Temperature-resolved thermal analysis of cisplatin by means of Li+ ion attachment mass spectrometry.
Li(+) ion attachment mass spectrometry (IAMS) was evaluated as an analytical methodology for measurement of the thermally labile, nonvolatile, and insoluble compound cisplatin, which is used as an anticancer agent in the treatment of testicular and ovarian cancers. We aimed to develop an improved method for the mass spectrometric determination of cisplatin, particularly in its molecular ion form. A uniquely designed quadrupole mass spectrometry system along with a Li(+) ion attachment technique and a direct inlet probe provided cisplatin molecular ions as Li(+) ion adducts; to our knowledge this is the first reported instance of cisplatin Li(+) ion adducts. Full-scan spectra were obtained with approximately 10 microg samples. Infrared image furnace-ion attachment mass spectrometry (IIF-IAMS) also was used to study the temperature-programmed decomposition of this drug. The slope of the plot of signal intensity versus temperature for cisplatin decomposition from 225 to 249 degrees C was used to determine an apparent activation energy (E(a)) of 38.0 kcal mol(-1) for the decomposition of cisplatin. This decomposition parameter is useful for predicting drug stability (shelf life). In this study, we have demonstrated that IAMS can be a valuable technique for the direct mass spectral analysis and kinetic study of d-metal complex platinum anticancer agents.


EDTA-Induced Pseudothrombocytopenia up to 9 Months after Initial COVID-19 Infection Associated with Persistent Anti-SARS-CoV-2 IgM/IgG Seropositivity.
Platelets have a role in vascular complications of COVID-19-related viral coagulopathy. Although immune-induced thrombocytopenia has been described mostly in moderate-to-severe COVID-19, the prognostic role of platelet count in COVID-19 is still controversial. Pseudothrombocytopenia has been reported to represent COVID-19-associated coagulopathy in critical illness, and transient EDTA-dependent pseudothrombocytopenia lasting less than 3 weeks was described in a patient with severe acute COVID-19 pneumonia. In our case study, EDTA-induced pseudothrombocytopenia was still present at 9 months after an initial SARS-CoV-2 virus infection in an apparently recovered 60 year old man. The persistence of antinucleocapside and antispike antibodies 9 months after the initial infection suggests that EDTA-induced pseudothrombocytopenia may be related to anti-SARS-CoV-2 IgG or IgM antibodies. We should acknowledge the possibility that pseudothrombocytopenia may also appear in some patients after seroconversion after the launch of large-scale vaccination programs.


Avoiding costly conservation mistakes: the importance of defining actions and costs in spatial priority setting.
The typical mandate in conservation planning is to identify areas that represent biodiversity targets within the smallest possible area of land or sea, despite the fact that area may be a poor surrogate for the cost of many conservation actions. It is also common for priorities for conservation investment to be identified without regard to the particular conservation action that will be implemented. This demonstrates inadequate problem specification and may lead to inefficiency: the cost of alternative conservation actions can differ throughout a landscape, and may result in dissimilar conservation priorities. We investigate the importance of formulating conservation planning problems with objectives and cost data that relate to specific conservation actions. We identify priority areas in Australia for two alternative conservation actions: land acquisition and stewardship. Our analyses show that using the cost surrogate that most closely reflects the planned conservation action can cut the cost of achieving our biodiversity goals by half. We highlight spatial differences in relative priorities for land acquisition and stewardship in Australia, and provide a simple approach for determining which action should be undertaken where. Our study shows that a poorly posed conservation problem that fails to pre-specify the planned conservation action and incorporate cost a priori can lead to expensive mistakes. We can be more efficient in achieving conservation goals by clearly specifying our conservation objective and parameterising the problem with economic data that reflects this objective.


[Clinical and genetic aspects of hereditary acro-osteolysis].
The report concerns a description of a case of hereditary acroosteolysis with peculiar clinical and X-ray symptoms. It is being stressed that the neurological changes in different cases differ by their manifold signs and are sometimes the prevalent syndrome. The authors conducted a genetical analysis of 11 cases of hereditary acroosteolysis, which were seen in Dagestan. The paper contains some considerations of the differencies of hereditary acroosteolysis from other similar disorders.


Determination and kinetics of producing glucosamine using fungi.
This work used three fungi, Rhizopus oligosorus BCRC 31996, Monascus pilosus BCRC31527, and Aspergillus sp. BCRC31742, to produce glucosamine by using submerged fermentation and flask cultures. The reaction of glucosamine with 1-naphthyl isothiocyanate as derivatizing agent was carried out in pyridine at 50 degrees C for 1 h. The derivative was accurately analyzed and quantified by using high performance liquid chromatography. The relative standard deviation of glucosamine determined between experimental and real values were less than 2%. The kinetic and strategy of producing glucosamine in a flask culture was investigated to achieve an optimum yield of glucosamine under different conditions including three kinds of fungi, medium, and pH values. The descending ability of producing glucosamine for the three fungi was Aspergillus sp. BCRC31742 > Monascus pilosus BCRC31527 > Rhizopus oligosorus BCRC 31996 under the conditions studied. The experimental result shows that the glucosamine concentration had an optimum value and was 3430 mg/L by using Aspergillus sp. BCRC31742 culture in glucose and peptone (GP) medium, the yield of which was the best amount using wild-type microorganisms in the past. The generation culture of fungi and the pH control played important roles in enhancing the yield of glucosamine. The specific growth rate of the microorganism and the biomass, content, yield, and productivity of glucosamine were calculated as well.


Oxytocin analysis from human serum, urine, and saliva by orbitrap liquid chromatography-mass spectrometry.
Oxytocin (OT) is a neurohormone that has gained interest recently due to its emerging role in cognition and social/emotional behaviors, including possibly depression and autism. OT is commonly measured using enzyme- or radio-based immunoassays (RIA, ELISA), which lack specificity or are complicated to perform and involve hazardous radioactive material. We have developed a high resolution accurate-mass (HRAM) liquid chromatography-mass spectrometry (LC-MS) method that separates interferences and selectively and accurately quantitates native OT from human serum, urine, and saliva after solid phase extraction. The doubly protonated OT ion m/z 562.25503 was selected for quantitation due its high signal intensity. With our method lower limit of detection (LLOD) of 5-25 pg/mL, we measured native OT in serum from pregnant women (16-24 pg/mL) and rats (350 pg/mL), and in serum, urine, and saliva from a healthy male after intranasal (IN) OT application of 100 IU and 20 IU and from a healthy post-menopausal female after IN OT application of 100 IU. Peak levels were detected in serum, urine, and saliva 15-30 minutes after each dose then decreased to below detection limits 1-2 hours thereafter. We were unable to detect native OT in serum from non-pregnant/non-lactating/non-medicated women due to levels known to occur below 5 pg/mL. The fast elimination of OT we found is in excellent agreement with the pharmacokinetics of OT in other studies. The effects on the central nervous system occurring after IN OT administration remains to be determined.


[Effects of once-daily low-dose administration of sustained-release theophylline on airway inflammation and airway hyperresponsiveness in patients with asthma].
Bronchial asthma is eosinophilic airway inflammation with enhanced airway responsiveness induced by eosinophilic granule proteins such as eosinophilic cationic protein (ECP) that are released from eosinophils. In the present study using 30 outpatients with mild to moderate asthma who had no history of treatment with steroid inhalation, we examined the effects of 4-week low-dose (200 mg/day) treatment with Uniphyl Tablets, a sustained-release theophylline formulated for once-daily dosing, on airway inflammation and airway hyperresponsiveness, as well as on respiratory function. Uniphyl Tablets significantly (p < 0.01) decreased peripheral blood eosinophil count from 647.00 to 444.17/mm3 and ECP level (geometric mean) from 1318 to 741 ng/ml and improved airway hyperresponsiveness as indicated by a decrease in airway hyperresponsiveness (Dmin, geometric mean) from 1.15 to 6.70 units. FEV1.0 and PEF showed statistically significant (p < 0.01) improvement from 2.39 to 2.69 L and from 6.21 to 7.14 L/sec, respectively. V25 and V50 also showed statistically significant (p < 0.05) improvement. Mean blood theophylline concentration at the time the improvements were seen was 3.95 mg/mL. These results suggest that low-dose administration of Uniphyl Tablets has anti-airway inflammatory and anti-airway hyperresponsiveness effects in mild to moderate asthmatic patients.


Association between the interleukin-17A -197G>A (rs2275913) polymorphism and risk of digestive cancer.
Interleukin-17A (IL-17A) is a multifunctional cytokine which plays a crucial role in the initiation and progression of cancer. To date, several studies have investigated associations between IL-17A -197G>A (rs2275913) polymorphism and digestive cancer risk, but the results remain conflicting. We here aimed to confirm the role of this single nucleotide polymorphism (SNP) in susceptibility to digestive cancer through a systemic review and meta-analysis. Ten eligible case-control studies were identified by searching electronic databases, involving 3,087 cases and 3,815 controls. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to estimate the strength of the association. The results of overall analyses indicated that the variant A allele was associated with an increased risk of digestive cancer (AA vs GG: OR=1.51, 95%CI=1.18-1.93; AA vs GG+GA: OR=1.45, 95%CI=1.12-1.87; A vs G: OR=1.21, 95%CI=1.05-1.39). In subgroup analysis stratified by specific cancer type, elevated risk among studies of gastric cancer was found (AA vs GG: OR=1.68, 95%CI=1.24-2.28; AA vs GG+GA: OR=1.62, 95%CI=1.16-2.26; A vs G: OR=1.23, 95%CI=1.04-1.46). According to ethnicity, there was evidence in the Asian populations for an association between this polymorphism and cancer risk (GA vs GG: OR=1.19, 95%CI=1.05-1.36; AA vs GG: OR=1.56, 95%CI=1.15-2.12; AA+GA vs GG: OR=1.28, 95%CI=1.13- 1.44; AA vs GG+GA: OR=1.42, 95%CI=1.01-2.00; A vs G: OR=1.24, 95%CI=1.08-1.44), while in the Caucasian populations an association was found in the recessive model (AA vs GG+GA: OR=1.62, 95%CI=1.17-2.24). In conclusion, the results of this meta-analysis suggest that the IL-17A -197G>A polymorphism contributes to an increased risk of human digestive cancer, both in the Asian and Caucasian populations and especially for gastric cancer.


