Low-grade myofibroblastic proliferations of the urinary bladder.
Myofibroblastic proliferations of the urinary bladder, which share some similarities with nodular fasciitis, were first reported in 1980. Since then, they have had several designations, the most frequently used being inflammatory myofibroblastic tumor. Based on both histopathologic and prognostic grounds, some authors prefer the term pseudosarcomatous myofibroblastic proliferation, at least for some of the proliferations. These same scientists also assimilate the so-called postoperative spindle cell nodules with the pseudosarcomatous myofibroblastic proliferations. Little is known about these low-grade myofibroblastic proliferations. To review the literature about low-grade myofibroblastic proliferations occurring in the urinary bladder. Textbooks and literature review. We obtained most of the clinicopathologic peculiarities from a patient population composed of the most-relevant, previously reported cases. The low-grade myofibroblastic proliferations of the urinary bladder are rare lesions affecting males more often than they do females. The most-common signs and symptoms are hematuria and dysuria. Histopathologically, they are spindle cell proliferations in a loose myxoid stroma, even though compact proliferations or hypocellular fibrous patterns can be found. Immunohistochemistry is quite nonspecific, except for ALK-1 positivity (20%-89%). Fluorescence in situ hybridization has demonstrated clonal genetic aberrations involving the ALK gene in 50% to 60% of cases. After surgery, only 6% of patients experience local recurrence, without metastases or deaths from the disease. Malignant transformation has been reported exceptionally. These myofibroblastic proliferations are probably part of a continuum with, at one end, benign pseudosarcomatous proliferations and, at the opposite end, more-aggressive lesions. Because of the frequently indolent clinical course, aggressive treatment would be unjustified.


Does adherence to lipid-lowering medications improve cancer survival? A nationwide study of breast and colorectal cancer, and melanoma.
Inconclusive findings of lipid-lowering medications (LLMs) on cancer survival benefit require more evidence. We tested the hypothesis that adherence to this drug is associated with reduced cancer-specific mortality in a homogeneous population who had used this drug before cancer diagnosis. The Australian Cancer Database was linked to the Pharmaceutical Benefits Scheme database, and to the National Death Index (up to 2015). Medication adherence was calculated by proportion of days covered. Cox regression models with time-varying covariates were used to derive multivariable-adjusted cause-specific hazard ratio (HR) and 95% confidence interval (CI) for the associations between adherence to LLMs, statins, lipophilic, and hydrophilic statins and cancer-specific mortality. From 2003 to 2013, 3 separate cohorts of 20 046, 11 719 and 6430 female patients with newly diagnosed breast, colorectal cancer, and melanoma respectively were identified. The 1-year adherence was similar at 1-year prediagnosis in the 3 cohorts, on average 82%. Each 10% increase in 1-year adherence to LLMs was inversely associated with cancer-specific mortality among women with breast cancer (fully adjusted HR = 0.92, 95% CI 0.91-0.93), colorectal cancer (fully adjusted HR = 0.92, 95% CI 0.91-0.93), or melanoma (fully adjusted HR = 0.97, 95% CI 0.94-1.00). The reductions in cancer-specific mortality were more pronounced for women who adhered to lipophilic than hydrophilic statins in all 3 cancers albeit not statistically significant for melanoma. Among LLM users, adherence to this drug is associated with a decrease in cancer-specific mortality. If confirmed, LLMs could be considered as an adjuvant cancer therapy to improve prognosis in cancer survivors.


Case report: analytical electron microscopy of lung granulomas associated with exposure to coating materials carried by glass wool fibers.
Man-made vitreous fibers (MMVFs) are noncrystalline inorganic fibrous material used for thermal and acoustical insulation (e.g., rock wool, glass wool, glass microfibers, and refractory ceramic fibers). Neither epidemiologic studies of human exposure nor animal studies have shown a noticeable hazardous effect of glass wools on health. However, MMVFs have been anecdotally associated with granulomatous lung disease in several case reports. Here, we describe the case of a patient with multiple bilateral nodular opacities who was exposed to glass wool fibers and coating materials for 7 years. Bronchoalveolar lavage fluid revealed an increased total cell count (predominantly macrophages) with numerous cytoplasmic particles. Lung biopsy showed peribronchiolar infiltration of lymphoid cells and many foreign-body-type granulomas. Alveolar macrophages had numerous round and elongated platelike particles inside the cytoplasm. X-ray microanalysis of these particles detected mainly oxygen/aluminum/silicon and oxygen/magnesium/silicon, compatible with kaolinite and talc, respectively. No elemental evidence for glass fibers was found in lung biopsy. The contribution of analytical electron microscopy applied in the lung biopsy was imperative to confirm the diagnosis of pneumoconiosis associated with a complex occupational exposure that included both MMVFs and coating materials. This case study points out the possible participation of other components (coating materials), beyond MMVFs, in the etiology of pneumoconiosis.


Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors.
M4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors. In preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects. In mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%). There were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration number NCT03306420.


[Hypertensive crisis in a 3-year-old boy - neurovascular conflict?]
Hypertensive crisis is a sudden rise in blood pressure with accompanying clinical symptoms. The disease is extremely rare in small children and is always a complication of secondary hypertension. 3-year-old boy (spontaneous delivery, 37 week of gestation, birth weight 2170g, 10 AS, unremarkable family history) was admitted to a hospital because of weight loss (1.5 kg, i.e. approx. 15% in 6 months), anorexia, abdominal and limb pain and lethargy. On admission, very high blood pressure values (190/150 mm Hg), lean subcutaneous tissue, frequent blinking, height 88 cm (<3c), body weight 9.5 kg (<3c). In additional tests: blood morphology, parameters of renal function, ions, gasometry, catecholamine urinary excretion, steroid profile and daily cortisol profile were within normal limits. Elevated plasma renin activity was found. In imaging studies kidneys, adrenal glands and renal arteries were normal. Normotension was not obtained on two antihypertensive drugs - metoprolol and amlodipine. In angio-CT tortuous right vertebral artery, extending to the left on the anterolateral surface of the medulla oblongata - possible compression of the vessel of the left side of medulla - was found. Diagnosis of neurovascular conflict was made. The patient was consulted by neurosurgeon who declare no possibility of surgical treatment of anomalies. In the treatment, according to the literature, a drug blocking the renin-angiotensin-aldosterone-enalapril system was used, which normalized blood pressure. At the same time, intensive nutritional treatment was used. Resolution of symptoms and weight gain was observed. In further follow-up patients' parents withdrew enalapril lawlessly, which did not lead to recurrent rise in blood pressure. The latter may suggest other, transient cause of hypertensive crisis e.g. intoxication. Severe hypertension in pediatric patients can give symptoms as weight loss and behavioral disorders. In the diagnostic of hypertensive crisis in children, neuroimaging studies and toxicological tests should be performed.


