition). Design of Experiment was used to optimize experiments involving 14 pharmaceutical compounds present in biological and/or environmental samples and with dissimilar physicochemical properties. The results showed the superiority of PARAFAC for the analysis of the three-way (column × drug × condition) data array over unfolding the multiway array to matrices and performing several classical principal component analyses. Thanks to the PARAFAC components, similarity in columns' function, chromatographic trend of drugs, and correlation between separation conditions could be simply depicted: columns were grouped according to their H-bonding forces, while gradient composition was dominating for condition classification. Also, the number of drugs could be efficiently reduced for columns classification as some of them exhibited a similar behavior, as shown by hierarchical clustering based on PARAFAC components.


Genetic and psychosocial factors for benzodiazepine addiction. An analysis based on the results of the authors' own research conducted in a group of benzodiazepine addicted and non-addicted individuals.
In spite of the fact that the addictive potential of benzodiazepine (BDZ) drugs has been known for a long time, benzodiazepine addiction remains a common problem for psychiatry to deal with. The etiology of benzodiazepine addiction is very complex. Among the risk factors, the course of the treatment, demographic status and psychological features of a patient seem to play an important role. The aim of this study was to investigate both psychological and genetic factors differentiating benzodiazepine addicts from non-addicted users. We analysed a cohort of 120 individuals treated with benzodiazepines divided into two groups: benzodiazepine addicts and non-addicted benzodiazepine users (the control group). In both groups we measured genetic polymorphisms of GABA A2 and MAOA. In both groups some psychometric measurements were performed - we investigated the level of depression, anxiety as a state and as a trait, personality features and the dominant coping style using the Beck Depression Scale, Hamilton Anxiety Scale, Five-Factor Personality Inventory NEO-FFI and the Coping Inventory for Stressful Situations [4,10,17,36,41,44]. There are some psychological and situational risk factors for benzodiazepine addiction such as high neuroticism, introversion and lack of the ability to release tension through interpersonal contacts, dominance of emotional coping style and high accumulation of critical life events during both childhood and adulthood. The genetic background still remains a field for further exploration.


C-reactive Protein Level in Type-2 Diabetic Patients Attending Mymensingh Medical College Hospital, Mymensingh.
C-reactive protein (CRP) is a sensitive physiological biomarker of sub-clinical inflammation associated with hyperglycemia, insulin resistance and type 2 diabetic patients. A cross sectional study of 120 subjects attending outpatient department of Mymensingh Medical College, Mymensingh was done with an aim to evaluate serum C-reactive protein in type 2 diabetic patients and compare with age matched non-diabetic persons from July 2014 to June 2015. Of the total cases, 60 were Type 2 diabetic patients and 60 were apparently healthy non-diabetic persons recruited for the study. These diabetic and non-diabetic subjects were classified as male (50%) and female (50%). Fasting blood glucose and CRP were measured by following the standard laboratory methods. The mean CRP level was 16.48±12.69mg/L and <6.00±0.00mg/L in diabetic patients and non-diabetics respectively. The study revealed that fasting blood glucose and C-reactive protein were significantly higher in diabetic patients compared with age matched non-diabetic subjects. There was no significant difference in CRP between diabetic males and diabetic females. It was concluded from the results of this study that, CRP level was elevated in both male and female diabetic patients. These data can support a possible role of inflammatory biomarker in diabetogenesis.


Impact of network topology on self-organized criticality.
The general mechanisms behind self-organized criticality (SOC) are still unknown. Several microscopic and mean-field theory approaches have been suggested, but they do not explain the dependence of the exponents on the underlying network topology of the SOC system. Here, we first report the phenomena that in the Bak-Tang-Wiesenfeld (BTW) model, sites inside an avalanche area largely return to their original state after the passing of an avalanche, forming, effectively, critically arranged clusters of sites. Then, we hypothesize that SOC relies on the formation process of these clusters, and present a model of such formation. For low-dimensional networks, we show theoretically and in simulation that the exponent of the cluster-size distribution is proportional to the ratio of the fractal dimension of the cluster boundary and the dimensionality of the network. For the BTW model, in our simulations, the exponent of the avalanche-area distribution matched approximately our prediction based on this ratio for two-dimensional networks, but deviated for higher dimensions. We hypothesize a transition from cluster formation to the mean-field theory process with increasing dimensionality. This work sheds light onto the mechanisms behind SOC, particularly, the impact of the network topology.


Extracellular Nampt (eNampt/visfatin/PBEF) directly and indirectly stimulates ACTH and CCL2 protein secretion from isolated rat corticotropes.
Nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF) acts both as an enzyme in the nicotinamide adenine dinucleotide (NAD) synthesis pathway as well as an extracellular hormone (eNampt). Among its effects, eNampt exerts potent pro-inflammatory effects. We have recently shown that, in rats, eNampt stimulates corticosterone secretion by acting through the pituitary rather than the hypothalamus. To investigate the mechanism of action of eNampt on the secretion of adrenocorticotropic hormone (ACTH) and chemokine (C-C motif) ligand 2 (CCL2), which are cytokines secreted by pituitary neuroendocrine tumors. The research was carried out on the AtT-20 murine cell line, primary rat pituitary cell culture, isolated pituitary corticotropes, and in vivo. The effects of the performed experiments were examined using the following methods: gene expression profiling using microarrays, quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). The results suggest that eNampt stimulates ACTH secretion from rat corticotropes both directly and indirectly. Indirect action most likely occurs through interleukin (IL)-6 secreted by folliculostellate cells of the pituitary gland. In isolated ACTH cells of the rat pituitary gland, eNampt stimulates the expression of genes involved in the immune response. Among them, the protein encoded by the CCL2 gene seems to also be involved in the regulation of corticotropin-releasing hormone (CRH)-dependent metabolism. Unlike rat corticotropes, murine AtT-20 corticotropic cells do not react to either eNampt or Fk866 (the inhibitor of Nampt enzymatic action). The eNampt stimulates the secretion of ACTH from rat corticotropes indirectly and directly, likely by stimulating IL-6 secretion from folliculostellate cells of the pituitary gland. This effect was not observed in the AtT-20 corticotropic cell cancer cell line.


A Triode Device with a Gate Controllable Schottky Barrier: Germanium Nanowire Transistors and Their Applications.
Electrical contacts often dominate charge transport properties at the nanoscale because of considerable differences in nanoelectronic device interfaces arising from unique geometric and electrostatic features. Transistors with a tunable Schottky barrier between the metal and semiconductor interface might simplify circuit design. Here, germanium nanowire (Ge NW) transistors with Cu3 Ge as source/drain contacts formed by both buffered oxide etching treatments and rapid thermal annealing are reported. The transistors based on this Cu3 Ge/Ge/Cu3 Ge heterostructure show ambipolar transistor behavior with a large on/off current ratio of more than 105 and 103 for the hole and electron regimes at room temperature, respectively. Investigations of temperature-dependent transport properties and low-frequency current fluctuations reveal that the tunable effective Schottky barriers of the Ge NW transistors accounted for the ambipolar behaviors. It is further shown that this ambipolarity can be used to realize binary-signal and data-storage functions, which greatly simplify circuit design compared with conventional technologies.


Examining the Contemporaneous, Short-Term, and Long-Term Effects of Secondary Exposure to Violence on Adolescent Substance Use.
The relationship between secondary exposure to violence-defined as witnessing violence in the home, community, or school-and adolescent substance use is well-documented. Yet, multi-wave empirical studies examining this relationship are sparse. In addition, studies have only begun to examine whether this relationship varies by the situational components of the violent event. Using data from the Project on Human Development in Chicago Neighborhoods (PHDCN), this study examines the contemporaneous, short-term, and long-term effects of secondary exposure to violence on substance use, and whether witnessing violence in which a weapon is present has a different impact on adolescent substance use than does witnessing violence without a weapon. Hierarchical logistic regression models on a racially and ethnically diverse sample of 1670 youth (51.5% female) residing in 79 neighborhoods indicated that: (1) the effects of secondary exposure to violence on alcohol and marijuana use were enduring, albeit attenuated, over time; (2) the effect of secondary exposure to violence on illicit drug use was suppressed in the short-term but significant in the long-term; (3) witnessing violence without a weapon was salient for alcohol and marijuana use at all time points; and (4) witnessing violence with a weapon impacted illicit drug use in the long-term. The results suggest that addressing the consequences of secondary exposure to violence requires prolonged intervention efforts and that the study of secondary exposure to violence requires a more nuanced approach that accounts for situational aspects of the violent event.


Effects of ulipristal acetate on sperm DNA fragmentation during in vitro incubation.
Ulipristal acetate (UPA) acts as an emergency contraceptive by inhibiting ovulation. This study explores possible additional effects on the fragmentation of sperm DNA during in vitro incubation. Motile spermatozoa from healthy donors were selected by swim-up and incubated under capacitating conditions in control medium or with UPA (1, 10, 100, 1,000 or 10,000 ng/ml). In some experiments, 200 μM of H2O2 were added to induce oxidative stress. The sperm chromatin dispersion test was performed to analyse DNA integrity (400 cells; 1000×). Lipid peroxidation (thiobarbituric acid assay), induced-acrosome reaction (AR) and sperm vitality (Eosin Y) were also evaluated in spermatozoa exposed to UPA and/or H2O2. During sperm incubation, the percentage of fragmented DNA increased significantly, from 15.0 ± 1.3 to 41.0 ± 4.5% (p < 0.001). In the presence of UPA, DNA fragmentation decreased significantly (p < 0.05), in a dose-dependent manner. At 100 and 1000 ng/ml, UPA also counteracted the effect of H2O2 and prevented DNA fragmentation. No effect on sperm vitality, lipid peroxidation or induced-AR was found with any treatment. During in vitro sperm capacitation DNA fragmentation increased but the latter was counteracted in the presence of UPA, which possibly acted as a scavenger of reactive oxygen species produced by spermatozoa.