Ultrafast gas chromatographic separation of organophosphor and organosulfur compounds utilizing a microcountercurrent flame photometric detector.
A microcountercurrent flame photometric detector (microcc-FPD) was adapted and optimized for ultrafast gas chromatographic (GC) separation and detection of organophosphor (OP) and organosulfur (OS) compounds on short chromatographic columns. Air and hydrogen are introduced to the microcc-FPD from opposite directions, creating a hydrogen-rich flame. In this microcc-FPD, combustion takes place between the burner tips without touching them. The separation between the tips and the flame reduces heat loss from the flame to the surrounding environment, resulting in low hydrogen consumption and a compact flame. The microcc-FPD is capable of detecting very narrow (13 ms) chromatographic peaks. An ultrafast GC separation of a group of six OP and OS compounds is achieved within less than 5 s using fast temperature programming of a 0.5-m-long microbore column. Very fast separations are also demonstrated on a 1-m-long microfabricated column consisting of 150-microm-wide, 240-microm-deep channels, etched in a 1.9-cm square silicon chip, covered with a Pyrex wafer, and statically coated with dimethyl polysiloxane. With a hydrogen flow rate of 10 mL/min, the detection limit for OP is 12 pg of P/s and 3 ng of S/s for OS compounds at a signal-to-noise ratio of 2. The coupling of a microfabricated column and a miniature FPD is an important step toward the development of a miniaturized GC-FPD capable of ultrafast detection of low levels of OP and OS compounds.


Dynamical density functional theory for the dewetting of evaporating thin films of nanoparticle suspensions exhibiting pattern formation.
Recent experiments have shown that the striking structure formation in dewetting films of evaporating colloidal nanoparticle suspensions occurs in an ultrathin "postcursor" layer that is left behind by a mesoscopic dewetting front. Various phase change and transport processes occur in the postcursor layer that may lead to nanoparticle deposits in the form of labyrinthine, network, or strongly branched "finger" structures. We develop a versatile dynamical density functional theory to model this system which captures all these structures and may be employed to investigate the influence of evaporation or condensation, nanoparticle transport, and solute transport in a differentiated way. We highlight, in particular, the influence of the subtle interplay of decomposition in the layer and contact line motion on the observed particle-induced transverse instability of the dewetting front.


The basis for self-tolerance of natural killer cells in beta2-microglobulin- and TAP-1- mice.
Cells from mice with mutations in the genes for beta2-microglobulin (beta2m) or for TAP-1 express only low levels of MHC class I proteins on their surfaces, and are thus sensitive to attack by normal NK cells. Although NK cells are present in beta2m- mice and TAP-1(-) mice, they are completely self-tolerant. The underlying mechanism for this tolerance is unknown. It has been proposed that education processes render NK cells from these mice hypersensitive to class I-mediated inhibition, so that they can be inhibited even by the low levels of class I expressed on autologous cells. In this study, we present evidence against this hypothesis, by demonstrating that NK cells from beta2m- mice and TAP-1(-) mice fail to attack beta2m(-)TAP-1(-) double-mutant cells in both in vitro and in vivo assays. The latter cells express substantially lower levels of class I than single-mutant cells, based on serologic tests, as well as a significantly diminished sensitivity to attack by class I-specific CTL. Furthermore, the Ly-49 repertoire on NK cells derived from beta2m(-)TAP-1(-) mice is highly similar to that of either single mutant, indicating that the developmental processes that shape the Ly-49 repertoire cannot respond to the differences in class I levels among these mice. We propose that self-tolerance of NK cells in beta2m- mice and TAP-1(-) mice is likely to result from hyporesponsiveness of the cells to activating signals, or alternatively, to induction of inhibitory signaling through receptors specific for non-class I MHC ligands.


[Metastasis of breast cancer to a uterine leiomyoma].
The authors report a case of metastasis of cancer from the breast in a uterine leiomyoma. The metastases into the body of the uterus from extragenital cancers are rare. If they occur they are usually in the myometrium where they are asymptomatic and where the diagnosis is difficult, or in the endometrium where the diagnosis can be made by biopsy after curettage. A few rare cases of metastases in uterine leiomyoma have been reported in the literature. They can be the cause of very sudden increase in size of fibroids with compression of the pelvic organs.


Modulation of mouse coagulation gene transcription following acute in vivo delivery of synthetic small interfering RNAs targeting HNF4α and C/EBPα.
Hepatocyte nuclear factor 4α (HNF4α) and CCAAT/enhancer-binding protein α (C/EBPα) are important for the transcriptional control of coagulation factors. To determine in vivo the direct role of HNF4α and C/EBPα in control of genes encoding coagulation factors, a synthetic small interfering (si)RNA approach was used that enabled strong reduction of mouse hepatic HNF4α and C/EBPα under conditions that minimized target-related secondary effects. For both HNF4α and C/EBPα, intravenous injection of specific synthetic siRNAs (siHNF4α and siC/EBPα) resulted in more than 75% reduction in their liver transcript and protein levels 2 days post-injection. For siHNF4α, this coincided with marked and significantly reduced transcript levels of the coagulation genes Hrg, Proz, Serpina5, F11, F12, F13b, Serpinf2, F5, and F9 (in order of magnitude of effect) as compared to levels in control siRNA injected animals. Significant decreases in HNF4α target gene mRNA levels were also observed at 5 days post-siRNA injection, despite a limited level of HNF4α knockdown at this time point. Compared to HNF4α, C/EBPα knockdown had a modest impact on genes encoding coagulation factors. A strong reduction in C/EBPα transcript and protein levels resulted in significantly affected transcript levels of the control genes Pck1 and Fasn and a modest downregulation for coagulation genes Fba, Fbg and F5. F5 and F11 were the sole coagulation genes that were significantly affected upon prolonged (5 day) C/EBPα knockdown. We conclude that in the mouse, HNF4α has a direct and essential regulatory role for multiple hepatic coagulation genes, while a role for C/EBPα is more restricted. In addition, this study demonstrates that synthetic siRNA provides a simple and fast means for determining liver transcription factor involvement in vivo.


Multi-target CW interferometric acoustic measurements on a single optical beam.
We present a free-space, continuous-wave laser interferometric system capable of multi-target dynamic phase measurement at acoustic frequencies up to a Nyquist bandwidth of 10.2 kHz. The system uses Digitally-enhanced Heterodyne Interferometry to range gate acoustic signals simultaneously from multiple in-line reflections while isolating coherent cross-talk between them. We demonstrate sub-nanometer displacement sensitivity across the audio band for each individual reflection surface and 1.2 m resolution between successive surfaces. Signals outside the 1.2 m range-gate of the system were suppressed by greater than 30 dB in amplitude, enabling high fidelity independent acoustic measurements.


Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement.
Kindler syndrome (online Mendelian Inheritance in Man No. 173650) is an autosomal recessive genodermatosis characterized by acral trauma-induced blistering that improves with age and by progressive poikiloderma in later life. Other clinical features include photosensitivity, webbing of the fingers and toes, nail dystrophy, periodontal disease, and mucosal alterations. Aside from esophageal or anal stenosis, gastrointestinal tract involvement seems to be rare in Kindler syndrome. Recently, mutations in the KIND1 gene that encodes for the membrane-associated protein kindlin-1 have been identified. Kindlin-1 links the actin cytoskeleton to the extracellular matrix and is supposed to have cell-signaling functions owing to different functional domains. In particular, a domain with high homology to 4.1/ezrin/radixin/moesin (FERM) proteins is closely related to the sequences of talin that mediate integrin binding and therefore may play a role in integrin-dependent processes such as cell growth, differentiation, and apoptosis. Complete loss of this multifunctional protein in our patient with Kindler syndrome resulted in severe gastrointestinal tract involvement with hemorrhagic colitis. Mucosa of the descending and sigmoid colon and the rectum showed erosions and ulcers with pseudomembranous alterations of an overall highly vulnerable mucosa. Mutation analysis revealed a homozygous status for the novel mutation 20/21delTT in exon 2 of the KIND1 gene resulting in a preterminal stop codon creating a nonfunctional peptide 17 amino acids in length. Because of our experience with this and another patient, we propose that gastrointestinal tract involvement should be looked at more frequently in Kindler syndrome.


Changes in photoperiod and nutrition and their effect on testicular growth of rams.
Groups of 6 Ile-de-France rams were housed in light-proof rooms and subjected in a factorial design to two light regimens, 180 degrees out of phase, and two levels of protein in their diets. The daily duration of daylight was varied sinusoidally to produce 6-month years with 'winters' of 8 h light and 'summers' of 16 h light. The diets were formulated to supply 50% above or 25% below maintenance requirements in protein. Testicular diameter and volume increased with decreasing light and decreased with increasing light but the diet had no effect. The frequency of LH pulses was measured monthly and was high (3/12 h per ram) when the daylight was being reduced and low (1/12 h per ram) when it was increased. At the extremes of the duration of dark or light the frequency of pulses was around 1.6/12 h per ram, regardless of the duration of light. The two diets had no effect on testicular dimensions but rams fed the 'high' protein diet had a total of 175 LH pulses, which was significantly higher (P less than 0.05) than the 131 pulses recorded from rams on the 'low' protein diet. It is concluded that, in these '6-month years', decreasing light stimulates LH pulsatility and testicular growth and increasing light is inhibitory. Pulsatility of LH appears to be influenced by the protein level in the diet.


Determination of size in invasive breast carcinoma: pathologic considerations and clinical implications.
The widespread use of mammography has made the detection of increasingly small, often impalpable, invasive breast carcinomas possible. An enhanced understanding of morphological factors, among the foremost of which is size of invasive component of carcinoma, is changing the management of breast cancer To the uninitiated, the determination of size of invasive component is seemingly simple but in practical terms is complicated by a number of ambiguous issues. Practical guidelines for the assessment of size of invasive carcinoma are proposed.