Antibody response to experimental Trypanosoma rangeli infection and its implications for immunodiagnosis of South American trypanosomiasis.
Differential immunodiagnosis of T. rangeli and T. cruzi infections in man poses a particular problem, not only because these parasites share antigenic determinants, as detected by immunofluorescence, but also because they have a similar geographical distribution, the same host range and often identical insect vectors. We show here that whereas mouse anti-T. rangeli sera have significant cross reactivity with T. cruzi by immunofluorescence, they are entirely specific when tested by ELISA, using apparently similar antigen preparations. Immunoprecipitation analysis detected relatively little cross-reactivity between heterologous antisera and parasite combinations. Intriguingly, immunization with T. rangeli epimastigotes was much more powerful than similar immunization with trypomastigotes, and the majority of the antibody was directed against a single polypeptide of apparent Mr 73kDa.


Breast cancer risk and common single nucleotide polymorphisms in homologous recombination DNA repair pathway genes XRCC2, XRCC3, NBS1 and RAD51.
The possible role for DNA repair deficiencies in cancer development, namely in breast cancer has been the subject of increasing interest since it has been reported that breast cancer patients might be deficient in the repair of DNA damage. Exposure to ionizing radiation has been pointed out as a risk factor for breast cancer, and the type of DNA lesions induced by this carcinogen can be repaired by homologous recombination DNA repair (HRR) pathway. To evaluate the potential modifying role of some single nucleotide polymorphisms (SNP) in HRR involved genes on the individual susceptibility to breast cancer we carried out a hospital based case-control study in a Caucasian Portuguese population (289 histological confirmed breast cancer patients and 548 control individuals). We genotyped 4 SNPs in 4 different HRR pathway genes, XRCC2 (Ex3+442G>A, R188H, rs3218536), XRCC3 (Ex8-5C>T, T241M, rs861539), NBS1 (Ex5-32C>G, E185Q, rs1805794) and RAD51 5'UTR (Ex1-59G>T, rs1801321), tagging 41 SNPs in these genes. The frequency of the different polymorphisms in the Portuguese control population is similar to the ones reported for other Caucasian populations, and the deviation of the Hardy-Weinberg equilibrium was only observed for the XRCC2 (Ex3+442G>A, R188H, rs3218536) polymorphism in the control population. The results obtained, after logistic regression analysis, did not reveal a major role of these polymorphisms on breast cancer susceptibility. However, when the population was stratified according to breast feeding (women that breast fed and women that never breast fed) it is observed, in women that never breast fed, that the heterozygous individuals for the XRCC2 (Ex3+442G>A, R188H, rs3218536) polymorphism have a decreased risk for breast cancer [adjusted OR=0.45; 95% CI=0.22-0.92] (P=0.03). Additionally, after stratification according to menopausal status, our results suggest that post-menopausal women carrying at least one variant allele for the XRCC3 (Ex8-5C>T, T241M, rs861539) polymorphism have a lower risk for breast cancer [adjusted OR=0.67; 95% CI, 0.47-0.94] (P=0.03). Most of the studies suggest that breastfeeding may be responsible for 2/3 of the estimate reduction of breast cancer. The longer the duration of breastfeeding the lower the potential risk associated with breast cancer. Therefore, in our study the potential protective role of the variant allele of XRCC2 (Ex3+442G>A, R188H, rs3218536), in never breast fed women, might be related with a more efficient DNA repair activity.


A Natural History of Disease Framework for Improving the Prevention, Management, and Research on Post-viral Fatigue Syndrome and Other Forms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
We propose a framework for the treatment, rehabilitation, and research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using a natural history of disease approach to outline the distinct disease stages, with an emphasis on cases following infection to provide insights into prevention. Moving away from the method of subtyping patients based on the various phenotypic presentations and instead reframing along the lines of disease progression could help with defining the distinct stages of disease, each of which would benefit from large prospective cohort studies to accurately describe the pathological mechanisms taking place therein. With a better understanding of these mechanisms, management and research can be tailored specifically for each disease stage. Pre-disease and early disease stages call for management strategies that may decrease the risk of long-term morbidity, by focusing on avoidance of further insults, adequate rest to enable recovery, and pacing of activities. Later disease stages require a more holistic and tailored management approach, with treatment-as this becomes available-targeting the alleviation of symptoms and multi-systemic dysfunction. More stringent and standardised use of case definitions in research is critical to improve generalisability of results and to create the strong evidence-based policies for management that are currently lacking in ME/CFS.


Elliptical dichroism: operating principle of planar chiral metamaterials.
We employ a homogenization technique based on the Lorentz electronic theory to show that planar chiral structures (PCSs) can be described by an effective dielectric tensor similar to that of biaxial elliptically dichroic crystals. Such a crystal is shown to behave like a PCS insofar as it exhibits its characteristic optical properties, namely, corotating elliptical polarization eigenstates and asymmetric, direction-dependent transmission for left- or right-handed incident wave polarization.


[Legal aspects of ritual circumcision].
Female circumcision (genital mutilation) is a criminal violation of human rights under German law. Even with consent of the person to be circumcised and/or her legal representative this procedure must not be carried out since a consent to female circumcision is unethical and therefore void. As much consent as there is on female circumcision the legal situation with ritual male circumcision is very unclear. In practice and unnoticed by the public male circumcision is carried out - be it for medical or ritual reasons - without deeper-going reflexions on the clearness of the medical indication or the legal situation with ritual circumcision. From the medical aspect there are big differences between female and male circumcision but also certain parallels. Various reasons, partly founded in prejudice and misinformation, make people refrain from regarding circumcision of boys also as illegal. Contrary to the prevailing opinion male circumcision also represents a bodily harm which a doctor can only carry out after a preoperative interview and with the consent of the affected person. Since ritual male circumcision does not serve the wellbeing of a child it is not possible for the parents to give their consent to the circumcision in lieu of the child. Male circumcision is only permitted if the child has given his consent and is thus only legally permitted if the child has reached an age at which he is mature enough to understand the meaning and extent of such an action which is hardly the case before he has completed his 16 (th) year.


Characterisation of Macrophage Polarisation in Mice Infected with Ninoa Strain of Trypanosoma cruzi.
Macrophages (MΦ) play a key role in the development of the protective immune response against Trypanosoma cruzi infection. To determine the role of MΦ subtypes M1 and M2 in the development of immunity against the Mexican strain of T. cruzi (Ninoa strain), we have analysed in a time course the infection and characterised the M1 and M2 subtypes in two mouse models, BALB/c and C57BL/6. After infection, BALB/c mice developed an increased blood parasite load and the parasites were cleared from the blood one week later than in C57BL/6 mice. However, similar cellular infiltrate and cardiac alterations were observed between BALB/c and C57BL/6 mice. At 36 days, the T. cruzi infection differentially modulated the expression of immune cells, and both the BALB/c and C57BL/6 mice significantly reduced TCD4+ cells. However, BALB/c mice produced significantly more TCD8+ than C57BL/6 mice in the spleen and lymph nodes. Furthermore, BALB/c mice produce significantly more MΦ in the spleen, while C57BL/6 produce similar levels to uninfected mice. The M1 MΦ ratio increased significantly at 3-5 days post-infection (dpi), but then decreased slightly. On the contrary, the M2 MΦ were low at the beginning of the infection, but the proportion of M1 and M2 MΦ at 36 dpi was similar. Importantly, the MΦ subtypes M2c and M2d significantly increased the induction of tissue repair by the end of the acute phase of the infection. These results indicate that the Ninoa strain has developed strategies to modulate the immune response, with fine differences depending on the genetic background of the host.