Non-invasive detection of colorectal tumours by the combined application of molecular diagnosis and the faecal occult blood test.
The treatment of early-stage tumours decreases the overall mortality of colorectal tumour patients. In this retrospective study we determined the sensitivity and the specificity of the faecal occult blood test (FOBT) and the molecular diagnosis (MD). We analysed 57 stool samples from patients with colorectal carcinomas for the presence of occult blood using a standard FOBT and for alterations in the three different tumour relevant markers APC, BAT26 and L-DNA. Stool samples from 44 control donors were analysed to determine the specificity of the applied methods. Twenty-nine (51%; 95% confidence interval (CI): 38-63%) stool samples of the cancer patients gave positive FOBT results. Thirty-seven (65%; CI: 52-76%) samples showed alterations in at least one DNA marker. Sixteen (28%) samples were positive only in the FOBT, and 24 (42%) samples showed a positive result exclusively in MD. The combined application of both methods resulted in a sensitivity of 93% (CI: 83-97%) and an overall specificity of 89% (CI: 76-95%). The combined application of FOBT and MD resulted in an overall sensitivity, which could not be achieved by any of the methods alone and which is in the range of invasive diagnostic methods.


Features of migraine aura in teenagers.
Complex migraine aura in teenagers can be complicated to diagnose. The aim of this study was to present detailed features of migraine aura in teenage migraineurs. This cross-sectional study was conducted in the period from 2008 till 2013. A total number of 40 teenage migraineurs (20 females and 20 males) met criteria for this study. The patients were interviewed using a specially designed questionnaire for collecting data about migraine aura features. Main outcome measures were frequency of visual, somatosensory and higher cortical dysfunction (HCD) symptoms in teenage migraineurs population during the aura, and also within each individual. Visual aura was reported in every attack, followed by somatosensory (60%) and dysphasic (36.4%) aura. Scintillating scotoma and blurry vision were mostly reported and predominant visual symptoms. The most common somatosensory symptom was numbness in hand. HCD were reported by 22 (55%) patients. Slowed speech was mostly reported symptom of HCD, followed by dyslexia, déjà vu phenomenon, color dysgnosia, and dyspraxia. In patients with HCD, aura frequency per year (6.18 ± 3.17 vs. 3.33 ± 2.03, p = 0.003) and prevalence of somatosensory symptoms (77.3% vs. 38.9%, p = 0.014) were significantly higher than in patients without HCD. Aura symptoms vary to a great extent in complexity in teenage migraineurs. Consequently, results obtained in this study provide useful information for clinicians when faced with unusual migraine aura.


Liquid chromatographic analysis of promethazine and its major metabolites in human postmortem material.
A method is described for the determination of promethazine and some of its major metabolites in postmortem specimens by enzymic digestion followed by high-pressure liquid chromatography of the extracts using a cyano-bonded (mu-Bondapak-CN) silica column packing and a mobile phase consisting of methanol, water, and n-octylamine (adjusted to pH 8). The system will separate and quantitate promethazine sulphoxide, desmonomethyl promethazine, didesmethyl promethazine, and promethazine. Pericyazine (2-cyano-10-[3-(4- hydroxypiperidino )propyl] phenothiazine) was used as internal standard. The parent drug and metabolites were extracted from a enzyme digested tissue homogenates with ethyl acetate using a simple, single micro-extraction procedure. The method was applied to four cases of fatal poisoning involving promethazine ingestion.


Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance.
In the present investigation, we studied the effects of thiazolidinedione (TZD) treatment on insulin-stimulated fatty acid (FA) and glucose kinetics in perfused muscle from high-fat (HF)-fed rats. We tested the hypothesis that TZDs prevent FA-induced insulin resistance by attenuating proinflammatory signaling independently of myocellular lipid levels. Male Wistar rats were assigned to one of three 3-wk dietary groups: control chow fed (CON), 65% HF diet (HFD), or TZD- (troglitazone or rosiglitazone) enriched HF diet (TZD + HFD). TZD treatment led to a significant increase in plasma membrane content of CD36 protein in muscle (red: P = 0.01, and white: P = 0.001) that correlated with increased FA uptake (45%, P = 0.002) and triacylglycerol (TG) synthesis (46%, P = 0.03) during the perfusion. Importantly, whereas HF feeding caused increased basal TG (P = 0.047), diacylglycerol (P = 0.002), and ceramide (P = 0.01) levels, TZD treatment only prevented the increase in muscle ceramide. In contrast, all of the muscle inflammatory markers altered by HF feeding ( upward arrowNIK protein content, P = 0.009; upward arrowIKKbeta activity, P = 0.006; downward arrowIkappaB-alpha protein, P = 0.03; and upward arrowJNK phosphorylation, P = 0.003) were completely normalized by TZD treatment. Consistent with this, HFD-induced decrements in insulin action were also prevented by TZD treatment. Thus our findings support the notion that TZD treatment causes increased FA uptake and TG accumulation in skeletal muscle under insulin-stimulated conditions. Despite this, TZDs suppress the inflammatory response to dietary lipid overload, and it is this mechanism that correlates strongly with insulin sensitivity.


FoxO4 is the main forkhead transcriptional factor localized in the gastrointestinal tracts of pigs.
Forkhead box (Fox) proteins play critical roles in the regulation of differentiation, proliferation, immunity and aging of cells. Most studies on Fox proteins are limited to cultured cells and rodent. The aim of the current study is to detect by immunohistrochemistry whether FoxO1, FoxO3a and FoxO4 proteins are localized in the stomach and intestine of the pig. The results showed that FoxO4 exists in the mucosa in all parts of the stomach and intestine; FoxO3a exists mainly in the lamina propria and muscularis of some parts. However, FoxO1 is not detectable in all parts of the stomach and intestine. Collectively, the results of the present study indicate that there exists a distinct expression pattern of Fox proteins, and that FoxO4 is a primary forkhead transcriptional factor localized in the gastrointestinal tracts of the pig.


Evaluation of Human Gingival Fibroblasts (HGFs) Behavior on Innovative Laser Colored Titanium Surfaces.
The use of ytterbium laser to obtain colored titanium surfaces is a suitable strategy to improve the aesthetic soft tissue results and reduce implant failures in oral rehabilitation. To investigate the relationship between novel laser-colored surfaces and peri-implant soft tissues, Human Gingival Fibroblasts (HGFs) were cultured onto 12 colored titanium grade 1 light fuchsia, dark fuchsia, light gold, and dark gold disks and their viability (MTT Assay), cytotoxicity (lactate dehydrogenase release), and collagen I secretion were compared to the machined surface used as control. Optical and electronic microscopies showed a HGF growth directly correlated to the roughness and wettability of the colored surfaces. A higher viability percentage on dark fuchsia (125%) light gold (122%), and dark gold (119%) samples with respect to the machined surface (100%) was recorded. All specimens showed a statistically significant reduction of LDH release compared to the machined surface. Additionally, a higher collagen type I secretion, responsible for an improved adhesion process, in light fuchsia (3.95 μg/mL) and dark gold (3.61 μg/mL) compared to the machined surface (3.59 μg) was recorded. The in vitro results confirmed the innovative physical titanium improvements due to laser treatment and represent interesting perspectives of innovation in order to ameliorate aesthetic dental implant performance and to obtain more predictable osteo and perio-osteointegration long term implant prognosis.


Active surveillance can reduce overtreatment in patients with low-risk prostate cancer.
The incidence of prostate cancer in Denmark rose approximately 50% from 2000 to 2009 in parallel with the introduction of prostate-specific antigen (PSA)-testing. Available evidence indicates a significant overtreatment of patients with low-risk prostate cancer. Active surveillance has been proposed as an observation strategy to reduce overtreatment and limit curatively intended therapy to those patients who need it. We reported the first Danish results from an active surveillance cohort. A total of 167 patients were prospectively followed in an active surveillance programme. The median follow-up was 3.4 years (1.1-9.5). At entry the median age was 65 years (51-73), 94% had a Gleason score ≤ 6, 87.4% had a PSA ≤ 10 ng/ml and 99% ≤ cT2a. Ten patients progressed on digital rectal examination, 40 patients progressed due to a short PSA doubling time, and 34 patients progressed on re-biopsy. A total of 59 patients discontinued active surveillance. The estimated five-year probability of remaining on active surveillance was 60.0% (95% confidence interval 50.9-69.1%). Active surveillance as a management strategy for patients with clinically localized, low-risk prostate cancer is accepted by patients, seems feasible and can reduce overtreatment. However, long-term follow-up data are lacking and considerable uncertainties about optimal selection and progression criteria remain. The authors received financial support from the IMK Almene Fond. not relevant.


Identification of characteristic components in frequency domain from signal singularities.
In rotating machinery condition monitoring, identification of characteristic components is fundamental in many engineering applications so as to obtain fault sensitive features for fault detection and diagnosis. This paper proposed a novel method for the identification of characteristic components in frequency domain based on singularity analysis. In this process, Lipschitz exponent function is constructed from the signal through wavelet-based singularity analysis. In order to highlight the periodic phenomena, autocorrelation transform is employed to extract the periodic exponents and Fourier transform is used to map the time-domain information into frequency domain. Case study with rolling element bearing vibration data shows that the proposed has very excellent capability for the identification of characteristic components compared with traditional methods.


Effect of a BK viruria reaction detected by qualitative polymerase chain reaction on the renal function of kidney transplant recipients.
The number of end stage renal failure patients receiving hemodialysis or peritoneal dialysis in Taiwan is on the increase. Of the various treatment options, kidney transplantation is considered to be the ultimate choice, however, it may lead to certain complications, including the infection or reactivation of the BK virus (BKV). Such viral complications may cause nephritis of the donated kidney and eventually dysfunction and transplantation failure. Therefore the early detection of BKV may be beneficial for kidney transplant recipients. The aim of the present study was to demonstrate the impact of BKV infection on renal function and to show the feasilibility of urine qualitative polymerase chain reaction (PCR) as a screening test in renal transplantation patients. A total of 250 patients were screened for the presence of BKV or John Cunningham virus (JCV) DNA in the urine via qualitative PCR. Subjects positive for urine screening were then further tested using blood sampling. The results showed that 16 patients (6.4%) were co‑infected by BKV and JCV with a prevalence of 20.4 and 38.4%, respectively. The correlations between viral infection and renal function were further analyzed to show that an infection of BKV has significant effects on the serum creatinine concentration. The mean serum creatinine concentration of the BKV‑positive patients was 1.39±0.09 mg/dl, which was significantly higher than that of the BKV‑negative patients (1.21±0.03 mg/dl; P<0.05). However, JCV infection has no such effect on renal function. Taken together, these results suggested that PCR monitoring of BKV with urine samples is a rapid, non‑invasive and beneficial method for the prevention of renal complications during the long‑term care of kidney transplant recipients.