Freeze-dried and irradiated allograft bone combined with fresh autologous coagula promotes angiogenesis in an ectopic bone allograft implantation model.
Freeze-dried and irradiated allograft bone (FIAB) is more easily impacted than fresh-frozen allograft bone (FAB), but has weaker incorporation efficiency. We combined FIAB with fresh autologous coagula to enhance donor-host incorporation after impaction during hip revision. Thirty adult male Sprague-Dawley (SD) rats were sacrificed for bone allograft harvesting, and nine male rats were subjected to ectopic bone allograft implantation. For each rat, the container on the left (study) side was filled with freeze-dried allograft bone powder and fresh autologous blood coagula, whereas the right (control) side was filled with freeze-dried allograft bone powder and physiological saline. The extent of angiogenesis (VEGFα) was investigated at postoperative weeks 1, 4, and 8. The deformability of the material was evaluated by performing a confined-impaction mechanical test. At postoperative weeks 4 and 8, angiogenesis within FIAB on the left side was more pronounced than that on the right side. At postoperative week 1, the left side showed significantly higher VEGFα expression than that on the right side. The delta ratios of compression of the allografts were found to be influenced by bone height and impaction frequency, but not by stiffness or elastic modulus (EM). Supplementation with fresh autologous coagula promoted angiogenesis within the FIABs. Moreover, FIABs were equivalent to FABs in terms of deformability.


Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of baicalein against oxidative stress-induced DNA damage and apoptosis in HEI193 Schwann cells.
Baicalein, a flavonoid extracted from the roots of Scutellaria baicalensis Georgi., has various pharmacological effects due to its high antioxidant activity. However, no study has yet been conducted on the protective efficacy of baicalein against oxidative stress in Schwann cells. In this study, we evaluated the protective effect of baicalein on DNA damage and apoptosis induced by hydrogen peroxide (H2O2) in HEI193 Schwann cells. For this purpose, HEI193 cells exposed to H2O2 in the presence or absence of baicalein were applied to cell viability assay, immunoblotting, Nrf2-specific small interfering RNA (siRNA) transfection, comet assay, and flow cytometry analyses. Our results showed that baicalein effectively inhibited H2O2-induced cytotoxicity and DNA damage associated with the inhibition of reactive oxygen species (ROS) accumulation. Baicalein also weakened H2O2-induced mitochondrial dysfunction, increased the Bax/Bcl-2 ratio, activated caspase-9 and -3, and degraded poly(ADP-ribose) polymerase. In addition, baicalein increased not only the expression but also the phosphorylation of nuclear factor-erythroid 2 related factor 2 (Nrf2) and promoted the expression of heme oxygenase-1 (HO-1), a critical target enzyme of Nrf2, although the expression of kelch-like ECH-associated protein-1 was decreased. However, the inhibition of Nrf2 expression by transfection with Nrf2-siRNA transfection abolished the expression of HO-1 and antioxidant potential of baicalein. These results demonstrate that baicalein attenuated H2O2-induced apoptosis through the conservation of mitochondrial function while eliminating ROS in HEI193 Schwann cells, and the antioxidant efficacy of baicalein implies at least a Nrf2/HO-1 signaling pathway-dependent mechanism. Therefore, it is suggested that baicalein may have a beneficial effect on the prevention and treatment of peripheral neuropathy induced by oxidative stress.


Oxygen vacancy origin of the surface band-gap state of TiO2(110).
Scanning tunneling microscopy and photoemission spectroscopy have been used to determine the origin of the band-gap state in rutile TiO2(110). This state has long been attributed to oxygen vacancies (O{b} vac). However, recently an alternative origin has been suggested, namely, subsurface interstitial Ti species. Here, we use electron bombardment to vary the O{b} vac density while monitoring the band-gap state with photoemission spectroscopy. Our results show that O{b} vac make the dominant contribution to the photoemission peak and that its magnitude is directly proportional to the O{b} vac density.


Effect of gonadal hormones on the plasma clearance and metabolite formation of antipyrine in the dwarf goat.
The effect of gonadal hormones on the plasma elimination and urinary metabolite profile of antipyrine was studied in dwarf goats. Female goats were treated with testosterone and male goats were treated with 17 beta-oestradiol. Castrated males were treated with either testosterone or 17 beta-oestradiol. Antipyrine (25 mg/kg, i.v.) was given both before and after the hormonal treatments. The effects of the hormonal status on the plasma elimination of the parent compound were not consistent. This was possibly due to the fact that formation of the main metabolite of antipyrine in the goat, 4-hydroxy antipyrine (OHA), was not affected by sex or hormonal treatment. On the other hand, there were clear effects of hormonal status on urinary excretion of the three other metabolites. In females and castrated males testosterone suppressed the formation of norantipyrine (NORA), 3-hydroxymethylantipyrine (HMA) and 4,4'-dihydroxyantipyrine (DOHA). Intact males produced smaller amounts of these metabolites than females. It is concluded that distinct xenobiotic metabolizing pathways exist in the dwarf goat, which are influenced in their activity by gonadal hormones. This confirms previous findings in rats and mice. The possibility that sex hormones influence drug metabolism in food-producing animals could have consequences for veterinary therapeutics and public health. This study also demonstrates that, when using the antipyrine test for the assessment of hepatic drug metabolism, it is very important to include the determination of metabolites.


Chromothripsis and progression-free survival in metastatic colorectal cancer.
Metastatic dissemination of the primary tumor is the major cause of death in colorectal cancer (CRC) patients. Multiple chromosomal breaks and chromothripsis, a phenomenon involving multiple chromosomal fragmentations occurring in a single catastrophic event, are associated with cancer genesis, progression and developing of metastases. The aim of this study was to evaluate the effect of chromothripsis and total breakpoint count (breakpoint instability index) on progression-free survival (PFS). A total of 19 patients with metastatic CRC (mCRC) receiving FOLFOX first-line palliative chemotherapy between August, 2011 and October, 2012 were selected for this study. The results indicated that the highest breakpoint count was observed in chromosomes 1, 2 and 6. Chromothripsis was detected in 52.6% of the study patients. Furthermore, chromothripsis was associated with an increased median PFS (mPFS; 14 vs. 8 months, respectively; P=0.03), but an association with overall survival was not identified. The present study demonstrated that chromothripsis affected CRC patient survival, suggesting a role for this event as a prognostic and predictive marker in mCRC treatment.


Nonlinear distortion mitigation of DML-based OFDM optical systems with non-orthogonal DFT-precoding.
We propose a non-orthogonal discrete Fourier transform (DFT) matrix precoding scheme for the mitigation of nonlinear distortion induced by the interaction between laser chirp and fiber dispersion in a directly modulated laser (DML)-based orthogonal frequency division multiplexing (OFDM) transmission system. Compared with conventional OFDM, the proposed method can decrease the peak-to-average power ratio (PAPR) and significantly reduce the nonlinear distortion without sacrificing spectral efficiency (SE). The cascaded binary-phase-shift-keying iterative detection (CBID) algorithm is used to eliminate the inter-carrier interference (ICI) that is purposely induced by the non-orthogonal precoding. The performance of the proposed scheme is experimentally evaluated, achieving ∼0.4-dB sensitivity improvement at the KP4-forward error correction (FEC) threshold over the T/2-spaced third-order Volterra nonlinear equalizer (VNLE). Meanwhile, compared to the VNLE, the reduction in computational complexity of one OFDM frame is 90% for multiplication and 88.32% for addition in this work.


The spectrum of injuries in buttock stab wounds.
Buttock stab wounds are a surprisingly common and increasing source of presentations to emergency departments. These injuries can have a significant impact on quality of life, and there are a number of often subtle, but significant, injuries that the radiologist must be alert to when interpreting computed tomography examinations in these patients. In this review, we will examine briefly the sociological reasons for the increase in these injuries, discuss appropriate imaging techniques, and provide imaging examples of the clinically important injuries that may be encountered in this region. These injuries include rectal or colonic perforation; genito-urinary trauma, for example urethral injury; injury to the sciatic nerve; and a spectrum of vascular trauma including transection and pseudoaneurysm or arteriovenous fistula formation.


Amino acids as transmitters of synaptic excitation in neocortical sensory processes.
Few synaptic transmitters are known to exist that are not represented in some region or another, or at some layer or other, in the cerebral cortex of mammalian brain. The more difficult job than mere identification of which substances are present, is that of the assignment of particular functional role(s) of such substances, and as well, of determining upon exactly which element(s) of the known synaptic circuitry of neocortex, such transmitters operate. Current wisdom subscribes to the view that the excitatory amino acids, most likely L-glutamate, and L-aspartate but perhaps also L-cysteate, L-homocysteate, L-cysteine sulfinate or even (although much less likely) the endogenous dipeptide substance, N-acetyl-L-aspartyl-L-glutamate, are the major excitatory synaptic transmitters of intracortical (associational) fibres, of corticofugal projections, and, as this article will attest, of thalamocortical inputs, as well. What particular limits, or restrictions, are imposed upon these generalizations, such as whether the data pertain only to primary sensory areas or follow some other yet to be determined rule, remains to be discovered in future experiments. This paper first presents an overview of the advances in understanding that have come about during the past few decades concerning the synaptic roles of amino acid transmitters. Next, an experimental section presents new evidence based on release studies and the microiontophoretic approach, which supports the view that the amino acids, glutamate and aspartate, interact with specific, pharmacologically identified subtypes of receptors in neocortex as transmitters of synaptic excitation released from thalamic afferent terminals.


Genetic and physical studies of lambda transducing bacteriophage carrying the beta subunit gene of the Escherichia coli ribonucleic acid polymerase.
The prophage lambdac1857 was inserted into the bfe gene located near rif (the structural gene for the beta subunit of deoxyribonucleic acid [DNA]-dependent ribonucleic acid polymerase) on the Escherichia coli chromosome. Induced lysates (low-frequency transducing lysates) of such a lysogen contained defective lambda phage particles (lambdadrif+) that can specifically transduce the wild-type rif+ gene. Upon transduction into a recipient strain carrying recA, heterogenotes harboring both the wild-type and the mutant rif genes were isolated. Rec+ derivatives of these heterogenotes produce high-frequency transducing lysates that contain lambdadrif+ and normal active phages at a ratio of 1 to 2. The results of marker rescue experiments and of density determination with several transducing phages indicate that most of the late genes are deleted and replaced by a segment of the chromosomal DNA carrying the bfe-rif region. The length of the chromosomal segment seems to vary between approximately 0.5 and 0.6% of the total bacterial DNA among the three independently isolated lambdadrif+ phages. Electron microscopy of heteroduplex DNA consisting of one strand from lambdadrif+-6 and the other from lambdaimm-21 phages directly confirmed that most of the phage DNA of the "left arm" was replaced by the bacterial DNA. The heteroduplex study also demonstrated that the integration of prophage lambda into the bfe region occurred at the normal cross-over point within the phage attachment site.