Future prospects and perspectives on microbicides.
As 'proof of concept' has now been well validated for topical microbicides, the progress has, appropriately, refined the questions of who, how, when and at what risk and cost. These are welcome challenges requiring intensified, cross-disciplinary responses. This is especially true in the areas of adherence and pharmacokinetic/pharmacodynamics (PK/PD) sampling and modeling to optimize preventive trials measuring "efficacy", which is well known to reduce when measured as "effectiveness" in real-world use. Intensified exploratory and Phase 1 safety trials to investigate acceptability, adherence, PK and ex vivo efficacy with drug-exposed tissue biopsies/compartment fluids even though they are complex in design, management, assays and monitoring are moving forward As well, great strides in recent efforts in a variety of delivery formulations are promising. These current and future efforts will provide potential insights earlier that at Phase IIb or III in the development pipeline.


Interference of plant extracts, phytoestrogens and antioxidants with the MTT tetrazolium assay.
The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay is a widely used screening method to measure cell viability and proliferation. When testing the effects of kaempferol on breast cancer cell number (crystal violet staining) and viability (MTT tetrazolium assay) conflicting results were obtained. Cell number decreased but MTT formazan formation increased, suggesting a direct interaction of kaempferol with the MTT tetrazolium reduction. Direct reductive potential was observed in a cell-free system for the presumptive phytoestrogens kaempferol and resveratrol, and extracts of Hypericum perforatum L. and Cimicifuga racemosa L. All agents led to instantaneous dark blue formazan formation in the absence of cells. Additionally, antioxidants such as ascorbic acid, vitamin E and N-acetylcysteine interfered with the MTT tetrazolium assay. When MCF7 and HS578 cells treated with kaempferol were washed before addition of MTT tetrazolium, the direct reduction of dye was reduced significantly. These results indicate that the MTT tetrazolium assay may lead to false positive results when testing natural compounds with intrinsic reductive potential.


Strain mapping in a nanoscale-triangular SiGe pattern by dark-field electron holography with medium magnification mode.
Recent years have seen a great deal of progress in the development of transmission electron microscopy-based techniques for strain measurement. Dark-field electron holography (DFEH) is a new technique offering configuration of the off-axis principle. Using this technique with medium magnification (Holo-M), we carried out strain measurements in nanoscale-triangular SiGe/(001) Si with (004), (2-20) and (-111) diffraction spots. The reconstruction of holograms and interpretation of strain maps in term of strain precision were discussed and the strain distributions in the SiGe/(001) Si patterns were visualized. Based on linear anisotropic elastic theory for strain simulation, the simulated results obtained by the finite element method compared with the experimental results acquired by DFEH. The strain values were found to be 0.9-1.0%, 1.1-1.2% and 1.0-1.1%, for the (004), (2-20) and (-111) diffracted beams, respectively, and the strain precisions were determined to be ~2.1 × 10-3, 3.2 × 10-3 and 9.1 × 10-3 for the corresponding diffraction spots. As a result, DFEH is highlighted as a powerful technique for strain measurement, offering high-strain precision, high-spatial resolution and a large field of view.


Molecular cloning and characterization of mouse St7r (St7-like, St7l).
Human ST7R (ST7-like, ST7L) is a paralog of tumor suppressor gene ST7 in the human genome. ST7R gene is clustered with WNT2B gene in human chromosome 1p13, while ST7 gene is clustered with WNT2 gene in human chromosome 7q31. Here, we have cloned mouse ortholog of human ST7R using bioinformatics and cDNA-PCR. Mouse St7r was found to encode 559 amino-acid polypeptide. Mouse St7r showed 90.7% total-amino-acid identity with human ST7R isoform 4 (ST7R4), and 71.6% total-amino-acid identity with human ST7 and mouse St7. Three tyrosine-phosphorylation sites as well as ST7R homologous domains (S7H1, S7H2, and S7H3) were conserved among mouse St7r, human ST7R, mouse St7, and human ST7. Leucine zipper domain of mouse St7r was conserved in human ST7R, but not in mouse St7 and human ST7. Mouse St7r was expressed almost ubiquitously in adult mouse tissues and also in mouse embryos. Although mouse genome draft sequence including mouse St7r gene has not yet been identified, rat genome draft sequence AC106372.1 was found to include rat St7r gene as well as rat Wnt2b gene. These results indicate evolutional conservation of ST7R-WNT2B gene cluster. This is the first report on molecular cloning and initial characterization of mouse St7r.


Rat alveolar epithelial cells concomitantly express plasminogen activator inhibitor-1 and urokinase.
There is considerable evidence to suggest that intra-alveolar plasminogen activation is instrumental in many aspects of inflammatory lung injury and subsequent tissue repair. Rat alveolar epithelial cells produce large quantities of urokinase-type plasminogen activator (uPA) in vitro, and uPA expression is modulated in association with cellular differentiation and exposure to inflammatory mediators. We now report that these cells also secrete heat-stable PA inhibitory activity having the characteristics of PA inhibitor type 1 (PAI-1). In particular, immunoreactive PAI-1 was demonstrable in conditioned media, cell lysates, and extracellular matrix from epithelial cell cultures. As alveolar epithelial cells differentiated in vitro, secreted PA inhibitor activity increased significantly from 104 +/- PAI U/ml (n = 5, mean +/- SE) on day 2 to 442 +/- 150 on day 7 in parallel with increases in secreted and matrix-associated immunoreactive PAI-1. PAI-1 mRNA expression decreased over this same period suggesting posttranscriptional regulation. The levels of both newly synthesized antigen and PAI-1 mRNA were increased by exposure to lipopolysaccharide and tumor necrosis factor-alpha. Thus, by the coexpression of uPA and PAI-1, the alveolar epithelium may actively regulate the generation of plasmin in both the normal and injured alveolus.