[3-dimensional topography of the optic papilla with laser scanning tomography: clinical correlation of cluster analysis].
BACKGROUND The evaluation of optic disc topography is essential for the clinical diagnosis of primary open angle glaucoma. The purpose of this study was (1) to establish a computerized cluster formation of optic nerve head topography based on quantitative three-dimensional parameter values and (2) to describe the resulting clusters according to morphological appearance and visual fields. PATIENTS AND METHODS 337 optic nerve heads (glaucomatous optic neuropathy (n = 99), glaucoma suspects (n = 159), normals (n = 79) were analyzed using laser scanning tomography. A hierarchical cluster analysis was performed based on standardized variables (optic disc area, rim area, area-ratio, cup depth, cup steepness, height variations along the contour-line). Visual fields were tested by computerized static threshold perimetry. RESULTS A seven cluster solution met the optimizing criteria. The characteristic morphology of the clusters can be described as "normal" (N), "normal, large" (NL), "supernormal" (SN), "pseudonormal" (PN), "glaucoma-like-flat" (GF), "glaucoma-like-steep" (GS) and "macropapillary" (M). Visual fields were normal in 180 eyes. 99 eyes had glaucomatous field defects, 58 eyes revealed isolated relative scotomas < 10 db. Presence and degree of visual field defects varied within the automatically classified optic disc groups considerably. Visual field defects were found in 7.7% (SN), 8.3% (N), 18.8% (NL), 33.3% (M), 37% (PN), 64.7% (GF) and 83.3% (GS) respectively. Pseudonormal discs were characterized by a flattening of the height variations along the disc border. CONCLUSIONS (1) Optic nerve heads may be automatically classified based upon a combination of three-dimensional topographic variables. (2) Analysis of optic disc topography and computerized perimetry are supplementary tools in the evaluation of the glaucoma patient. Visual field defects may be present within any cluster. However, the likelyness of the presence of visual field defects differs considerably among the topometrically defined groups of optic nerve heads. Functional damage is to be expected in association with reduced height variations along the disc border, a small rim area and a steep cupping of the optic nerve head.


Zinc oxide nanoparticles inhibit malignant progression and chemotherapy resistance of ovarian cancer cells by activating endoplasmic reticulum stress and promoting autophagy.
The mortality rate of ovarian cancer (OC) is high, posing a serious threat to women's lives. Zinc oxide nanoparticles (ZnO-NPs) show great potential in the treatment of cancer. However, the mechanism of ZnO-NPs in inhibiting the malignant proliferation and chemotherapy resistance of OC has remained elusive. In the present study, ZnO-NPs at different concentrations were used to treat SKOV3 cells, and subsequently, analyses including the Cell Counting Kit-8 assay, EDU staining, colony-formation assay, flow cytometry, wound-healing assay, Transwell assay and western blot were used to detect cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT) and chemotherapy resistance, as well as endoplasmic reticulum stress (ERS)- and autophagy-related indicators. Finally, the mechanisms of action of ZnO-NPs on OC were examined by adding ERS inhibitor 4-phenylbutyric acid (4-PBA) and autophagy inhibitor 3-methyladenine (3-MA). It was found that ZnO-NPs inhibited SKOV3 cell proliferation, facilitated apoptosis and induced cell cycle arrest. Furthermore, ZnO-NPs inhibited the invasion, migration and EMT of SKOV3 cells. ZnO-NPs also inhibited chemotherapy resistance of SKOV3 cells. ZnO-NPs activated ERS and promoted autophagy. The addition of 4-PBA or 3-MA significantly reversed the effects of ZnO-NPs on SKOV3 cells. Overall, ZnO-NPs inhibit the malignant progression and the chemotherapy resistance of SKOV3 cells by activating ERS and promoting autophagy.


Protein glycosylation in Archaea: sweet and extreme.
While each of the three domains of life on Earth possesses unique traits and relies on characteristic biological strategies, some processes are common to Eukarya, Bacteria and Archaea. Once believed to be restricted to Eukarya, it is now clear that Bacteria and Archaea are also capable of performing N-glycosylation. However, in contrast to Bacteria, where this posttranslational modification is still considered a rare event, numerous species of Archaea, isolated from a wide range of environments, have been reported to contain proteins bearing Asn-linked glycan moieties. Analysis of the chemical composition of the Asn-linked polysaccharides decorating archaeal proteins has, moreover, revealed the use of a wider variety of sugar subunits than seen in either eukaryal or bacterial glycoproteins. Still, although first reported some 30 years ago, little had been known of the steps or components involved in the archaeal version of this universal posttranslational modification. Now, with the availability of sufficient numbers of genome sequences and the development of appropriate experimental tools, molecular analysis of archaeal N-glycosylation pathways has become possible. Accordingly using halophilic, methanogenic and thermophilic model species, insight into the biosynthesis and attachment of N-linked glycans decorating archaeal glycoproteins is starting to amass. In this review, current understanding of N-glycosylation in Archaea is described.


A combined assay of hTERT and E6 oncoprotein to identify virus-infected keratinocytes with higher telomerase activity in human papillomaviruses 16 and 18-related bowenoid papulosis.
In the present study, we aim to evaluate the application potential of a combined assay of human telomerase reverse transcriptase (hTERT) and E6 oncoprotein in screening the virus-infected keratinocytes with higher telomerase activity in human papillomaviruses (HPV) 16- and 18-related bowenoid papulosis (BP). HPV16/18 DNA in BP (n = 123) was identified by in situ hybridization, the expression of hTERT and E6 in HPV16/18-related BP (n = 68) was determined by immunohistochemistry. We demonstrated that the expression of hTERT correlated well with that of E6 oncoprotein in HPV16/18-related BP lesions (Spearman rho = 0.868, P < 0.01). Furthermore, the majority of keratinocytes with positive nuclear staining for hTERT or E6 in the consecutive sections of each HPV16/18-related BP lesion showed nuclear paleomorphism or nuclear mitosis. In conclusion, we suggested that a combined assay of hTERT and E6 oncoprotein can be used to screen the HPV-infected keratinocytes with higher telomerase activity in HPV16-related and HPV18-related BP lesions.


Synergies between mycorrhizal fungi and soil microbial communities increase plant nitrogen acquisition.
Nitrogen availability often restricts primary productivity in terrestrial ecosystems. Arbuscular mycorrhizal fungi are ubiquitous symbionts of terrestrial plants and can improve plant nitrogen acquisition, but have a limited ability to access organic nitrogen. Although other soil biota mineralize organic nitrogen into bioavailable forms, they may simultaneously compete for nitrogen, with unknown consequences for plant nutrition. Here, we show that synergies between the mycorrhizal fungus Rhizophagus irregularis and soil microbial communities have a highly non-additive effect on nitrogen acquisition by the model grass Brachypodium distachyon. These multipartite microbial synergies result in a doubling of the nitrogen that mycorrhizal plants acquire from organic matter and a tenfold increase in nitrogen acquisition compared to non-mycorrhizal plants grown in the absence of soil microbial communities. This previously unquantified multipartite relationship may contribute to more than 70 Tg of annually assimilated plant nitrogen, thereby playing a critical role in global nutrient cycling and ecosystem function.


Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1.
Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients. We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo. We applied flow cytometry and western blotting to explore the mechanism of the combined therapy. Knockdown and overexpression of PLK1 are also applied for validation. We confirmed that dasatinib has synergistic effect with irinotecan (or SN38) on HCC both in vitro and in vivo. The effect is due to arisen apoptosis rate of HCC cells that is accompanied by mitochondria dysfunction. The enhanced antitumour efficacy of SN38 could be explained by additional inhibition of PLK1, which is triggered by dasatinib. Unlike existed PLK1 inhibitors, dasatinib does not inhibit PLK1 activity in a direct way. Instead, we found that dasatinib reduces PLK1 level by interfering with its protein synthesis progress. We validated that this kind of downregulation of PLK1 level has a key role in the synergistic effect of the two agents. Dasatinib is able to reinforce the anti-HCC efficacy of irinotecan/SN38 by downregulation of PLK1 synthesis. The combination of the two agents might be a potential medical choice for HCC therapy.


[Clinicopathological analysis of IgA nephropathy with crescentic formation in childhood].
To understand the clinical and pathological characteristics of IgA nephropathy (IgAN) with crescentic formation in children. Clinicopathological data of 29 children with IgAN accompanied by crescents were analyzed. These patients were divided into two groups according to the percentage of glomeruli affected by crescents more or less than 50%, and their data were compared. (1) CLINICAL FEATURES: all the patients had hematuria and proteinuria, and macrohematuria (86%) and proteinuria were also common, protein excreted in urine was more than 1 g per day in 76% of the patients. The patients with edema, hypertension, and renal insufficiency were less than fifty percent. Nine patients in Group A (glomeruli affected by crescents > or = 50%) were crescentic IgAN. Significantly more cases in Group A had persistent macrohematuria, hypertension and renal failure than in Group B (glomeruli affected by crescents < 50%) (P < 0.05), with especially severe proteinuria (P < 0.01). It was easy to find nephritic syndrome in Group A, and asymptomatic hematuria combined with proteinuria in Group B. (2) Renal pathology: the glomeruli were affected by crescents from 5% to 85%. There were 52% to 85% in Group A, and 5% to 40% in Group B. Most crescents were cellular. All the cases had a diffuse mesangial proliferation and tubular-interstitial injury to different degree. Three cases had crescentic IgAN. Glomerulosclerosis was significantly more often seen in Group A (P < 0.05) and tuft adhesion was more frequently seen in Group B (P < 0.05). (3) Immunofluorescence: All the patients presented deposition of IgA, IgM and C3. There were 45% specimens combined with the deposition of IgG. Five cases showed 'full house' (17%), four of them were in Group A. None had IgA deposition alone. The main clinical feature of IgAN with crescentic formation were hematuria combined with proteinuria, especially persistent gross hematuria and severe proteinuria. All of them showed diffuse mesangial proliferation and tubular-interstitial injury in morphology of kidney. Most of them had tuft adhesion. The main type of immunofluorescence were IgA + IgM and IgA + IgM + IgG deposition. Some showed 'full house' phenomenon. The clinical manifestation and renal lesions of IgAN with diffuse crescentic formation were worse than IgAN with glomeruli affected by crescents < 50%.