A Multilevel Person-Centered Examination of Teachers' Workplace Experiences: Replication and Extension With Links to Instructional Support and Achievement.
In a replication and extension of an earlier study, we relied on person-centered analyses to identify teacher (Level 1) and school (Level 2) profiles based on teachers' experiences of job demands (barriers to professional development, disruptive student behavior), job resources (teacher collaboration, input in decision-making), and personal resources (self-efficacy). We examined data from 5,439 teachers working in 364 schools in Australia and 2,216 teachers working in 149 schools in England. Latent profile analysis revealed six teacher profiles: Low-Demand-Flourisher (11%), Mixed-Demand-Flourisher (17%), Job-Resourced-Average (11%), Balanced-Average (14%), Mixed-Resourced-Struggler (11%), and Low-Resourced-Struggler (36%). Two school profiles were identified: an Unsupportive school profile (43%) and a Supportive school profile (57%). Several significant relations between these profiles and teacher/school characteristics and work-related outcomes were also identified at both levels. Although our results generally replicated prior findings, some differences were also observed, possibly as a results of recent changes in policies regarding in teacher support and accountability. Next, we extended prior work using a subsample of the Australian teachers for whom we had matching student data. This second set of results revealed that schools with a greater proportion of low-SES students were more likely to present an Unsupportive school profile. Moreover, the Supportive school profile was associated with higher levels of student-reported instructional support and school-average achievement in reading, mathematics, and science.


Effect of Universal Adhesives on Long-term Bond Strength to Zirconia.
To evaluate the effect of universal adhesives on the long-term bond strength to yttria-stabilized tetragonal zirconia polycrystal (Y-TZP). Polyethylene tubes filled with composite cement containing 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP) were adhesively luted to 60 fully sintered Y-TZP slabs (7 x 7 x 2 mm) with or without (control) previous application of a 10-MDP-based adhesive (All Bond Universal, Bisco) - ABU; Clearfil Universal Bond Quick, Kuraray Noritake - CUB; Scotchbond Universal Adhesive, 3M Oral Care - SUA) on the zirconia surface. The bonded specimens were stored in water for 24 h, 6 months, or 1 year and subjected to microshear bond strength testing. The data were analyzed by one-way ANOVA and Tukey's test (p < 0.05). The contact angle was measured after adhesive application to evaluate surface wettability. The adhesive-treated specimens were analyzed with x-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) for chemical characterization. The application of a 10-MDP-based adhesive significantly improved bond strength of composite cement to zirconia when compared to the control group (no adhesive application) (p < 0.05). One-year water storage significantly decreased bond strength for ABU- and CUB-bonded specimens, but not for SUA-bonded specimens. The analysis by XPS and ToF-SIMS showed peaks of carbon, phosphorus, and silicon in all adhesive-treated specimens. One-year water storage affected the bond strength of composite cement to zirconia when All Bond Universal or Clearfil Universal Bond Quick were used.


Maintaining transparency: a review of the developmental physiology and pathophysiology of two avascular tissues.
The lens and cornea are transparent and usually avascular. Controlling nutrient supply while maintaining transparency is a physiological challenge for both tissues. During sleep and with contact lens wear the endothelial layer of the cornea may become hypoxic, compromising its ability to maintain corneal transparency. The mechanism responsible for establishing the avascular nature of the corneal stroma is unknown. In several pathological conditions, the stroma can be invaded by abnormal, leaky vessels, leading to opacification. Several molecules that are likely to help maintain the avascular nature of the corneal stroma have been identified, although their relative contributions remain to be demonstrated. The mammalian lens is surrounded by capillaries early in life. After the fetal vasculature regresses, the lens resides in a hypoxic environment. Hypoxia is likely to be required to maintain lens transparency. The vitreous body may help to maintain the low oxygen level around the lens. The hypothesis is presented that many aspects of the aging of the lens, including increased hardening, loss of accommodation (presbyopia), and opacification of the lens nucleus, are caused by exposure to oxygen. Testing this hypothesis may lead to prevention for nuclear cataract and insight into the mechanisms of lens aging. Although they are both transparent, corneal pathology is associated with an insufficient supply of oxygen, while lens pathology may involve excessive exposure to oxygen.


Endometrial osseous metaplasia and infertility: a case report.
Endometrial osseous metaplasia is a rare clinical entity. It causes infertility and occurs in more than 80% of cases after an abortion. Various theories have been proposed and the most accepted theory is metaplasia of the stromal cells into osteoblastic cells that produce bone. This disease may be misdiagnosed. However once diagnosed, the complete removal of bone spicules by hysteroscopy allows, in most cases, fertility to be restored. We present the case of a 36-year-old patient nulliparous with a history of abortion for eight years who consulted May 5, 2008 to become pregnant. Detailed examination showed chronic endometritis with bone metaplasia as a possible cause of her infertility. Seven months after complete removal of bone fragments by hysteroscopy, the patient had a spontaneous pregnancy with normal development. She gave birth to a male infant weighing 3,000 g with an Apgar score of 9 at 1 and 5 min. Delivery and postpartum were normal.


A novel local anesthetic system: transcriptional transactivator peptide-decorated nanocarriers for skin delivery of ropivacaine.
Barrier properties of the skin and physicochemical properties of drugs are the main factors for the delivery of local anesthetic molecules. The present work evaluates the anesthetic efficacy of drug-loaded nanocarrier (NC) systems for the delivery of local anesthetic drug, ropivacaine (RVC). In this study, transcriptional transactivator peptide (TAT)-decorated RVC-loaded NCs (TAT-RVC/NCs) were successfully fabricated. Physicochemical properties of NCs were determined in terms of particle size, zeta potential, drug encapsulation efficiency, drug-loading capacity, stability, and in vitro drug release. The skin permeation of NCs was examined using a Franz diffusion cell mounted with depilated mouse skin in vitro, and in vivo anesthetic effect was evaluated in mice. The results showed that TAT-RVC/NCs have a mean diameter of 133.2 nm and high drug-loading capacity of 81.7%. From the in vitro skin permeation results, it was observed that transdermal flux of TAT-RVC/NCs was higher than that of RVC-loaded NCs (RVC/NCs) and RVC injection. The evaluation of in vivo anesthetic effect illustrated that TAT-RVC/NCs can enhance the transdermal delivery of RVC by reducing the pain threshold in mice. These results indicate that TAT-decorated NCs systems are useful for overcoming the barrier function of the skin, decreasing the dosage of RVC and enhancing the anesthetic effect. Therefore, TAT-decorated NCs can be used as an effective transdermal delivery system for local anesthesia.


Folding versus self-assembling.
Model foldable polymers with sequences of rigid hydrophobic chromophores and flexible hydrophilic tetra(ethylene glycol) were synthesized and used as a paradigm for studying molecular-folding and self-assembly phenomena. Our results demonstrate that intramolecular association or folding prevails over intermolecular interaction or self-assembling in the concentration region from 1 microM to 0.1 M. Importantly, folded polymeric nanostructures have absorption and fluorescence properties that are distinct from those of unfolded polymers or free monomers. We hypothesize that the origins of folding and self-assembly come from interactions between molecular units, and that the key parameter that regulates the on-and-off of such interactions is the distance R separating the two molecular units. Each molecular unit produces a characteristic force field, and when another molecular unit enters this field, the probability that the two units will interact increases significantly. A preliminary estimate of the radius of such a force field for the perylene tetracarboxylic diimide chromophore is about 90-120 A. As a result, phenomena associated with folding or self-assembly of molecular species are observed when these conditions are met in solution.


Accelerometer Data Processing and Energy Expenditure Estimation in Preschoolers.
To assess the capacity of different acceleration metrics from wrist accelerations to estimate total energy expenditure (TEE) and activity energy expenditure (AEE) using doubly labeled water in preschool children. Thirty-nine preschoolers (5.5 ± 0.1 yr) were included. Total energy expenditure was measured using doubly labeled water during 14 d, and AEE was then calculated using a predicted basal metabolic rate. Participants wore a wGT3X-BT accelerometer on their nondominant wrist for ≥5 d. We derived the following metrics from raw accelerations: raw ActiGraph activity counts using the normal filter and the low-frequency extension; and alternate summary metrics, such as the Euclidian norm minus 1g (ENMO), Euclidian norm of the high-pass-filtered accelerations (HFEN), the bandpass-filtered accelerations, the HFEN plus Euclidean norm of low-pass filtered accelerations minus 1g (HFEN+) and the mean amplitude deviation. Alternate summary metrics explained a larger proportion of the variance in TEE and AEE than ActiGraph's activity counts (counts, 7-8 and 25% of TEE and AEE; alternate summary metrics, 13%-16% and 35%-39% of TEE and AEE). Adjustments for body weight and height resulted in an explanation of 51% of AEE by ENMO. All of the metrics adjusted for fat mass and fat-free mass explained up to 84% and 67% of TEE and AEE, respectively. ENMO and the other alternate summary metrics explained more of the variance in TEE and AEE than the ActiGraph's activity counts in 5-yr-old children, suggesting further exploration of these variables in studies on physical activity and energy expenditure in preschoolers. Our results need confirmation in other populations with wider age groups and varying body compositions.