Investigating the Effect of Low-Temperature Drilling Process on the Mechanical Behavior of CFRP.
Previous research has found that lower temperature drilling is helpful to improve the hole quality of carbon fiber reinforced polymer (CFRP). However, the influence of the lower temperature drilling process on the mechanical behavior of composites is yet not fully understood. To examine the influence of the lower temperature drilling process on the mechanical behavior of CFRP, the open hole CFRP specimens used for mechanical tests were obtained with three cases: drilling with -25 °C/uncoated carbide drills/(1000 rpm, 0.02 mm/r), 23 °C/coated carbide drills/(4000 rpm, 0.03 mm/r), and 23 °C/uncoated carbide drills/(1000 rpm, 0.02 mm/r), respectively; corresponding, three groups of open-hole specimens are obtained: specimens drilling at low-temperature with low damage, specimens drilling at room-temperature with low damage and specimens drilling at room-temperature with low damage; the mechanical behavior of the three groups specimens were obtained by static tensile, tensile-tensile fatigue cyclic tests and residual tensile strength test. The results have shown that the mechanical properties of specimens with a low-temperature drilling process is lower than those of the specimen with a normal drilling process due to the better drilling quality. The damage accumulation in specimens was increased with the damage degree of the original hole, the greater the damage degree, the worse the mechanical properties.


Local Rank Deficiency Caused Problems in Analyzing Chemical Data.
Multivariate curve resolution (MCR) is a powerful methodology for analyzing chemical data in different application fields such as pharmaceutical analysis, agriculture, food chemistry, environment, and industrial and clinical chemistry. However, MCR results are often complicated by rotational ambiguity, meaning that there is a range of feasible solutions that fulfill the constraints and explain equally well the observed experimental data. Constraints determine the properties of resolved profiles in MCR methods by enforcing different assumptions on data. The applied constraints on chemical data sets should be derived from the physical nature and prior knowledge of the system under study. Therefore, the reliability of the constraints in order to get accurate results is a critical aspect that should be considered by analytical chemists who use MCR methods. Local rank information plays a key role in the curve resolution of multicomponent chemical systems. Applying the local rank constraint can reduce the extent of rotational ambiguity considerably, and in some cases, unique solutions can be achieved. Local rank exploratory methods like Evolving Factor Analysis (EFA) method provide local rank maps in order to obtain the presence pattern of components on the main assumption that the number of components in each window is equal to its rank. It is shown in this work that the local rank is a mathematical concept that may not be in concordance with chemical information. Thus, applying the local rank constraint for restricting the rotational ambiguity in MCR methods can lead to incorrect solutions! This problem is due to "local rank deficiency", which is introduced in this contribution.


[Etiology of mongolism].
Beside the rare cares of translocation mongolism, Down syndrome is caused by meiotic malsegregation of chromosomes, No. 21. The meiotic error can take place in both sexes and was found twice as frequently in the female as in the male. The same 2:1 ratio was found concerning nondisjunction in the first and in the second meiotic division. The rate of meiotic errors, which occur at random, is largely dependent on age; this tendency is more pronounced in oogenesis than in spermatogenesis. The results of prenatal chromosomal diagnosis indicate that the recurrence risk of trisomy 21 is not above the age-dependent average.


Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.
Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response. We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection. Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.


[Induction of liaison-clinical pathway for patients with gastric cancer undergoing adjuvant chemotherapy using S-1 after curative gastrectomy].
The efficacy of adjuvant chemotherapy using S-1 for one year after curative surgical treatment for patients with gastric cancer of stage II or III was reported as the result of randomized controlled trial named ACTS-GC in 2007. Therefore the number of patients undergoing this adjuvant chemotherapy is predicted to be rapidly increasing in near future. On the other hand, the government promotes to construct the liaison-clinical pathway for patients with major carcinoma as a policy in 2007. According to these two backgrounds, liaison-clinical pathway for patients with gastric cancer undergoing adjuvant chemotherapy using S-1 after curative gastrectomy has been induced in our institute from November 2007. Not only alliance among doctors, nurses and pharmacologist in our institute but also communication with clinic is important to construct and manage this pathway. Three patients have been undergoing this pathway until now. All of them are satisfied with this pathway because of reliable feelings supported by intensive alliance between our institute and local clinic.


Implementing the 4R and 9H regimens for TB preventive treatment in Indonesia.
BACKGROUND: The implementation of tuberculosis preventive treatment (TPT) is challenging especially in resource-limited settings. As part of a Phase 3 trial on TPT, we described our experience with the use of rifampicin for 4 months (4R) and isoniazid for 9 months (9H) in Indonesia.METHODS: In 2011-2017, children and adults with latent TB infection were randomised to either 4R or 9H and followed until 16 months after randomisation for children and 28 months for adults. The primary outcome was the treatment completion rate. Secondary outcomes were Grade 3-5 adverse events (AEs), active TB occurrence, and health costs.RESULTS: A total of 157 children and 860 adults were enrolled. The 4R treatment completion rate was significantly higher than that of 9H (78.7% vs. 65.5%), for a rate difference of 13.2% (95% CI 7.1-19.2). No Grade 3-5 AEs were reported in children; in adults, it was lower in 4R (0.4%) compared to 9H (2.8%). The incidence of active TB was lower with 4R than with 9H (0.09/100 person-year vs. 0.36/100 person-year) (rate difference: -0.36/100 person-year). The total cost per patient was lower for the 4R regimen than for the 9H regimen (USD151.9 vs. USD179.4 in adults and USD152.9 vs. USD206.5 in children)CONCLUSIONS: Completion and efficacy rates for 4R were better than for 9H. Compared to 9H, 4R was cheaper in all age groups, safer in adults and equally safe in children. The Indonesian TB program could benefit from these benefits of the 4R regimen.


Improving safe sanitation practices using groundwater transport modelling and water quality monitoring data.
In many developing countries, poorly constructed pit latrines are the primary source of groundwater contamination. Approaches are needed to identify site-specific separation distances between domestic wells and pit latrines. In this study, tracer transport simulations are combined with water quality monitoring data to identify separation distances in peri-urban Dar es Salaam. Bivariate correlation and linear regression models were used to find the relationships between (1) simulated tracer and distances from the wells to the nearest pit latrines (2) simulated tracer and observed contaminants (nitrate, E. coli, and total dissolved solids). The results showed a strong correlation between tracer with nitrate and E. coli, with Pearson coefficient (r) values of 0.80 and 0.79, but a weak correlation with total dissolved solids (TDS) (r = 0.23). A strong correlation between tracer and distance for shallow and deep wells (r = -0.96, -0.76) was found. Based on the soil type and aquifer properties in the area, wells must be placed at least 34 m from a pit latrine to minimize contamination. With recent advances in sensor technologies and the availability of low-cost sensors, linking simulated tracer with observed contaminant levels may provide an alternative first approach to quickly assess human health risks associated with groundwater contamination.


Infrared spectroscopy of hydrogen-bonded 2-fluoropyridine-water clusters in supersonic jets.
The hydrogen-bonded clusters of 2-fluoropyridine with water were studied experimentally in a supersonic free jet and analyzed with molecular orbital calculations. The IR spectra of 2-fluoropyridine-(H2O)(n) (n = 1 to 3) clusters were observed with a fluorescence detected infrared depletion (FDIR) technique in the OH and CH stretching vibrational regions. The frequencies of OH stretching vibrations show that water molecules bond to the nitrogen atom of 2-fluoropyridine in the clusters. The hydrogen-bond formation between aromatic CH and O was evidenced in the 1:2 and 1:3 clusters from the experimental and calculated results. The overtone vibrations of the OH bending mode in hydrogen-bonded water molecules appear in the IR spectra, and these frequencies become higher with the increase of the number of water molecules in the clusters. The band structure of the IR spectra in the CH stretching region changes depending on the number of coordinating water molecules.