Expression of the receptor tyrosine kinase Tie2 in neoplastic glial cells is associated with integrin beta1-dependent adhesion to the extracellular matrix.
The abnormal function of tyrosine kinase receptors is a hallmark of malignant gliomas. Tie2 receptor tyrosine kinase is a specific endothelial cell receptor whose function is positively regulated by angiopoietin 1 (Ang1). Recently, Tie2 has also been found in the nonvascular compartment of several tumors, including leukemia as well as breast, gastric, and thyroid cancers. There is, however, little information on the function of the Ang1/Tie2 pathway in the non-stromal cells within human tumors. We found that surgical glioblastoma specimens contained a subpopulation of Tie2+/CD31- and Tie2+/GFAP+ cells, suggesting that Tie2 is indeed expressed outside the vascular compartment of gliomas. Furthermore, analysis of a tissue array consisting of 116 human glioma samples showed that Tie2 expression in the neoplastic glial cells was significantly associated with progression from a lower to higher grade. Importantly, Ang1 stimulation of Tie2+ glioma cells resulted in increased adherence of the cells to collagen I and IV, suggesting that Tie2 regulates glioma cell adhesion to the extracellular matrix. Conversely, the down-regulation of Tie2 levels by small interference RNA or the addition of soluble Tie2 abrogated the Ang1-mediated effect on cell adhesion. In studying the expression of cell adhesion molecules, we found that Tie2 activation was related to the up-regulation of integrin beta1 levels and the formation of focal adhesions. These results, together with the reported fact that malignant gliomas express high levels of Ang1, suggest the existence of an autocrine loop in malignant gliomas and that a Tie2-dependent pathway modulates cell-to-extracellular matrix adhesion, providing new insights into the highly infiltrative phenotype of human gliomas.


Cost-effectiveness of percutaneous patent foramen ovale closure as secondary stroke prevention.
Compared to medical therapy alone, percutaneous closure of patent foramen ovale (PFO) further reduces risk of recurrent ischemic strokes in carefully selected young to middle-aged patients with a recent cryptogenic ischemic stroke. The objective of this study was to evaluate the cost-effectiveness of this therapy in the context of the United Kingdom (UK) healthcare system. A Markov cohort model consisting of four health states (Stable after index stroke, Post-Minor Recurrent Stroke, Post-Moderate Recurrent Stroke, and Death) was developed to simulate the economic outcomes of device-based PFO closure compared to medical therapy. Recurrent stroke event rates were extracted from a randomized clinical trial (RESPECT) with a median of 5.9-year follow-up. Health utilities and costs were obtained from published sources. One-way and probabilistic sensitivity analyses (PSA) were performed to assess robustness. The model was discounted at 3.5% and reported in 2016 Pounds Sterling. Compared with medical therapy alone and using a willingness-to-pay (WTP) threshold of £20,000, PFO closure reached cost-effectiveness at 4.2 years. Cost-effectiveness ratios (ICERs) at 4, 10, and 20 years were ₤20,951, ₤6,887, and ₤2,158, respectively. PFO closure was cost-effective for 89% of PSA iterations at year 10. Sensitivity analyses showed that the model was robust. Considering the UK healthcare system perspective, percutaneous PFO closure in cryptogenic ischemic stroke patients is a cost-effective stroke prevention strategy compared to medical therapy alone. Its cost-effectiveness was driven by substantial reduction in recurrent strokes and patients' improved health-related quality-of-life.


Synthesis of novel quinine analogs and evaluation of their effects on Trypanosoma cruzi.
Chagas disease is a tropical disease caused by the hemoflagellate protozoan Trypanosoma cruzi. There is no vaccine for Chagas disease and available drugs (e.g., benznidazole) are effective only during the acute phase, displaying a variable curative activity in the established chronic form of the disease. New leads with high efficacy and better toxicity profiles are urgently required. Materials & methods: A library of novel quinine derivatives was synthesized using Heck chemistry and evaluated against the various developmental forms of T. cruzi. Several novel quinine analogs with trypanocidal activity have been identified with the para-nitro-substituted derivative displaying a submicromolar IC50, which is 83-times lower than quinine and three-times lower than benznidazole. Transmission electron microscopy analysis demonstrated that these compounds induced a marked vacuolization of the kinetoplast of intracellular amastigotes and cell-derived trypomastigotes.


Traumatic brain injuries: the influence of the direction of impact.
Head impact direction has been identified as an influential risk factor in the risk of traumatic brain injury (TBI) from animal and anatomic research; however, to date, there has been little investigation into this relationship in human subjects. If a susceptibility to certain types of TBI based on impact direction was found to exist in humans, it would aid in clinical diagnoses as well as prevention methods for these types of injuries. To examine the influence of impact direction on the presence of TBI lesions, specifically, subdural hematomas, subarachnoid hemorrhage, and parenchymal contusions. Twenty reconstructions of falls that resulted in a TBI were conducted in a laboratory based on eyewitness, interview, and medical reports. The reconstructions involved impacts to a Hybrid III anthropometric dummy and finite element modeling of the human head to evaluate the brain stresses and strains for each TBI event. The results showed that it is likely that increased risk of incurring a subdural hematoma exists from impacts to the frontal or occipital regions, and parenchymal contusions from impacts to the side of the head. There was no definitive link between impact direction and subarachnoid hemorrhage. In addition, the results indicate that there is a continuum of stresses and strain magnitudes between lesion types when impact location is isolated, with subdural hematoma occurring at lower magnitudes for frontal and occipital region impacts, and contusions lower for impacts to the side. This hospital data set suggests that there is an effect that impact direction has on TBI depending on the anatomy involved for each particular lesion.


Connecting Neuroinflammation and Neurodegeneration in Multiple Sclerosis: Are Oligodendrocyte Precursor Cells a Nexus of Disease?
The pathology in neurodegenerative diseases is often accompanied by inflammation. It is well-known that many cells within the central nervous system (CNS) also contribute to ongoing neuroinflammation, which can promote neurodegeneration. Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease in which there is a complex interplay between resident CNS cells to mediate myelin and axonal damage, and this communication network can vary depending on the subtype and chronicity of disease. Oligodendrocytes, the myelinating cell of the CNS, and their precursors, oligodendrocyte precursor cells (OPCs), are often thought of as the targets of autoimmune pathology during MS and in several animal models of MS; however, there is emerging evidence that OPCs actively contribute to inflammation that directly and indirectly contributes to neurodegeneration. Here we discuss several contributors to MS disease progression starting with lesion pathology and murine models amenable to studying particular aspects of disease. We then review how OPCs themselves can play an active role in promoting neuroinflammation and neurodegeneration, and how other resident CNS cells including microglia, astrocytes, and neurons can impact OPC function. Further, we outline the very complex and pleiotropic role(s) of several inflammatory cytokines and other secreted factors classically described as solely deleterious during MS and its animal models, but in fact, have many neuroprotective functions and promote a return to homeostasis, in part via modulation of OPC function. Finally, since MS affects patients from the onset of disease throughout their lifespan, we discuss the impact of aging on OPC function and CNS recovery. It is becoming clear that OPCs are not simply a bystander during MS progression and uncovering the active roles they play during different stages of disease will help uncover potential new avenues for therapeutic intervention.


Degradation Behavior of Biodegradable Man-Made Fibers in Natural Soil and in Compost.
In open environment applications, fibers are increasingly being used that are expected to biodegrade in the soil after their desired service life. Biodegradable polymer fibers are a versatile alternative to natural fibers. In this study, the degradation behavior of fibers made from polylactic acid (PLA) and a polyhydroxy alkanoate (PHA) blend with PLA, as well as a bicomponent fiber (BICO) made from polybutylene succinate (PBS) and PLA, was investigated. The fibers were stored in topsoil at 23 °C for 12 weeks. In addition, fibers were stored in compost at 58 °C for 4 weeks to investigate the degradation behavior in an industrial composting plant. Reference materials were also stored without substrate under the same temperatures and humidity conditions. Samples were taken regularly, and mechanical testing, scanning electron microscopy (SEM), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and infrared spectroscopy (IR) were used to study the degradation of the fibers. After 12 weeks in soil at ambient temperatures, the PLA and BICO fibers showed no degradation. The PHA fibers showed cracks in SEM, a decrease in molecular weight, and changes in the IR spectrum. No evidence of biological influence (bacteria or fungi) was found. Under industrial composting conditions, all fibers showed a decrease in strength and molecular weight. For the BICO and the PHA fibers, the SEM images show significant changes. Especially in the PHA fibers, fungal mycelia can be seen. The studies provide a better insight into the processes involved in the degradation behavior under different environmental conditions.


[Murder of the doctor].
To examine possible risk factors for the doctor to be killed by the patient in the clinical practice by examining a series of murders that involved physicians. This aim has been achieved through a retrospective review on clinical cases of doctors killed by patients within the period between 1988 and 2013, in Italy. In this period 18 Italian doctors have been killed in the workplace, with a rate of 0.3/100,000. In 7 cases, the murder resulted in the context of doctor-dissatisfaction; in 7 cases the murder was committed by a psychiatric patient; 1 case in the context of a stalking; 3 cases occurred in a workplace which was not safe enough. Four categories of at-risk contexts have been identified. One category includes a murder in the context of a doctor-dissatisfaction, perceived by patient. The second category concerns murders committed by patients suffering from mental illness. A third category includes homicides in a workplace which is not safe. The last category comprises the murder in the context of stalking. These categories identify specific dangerous situations for physicians, in which are highlighted elements that have played a crucial role in the murder and for which special precautions are suggested preventive.