Complete pathologic response is independent of the timing of esophagectomy following neoadjuvant chemoradiation for esophageal cancer.
The relationship of complete pathologic response (cPR) with the timing of esophagectomy after neoadjuvant chemoradiation (nCRT) is not well defined. We sought to determine if a delay in esophagectomy after nCRT would result in increased likelihood of cPR and improved survival. This is a retrospective analysis of a prospectively maintained database of all patients treated with nCRT and esophagectomy between 2004 and 2014. Patients were divided into two groups based on timing of esophagectomy (≤50 vs. >50 days) after completion of nCRT. Survival outcomes were compared using standard Kaplan-Meier curves, and multivariable analyses were performed using Cox regression models. This study included 226 patients (males, 211 and median age, 61 years) for analysis. Fifty-two patients (23%) in the early group (≤50 days) were compared to 174 patients (77%) in the delayed group (>50 days). The two groups were similar with respect to age, gender, comorbid conditions, ECOG status, location, grade, and tumor histology. There was no statistically significant difference in cPR rate between the early and late groups (26.9% vs. 19.0%, respectively, P=0.24). On multivariable analysis, lower age, absence of signet cell histology, better ECOG status, shorter length of stay and cPR were independent predictors of improved survival. The median follow-up was 52 months (range, 2-110 months), and there was no difference in the median overall survival (OS) between the early and late groups (48.9 vs. 42.6 months, respectively, P=0.73). This analysis of a large cohort of patients with esophageal cancer undergoing multi-modality therapy shows that cPR is independent of the timing of esophagectomy. Other considerations for the timing of surgery, including recovery from nCRT and patient performance, may have more relevant roles than cPR when deciding when to perform esophagectomy.


Direct and indirect methods for the determination of vitamin K3 using differential pulse polarography and application to pharmaceuticals.
Two methods for the determination of vitamin K(3) have been developed. Vitamin K(3) in its oxidized form is determined by direct and indirect methods. Its standard solution was prepared by the indirect method using Ti(III) as reducing agent. For this purpose vitamin K(3) (menadion) in a clinical injection solution, which is in its hydroquinone form in the presence of sulfite, is oxidized with oxygen. In 0.2 M HAc and 0.02 M HCl electrolyte vitamin K(3) and Ti(IV) have reduction peaks at -0.58 V at -0.82 V respectively. The reaction between Ti(III) and vitamin takes place quantitatively in a medium of 0.2 M HAc and 0.002 M HCl. After the reduction, the reaction product Ti(IV) is followed from its polarographic peak at about -0.82 V. The most important result in this work is that, with this method vitamin K(3) can be standardized and after standardization this solution can be used for the direct determination in routine analysis with a very simple and fast method, using only the peak at -0.71 V in 0.2 M HAc medium. Both direct and indirect methods have been used for the determination of Vitamin K(3) in a clinical injection solution. The limit of quantification (LOQ) was 1.5x10(-6) M and in both methods the detection limit found was 7x10(-7) M.


Potassium permanganate modification of hydrochar enhances sorption of Pb(II), Cu(II), and Cd(II).
Hydrochars formed by hydrothermal carbonization of hickory wood, bamboo, and wheat straw at 200 °C were modified by potassium permanganate (KMnO4) for the sorption of Pb(II), Cd(II), and Cu(II). The wheat straw hydrochar (WSHyC) modified with 0.2 M KMnO4 resulted in the most promising adsorbent (WSHyC-0.2KMnO4). Characterization of WSHyC and WSHyC-0.2KMnO4 revealed that the modified hydrochar features large specific surface area, rich of surface oxygenic functional groups (OCFG), and a significant amount of MnOx micro-particles. Batch adsorption experiments indicated that the adsorption rate by WSHyC-0.2KMnO4 was faster than for WSHyC, attaining equilibrium after around 5 h. The optimum adsorption capacity (Langmuir) of Pb(II), Cd(II), and Cu(II) by WSHyC-0.2KMnO4 was 189.24, 29.06 and 32.68 mg/g, respectively, 12 ∼ 17 times greater than by WSHyC. The significantly enhanced heavy metal adsorption can be attributable to the increased OCFG and MnOx microparticles on the surface, thereby promoting ion exchange, electrostatic interactions, and complexation mechanisms.


The role of radiologic studies in the evaluation and management of primary hyperaldosteronism.
Surgical treatment of primary hyperaldosteronism (PHA) requires demonstration of unilateral adrenal hypersecretion. Optimal methods for interpretation of imaging and invasive testing are still in development. A retrospective review from 1996-2007 of 106 patients with PHA was undertaken. Patient demographics, biochemical studies, radiologic imaging, operative reports, and pathology were reviewed and comparisons made. Optimal ratios for adrenal vein sampling were tested with regard to sensitivity and specificity. Preoperative and postoperative medication requirements and blood pressures were compared among different treatment groups. Seventy-eight patients (62 surgically treated) met criteria for inclusion. Median arterial blood pressure at diagnosis was 150/86 mm Hg while taking 3 antihypertensive medications. 69.2% required potassium supplementation. Median aldosterone:renin ratio was 107.0. Forty-two AVS procedures changed the management of 15 patients (35.7%) when compared to CT results. AVS accuracy was 96.6 vs 88.9% for NP-59 scintigraphy. Operative patients remained on fewer antihypertensive medications (1 vs 3), and mean systolic pressure was lower (130 vs 146 mm Hg) compared with medically managed patients. When used together, pre-ACTH aldosterone ratios, normalized A/C:A/C ratios, ratios to define contralateral suppression, and post-ACTH stimulated values allowed for capture of episodically secreting tumors and subtle unilateral or bilateral hyperaldosteronism.


A molecular approach to an electrocatalytic hydrogen evolution reaction on single-layer graphene.
A major challenge in the development of electrocatalysts is to determine a detailed catalysis mechanism on a molecular level for enhancing catalytic activity. Here, we present bottom-up studies for an electrocatalytic hydrogen evolution reaction (HER) process through molecular activation to systematically control surface catalytic activity corresponding to an interfacial charge transfer in a porphyrin monolayer on inactive graphene. The two-dimensional (2D) assembly of porphyrins that create homogeneous active sites (e.g., electronegative tetrapyrroles (N4)) on graphene showed structural stability against electrocatalytic reactions and enhanced charge transfer at the graphene-liquid interface. Performance operations of the graphene field effect transistor (FET) were an effective method to analyse the interfacial charge transfer process associated with information about the chemical nature of the catalytic components. Electronegative pristine porphyrin or Pt-porphyrin networks, where intermolecular hydrogen bonding functioned, showed larger interfacial charge transfers and higher HER performance than Ni-, or Zn-porphyrin. A process to create surface electronegativity by either central N4 or metal (M)-N4 played an important role in the electrocatalytic reaction. These findings will contribute to an in-depth understanding at the molecular level for the synergetic effects of molecular structures on the active sites of electrocatalysts toward HER.


Assessing the capacity of Iowa's community health centers to respond to the opportunities and challenges of the Affordable Care Act.
To determine the current and future capacity of Iowa CHCs as the ACA is implemented. We conducted an online survey among executive directors of all 13 Iowa CHCs, asking about current capacity and demand for services, projected increases in capacity and demand, and organizational readiness for change. Our survey response rate was 84.6%. Respondents reported shortages of physicians (72.7%), nurse practitioners (64%) and registered nurses (64%), and most CHCs attempting to recruit physicians (80%) indicated difficulty doing so. All respondents anticipate that the ACA will increase their provider needs and nearly 73% of CHCs anticipate an increase in the size of their patient population. Only 50% of CHCs agree that they have the resources to respond to the ACA's challenges. Community health centers are embracing the opportunities before them and are willing to meet the challenges, but resource constraints may limit their ability to do so.


The effect of size and density on nut removal in Syagrus loefgrenii Glassman (Arecaceae) in the Brazilian Cerrado.
In this study I tested the effect of Syagrus loefgrenii nut size and number on the intensity of removal by rodents across seasons. Trials were performed in which piles of either small or large endocarps (1, 3, 6, 12, and 25) were subjected to removal by rodents in the Cerrado (Brazilian savanna). Despite of variations in the intensity of removal, always this process decrease conform endocarp number. Also, mean proportion of endocarp removal was unrelated to year period, initial number, and size of endocarps. Hence, endocarp removal was consistently negative density-dependent. As, in principle, the observed patterns of nut removal point out similar survival chances for both nut sizes, the pervasive negative density-dependent response emerges as a strategy in S. loefgrenii to swamp rodents all year round irrespective of seed size.


Assessing the activity of perianal Crohn's disease: comparison of clinical indices and computer-assisted anal ultrasound.
Assessing perianal disease activity is important for the treatment and prognosis of Crohn's disease (CD) patients, but the diagnostic accuracy of the activity indices has not yet been established. The aim of this study was to determine the accuracy and agreement of the Fistula Drainage Assessment (FDA), Perianal Disease Activity Index (PDAI), and computer-assisted anal ultrasound imaging (AUS). Sixty-two consecutive patients with CD and perianal fistulae underwent clinical, FDA, PDAI, and AUS evaluation. Perianal disease was considered active in the presence of visible fistula drainage and/or signs of local inflammation (induration and pain at digital compression) upon clinical examination. The AUS images were analyzed by calculating the mean gray-scale tone of the lesion. The PDAI and gray-scale tone values discriminating active and inactive perianal disease were defined using receiver operating characteristics statistics. Perianal disease was active in 46 patients. The accuracy of the FDA was 87% (confidence interval [CI]: 76%-94%). A PDAI of >4 and a mean gray-scale tone value of 117 maximized sensitivity and specificity; their diagnostic accuracy was, respectively, 87% (CI: 76%-94%) and 81% (CI: 69%-90%). The agreement of the 3 evaluations was fair to moderate. The addition of AUS to the PDAI or FDA increased their diagnostic accuracy to respectively 95% and 98%. The diagnostic accuracy of the FDA, PDAI, and computer-assisted AUS imaging was good in assessing perianal disease activity in patients with CD. The agreement between the techniques was fair to moderate. Overall accuracy can be increased by combining the FDA or PDAI with AUS.


Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.
The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens. A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use. A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them. While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.