The professional image anticipated by anaesthesiologists.
The perspective of anaesthesiologists regarding their professional image in the eyes of colleagues and the public was assessed. A self-reporting questionnaire (Instrument for Stress-related Job Analysis) was completed by 125 anaesthesiologists. Respondents' self-image and presumed image in the eyes of colleagues do not give a bright picture of the anaesthesiologist's role. The anticipated image showed significantly more anaesthesiologists who presumed low professional recognition by their colleagues from other specialties (P = 0.002) and the lay public (P = 0.015) than those who assumed high marks. Presumed colleague opinion correlated significantly with characteristics of job satisfaction including the possibility to co-determine sequence of operations (P = 0.006), recognition of suggestions and ideas (P = 0.007) and fellow support (P = 0.001). Regarding working conditions the possibility to actively control operational procedures also significantly correlated with colleague opinion (P = 0.003). The authors conclude that the possibility to actively influence quality and pace of work on a par with surgical colleagues could help boost self-esteem and self-confidence in anaesthesiologists. Furthermore, positive image promotion in cooperating medical professions and the public could help focus more attention on the important contribution of anaesthesiology to modern medicine.


CD40 Pathway and IL-2 Expression Mediate the Differential Outcome of Colorectal Cancer Patients with Different CSF1R c.1085 Genotypes.
Colony-stimulating factor 1 receptor (CSF-1R) acts as the receptor for colony stimulating factor 1, a cytokine that controls the production, differentiation, and function of macrophages. Prior studies showed cancer patients harboring germline CSF1R c.1085A>G genetic variant had better survival. Here, primary tumor samples from a stage III colorectal cancer (CRC) cohort were analyzed by a targeted gene expression assay containing 395 immune-related genes to study the immune mechanism underlying the different outcomes. CRC patients with CSF1R c.1085 genotype A_G had a better disease-free and overall survival than those with CSF1R genotype A_A. Compared to the group of patients without CSF1R variant, higher CD40LG expression, a surface marker of T cells, was found in the tumor tissues of patients with CSF1R c.1085 variant. In parallel with the higher CD40LG gene expression, immunofluorescent staining also showed more CD3+CD40L+ T cell infiltrates in tumors with CSF1R c.1085 genotype A_G. Moreover, higher IL-2 expression, known to be regulated by CD40 pathway, was also observed in tumors with CSF1R c.1085 genotype A_G than genotype A_A. Higher IL-2 expression generated by the interaction of CD40 ligand and CD40 between T cells and macrophages with CSF1R c.1085A>G variant is the potential mechanism explaining the different outcomes.


[Safety of maximal ergometric loading in a population of 37,250 individuals at risk (1969-1994)].
No fatal complications occurred in 37,250 exercise tests (98.7% symptom limited) including 683 predischarge maximal tests in patients soon after myocardial infarction. Acute myocardial infarction was observed in 4 patients, ventricular fibrillation in 1 patient was successfully resolved by defibrillation. Extension of infarct area was recorded in 1 patient soon after myocardial infarction. Complication rates decreased from 1:3,400 in years 1969-1984 to 11,700 in years 1985-1994. Maximal exercise testing soon after myocardial infarction appears to be safe too. It cannot be replaced by submaximal testing. It appears to define high-risk patients suitable for revascularization procedures.


A pharmacogenetic association between a variation in calpain 10 (CAPN10) gene and the response to metformin treatment in patients with type 2 diabetes.
The aim of the present study was to investigate possible associations of the single-nucleotide variants in six genes encoding the key molecules mediating the metformin pharmacodynamic effect with the response to treatment with metformin in patients with type 2 diabetes. One hundred forty-eight drug-naïve patients with type 2 diabetes were included in the study. PRKAA1 rs249429, STK11 rs741765, PCK1 rs4810083, PPARGC1A rs10213440, HNF1A rs11086926, and CAPN10 rs3792269 variants were genotyped. The outcomes of the study were treatment success defined by achieving HbA1c <7 % and absolute reduction in HbAlc after 6-month metformin therapy. The relationships between genotypes and outcomes were evaluated in multivariate logistic and linear models. The level of statistical significance after Bonferroni correction was predefined as p<0.0083. The minor G-allele of CAPN10 rs3792269 A>G polymorphism was significantly associated with less treatment success with an odds ratio of 0.27 (95 % CI 0.12-0.62, p=0.002) per variant allele. When the reduction in HbA1c was analyzed as a quantitative trait, G-allele was nominally associated with a smaller reduction in HbA1c (per allele β=-0.26, 95 % CI -0.50 to -0.02, p=0.032). The reduction in HbA1c in minor allele carriers (24 % of study population) was smaller by 0.3 % in comparison with the major allele homozygotes. The present study provides the first observation of an association between a variant in CAPN10 gene and the response to metformin therapy in patients with type 2 diabetes. This observation needs to be replicated in further studies in different populations.


An experimental task to measure preschool children's frustration induced by having to wait unexpectedly: The role of sensitivity to delay and culture.
The ability to manage frustration induced by having to wait for valued outcomes emerges across childhood and is an important marker of self-regulatory capacity. However, approaches to measure this capacity in preschool children are lacking. In this study, we introduced a new task, the Preschool Delay Frustration Task (P-DeFT), designed specifically to identify children's behavioral and emotional markers of waiting-induced frustration during the imposed wait period and after the release from waiting. We then explored how waiting-induced frustration relates to individual differences in delay sensitivity and whether it differs between two cultural groups thought to have different attitudes toward children's conduct and performance: Hong Kong (HK) and the United Kingdom (UK). A total of 112 preschool children (mean age = 46.22 months) completed the P-DeFT in a quiet laboratory. Each trial had two stages; first, a button press elicited a Go signal; second, this Go signal allowed children to go to a "supermarket" to pick a target toy. On most trials, the Go signal occurred immediately on the first press. On 6 trials, an unexpected/unsignaled 5- or 10-s pre-Go-signal period was imposed. Frustration was indexed by performance (button presses and press duration), behavioral agitation, and negative affect during the pre-Go-signal wait period and the post-Go-signal shopping task. Parents rated their children's delay sensitivity. Waiting-related frustration expressed during both the pre-Go-signal wait period and the post-Go-signal task varied with (a) the length of wait and (b) individual differences in parent-rated delay sensitivity. UK children displayed more negative affect during delay than their HK counterparts, although the relationship between delay sensitivity and frustration was culturally invariant.