Dietary influence on some proposed risk factors for colon cancer: fecal and urinary mutagenic activity and the activity of some intestinal bacterial enzymes.
This investigation studied the effects of a shift from a well-balanced mixed diet to a lacto-vegetarian diet on the mutagenic activity in urine and feces and on some cancer-associated bacterial enzymes in human feces (beta-glucuronidase, beta-glucosidase, and sulphatase). Three months after the shift to the lacto-vegetarian diet, there was a significant decrease in mutagenic activity in urine and feces, beta-glucuronidase, beta-glucosidase, and sulphatase per gram feces wet weight. In contrast, the fecal mutagenic activity and the enzyme activities remained unchanged if expressed per daily output. However, the urinary mutagenic activity expressed as total daily output decreased. Part of the explanation for the decreased fecal mutagenic activity and the decreased enzyme activities is obviously a dilution effect, because much of the increased fecal weight after the shift in diet was associated with a higher water content.


[Cervical necrotizing fasciitis].
Necrotizing fasciitis of the head and neck is a rare infection caused by a mixed bacterial flora with anaerobic predominance. Mortality is due to misdiagnosis which results in late and inadequate treatment. The natural course of this serious infection involves spreading necrosis of the soft tissues of the neck with erosion of major blood vessels. A 33-year-old man and a 66-year-old woman are presented to demonstrate the usual etiological factors of cervical necrotizing fasciitis, mainly dental and pharyngeal infections. Diagnosis is by bacteriological culture and CT-scan; a high degree of clinical suspicion is necessary. Treatment included aggressive surgery, appropriate antibiotic coverage and hyperbaric oxygen, and resulted in successful outcomes in our 2 cases.


Therapeutic use of the rebound effect of modern drugs: "New homeopathic medicines".
The homeopathic treatment is based on the principle of therapeutic similitude, employing medicines that cause certain disorders to treat similar manifestations, stimulating a reaction of the organism against its own ailments. The occurrence of this secondary reaction of the organism, opposite in nature to the primary action of the medicines, is evidenced in the study of the rebound (paradoxical) effect of several classes of modern drugs. In this work, in addition to substantiate the principle of similitude before the experimental and clinical pharmacology, we suggest a proposal to employ hundreds of conventional drugs according to homeopathic method, applying the therapeutic similitude between the adverse events of medicines and the clinical manifestations of patients. Describing existing lines of research and a specific method for the therapeutic use of the rebound effect of modern drugs (http://www.newhomeopathicmedicines.com), we hope to minimize prejudices related to the homeopathy and contribute to a broadening of the healing art.


Aspergillus PCR testing: results from a prospective PCR study within the AmBiLoad trial.
Invasive fungal infection (IFI) is a major cause of morbidity and mortality in severely immunocompromised patients and is difficult to diagnose. The significance of molecular methods for diagnosis of IFI is still controversial. In a subset of patients treated within the AmBiLoad Trial, samples were investigated prospectively by a nested Aspergillus PCR assay to re-evaluate the significance of PCR in this setting. In the randomized, prospective multicenter AmBiLoad trial, patients with proven or probable IFI were randomized to receive liposomal amphotericin B (L-AMB) 3 or 10 mg/kg QD for 14 d followed by L-AMB 3 mg/kg QD. From 91 patients, 459 serial samples (98% blood samples) were investigated by a nested PCR assay for Aspergillus DNA. All samples were investigated in our laboratory with a previously described nested and a quantitative PCR assay. As required by the study protocol, serial Aspergillus antigen galactomannan was performed. IFI was defined according to modified EORTC/MSG 2002 criteria as applied in the AmBiLoad trial. Seven and 52 patients had proven and probable IFI according to modified EORTC/MSG criteria, respectively. The median number of samples investigated per patient was 4. Seventy percent of samples were obtained during treatment with antifungal study medication. Forty-three samples gave positive PCR results. Patients with an unfavorable outcome had a significantly higher rate of positive PCR results (48% versus 21%). The sensitivity of Aspergillus PCR testing is limited during antifungal therapy. The tendency for persistently positive PCR results to indicate a poor prognosis has to be confirmed in further studies.


Monocyclic and tricyclic analogs of quinolones: mechanism of action.
The mode of action of Ro 13-5478 and Ro 14-9578, monocyclic and tricyclic quinolone analogs, respectively, was examined for Escherichia coli and Staphylococcus aureus. The compounds showed antibacterial activity and effects on cell morphology, replicative DNA biosynthesis, and gyrase-catalyzed DNA supercoiling that were comparable to those shown by nalidixic acid and by oxolinic acid compounds. The results suggest that their site of action is DNA gyrase and that a bicyclic quinolone nucleus is not essential for activity.


Hemizona index (HZI) demonstrates excellent predictability when evaluating sperm fertilizing capacity in in vitro fertilization patients.
The objective of this work was to assess the power of the hemizona assay to predict in vitro fertilization (IVF) results using receiving operating characteristics (ROC) analysis. In a tertiary medical center setting, 94 couples undergoing IVF were included in the study comparing their fertilization results to sperm function during the hemizona assay. Using ROC analysis, fertilization in IVF (mature oocytes only) was compared to performance of the sperm in the sperm-zona pellucida binding test as expressed by hemizona index (HZI; [number of test sperm bound/number of control sperm bound] x 100). The IVF results were as follows: 32 patients had no fertilization (0%), 55 patients fertilized all of the oocytes (100%), and 7 patients fertilized between 14% and 85% of the oocytes. Modified ROC analysis was used to determine the best threshold for fertilization success or failure, depending upon how the data are viewed. A HZI of 40-43 separated the 100% fertilization group from the other groups, with a true positive rate of 87% and a true negative of 83%. Conversely, a HZI of 4-5 separated the 0% fertilization versus partial or total fertilization, with a true positive rate of 100% and true negative rate of 71%. Sperm performance in the hemizona assay as measured by the HZI reflects performance in IVF and benefits couple evaluation and counseling.


Small hepatocellular carcinoma with peripheral enhancement: pathological correlation with dual phase images by helical CT.
The peripheral enhancement of small hepatocellular carcinoma (SHCC) is a rare appearance in dual phase images by helical computed tomography (CT). This study discusses this phenomenon and its correlative histopathology. The helical CT dual phase appearance of peripheral enhancement in SHCC was analyzed in 21 cases (22 lesions). All lesions were confirmed as SHCC by histopathological examination. In these 22 lesions, enhanced peripheral ring in 20 lesions was incomplete, the thickness of enhanced peripheral ring varied and mural node could be found in hepatic arterial phase; only 2 lesions had complete peripheral ring enhancement and ring of uniform thickness in hepatic arterial phase. The enhancement of some peripheral rings and mural nodes dropped to very low density in portal venous phase. The tumour cells were grade I in 3 lesions, II in 16, III in 2 and IV in 1. The vascular supply was more abundant at the border than in the centre of 15 lesions and the vascular supply was deficient in both centre and border of the remaining 7 lesions. In 3 lesions, the pseudocapsule showed in the border of the lesion. In 12 lesions, flecks of necrosis were found in the border and/or centre of the lesion. The characteristic peripheral enhancement in helical CT dual phase images of small hepatocellular carcinoma correlates with different vascular supplies, fibrous capsule and necrosis of the lesion.


Early childhood mental health consultation: Care providers' experiences of the consultative relationship.
This article presents findings from a qualitative research study exploring child care teachers' experiences receiving early childhood mental health consultation (ECMHC). As an emerging intervention in early childhood education, ECMHC is already yielding promising results, namely in helping teachers better address challenging behaviors in their classroom and promote a more nurturing classroom environment. However, there remains a lack of personal testimony from teachers who receive this intervention. Considering that teachers are the primary focus of most ECMHC interventions, the purpose of this study was to examine child care teachers' personal experiences receiving consultation. Eight child care teachers were interviewed for this study. Results from this study illuminate key interpersonal processes in the development of the consultant-consultee relationship, indicate what teachers consider to be the most helpful components of consultation, and speak to the challenges that teachers experience in consultation. By examining the personal testimony of child care teachers who have received ECMHC services, consultants and researchers can consider ways to expand and improve future implementation of ECMHC.


Rapid radial optical coherence tomography image acquisition.
We demonstrate how compressive sampling can be used to expedite volumetric optical coherence tomography (OCT) image acquisition. We propose a novel method to interpolate OCT volumetric images from data acquired by radial B-scans in the Cartesian coordinate system. Due to the inherent polar symmetry in the human eye, the (r, θ, z) coordinate system provides a natural domain to perform the interpolation. We demonstrate that the method has minimal effect on image quality even when up to 88% of the data is not acquired. The potential outcome of this work could lead to significant reductions in OCT volume acquisition time in clinical practice.


Peripheral blood neutrophils in inflammatory bowel disease: morphological evidence of in vivo activation in active disease.
Morphological evidence of activation in vivo of circulating neutrophils in patients with inflammatory bowel disease (IBD) was sought by quantitative light microscope examination of toluidine blue-stained preparations made from peripheral venous bloods that had been fixed immediately ex vivo. The proportion of spherical (unactivated) circulating neutrophils was reduced in active Crohn's disease (73%; 46-96 (median; range), n = 11) compared with inactive Crohn's (90%; 45-99; n = 18, P less than 0.01) and normal subjects (94%; 44-98; n = 13, P less than 0.05). There tended to be fewer spherical neutrophils in active ulcerative colitis (77%; 13-96; n = 17) than in quiescent colitis (88%; 57-99, n = 13, P less than 0.1) or normal subjects (P less than 0.05). Activated neutrophils occur in the circulating pool of patients with active IBD and can be detected by light microscopy of peripheral venous blood leucocyte preparations.