[Effects of Qilong Capsules on myocardial fibrosis and insufficient blood circulation in ischemic cardiomyopathy with Qi deficiency and blood stasis].
Protective effect of Qilong Capsules(QL) on the myocardial fibrosis and blood circulation of rats with coronary heart disease of Qi deficiency and blood stasis type was investigated. Sleep deprivation and coronary artery ligation were used to construct a disease-symptom combination model, and 60 SD rats were divided into sham operation(sham) group, syndrome(S) group, disease and syndrome(M) group and QL group randomly. The treatment group received administration of QL 0.4 g·kg~(-1)·d~(-1). Other groups were given the same amount of normal saline. The disease indexes of each group [left ventricular end diastolic diameter(LVESD), left ventricular end systolic diameter(LVEDD), left ventricular ejection fraction(LVEF), left ventricular axis shortening rate(LVFS), myocardial histopathology, platelet morphology, peripheral blood flow] and syndrome indexes(tongue color, pulse, grip power) were detected. In sham group, cardiomyocytes and myocardial fibers were arranged neatly and densely with clear structures. The tongues' color in sham were light red, and the pulse shape were regular. RGB is a parameter reflected the brightness of the image of the tongue. In the S group, the amplitude and frequency of the animal's pulse increased accompanied by decreasing R,G,B, however, the decreased R,G,B was accompanied by reduced pulse amplitude in M group. And in M group, we observed fuzzy cell morphology, hypertrophied myocytes, disordered arrangement of cardiomyocytes and myocardial fibers, reduced peripheral blood flow and increased collagen volume fraction(CVF). Increased LVESD and LVEDD, and decreased LVEF and LVFS represented cardiac function in S group was significantly lower than that in sham. In QL group, the tongue's color was red and the pulse was smooth. The myocardial fibers of the QL group were arranged neatly and secreted less collagen. It improved the blood circulation in the sole and tail, and reversed the increasing of LVEDD, LVESD and the decreasing of LVEF and LVFS of M group. Platelets in M and S group showed high reactivity, and QL could decrease aggregation risk. In conclusion, Qilong Capsules has an obvious myocardial protective effect on ischemic cardiomyopathy, which may inhibit the degree of myocardial fibrosis and reduce platelet reactivity.


[Modification and validation of the spectrophotometric method of trace amounts of antimony determination in different types of mineral water].
In order to improve limit of determination, a modification of the analytical procedure for spectrophotometric determination of antimony in water recommended by Polish Standards has been proposed. The modified procedure was validated on the basis of the analytical studies of samples of deionised water enriched in different amounts of the analyte, and its precision, limit of determination, sensitivity, accuracy and linearity range were established. A correction describing the effect of the matrix, determined on the basis of analyses of four types of mineral water differing in the degree of total mineralisation and chemical composition, and allowing the use of the procedure proposed for determination of antimony at the level of < or = 0.005 mg/dm3, has been derived.


Full color holographic display system based on intensity matching of reconstructed image.
In this paper, a full color holographic display system based on the intensity matching of the reconstructed image is proposed. The system consists of three color collimated beams, three spatial light modulators (SLMs), three beam splitters, three lenses, three irises, a prism and a receiving screen. The three SLMs are used to load three color holograms, respectively. In order to eliminate the undesirable light in the reconstructed images and adjust the light intensities, the irises which contain two functions of both light intensity attenuation and aperture variation are cleverly produced. Finally, by using the prism, three color images can be coincident on the receiving screen. Experimental results verify the feasibility of the proposed system.


Aggressive angiomyxoma of the vulva presenting as a pedunculated swelling.
Aggressive angiomyxoma is a rare, locally aggressive soft tissue tumor that has high propensity for local recurrence. It involves mainly the pelvis, vulva, perineum, vagina and urinary bladder in adult women in the reproductive age. Considering its locally aggressive nature, appropriate management and long-term follow-up is necessary. We describe a case of a 22-year-old young pregnant patient presenting with a large pedunculated swelling on the left labia majora.


Identification of inner and outer cell proliferation centers during fetal tooth morphogenesis.
Patterns of cell division have been examined in the proliferative cervical loop tissues of fetal rabbit incisor tooth organs. Evaluation of the distribution patterns of silver grains, resulting from the incorporation of [3H]-thymidine into newly synthesized DNA within tooth organs in vitro, resulted in identification of two proliferation centers: (1) an inner center consisting of inner enamel epithelial cells (i.e., preameloblasts) and predontoblasts ; and (2) an outer center consisting of outer enamel epithelium and adjacent mesenchyme. In contrast to the classically held description of epithelial cell differentiation during tooth morphogenesis, our data suggest that outer enamel epithelial cells do not migrate around the cervical loop and do not provide progenitor cells for subsequent ameloblast cytodifferentiation. During tooth development, epithelial and mesenchymal cells, which arise from either an inner or outer proliferative center, migrate in distal directions relative to the proliferative sites. Therefore, the progenitor cells for ameloblasts and odontoblasts were found to be localized in the inner proliferation zone. The implications of these findings regarding the development of continuously erupting rabbit and rodent incisor tooth organs are discussed in the context of a model.


Xanthogranulomatous pyelonephritis. Angiographic observations made in one case at an interval of six years.
In a woman aged 67, comprehensive angiographic examination revealed an extensive renal process which had led to thrombosis of the inferior vena cava. At exploratory surgery the process seemed inoperable. The angiographic study was repeated after an asymptomatic period of 6 years and disclosed shrinking of the kidney involved. Revision of the microscopic findings altered the initial diagnosis of renal carcinoma in favour of xanthogranulomatous pyelonephritis. The observation is of interest by virtue of the characteristic angiographic findings, extension of the process to the venous system, and angiographic evidence that spontaneous regression is possible.


Human papillomavirus and blastocyst apoptosis.
The effect of human papillomavirus (HPV) DNA from the E6-E7 region on the integrity of DNA in blastocyst stage embryonic cells was studied. The study design paralleled the event whereby HPV DNA from the infecting virus would target host cell DNA. The objectives were (a) to determine if the DNA of blastocysts were disrupted by the presence of HPV DNA and (b) to determine if the intensity of DNA damage was associated with the type of HPV. This study involved superovulating female mice, mating, collecting one-cell embryos, and culturing to the expanded blastocyst stage. The blastocysts were infected with PCR-synthesized DNA fragments from either HPV type 16, 18, 31, or 33. The blastocyst DNA were analyzed by comet assay after 24 h of incubation. The fluorescent images were digitized and the pixel intensity of each blastocyst was measured. Only the DNA of HPV type 16 was associated with significant DNA fragmentation in comparison with the other HPV types. There was no relationship between HPV DNA fragment size and the intensity of DNA fragmentation. The data suggested that one mode of action of HPV type 16 was to initiate apoptosis of embryonic cells through DNA fragmentation. The effect of HPV 16 occurred rapidly within 24 h. The intensity of DNA damage was not linked to the specific type of HPV. However, the results do not rule out the other HPV types affecting embryos under conditions different from this study.


Progress in measles control--Nepal, 2000-2006.
In 2002, the United Nations General Assembly Special Session on Children set a goal to reduce global measles deaths by half (compared with 1999) by 2005. Nepal, a southeast Asian country with an estimated population of 27 million, adopted the measles mortality reduction strategies of the World Health Organization (WHO) in 2003, with a goal of reducing measles deaths by half (compared with 2003) by 2005. The strategies consisted of strengthening routine childhood immunization programs, providing a second opportunity for measles vaccination through supplementary immunization activities (SIAs), improving surveillance, and improving measles case management. This report describes routine immunization activities in Nepal, the implementation of measles SIAs, and measles surveillance data for the period 2000-2006. The findings demonstrate a substantial decrease in reported measles incidence. Assuming a reduction in measles deaths that paralleled the decrease in incidence, the findings also suggest progress toward the goal of measles mortality reduction.


Sunscreens and occupation: the Austrian experience.
Since the nineteen fifties the attitude of the fair-skinned world population towards the sun has changed dramatically. Tanned skin, which before was regarded as the stigma of the underprivileged working classes, became fashionable and desirable. The science of photoprotection primarily focuses on ultraviolet exposure during leisure time activities, whereas ultraviolet radiation is still underestimated as a risk factor for UV-induced skin and eye problems. The actual discussion on the registration of UV-induced skin tumours as occupational diseases, however, has drawn more attention to this important issue. Ambient radiation, the working process itself and the photoprotective behaviour of an outdoor worker are the main factors which influence the actual UV exposure. However, the total risk for the development of actinic damage results from the interaction of both the occupational and the leisure time exposure. It is evident that there is a high need for photoprotective measures for outdoor workers. Topical sunscreens as a part of a comprehensive UV protection strategy for outdoor workers have to fulfil special requirements: reasonable price, high water resistance, non-sticky appearance. At present only a few products are available which meet these criteria. This is the reason why sunscreens are not so well accepted by outdoor workers. Great efforts have to be undertaken to improve sunscreen formulations and to convince people to apply them correctly and regularly.


Antibiotic use for upper respiratory tract infections: how well do pediatric residents do?
Antibiotics are often used inappropriately for the treatment of upper respiratory tract infections in children, and the emergence of resistant bacteria is a growing public health concern. To assess awareness and compliance with the Centers for Disease Control and Prevention (Atlanta, Ga) and American Academy of Pediatrics (Elk Grove Village, Ill) principles for judicious antibiotic use for upper respiratory tract infections among residents from a sample of pediatric residency programs in the mid-Atlantic region of the United States. Residents at the participating programs were requested to complete a survey questionnaire. Of the 524 pediatric residents surveyed, 74% (388 participants) completed the questionnaire. Familiarity with the principles increased with a year of training; 16%, 36%, and 50% of first-year (PL1), second-year (PL2), and third- or fourth-year (PL3/PL4) residents, respectively, had heard or read about the principles (chi(2)(trend); P<.001). In response to a direct question about the use of antibiotics for an otherwise well, afebrile 18-month-old child with purulent rhinorrhea, 29%, 25%, and 15% of PL1, PL2, and PL3/PL4 residents, respectively, would prescribe antibiotics within 10 days of onset of illness (chi(2)(trend); P =.008). A significant difference was found between PL1 vs PL3/PL4 participants (difference = 20%; 95% CI = 3%-26%). If the same infant had a temperature of 38.8 degrees C, then 63%, 45%, and 47% of PL1, PL2, and PL3/PL4 residents, respectively, would prescribe antibiotics (chi(2)(trend); P =.008). Awareness among pediatric residents about the judicious use of antibiotics for upper respiratory tract infections is often lacking, and inappropriate use of antibiotics for this condition continues to be prevalent. This was especially noted among PL1 residents, with an improving trend noted with increasing years of training.