alpha-Mannosidase-catalyzed trimming of high-mannose glycans in noninfected and baculovirus-infected Spodoptera frugiperda cells (IPLB-SF-21AE). A possible contributing regulatory mechanism for assembly of complex-type oligosaccharides in infected cells.
Incubation of a Spodoptera frugiperda (IPLB-SF-21AE) cell extract with the oligosaccharide Man9GlcNAc2, the aglucosyl derivative of the glycan that is normally transferred from the dolichol carrier to the relevant Asn residue in the nascent protein, results in its trimming to Man6GlcNAc2, an intermediate that is relatively stable to further alpha-D-mannosidase action in these cells. On the other hand, incubation of a similar extract from cells that had been infected for various times with a wild-type baculovirus (Autographa californica nuclear polyhedrosis virus) or a recombinant baculovirus (r-BAC)/human plasminogen (HPg) construct employed for expression of HPg led to rapid trimming of Man6GlcNAc2 to Man5GlcNAc2 and Man3GlcNAc2. These latter reactions displayed temporal effects, in that an enhancement of this latter trimming process occurred as a function of the time of infection of the cells with the wild-type and recombinant viral constructs. We have previously demonstrated that the nature of the oligosaccharide assembled on Asn289 of HPg expressed in several lepidopteran insect cell lines was dependent on the time of infection of the cells with r-BAC/HPg and that the amount of complex glycan found on this recombinant protein increased with an increase in infection times [Davidson, D. J., & Castellino, F. J. (1991) Biochemistry 30, 6167-6174].(ABSTRACT TRUNCATED AT 250 WORDS)


Methicillin-Resistant Staphylococcus aureus ST398 from human patients, upper Austria.
Methicillin-resistant Staphylococcus aureus (MRSA) clonal type ST398 is usually associated with animals. We examined 1,098 confirmed MRSA samples from human patients and found that 21 were MRSA ST398. Most (16) patients were farmers. Increasing prevalence from 1.3% (2006) to 2.5% (2008) shows emergence of MRSA ST398 in humans in Austria.


Characterization of isolated nitrogenase FeVco.
The cofactors of the Mo- and V-nitrogenases (i.e., FeMoco and FeVco) are homologous metal centers with distinct catalytic properties. So far, there has been only one report on the isolation of FeVco from Azotobacter chroococcum. However, this isolated FeVco species did not carry the full substrate-reducing capacity, as it is unable to restore the N(2)-reducing ability of the cofactor-deficient MoFe protein. Here, we report the isolation and characterization of a fully active species of FeVco from A. vinelandii. Our metal and activity analyses show that FeVco has been extracted intact, carrying with it the characteristic capacity to reduce C(2)H(2) to C(2)H(6) and, perhaps even more importantly, the ability to reduce N(2) to NH(3). Moreover, our EPR and XAS/EXAFS investigations indicate that FeVco is similar to, yet distinct from FeMoco in electronic properties and structural topology, which could account for the differences in the reactivity of the two cofactors. The outcome of this study not only permits the proposal of the first EXAFS-based structural model of the isolated FeVco but also lays a foundation for future catalytic and structural investigations of this unique metallocluster.


A comprehensive literature review and meta-analysis of the prevalence of pan-cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies.
There is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta-analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI = 48%-64%). The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications.


Listeriosis in a peri-urban area: Cultural and molecular characterization of Listeria monocytogenes isolated from encephalitic goats.
Listeriosis in food animals bears a significant threat to human health. Detailed investigations into the cause facilitate proper management of the disease. This study reports the cultural, pathological, and molecular characterization of Listeria monocytogenes isolated from encephalitic goats from peri-urban Guwahati, Assam. Out of nine suspected samples, five positive isolates of L. monocytogenes were subjected to bacteriological, biochemical, and molecular tests. The genus and species-specific L. monocytogenes 16S rRNA and prs genes were amplified by polymerase chain reaction (PCR) to yield 1200 and 370 bp sized products, respectively. The encephalitic form of the disease was characterized by circling movement, high fever, and terminal recumbence. All the five isolates were confirmed to be L. monocytogenes based on PCR amplification of genus and species-specific 16S rRNA and prs gene products. The isolates were sensitive to ciprofloxacin, oxytetracycline (OTC), and norfloxacin, but resistant to doxycycline and erythromycin. A high dose of OTC was used in a goat at the early stage of clinical symptom and the animal recovered clinically. Listeriosis in goats could pose a significant public health threat as the meat (occasionally milk) or meat products from goats are widely consumed by the people of Assam. Understanding the molecular epidemiological aspects of L. monocytogenes infections of food animal species should, therefore, be the priority in this part of the country.


Mechanics of the middle ear system: age-related changes in viscoelastic properties.
Morphological studies of age-related changes in the tympanic membrane have suggested a decreased elasticity for increasing age, whereas age-related changes in admittance measured by tympanometry have revealed inconsistent results. In this study we report on the viscoelastic properties of the middle ear system by means of a new method in two different age groups. This method measures hysteresis (microJ), which describes the viscous properties of the system, and compliance (mm(3)/kPa) reflecting its elasticity. Moreover, P(ec0) (kPa) was recorded, which corresponds to middle ear pressure measured by tympanometry. Recordings were made in a group of 30 older normal subjects (mean age 77 years) and results were compared to previous findings in a group of 39 younger normal subjects (mean age 29). Hysteresis was markedly decreased in the older normal group compared to the younger one (p = 0.057). This may reflect morphological changes previously reported in the tympanic membrane and can be related to theoretical considerations on tympanic membrane rupture pressures. Compliance and P(ec0) were not influenced by variation in age (p = 0.645 and 0.966).


Synthesis and Characterization of pH-Responsive Copolypeptides Vesicles for siRNA and Chemotherapeutic Drug Co-Delivery.
Novel diblock copolypeptides are synthesized and evaluated as a pH-sensitive drug delivery vector for anticancer drugs and siRNA co-delivery. The synthetic process involve the ring opening polymerization of α-amino acid N-carboxyanhydrides as well as aminolysis and deprotection reactions, and the structures are characterized. The copolypeptides can self-assemble into stable vesicles at neutral pH, and disassemble in acidic endosomal/lysosomal, which shown the pH-responsive behavior. The cell uptake results indicated that the vesicles can co-deliver DOX and siRNA inside the same cell and exhibit a pH-sensitive release behavior. Therefore, the novel polymeric vesicles are a promising carrier for co-delivery anticancer drug and siRNA to overcome the drug resistance and enhance cancer treatment.