Double-blind comparison of levocabastine eye drops with sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis.
The efficacy and tolerance of topical administration (one drop in each eye q.i.d.) of levocabastine (0.5 mg/ml) was compared with that of sodium cromoglycate (20 mg/ml) and placebo in a 4-week double-blind trial in patients with seasonal allergic conjunctivitis. The investigator rated the treatment as globally good or excellent in significantly more patients treated with levocabastine (89%) than with cromoglycate (67%, P = 0.03) or placebo (48%, P = 0.007). The patients felt that the treatment was more efficacious in 95% (levocabastine), 35% (cromoglycate) and 36% (placebo) of the cases in which they had taken previous antiallergic medication. Total symptom severity according to the patients' diary data was consistently lower with levocabastine than with cromoglycate or placebo for all ocular symptoms. The difference was mainly apparent at the beginning of treatment. The percentage of symptom-free days was higher in the levocabastine group (53%) than in the cromoglycate (31%, P = 0.02) and the placebo group (34%, P = 0.08). Particularly at high-pollen days, levocabastine was superior to cromoglycate in eliminating moderate or severe symptoms. Adverse effects did not occur more frequently with levocabastine or cromoglycate than with placebo. It is concluded that levocabastine is an efficacious, fast-acting and well-tolerated drug in the management of seasonal allergic conjunctivitis.


Performance of a novel artificial intelligence software developed to derive coronary fractional flow reserve values from diagnostic angiograms.
Although invasive measurement of fractional flow reserve (FFR) is recommended to guide revascularization, its routine use is underutilized. Recently, a novel non-invasive software that can instantaneously produce FFR values from the diagnostic angiograms, derived completely from artificial intelligence (AI) algorithms has been developed. We aim to assess the accuracy and diagnostic performance of AI-FFR in a real-world retrospective study. Retrospective, three-center study comparing AI-FFR values with invasive pressure wire-derived FFR obtained in patients undergoing routine diagnostic angiography. The accuracy, sensitivity, and specificity of AI-FFR were analyzed. A total of 304 vessels from 297 patients were included. Mean invasive FFR was 0.86 vs. 0.85 AI-FFR (mean difference: -0.005, P = 0.159). The diagnostic performance of AI-FFR demonstrated sensitivity of 91%, specificity 95%, positive predictive value 83% and negative predictive value 97%. Overall accuracy was 94% and the area under curve was 0.93 (95% CI 0.88-0.97). 105 lesions fell around the cutoff value (FFR = 0.75-0.85); in this sub-group, AI-FFR demonstrated sensitivity of 95%, and specificity 94%, with an AUC of 0.94 (95% CI 88.2-98.0). AI-FFR calculation time was 37.5 ± 7.4 s for each angiographic video. In 89% of cases, the software located the target lesion and in 11%, the operator manually marked the target lesion. AI-FFR calculated by an AI-based, angio-derived method, demonstrated excellent diagnostic performance against invasive FFR. AI-FFR calculation was fast with high reproducibility.


Deep brain stimulation in headache.
The therapeutic use of deep brain stimulation to relieve intractable pain began in the 1950s. In some patients, stimulation of the periaqueductal grey matter induced headache with migrainous features, indicating a pathophysiological link between neuromodulation of certain brain structures and headache. Neuroimaging studies have revealed specific activation patterns in various primary headaches. In the trigeminal autonomic cephalgias, neuroimaging findings support the hypothesis that activation of posterior hypothalamic neurons have a pivotal role in the pathophysiology and prompted the idea that hypothalamic stimulation might inhibit this activation to improve or eliminate the pain in intractable chronic cluster headache and other trigeminal autonomic cephalgias. Over the past 6 years, hypothalamic implants have been used in various centres in patients with intractable chronic cluster headache. The results are encouraging: most patients achieved stable and notable pain reduction and many became pain free. All deep-brain-electrode implantation procedures carry a small risk of mortality due to intracerebral haemorrhage. Before implantation, all patients must undergo complete preoperative neuroimaging to exclude disorders associated with increased haemorrhagic risk. No substantial changes in hypothalamus-controlled functions have been reported during hypothalamic stimulation. Hypothalamic stimulation may also be beneficial in patients with SUNCT (short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing)--a disorder with close clinical and neuroimaging similarities to the cluster headache. WHERE NEXT?: Neuroimaging findings in patients undergoing posterior hypothalamic stimulation have shown activation of the trigeminal nucleus and ganglion. This evidence supports the hypothesis that hypothalamic stimulation exerts its effect by modulating the activity of the trigeminal nucleus caudalis, which in turn might control the brainstem trigeminofacial reflex--thought to cause cluster headache pain. Future studies might determine whether other areas of the pain matrix are suitable targets for neuromodulation in patients with cluster headache who do not respond to hypothalamic modulation.


Research on Adaptive 1DCNN Network Intrusion Detection Technology Based on BSGM Mixed Sampling.
The development of internet technology has brought us benefits, but at the same time, there has been a surge in network attack incidents, posing a serious threat to network security. In the real world, the amount of attack data is much smaller than normal data, leading to a severe class imbalance problem that affects the performance of classifiers. Additionally, when using CNN for detection and classification, manual adjustment of parameters is required, making it difficult to obtain the optimal number of convolutional kernels. Therefore, we propose a hybrid sampling technique called Borderline-SMOTE and Gaussian Mixture Model (GMM), referred to as BSGM, which combines the two approaches. We utilize the Quantum Particle Swarm Optimization (QPSO) algorithm to automatically determine the optimal number of convolutional kernels for each one-dimensional convolutional layer, thereby enhancing the detection rate of minority classes. In our experiments, we conducted binary and multi-class experiments using the KDD99 dataset. We compared our proposed BSGM-QPSO-1DCNN method with ROS-CNN, SMOTE-CNN, RUS-SMOTE-CNN, RUS-SMOTE-RF, and RUS-SMOTE-MLP as benchmark models for intrusion detection. The experimental results show the following: (i) BSGM-QPSO-1DCNN achieves high accuracy rates of 99.93% and 99.94% in binary and multi-class experiments, respectively; (ii) the precision rates for the minority classes R2L and U2R are improved by 68% and 66%, respectively. Our research demonstrates that BSGM-QPSO-1DCNN is an efficient solution for addressing the imbalanced data issue in this field, and it outperforms the five intrusion detection methods used in this study.


Structured modeling of a microbial system: III. Growth on mixed substrates.
A two-compartment model is extended to describe growth and product formation on a mixture of different carbohydrate sources. The open-ended structure of the compartment model is utilized to include description of the basic mechanisms of catabolite repression. The model is used to simulate batch triauxic, steady-state, and transient fermentation, and the simulations are compared with experimental results obtained with growth of the lactic acid bacteria Streptococcus cremoris on mixtures of glucose, galactose, and lactose. The model adequately describes characteristic experimental observations such as substrate preference and carbohydrate adoption.


Practical Management of Deep Cutaneous Fungal Infections.
Understanding deep cutaneous fungal infection requires not only reading many case reports and checking the typical clinical images of skin lesions, but also managing the patients properly to prevent misdiagnosis. Herein, I review my recent experiences with eight typical cases of deep cutaneous infections (including protothecosis and nocardiosis) in Japan. It is very important to do the four management processes; namely, KOH direct microscopic examination, skin biopsy, fungal culture, and microscopic examination of the histopathological specimen of PAS and Grocott staining. Also, to aid in memorizing the names of important diseases, I recommend the mnemonic "AC PPPS MD" (Aspergillosis, Cryptococcosis, Phaeohyphomycosis, Protothecosis, Pseudoallescheriosis, Sporotrichosis, Mycetoma, and Dermatophytosis). Isolation of the fungus by culturing from the skin lesion is the best way to carry out quick and correct diagnosis.


The Demographic Data and Prevalence of Thromboembolic Events Among Inflammatory Bowel Disease Patients in Buraydah, Al-Qassim Region.
Introduction Inflammatory bowel diseases (IBD) (Crohn's disease (CD) and ulcerative colitis (UC)) are considered among the commonest gastrointestinal (GI) tract diseases manifesting with chronic, recurring episodes of gut inflammation, especially in the colon. Each disease has its pattern, symptoms, severity of pain, extension, management, and prognosis. However, these diseases share most of the various complications, including the GI tract and extending it to other systems such as musculoskeletal, skin, liver, and pulmonary systems. Objectives We aim to identify the demographic data, prevalence, risk factors, clinical presentation, and management (medications given and investigations ordered) of thromboembolic events (TEE) among inflammatory bowel disease patients at King Fahad Specialist Hospital (KFSH) in Buraydah, Al-Qassim, Saudi Arabia. Materials and methods This is a retrospective, cross-sectional study. All included patients with IBD who meet the inclusion criteria between January 2020 and January 2022 in KFSH were reviewed, and data were analyzed using the Statistical Package for the Social Sciences (SPSS) Statistics version 23.0 (IBM Corp., Armonk, NY, USA). Results A total of 187 participants were included in the current study. The mean age of the participants ± standard deviation (SD) was 28.7 ± 10.8 years old. Of the participants, 107 (57.2%) were males. A total of 121 (64.7%) participants were diagnosed with Crohn's disease (CD), 56 (29.9%) with ulcerative colitis (UC), and 10 (5.3%) with both CD and UC. In 156 (83%) participants, the duration of the disease was 1-5 years. Among the IBD patients, two (1.1%) had TEE in the interval resolution middle and left portal vein, as well as the inferior mesenteric vein. The majority of the participants (73.3%) were with no history of comorbid conditions. The most reported clinical symptoms were chest pain as reported by 3.2% of the participants. Abdominal computed tomography (CT) was the most reported method of diagnosis as reported by 35.8% of the participants. Of the participants, 8.6% used heparin prophylactically, 0.5% used heparin as a treatment, and 0.5% used enoxaparin as a treatment. Moreover, 20.3% of the participants used prophylactic treatment, whereas about 79.7% did not use prophylactic treatment. Old age, extensive disease, colorectal surgery, and pregnancy were not found to be associated with thromboembolic events (p = 1.000, 0.400, 0.164, and 0.053, respectively). Age, gender, and nationality were not significantly associated with thromboembolic events (p = 0.915, 1.000, and 1.000, respectively). Conclusion Despite IBD being one of the emerging health concerns in the Kingdom of Saudi Arabia, records showed that the prevalence of thromboembolic events was found to be lower when compared to the prevalence reported in the relevant multinational studies. The was no difference in factors affecting the development of thromboembolic events between IBD patients and the general population. Recommendations We should stress raising awareness of IBD patients about their condition, the increased risks of developing thromboembolic events, and the proper prevention methods.