Rho GTPases and cell cycle control.
Members of the Rho family of small GTPases are crucial regulators of biological responses in eukaryotic cells, including cytoskeletal dynamics, cell motility and cell cycle progression. In the present review, we summarize our current understanding of the role of Rho proteins in cell cycle control, highlighting the contribution of specific members of the Rho family and their downstream targets to the regulation of key elements from the core cell cycle machinery, mostly involved in the G1/S transition.


Acute lower gastrointestinal haemorrhage: outcomes and risk factors for intervention in 949 emergency cases.
Outcomes of acute lower gastrointestinal haemorrhage (ALGIH) are mostly derived from studies performed in the sub-acute/elective rather than the emergency department (ED) setting. The aims of this study were to determine the incidence and outcomes of patients presenting to a tertiary hospital ED with ALGIH and to identify associated clinicopathological risk factors. A retrospective observational cohort study of consecutive patients presenting with ALGIH to a tertiary hospital ED was performed. Primary outcome measures included mortality and hospital (including high dependency [HDU]) admission. Secondary outcome measures included rates of (i) blood transfusion, (ii) radiological/endoscopic investigation(s) and (iii) therapeutic intervention. ALGIH accounted for 949 (512 M, mean age 62.3 years) of 130,262 (0.73%) ED presentations, of which 285 patients (30.1%) were on anti-platelet/coagulant therapy. There were five deaths (0.5%). Hospital admission was required in 498 patients (52.5%), of which 19 (3.8%) required HDU monitoring. Hospital admission was twice as likely in males and four times more likely in patients >75 years old and those taking multiple anti-platelet/coagulant therapy (P < 0.05). Blood product transfusion was required in 172 patients (34.5%), specialist investigations in 230 (46.2%) and therapeutic intervention in 51 (10.2%) (surgery in 24 [4.8%]; endoscopic haemostasis in 20 [4.0%] and angiographic embolisation in 9 [1.8%] patients). ALGIH accounts for 1% of all ED presentations, with half requiring hospital admission. Mortality and surgical intervention rates are low and although most patients can be managed supportively, access to interventional radiology/endoscopy is important.


Virus safety in xenotransplantation: first exploratory in vivo studies in small laboratory animals and non-human primates.
For xenotransplantation, the transplantation of animal cells, tissues and organs into human recipients, to date, pigs are favored as potential donors. Beside ethical, immunological, physiological and technical problems, the microbiological safety of the xenograft has to be guaranteed. It will be possible to eliminate all of the known porcine microorgansims in the nearby future by vaccinating or specified pathogen-free breeding. Thus, the main risk will come from the porcine endogenous retroviruses (PERVs) which are present in the pig genome as proviruses of different subtypes. PERVs will therefore be transmitted, with the xenograft, to the human recipient. PERVs can infect numerous different types of human primary cells and cell lines in vitro and were shown to adapt to these cells by serial passaging on uninfected cells. Furthermore, PERVs have high homology to other retroviruses, such as feline leukemia virus (FeLV) or murine leukemia virus (MuLV), which are known to induce tumors or immunodeficiencies in the infected host. To evaluate the potential risk of a trans-species transmission of PERV in vivo, naive and immunosuppressed rats, guinea pigs and minks were inoculated with PERV and screened over a period of 3 months for an antibody reaction against PERV proteins or for the integration of proviral DNA into the genomic DNA of the host's cells. Furthermore, we inoculated three different species of non-human primates, rhesus monkey (Macaca mulatta), pig-tailed monkey (Macaca nemestrina) and baboon (Papio hamadryas) with high titers of a human-adapted PERV. To simulate a situation in xenotransplantation, the animals received a daily triple immunosuppression using cyclosporine A, methylprednisolone and RAD, a rapamycin derivative, presently under development by Novartis. None of the small laboratory animals or the non-human primates showed production of antibodies against PERV or evidence of integration of proviral DNA in blood cells or cells of several organs, 3 months after virus inoculation, despite the observation that cells of the animals used in the experiment were infectible in vitro. This apparent difference in the outcome of the in vitro and the in vivo data might be explained by an efficient elimination of the virus by the innate or adaptive immunity of the animals.


An RNA symbiont enhances heat tolerance and secondary homothallism in the oomycete Phytophthora infestans.
Some strains of Phytophthora infestans, the potato late blight pathogen, harbour a small extrachromosomal RNA called PiERE1. A previous study reported that this RNA symbiont does not noticeably affect its host. Here it is revealed that PiERE1 exerts subtle effects on P. infestans, which result in greater thermotolerance during growth and an increase in secondary homothallism, i.e. oospore formation in the absence of the opposite mating type. The interaction can be considered mutualistic since these traits may increase the fitness of P. infestans in nature. Assays of biomarkers for cellular stress revealed that an Hsp70 chaperone was upregulated by PiERE1. A genome-wide search for more members of the Hsp70 family identified ten belonging to the DnaK subfamily, one in the Hsp110/SSE subfamily, and pseudogenes. Four DnaK subfamily genes encoding predicted cytoplasmic or endoplasmic reticulum proteins were upregulated in strains harbouring PiERE1. This may explain the greater thermotolerance conferred by the RNA element, and suggests that Hsp70 may be a useful biomarker for testing organisms for the cellular effects of symbiotic elements.


Testicular Mixed Germ Cell Tumor Combined with Malignant Transformation to Chondrosarcoma: A Very Rare and Aggressive Disease.
BACKGROUND Testicular mixed germ cell tumors (GCTs) represent a spectrum of malignancies that differ in terms of histopathology, clinical complications, and overall outcome. A variety of aggressive combinations containing different histological types have been described among such testicular tumors. However, a histopathology characterized by a combination of teratoma and choriocarcinoma, as seen in this case, in which the teratomatous component shows a secondary transformation to chondrosarcoma, is considered very rare. CASE REPORT The patient presented with progressive hemoptysis and dyspnea secondary to bilateral pulmonary cannon-ball lesions indicative of a metastatic process. His workup was remarkable for primary testicular cancer complicated by liver metastasis and very high levels of B-HCG at more than 175 000 mlU/ml. He deteriorated quickly with no improvement following the first cycle of Etoposide/Cisplatin (EP) chemotherapy regimen and died 15 days after starting cancer treatment. Such non-seminomatous GCTs with extrapulmonary visceral metastasis associated with very high tumor markers are deemed poor risk based on the International Germ Cell Cancer Collaborative Group (IGCCCG) criteria, with a reported 5-year overall survival rate reaching up to 73%. CONCLUSIONS This case is considered unique in terms of rapid clinical deterioration and lack of improvement following the standard EP chemotherapy regimen. This unusual dramatic presentation should draw attention to the possible association between the aggressiveness of the disease and its very rare histopathology.


[The hemagglutinating activity of bacteria in the genus Klebsiella and the morphofunctional characteristics of their fimbriae].
The hemagglutinating activity of 77 Klebsiella strains from the international collection, grown in a culture medium prepared on the basis of soy-bean flour enzymatic hydrolysate, was studied. These strains could be divided into four groups according to their capacity for synthesizing different types of hemagglutinins on their surface: 2 strains carried mannose-sensitive hemagglutinins, 18 strains had mannose-resistant K-type hemagglutinins, 48 strains exhibited the signs indicating the presence of both mannose-sensitive and mannose-resistant hemagglutinins, and 9 strains showed no hemagglutinating activity. The hemagglutinating activity of strains K-74, K-79, K-80, K-81 and K-82 was characterized. Of the reference strains under study, 22 strains were found to have mannose-resistant hemagglutinating activity with respect to fresh chick red blood cells. The occurrence of hemagglutinins in Klebsiella was shown to depend on the temperature of cultivation and the consistency of the culture medium. The formation of large-sized capsules in Klebsiella grown in the Werfel-Fergusson medium with a considerable content of saccharose was shown to cause the absorption of their fimbrial structures by the capsular substance and, as a consequence, the suppression of their hemagglutinating activity.


Ventricular Fibrillation Associated With Dynamic Changes in J-Point Elevation in a Patient With Silent Thyroiditis.
A J wave is a common electrocardiographic finding in the general population. Individuals with prominent J waves in multiple electrocardiogram (ECG) leads have a higher risk of lethal arrhythmias than those with low-amplitude J waves. There are few reports about the relationship between thyroid function and J-wave amplitude. We report the case of a 45-year-old man who had unexpected ventricular fibrillation (VF). He had dynamic J-point elevation in multiple ECG leads. Possible early repolarization syndrome was diagnosed. He also had thyrotoxicosis caused by silent thyroiditis, and his J-wave amplitude decreased according to changes in thyroid function because of spontaneous remission of silent thyroiditis. There was a positive correlation between serum triiodothyronine levels and J-wave amplitudes. The findings in case suggested silent thyroiditis may contribute to the occurrence of VF in a patient with dynamic changes in J-point elevation in multiple ECG leads. Thyrotoxicosis is a relatively common endocrine disease; therefore, clinicians should pay attention to J-wave amplitude in the ECG of patients with thyrotoxicosis.


A typology of neighborhoods and blood pressure in the RECORD Cohort Study.
Studies of associations between neighborhood environments and blood pressure (BP) have relied on imprecise characterizations of neighborhoods. This study examines associations between SBP and DBP and a neighborhood typology based on numerous residential environment characteristics. Data from the Residential Environment and Coronary Heart Disease Study involving 7290 participants recruited in 2007-2008, aged 30-79 years, and residing in the Paris metropolitan area were analyzed. Cluster analysis was applied to measures of the physical, services and social interactions aspects of neighborhoods. Six contrasting neighborhood types were identified and examined in relation to SBP and DBP using multivariable linear regression, adjusting for individual/neighborhood socioeconomic status and individual risk factors for hypertension. The neighborhood typology included suburban to central urban neighborhood types with varying levels of adverse social conditions. SBP was 2-3 mmHg higher among participants residing in suburban neighborhood types and in the urban with low social standing neighborhood type, compared to residents of central urban with intermediate social standing neighborhoods (reference). The association between residing in urban low social standing neighborhoods and SBP remained after adjusting for individual/neighborhood socioeconomic status and individual risk factors for hypertension. Overall, an inverse association between DBP and level of urbanicity of the neighborhood was observed, even after adjustment for individual risk factors for hypertension. Variations in BP were observed by levels of urbanicity and social conditions of residential neighborhoods, with different patterns for SBP and DBP. Population interventions to reduce hypertension targeted towards specific neighborhood types hold promise.