Access to Triptans for Acute Episodic Migraine: A Qualitative Study.
Our study aims to examine factors related to access of triptans among multiple stakeholder groups. Triptans are a cornerstone of pain management for the acute treatment of migraine, but actual utilization of triptans is lower than ideal. Initial and continued access to triptans may be an important clinical issue in the acute treatment of migraines, but factors affecting access at the patient, provider, and health-care system levels have not been comprehensively explored. A qualitative study was conducted in Ontario, Canada, between August 2013 and January 2014. Three participant groups were recruited to the qualitative study: (1) migraineurs who have experience accessing triptans; (2) physicians, including primary care physicians (PCPs) and neurologists, who have prescribed triptans; and (3) pharmacists who have dispensed triptans. Qualitative data were collected through one-on-one, semi-structured telephone interviews. The framework approach was used for data collection and analysis. Data collected from 19 migraineurs, 6 physicians, and 8 pharmacists were included in the analysis. Study participants discussed various factors that facilitate or hinder access to triptans, which were synthesized into four themes that emerged at the patient, provider, and health-care systems levels: (1) awareness; (2) apathy; (3) advocacy; and (4) affordability. Across all participant groups, awareness of available treatments and coverage policies for those treatments were potential factors relating to timely drug provision. Participants describe apathy in terms of patients' health-seeking behaviors and physicians' lack of concern toward migraine, which were seen as factors that could delay diagnosis and provision of appropriate treatment. Patients engaging in self-advocacy enhanced their ability to seek timely and appropriate provision of triptans at the patient level. At the health-care provider level, pharmacists were identified by patients as advocates for receiving more effective treatments for their migraines; pharmacists also self-identified with the advocate role. The affordability of triptans was a key concern impacting access at the systems level, but coverage limitations (eg, quantity limits) were also described to influence the appropriateness of prescribed migraine treatment. This study fills a gap in knowledge about access to triptans and how this may be impacted by patient, provider, and health-care systems barriers. Overall, our study sheds light on the experiences of prescribing, dispensing, and accessing triptans for migraine treatment, and unveils important information that can impact how patients access these drugs.


Expression of inflammation-related cytokines following intratracheal instillation of nickel oxide nanoparticles.
The objective of this study was to examine what kinds of cytokines are related to lung disorder by well-dispersed nanoparticles. The mass median diameter of nickel oxide in distilled water was 26 nm. Rats intratracheally received 0.2 mg of nickel oxide suspended in distilled water, and were sacrificed from three days to six months. The concentrations of 21 cytokines including inflammation, fibrosis and allergy-related ones were measured in the lung. Infiltration of alveolar macrophages was observed persistently in the nickel oxide-exposed group. Expression of macrophage inflammatory protein-1alpha showed a continued increase in lung tissue and broncho-alveolar lavage fluid (BALF) while interleukin-1alpha (IL-1alpha), IL-1beta in lung tissue and monocyte chemotactic protein-1 in BALF showed transient increases. Taken together, it was suggested that nano-agglomerates of nickel oxide nanoparticles have a persistent inflammatory effect, and the transient increase in cytokine expression and persistent increases in CC chemokine were involved in the persistent pulmonary inflammation.


A Thematic Literature Review: The Importance of Providing Spiritual Care for End-of-Life Patients Who Have Experienced Transcendence Phenomena.
The purpose of this review was to investigate within the literature the link between transcendent phenomena and peaceful death. The objectives were firstly to acknowledge the importance of such experiences and secondly to provide supportive spiritual care to dying patients. Information surrounding the aforementioned concepts is underreported in the literature. The following 4 key themes emerged: spiritual comfort; peaceful, calm death; spiritual transformation; and unfinished business The review established the importance of transcendence phenomena being accepted as spiritual experiences by health care professionals. Nevertheless, health care professionals were found to struggle with providing spiritual care to patients who have experienced them. Such phenomena are not uncommon and frequently result in peaceful death. Additionally, transcendence experiences of dying patients often provide comfort to the bereaved, assisting them in the grieving process.


Angiotensin II mediates cell hypertrophy in vascular smooth muscle cultures from hypertensive Ren-2 transgenic rats by an amiloride- and furosemide-sensitive mechanism.
We have reported that cultured vascular smooth muscle cells (VSMC) from hypertensive Ren-2 transgenic rats (TGR) are constitutively hypertrophic when compared to matched cells from normotensive Sprague-Dawley rats (SD), by a mechanism involving the endogenous production of angiotensin II (AII). In the present work, we analyzed the possible involvement of two Na+ transport mechanisms in TGR-VSMC hypertrophy. In both SD- and TGR-VSMC, AII increased both cell size, by a furosemide- and amiloride-sensitive mechanism, and Na+/K+/2Cl- cotransport activity, by an amiloride-sensitive mechanism. Under basal unstimulated conditions, TGR-VSMC showed higher cell size and Na+/K+/2Cl- cotransport activity than SD-VSMC. Under these same conditions, losartan, furosemide, or amiloride reduced cell size only in TGR-VSMC. Similarly, basal cotransport activity was reduced by losartan and amiloride to levels similar to those observed in SD-VSMC. We conclude that hypertrophy of TGR-VSMC is dependent on the endogenous production of AII and mediated by increased Na(+)-H+ exchange and Na+/K+/2Cl- cotransport activities.


Preventing transfusion-transmitted HIV infection in Latin America and the Caribbean: issues associated with blood donor interviews and sex between men.
Blood-borne transmission is the most efficient route for acquiring HIV infection, particularly through transfusion. Availability of noninfectious blood units for hemotherapy is a necessary condition for efficient functioning of health services. They have the obligation to ensure that the blood supply is safe, which includes interviewing potential donors to ascertain whether they might be at risk of being HIV infected. The interview procedures demand that blood services staff inquire potential blood donors about sexual practices associated to HIV transmission. Assumptions and misconceptions may unnecessary exclude adequate donors. Review of published and unpublished country reports in Latin America regarding blood safety and deferral criteria related to same sexual behavior among males. An analysis of criteria for deferral of potential blood donors shows inconsistencies that may impact the necessary safe blood supply. The blood donor deferral criteria should be revised according to relevant epidemiological evidence and social legitimacy. Personnel in blood banks and hemotherapy services should be educated to conduct appropriate interviews for accepting or deferring potential donors. Potential donors and the public should be knowledgeable for them to understand the reasons why some individuals may be deferred. Health authorities should work to reduce the stigma associated with HIV, prioritize building strong and meaningful partnerships with civil society, and engage diverse sectors in the national AIDS response.


Therapy of Patients with Neuroendocrine Neoplasia-Evidence-Based Approaches and New Horizons.
Neuroendocrine tumors (NETs) show low but increasing incidence and originate in multiple organs, including the pancreas, midgut, caecum, rectum, appendix, colon, and lungs. Due to their stunning genetic, histological, and clinical variability, diagnosis and treatment of NETs are challenging. In addition, low incidence and high variability hamper the implementation of high evidence trials. Therefore, guidelines do not cover the complexity of NETs and, frequently, treatment decisions are taken by interdisciplinary tumor conferences at comprehensive cancer centers. Treatment aims are (i) control of tumor growth, (ii) symptom control, as well as (iii) the improvement of progression-free survival (PFS) and overall survival (OS). Here, we discuss high evidence trials facilitating the achievement of these treatment aims. The majority of the evidence exists for treatment with somatostatin analogue, everolimus, peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE, sunitinib, and telotristat. Among those, PRRT is the only treatment option that has the potential to control symptoms, stop tumor growth, and to improve PFS and OS. In contrast, only a low level of evidence exists for treatment with cytotoxic drugs such as streptozotocin and doxorubicine. Finally, we discuss novel treatment options by a combination of cytotoxic drugs, 177Lu-DOTATATE, and tyrosine kinase inhibitors to be tested in randomized prospective trials in the future. In addition, the application of innovative isotopes, such as 225Ac, for PRRT is discussed.