A Nonlinear Model for Gene-Based Gene-Environment Interaction.
A vast amount of literature has confirmed the role of gene-environment (G×E) interaction in the etiology of complex human diseases. Traditional methods are predominantly focused on the analysis of interaction between a single nucleotide polymorphism (SNP) and an environmental variable. Given that genes are the functional units, it is crucial to understand how gene effects (rather than single SNP effects) are influenced by an environmental variable to affect disease risk. Motivated by the increasing awareness of the power of gene-based association analysis over single variant based approach, in this work, we proposed a sparse principle component regression (sPCR) model to understand the gene-based G×E interaction effect on complex disease. We first extracted the sparse principal components for SNPs in a gene, then the effect of each principal component was modeled by a varying-coefficient (VC) model. The model can jointly model variants in a gene in which their effects are nonlinearly influenced by an environmental variable. In addition, the varying-coefficient sPCR (VC-sPCR) model has nice interpretation property since the sparsity on the principal component loadings can tell the relative importance of the corresponding SNPs in each component. We applied our method to a human birth weight dataset in Thai population. We analyzed 12,005 genes across 22 chromosomes and found one significant interaction effect using the Bonferroni correction method and one suggestive interaction. The model performance was further evaluated through simulation studies. Our model provides a system approach to evaluate gene-based G×E interaction.


Hydrogen polysulfide (H2S n ) signaling along with hydrogen sulfide (H2S) and nitric oxide (NO).
Hydrogen sulfide (H2S) is a physiological mediator with various roles, including neuro-modulation, vascular tone regulation, and cytoprotection against ischemia-reperfusion injury, angiogenesis, and oxygen sensing. Hydrogen polysulfide (H2S n ), which possesses a higher number of sulfur atoms than H2S, recently emerged as a potential signaling molecule that regulates the activity of ion channels, a tumor suppressor, transcription factors, and protein kinases. Some of the previously reported effects of H2S are now attributed to the more potent H2S n . H2S n is produced by 3-mercaptopyruvate sulfurtransferase (3MST) from 3-mercaptopyruvate (3MP) and is generated by the chemical interaction of H2S with nitric oxide (NO). H2S n sulfhydrates (sulfurates) cysteine residues of target proteins and modifies their activity, whereas H2S sulfurates oxidized cysteine residues as well as reduces cysteine disulfide bonds. This review focuses on the recent progress made in studies concerning the production and physiological roles of H2S n and H2S.


Community intravenous therapy provision.
Many healthcare services that were once only available in acute settings are now common in the community. Intravenous (IV) therapy is increasingly available as a community service. Given the option, most patients would choose to receive their treatment in a community setting, rather than in hospital. This article describes several outpatient parenteral antimicrobial therapy services, including their advantages and disadvantages. It explores the ways one community NHS trust has developed its community IV therapy service over the past ten years and examines issues pertinent to effective service delivery.


Potential Beneficial Effects and Pharmacological Properties of Ergosterol, a Common Bioactive Compound in Edible Mushrooms.
Ergosterol is an important sterol commonly found in edible mushrooms, and it has important nutritional value and pharmacological activity. Ergosterol is a provitamin. It has been well established that edible mushrooms are an excellent food source of vitamin D2 because ergosterol is a precursor that is converted to vitamin D2 under ultraviolet radiation. The pharmacological effects of ergosterol, which include antimicrobial, antioxidant, antimicrobial, anticancer, antidiabetic, anti-neurodegenerative, and other activities, have also been reported. This review aims to provide an overview of the available evidence regarding the pharmacological effects of ergosterol and its underlying mechanisms of action. Their potential benefits and applications are also discussed.


Direct coronal view of the shoulder with arthrographic CT.
Direct coronal oblique views of the shoulder were obtained with arthrographic computed tomography (CT) in 35 shoulders with surgical correlation. There were 18 complete cuff tears, four partial ones, two type 3 superior labral, anterior, and posterior (SLAP) lesions, and one type 4 SLAP lesion. The coronal sections were obtained after double-contrast shoulder arthrography and axial CT sections had already been obtained. The patient was seated directly on the slope of the gantry, and the shoulder to be studied was positioned in the center of the gantry. The maximal time needed for this procedure was 5 minutes. Rotator cuff tears were detected with a sensitivity of 95% and a specificity of 100%. The size of the tears as determined on the coronal sections was strongly correlated with surgical measurement (r = .939). All SLAP lesions were detected. The authors' experience shows that obtaining coronal oblique sections is an effective way to improve arthrographic CT.


Cloning of the gene for the surface array protein of Aeromonas salmonicida and evidence linking loss of expression with genetic deletion.
A gene bank of DNA from the fish pathogenic bacterium Aeromonas salmonicida was constructed in the bacteriophage lambda gt11. Phage lambda gt11/10G, a recombinant carrying a 4.0-kilobase fragment of A. salmonicida DNA, was found to express the surface array protein (A protein) in Escherichia coli. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the protein expressed from the cloned gene had a subunit molecular weight of 49,000, which was identical to that of subunits in the native assembled A layer. Genomic Southern analysis showed that the gene coding for this predominant cellular protein was in a single copy on the chromosome and was conserved among a wide range of A. salmonicida strains with different phenotypic characteristics and isolated from diverse geographic locations, fish species, and means of pathogenesis. Results of genomic blotting experiments also showed that loss of expression of the A layer resulting from growth at 30 degrees C was accompanied by genetic rearrangement in which N-terminal sequences of the gene for A protein were lost by deletion.


Metrics of early childhood growth in recent epidemiological research: A scoping review.
Metrics to quantify child growth vary across studies of the developmental origins of health and disease. We conducted a scoping review of child growth studies in which length/height, weight or body mass index (BMI) was measured at ≥ 2 time points. From a 10% random sample of eligible studies published between Jan 2010-Jun 2016, and all eligible studies from Oct 2015-June 2016, we classified growth metrics based on author-assigned labels (e.g., 'weight gain') and a 'content signature', a numeric code that summarized the metric's conceptual and statistical properties. Heterogeneity was assessed by the number of unique content signatures, and label-to-content concordance. In 122 studies, we found 40 unique metrics of childhood growth. The most common approach to quantifying growth in length, weight or BMI was the calculation of each child's change in z-score. Label-to-content discordance was common due to distinct content signatures carrying the same label, and because of instances in which the same content signature was assigned multiple different labels. In conclusion, the numerous distinct growth metrics and the lack of specificity in the application of metric labels challenge the integration of data and inferences from studies investigating the determinants or consequences of variations in childhood growth.


Optimal use of available claims to identify a Medicare population free of coronary heart disease.
We examined claims-based approaches for identifying a study population free of coronary heart disease (CHD) using data from 8,937 US blacks and whites enrolled during 2003-2007 in a prospective cohort study linked to Medicare claims. Our goal was to minimize the percentage of persons at study entry with self-reported CHD (previous myocardial infarction or coronary revascularization). We assembled 6 cohorts without CHD claims by requiring 6 months, 1 year, or 2 years of continuous Medicare fee-for-service insurance coverage prior to study entry and using either a fixed-window or all-available look-back period. We examined adding CHD-related claims to our "base algorithm," which included claims for myocardial infarction and coronary revascularization. Using a 6-month fixed-window look-back period, 17.8% of participants without claims in the base algorithm reported having CHD. This was reduced to 3.6% using an all-available look-back period and adding other CHD claims to the base algorithm. Among cohorts using all-available look-back periods, increasing the length of continuous coverage from 6 months to 1 or 2 years reduced the sample size available without lowering the percentage of persons with self-reported CHD. This analysis demonstrates approaches for developing a CHD-free cohort using Medicare claims.


Global prevalence of chronic fatigue syndrome among long COVID-19 patients: A systematic review and meta-analysis.
Chronic fatigue syndrome is a persistent and debilitating disorder. According to several studies, chronic fatigue syndrome has been identified among recovered COVID-19 patients as the most common symptom of long COVID. The aim of this systematic review and meta-analysis study was to obtain the prevalence of chronic fatigue syndrome in long COVID cases. In this systematic review and meta-analysis, we analysed reported results of studies that assessed the occurrence of chronic fatigue syndrome among COVID-19 patients four weeks after the onset of symptoms. The study selection was commenced by searching PubMed, Web of Science, Science Direct, Scopus, Embase, and Google scholar using the keywords of Chronic fatigue syndrome, COVID-19, and post-COVID-19 syndrome. The searches were without a lower time limit and until April 2022. Heterogeneity of studies was assessed using the I2 index, and a random effects model was used for analysis. Data analysis was performed within the Comprehensive Meta-Analysis software (version 2). The pooled prevalence of chronic fatigue syndrome four weeks after the onset of COVID-19 symptoms, in 52 studies with a sample size of 127,117, was 45.2% (95% CI: 34.1-56.9%). Meta-regression analysis in examining the effects of the two factors of sample size, and year of study on the changes in the overall prevalence, showed that with increasing sample size, and year of study, the prevalence of chronic fatigue syndrome among long COVID patients (p < 0.05). Our results show that the overall prevalence of chronic fatigue syndrome as a long COVID symptom is 45.2%. Chronic fatigue after infection with COVID-19 can negatively affect personal and social lives. Given such significant negative consequences caused by the syndrome, it is recommended that health policymakers allocate funds to reduce the adverse effects of this syndrome, by creating programs to support long COVID patients.