Microplastics in eviscerated flesh and excised organs of dried fish.
There is a paucity of information about the occurrence of microplastics (MPs) in edible fish tissues. Here, we investigated the potential presence of MPs in the excised organs (viscera and gills) and eviscerated flesh (whole fish excluding the viscera and gills) of four commonly consumed dried fish species (n = 30 per species). The MP chemical composition was then determined using micro-Raman spectroscopy and elemental analysis with energy-dispersive X-ray spectroscopy (EDX). Out of 61 isolated particles, 59.0% were plastic polymers, 21.3% were pigment particles, 6.55% were non-plastic items (i.e. cellulose or actinolite), while 13.1% remained unidentified. The level of heavy metals on MPs or pigment particles were below the detection limit. Surprisingly, in two species, the eviscerated flesh contained higher MP loads than the excised organs, which highlights that evisceration does not necessarily eliminate the risk of MP intake by consumers. Future studies are encouraged to quantify anthropogenic particle loads in edible fish tissues.


Additional Treatment with Fenofibrate for Patients Treated with Pitavastatin Under Ordinary Medical Practice for Hypertriglyceridemia in Japan (APPROACH-J Study).
Safety and efficacy of combination therapy of pitavastatin and fenofibrate were examined in consecutive case series with fasting serum triglycerides ≥ 150 mg/dL despite receiving pitavastatin 1 or 2 mg daily for over 2 months and additionally administered micronized fenofibrate 67 mg daily for another 4 to 16 weeks. Such low doses were selected in consideration of safety, and normal liver and renal functions were incorporated in inclusion criteria. In result, a total of 56 cases were examined. The addition of fenofibrate 67 mg to pitavastatin 1 mg/2 mg yielded a 36.8%/35.6% reduction in triglycerides and 6.4%/12.4% elevation in high-density lipoprotein cholesterol, respectively. Almost 70% of the patients achieved triglycerides <150 mg/dL. Statistically significant elevation and decrease were observed in high-density lipoprotein cholesterol level and low-density lipoprotein cholesterol, respectively. Laboratory tests for liver, renal and muscle function statistically significantly elevated after starting fenofibrate co-administration, which were considered comparable to the effect of fenofibrate alone. No myopathy or serious adverse events were reported. In conclusion, while the safety and tolerability need to be further examined over the longer term, and careful monitoring is still needed, this regimen could be considered as one of the treatment option for hypercholesterolemia associated with hypertriglyceridemia.


Variability of the innate immune response is globally constrained by transcriptional bursting.
Transcription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability.


[The way for carrying medicine and its containers (X): "patent medicine and carrying it in the Edo Period"].
A patent medicine and prescribed one coexisted in the Edo period, as they do in these days. A patent medicine was generally taken for curing slight illness and a prescribed one was used for curing serious one. As the former was more useful for carrying and taking it than the latter, a patent medicine was spread not only in town, but also in the country. Manufacturers of a patent medicine were eager to develop new markets for it and they were also active to innovate new preparations which were convenient for taking it and carrying it.


Rest-activity rhythm associated with depressive symptom severity and attention among patients with major depressive disorder: a 12-month follow-up study.
Patients with depressive disorder demonstrate rest-activity rhythm disturbances and cognitive function impairment. This study examined the association of individual rest-activity rhythm changes over time with mood symptoms and attention. We recruited 15 adult outpatients with a diagnosis of major depressive disorder from a single medical center and observed them for 12 months. Weekly rest-activity parameters, including rhythm characteristics generated from nonparametric circadian rhythm analysis, were retrieved from actigraphy data. Attention was evaluated weekly with a smartphone-based psychomotor vigilance test upon awakening. Depressive symptom severity was evaluated using the Beck Depression Inventory (BDI) fortnightly. The association of rest-activity parameters with BDI score and attention was examined using generalized linear mixed regression. A fixed-effects analysis was used to examine the association between rest-activity parameters and depressive episodes. An advanced bedtime and most active continuous 10 h starting time were associated with depressive symptom severity but also associated with higher vigilance test performance. A longer sleep duration, mainly due to an earlier bedtime, was associated with depressive symptom severity. Compared to remission, sleep duration was 27.8 min longer during depressive episodes, and bed time was 24 min earlier. A shorter sleep duration and increased activity during sleep were associated with poorer attention. Rest-activity rhythms change with mood symptoms among patients with depressive disorder. The circadian rhythms of rest-activity among patients with depressive disorder should be distinguished during various mood states in future studies.


Traumatic rupture of the medial rectus muscle.
Traumatic rupture of an extraocular muscle, in the absence of significant injury to the globe and adnexa, is uncommon. We report the case of a patient with an isolated mid-belly rupture of the medial rectus muscle following ocular trauma and describe the technique of repairing the ruptured muscle by suturing the distal segment to the Tenon sleeve of the proximal segment. This was combined with postoperative botulinum toxin injection to the ipsilateral lateral rectus muscle. Good primary position alignment was achieved 7 months after surgery. The patient regained a useful horizontal field of binocular single vision totaling 27 degrees.


The Third Intron of the Interferon Regulatory Factor-8 Is an Initiator of Repressed Chromatin Restricting Its Expression in Non-Immune Cells.
Interferon Regulatory Factor-8 (IRF-8) serves as a key factor in the hierarchical differentiation towards monocyte/dendritic cell lineages. While much insight has been accumulated into the mechanisms essential for its hematopoietic specific expression, the mode of restricting IRF-8 expression in non-hematopoietic cells is still unknown. Here we show that the repression of IRF-8 expression in restrictive cells is mediated by its 3rd intron. Removal of this intron alleviates the repression of Bacterial Artificial Chromosome (BAC) IRF-8 reporter gene in these cells. Fine deletion analysis points to conserved regions within this intron mediating its restricted expression. Further, the intron alone selectively initiates gene silencing only in expression-restrictive cells. Characterization of this intron's properties points to its role as an initiator of sustainable gene silencing inducing chromatin condensation with suppressive histone modifications. This intronic element cannot silence episomal transgene expression underlining a strict chromatin-dependent silencing mechanism. We validated this chromatin-state specificity of IRF-8 intron upon in-vitro differentiation of induced pluripotent stem cells (iPSCs) into cardiomyocytes. Taken together, the IRF-8 3rd intron is sufficient and necessary to initiate gene silencing in non-hematopoietic cells, highlighting its role as a nucleation core for repressed chromatin during differentiation.


The stereospecific biosynthesis of phytoene and polyunsaturated carotenes.
1. The incorporation of [2-(14)C,(5R)-5-(3)H(1)]mevalonic acid and [2-(14)C,5-(3)H(2)]-mevalonic acid into phytoene, phytofluene, zeta-carotene, neurosporene, alpha-, beta-, gamma- and delta-carotene and lycopene by slices of fruit from two tomato mutants (delta and tangerine) and into alpha- and beta-carotene by bean leaves has been studied. 2. In the formation of phytoene, all the pro-R-hydrogen atoms from C-5 of mevalonic acid are retained whereas two pro-S-hydrogen atoms are lost. 3. Possible mechanisms for the condensation of two molecules of all-trans-geranylgeranyl pyrophosphate are outlined. 4. In each dehydrogenation step from phytoene to the fully unsaturated carotenes, one pro-R-hydrogen atom from C-5 of mevalonic acid is lost, indicating that the sequential dehydrogenation is stereospecific and in the same sense at each step.


What approaches to social prescribing work, for whom, and in what circumstances? A protocol for a realist review.
The use of non-drug, non-health-service interventions has been proposed as a cost-effective alternative to help those with long-term conditions manage their illness and improve their health and well-being. Interventions typically involve accessing activities run by the third sector or community agencies and may also be described as non-medical referral, community referral or social prescribing. To be effective, patients need to be "transferred" from the primary care setting into the community and to maintain their participation in activities. However, it is not currently known how and why these approaches enable which people under what circumstances to reach community services that may benefit their health and well-being. Database searches and extensive searching of grey sources will be carried out in an attempt to find evidence associated with referral and retention in social prescribing. After initial scoping searches, two main phases of searching will be conducted: (a) will focus on the identification of programme theories to illustrate how approaches to social prescribing work for different people and in different contexts and (b) will consist of targeted searches to locate evidence to refine these candidate theories into configurations of the contexts in which populations and the main mechanisms outcomes are achieved. Inclusion criteria will initially be broad in order to develop a clear picture of the ways in which social prescriptions might operate but may iteratively become more focused in response to initially identified evidence, for example, in terms of the population group. An expert advisory group consisting of professionals working in a range of organisations involved in social prescribing will be convened to check the approaches in the review and provide real-life experience of social prescribing. Findings from the review will be disseminated to commissioners, published in a peer-reviewed journal and used to help refine an intervention model for an outdoor nature-based group intervention. This realist review will explore why mechanisms of social prescribing work, for what groups of people and their impact on enrolment, attendance and adherence to programmes. The use of realist approaches to detail the social prescribing process is novel and will offer insights into effective transfer of patients. PROSPERO CRD42016039491.


Exogenous corticosterone administration during pregnancy alters placental and fetal thyroid hormone availability in females.
Maternal prenatal stress is associated with adverse pregnancy outcomes and predisposition to long-term adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress. Using a mouse model of maternal prenatal stress, we conducted RNA-seq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta. Dio2 was amongst the top differentially expressed genes in response to elevated maternal stress hormone. Dio2 expression was more downregulated in female placenta from stressed dams than both female control and male placenta. Consistent with Dio2's role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from stressed dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the female placenta from stressed dams at E16.5. Stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams. The placental thyroid hormone synthesis pathway may be a target of maternal stress and modulate fetal programming of health and disease of offspring in a sex-specific fashion.