Combined effect of fluoride and arsenate on gene expression of osteoclast differentiation factor and osteoprotegerin.
To study the combined effect of fluoride and arsenate on the expression of SD rat osteoblastic osteoclast differentiation factor (ODF) mRNA and osteoprotegerin (OPG) mRNA. Osteoblasts were obtained by enzymatic isolation from newborn SD rats. A factorial experiment was performed. Osteoblasts were exposed to NaF (0.5 mmolF/L, 4 molF/L) and Na3AsH2 (12.5 micromolAs/L and 200 micromolAs/L) separately or F plus As and cultured for 48 h. The gene expression of osteoblastic ODF and OPG was observed by RT-PCR. The expression of ODF mRNA increased in F0.5, F4 groups compared with control group and two groups of F0.5As200, F4As200 compared with As200 group, and decreased significantly in groups of F4Asl2.5, F0.5As200, and F4AS200. The expression of OPG mRNA decreased in groups of F4, As200, F4As12.5, F0.5AS200, and F4AS200. The joint effect of fluoride and arsenate on the gene expression of ODF is antagonistic, while the combined effect on the gene expression of OPG is synergistic. F4, F4As12.5, and F0.5As200 promote bone resorption of rat osteoclasts, whereas F0.5As12.5 inhibits osteolytic effect of rat osteoclasts.


Surgery for Localized Pancreatic Cancer: The Trend Is Not Improving.
The aim of this study was to examine the trend in the use of surgery for localized pancreatic adenocarcinoma for the past 2 decades using the Surveillance, Epidemiology, and End Results database. We identified a cohort of patients who received a diagnosis of localized pancreatic adenocarcinoma between 1988 and 2010 in the United States. Univariate and multivariate methods were used to determine factors associated with not receiving surgery. Cox proportional hazards regression modeling was used to determine factors associated with survival. Of 6742 patients with a diagnosis of localized pancreatic adenocarcinoma, 1715 patients (25.4%) underwent surgery. There was no significant change in use of surgery over time. Patients were less likely to undergo surgery if they were older than 50 years, black, unmarried, and located outside the East and had pancreatic head or body lesions, higher tumor grades, or tumor size greater than 2 cm (P < 0.0001). Receiving surgery had the most significant impact on the hazard of disease-specific death (hazards ratio, 1.41; 95% confidence interval, 1.29-1.53; P < 0.0001). In contrast to recent studies that suggest an increasing use of surgery, the present study demonstrates that there has been no change in the rate of use of surgery in patients with localized pancreatic disease.


Regulation of tyrosinase expression and activity in human melanoma cells via histamine receptors.
In cultured human melanoma cells, histamine H1 (mepyramine) and H2 receptor antagonists (cimetidine, ranitidine, impromidine) increased tyrosinase activity, whereas H2 agonists (dimaprit, nordimaprit) decreased activity. Mixtures of agonist and antagonist either decreased or increased tyrosinase activity, depending on the relative concentrations of each drug. Nordimaprit, the most effective inhibitor, lowered tyrosinase activity significantly within 36 h and caused a slower loss of tyrosinase protein as judged by reactivity with two monoclonal antibodies. Prolonged treatment of a melanotic cell line with nordimaprit led to complete loss of pigment, with no loss of the 56-kDa melanosomal antigen 1C11. Cells remained amelanotic for 8 weeks after removal of the drug and, even after 26 weeks, melanin content and tyrosinase expression and activity had not fully recovered. Nordimaprit increased the rate of degradation of tyrosinase and of nordimaprit binding proteins. Whereas nordimprit did not directly inhibit tyrosinase, lysates of treated cells contained an inhibitory activity that partitioned approximately equally across a 10-kDa ultrafiltration membrane. Overall, these results showed that melanogenesis can be controlled via histamine receptors, the mechanism for the H2 agonist nordimaprit consisting of three components: induction of a tyrosinase inhibitor, increased degradation of tyrosinase, and long-term down-regulation of tyrosinase expression.


Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p.
Ibrutinib is a novel oral therapy that has shown significant efficacy as initial treatment of chronic lymphocytic leukemia (CLL). It is a high-cost continuous therapy differing from other regimens that are given for much shorter courses. Our objective was to evaluate the cost-effectiveness of ibrutinib for first-line treatment of CLL in patients older than age 65 years without a 17p deletion. We developed a semi-Markov model to analyze the cost-effectiveness of ibrutinib vs a comparator therapy from a US Medicare perspective. No direct comparison between ibrutinib and the best available treatment alternative, obinutuzumab plus chlorambucil (chemoimmunotherapy), exists. Therefore, we compared ibrutinib to a theoretical treatment alternative, which was modeled to confer the effectiveness of an inferior treatment (chlorambucil alone) and the costs and adverse events of chemoimmunotherapy, which would provide ibrutinib with the best chance of being cost-effective. Even so, the incremental cost-effectiveness ratio of ibrutinib vs the modeled comparator was $189 000 per quality-adjusted life-year (QALY) gained. To reach a willingness-to-pay threshold (WTP) of $150 000 per QALY, the monthly cost of ibrutinib would have to be at most $6800, $1700 less than the modeled cost of $8500 per month (a reduction of $20 400 per year). When the comparator efficacy is increased to more closely match that seen in trials evaluating chemoimmunotherapy, ibrutinib costs more than $262 000 per QALY gained, and the monthly cost of ibrutinib would need to be lowered to less than $5000 per month to be cost-effective. Ibrutinib is not cost-effective as initial therapy at a WTP threshold of $150 000 per QALY gained.


Oxynitride K2Ba6.72Si16O40-1.5yNy:0.28Eu2+ phosphor with high thermal stability realized by crystal field engineering.
Extensive research has gone into modifying the chemical composition of phosphors to achieve desirable optical properties. Here, oxynitride phosphors K2Ba6.72Si16O40-1.5yNy:0.28Eu2+ were synthesized by introducing N3- (y) into a K2Ba6.72Si16O40:0.28Eu2+ lattice. An uneven shrinking of the cell parameters a, b, and c was observed through a combination of X-ray diffraction studies and Rietveld refinements. This shrinking caused a large centroid shift (εc) and splitting of the 5d energy level (εcfs), thus inducing the broadening of the excitation spectra (104 → 127 nm, y = 0 → y = 12) and the red shift of the emission spectra (501 → 543 nm, y = 0 → y = 12). The modified series of samples have a broad excitation spectrum, suitable of use in UV, near-UV, and blue light-emitting LEDs. In addition, the optimal sample, K2Ba6.72Si16O31N6:0.28Eu2+, benefits from an increased activation energy and thermal stability.


Rapid axoplasmic transport of tyrosine hydroxylase in relation to other cytoplasmic constituents.
The transport of norepinephrine and two key enzymes involved in its synthesis, tyrosine hydroxylase (EC 1.14.3a) and dopamine beta-hydroxylase (EC 220.127.116.11), has been studied in relation to other axonal constituents in ligated chicken sciatic nerves. Norepinephrine, tyrosine hydroxylase, and dopamine beta-hydroxylase activity all increased proximal to the constriction over a 20-hr period. The rate of transport of norepinephrine, tyrosine hydroxylase, and dopamine beta-hydroxylase were calculated as 2.6, 1.9, and 3.4 mm/hr, respectively. The only enzyme marker to show a similar rate of accumulation was acetylcholinesterase (EC 126.96.36.199), a putative marker for endoplasmic reticulum. The rapid axoplasmic transport of tyrosine hydroxylase from the cell bodies to the terminals of sympathetic neurons may be adequate to account for the elevated amounts of this enzyme in chronically active axon terminals, without the necessity to invoke peripheral axonal synthesis of the enzyme to explain such elevated amounts.


A comparison of the biological activities of wild-type and mutant p53.
Tumorigenesis is characterized by a series of genetic alterations in both dominant oncogenes and tumor suppressor genes. A hallmark of tumor suppressor genes is that both alleles are generally altered during transformation, which usually represents a loss of function phenotype. The p53 tumor suppressor gene is the most frequently affected gene detected in human cancer. There is now growing evidence suggesting that mutation of p53 may involve not only a loss of function of wild-type p53 activity but also a gain of function phenotype contributed by the mutant p53 protein. The study of the biological properties and functions of both wild-type and mutant p53 is central to our understanding of human cancer. These properties and functions of wild-type and mutant p53 will be compared and contrasted here and elsewhere within this thematic issue. In addition, the mechanisms of inactivation of p53 function, which include: 1) mutation, 2) inhibition by viral oncogene products, 3) inhibition by cellular regulators, and 4) alteration in subcellular localization, will be discussed.


Hydrogen-bonding interactions in (3,4-dimethoxyphenyl)acetic acid monohydrate.
The crystal structure of the title compound, C(10)H(12)O(4).H(2)O, consists of (3,4-dimethoxyphenyl)acetic acid and water molecules linked by O-H...O hydrogen bonds to form cyclic structures with graph-set motifs R(1)(2)(5) and R(4)(4)(12). These hydrogen-bond patterns result in a three-dimensional network with graph-set motifs R(4)(4)(20) and R(4)(4)(22), and the formation of larger macrocycles, respectively. The C-C bond lengths and the endocyclic angles of the benzene ring show a noticeable asymmetry, which is connected with the charge-transfer interaction of the carboxyl or methoxy groups and the benzene ring. The title compound is one of the simple carboxylic acid systems that form hydrates. Thus, the significance of this study lies in the analysis of the interactions in this structure and the aggregations occurring via hydrogen bonds in two crystalline forms of (3,4-dimethoxyphenyl)acetic acid, namely the present hydrate and the anhydrous form [Chopra, Choudhury & Guru Row (2003). Acta Cryst. E59, o433-o434]. The correlation between the IR spectrum of this compound and its structural data are also discussed.


Disseminated cutaneous sporotrichosis treated with itraconazole.
A 72-year-old Hispanic man with diabetes presented with a 4-week history of a tender non-healing ulcer on the fifth digit of the left hand and a 3-day history of fever, chills, malaise, anorexia, and tender fluctuant nodules on the abdomen and left elbow. The patient, an avid gardener, was using prednisone and methotrexate for a debilitating seronegative polyarthropathy. A diagnosis of disseminated cutaneous sporotrichosis was made based on epidemiologic risk factors, clinical appearance, histopathologic examination, and a positive fungal culture. Use of prednisone was discontinued, the dosage of methotrexate was decreased, and use of oral itraconazole 400 mg/day was instituted. The patient's lesions cleared within 5 months, and no recurrence was noted during a 3-month follow-up. This case illustrates the typical association of the rare entity of disseminated cutaneous sporotrichosis with immunosuppression, an unusual lack of internal involvement, and a gratifying response to itraconazole.