Immunogenicity, Safety, and Tolerability of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Immunocompetent Adults Aged 18-49 Years With or Without Risk Factors for Pneumococcal Disease: A Randomized Phase 3 Trial (PNEU-DAY).
Adults with certain medical and behavioral factors are at increased risk for pneumococcal disease (PD). Sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults in some countries. This phase 3 trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults aged 18-49 years with or without predefined risk factors for PD (NCT03547167). Overall, 1515 participants were randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. Most common solicited adverse events (AEs) following administration of V114 or PCV13 as well as PPSV23 were injection-site pain and fatigue. The proportion of participants with AEs was comparable in both groups. V114 and PCV13 were immunogenic based on opsonophagocytic activity (OPA) geometric mean titers (GMTs) 30 days postvaccination for all serotypes contained in each respective vaccine. OPA GMTs to the 2 unique serotypes in V114 were robust in the V114 group. PPSV23 was immunogenic for all 15 serotypes contained in V114 in both vaccination groups, including 22F and 33F. V114 administered alone or sequentially with PPSV23 is well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, in immunocompetent adults aged 18-49 years with or without certain medical or behavioral risk factors for PD. NCT03547167 and EudraCT 2017-004915-38.


Anharmonic RRKM calculation for the dissociation of (H(2)O)(2)H(+) and its deuterated species (D(2)O)(2)D(+).
Investigations on the dissociation kinetics of hydrated protonium ions, (H(2)O)(2)H(+) and their deuterated species (D(2)O)(2)D(+), are reported based on the harmonic and anharmonic oscillator model using the transition state theory and ab initio calculations. We find that the dissociation of (H(2)O)(2)H(+) and (D(2)O)(2)D(+) exhibits a distinct threshold behavior due to the existence of activation energies. Moreover, the deviation between the harmonic and anharmonic dissociation rate constants becomes larger in the high energy or temperature range, with the rate constants becoming unreasonably large under the harmonic oscillator model. The isotope effect is found to become more distinct but only in the case of the anharmonic oscillator model. These results show that the anharmonic Rice-Ramsperger-Kassel-Marcus (RRKM) theory can provide a reasonably good description for the dissociation of (H(2)O)(2)H(+) and (D(2)O)(2)D(+). Furthermore, a theoretical model to demonstrate the principle of vibrational predissociation spectroscopy (VPS) is established from the viewpoint of RRKM theory and applied in determining the experimental conditions and understanding the role of the dissociation rate constant k(E) played in the VPS experiment, using (H(2)O)(2)H(+) and (D(2)O)(2)D(+) as examples.


Maturation of the neuromuscular junction in masseters of human fetus.
The aim of the present investigation is to examine if the histological maturation of the neuromuscular junction in the masseters of human fetuses has already begun by the 12-th week of gestation or not. Twenty-four masseter muscles from 14 human fetuses at gestational age 12 weeks were divided into two groups. In the first group, muscle sections were stained with Bielschowsky and Holzer stains for examination of neurofibrils and glial cells respectively. In the second group, rhodamine and fluorescein conjugated alpha-bungarotoxin were used to detect nicotinic receptors and anti-GAD for neuronal terminals. It was observed the presence of one axon for each end-plate and glial cells spread over a branched axon. The nicotinic receptors clustered in the neuromuscular junction, neuronal terminals and large oval nucleus were detected. These observations suggest that the maturation of the neuromuscular junctions of the masseter muscles in the human fetuses has already begun at the 12-th week of gestation.


Calcium and proton transport in membrane vesicles from barley roots.
Ca(2+) uptake by membrane fractions from barley (Hordeum vulgare L. cv CM72) roots was characterized. Uptake of (45)Ca(2+) was measured in membrane vesicles obtained from continuous and discontinuous sucrose gradients. A single, large peak of Ca(2+) uptake coincided with the peak of proton transport by the tonoplast H(+)-ATPase. Depending on the concentration of Ca(2+) in the assay, Ca(2+) uptake was inhibited 50 to 75% by those combinations of ionophores and solutes that eliminated the pH gradient and membrane potential. However, 25 to 50% of the Ca(2+) uptake in the tonoplast-enriched fraction was not sensitive to ionophores but was inhibited by vanadate. The results suggest that (45)Ca uptake was driven by the low affinity, high capacity tonoplast Ca(2+)/nH(+) antiporter and also by a high affinity, lower capacity Ca(2+)-ATPase. The Ca(2+)-ATPase may be associated with tonoplast, Golgi or contaminating vesicles of unknown origin. No Ca(2+) transport was specifically associated with the distinct peak of endoplasmic reticulum that was identified by NADH cytochrome c reductase, choline phosphotransferase, and dolichol-P-man-nosyl synthase activities. A small shoulder of Ca(2+) uptake in the plasma membrane region of the gradient was inhibited by vanadate and erythrosin B and may represent the activity of a separate plasma membrane Ca(2+)-ATPase. Vesicle volumes were estimated using electron spin resonance techniques, and intravesicular Ca(2+) concentrations were estimated to be as high as 5 millimolar. ATP-driven uptake of Ca(2+) created 800- to 2000-fold concentration gradients within minutes. Problems in interpreting the effects of Ca(2+) on ATP-generated pH gradients are discussed and the suggestion is made that Ca(2+) dissipates pH gradients by a different mechanism than is responsible for Ca(2+) uptake into tonoplast vesicles.


Near-infrared oxidative phosphorylation inhibitor integrates acute myeloid leukemia-targeted imaging and therapy.
Acute myeloid leukemia (AML) is a deadly hematological malignancy with frequent disease relapse. The biggest challenge for AML therapy is the lack of methods to target and kill the heterogeneous leukemia cells, which lead to disease relapse. Here, we describe a near-infrared (NIR) fluorescent dye, IR-26, which preferentially accumulates in the mitochondria of AML cells, depending on the hyperactive glycolysis of malignant cell, and simultaneously impairs oxidative phosphorylation (OXPHOS) to exert targeted therapeutic effects for AML cells. In particular, IR-26 also exhibits potential for real-time monitoring of AML cells with an in vivo flow cytometry (IVFC) system. Therefore, IR-26 represents a novel all-in-one agent for the integration of AML targeting, detection, and therapy, which may help to monitor disease progression and treatment responses, prevent unnecessary delays in administering upfront therapy, and improve therapeutic efficiency to the residual AML cells, which are responsible for disease relapse.


Atomically Precise Gold Nanoclusters: Towards an Optimal Biocompatible System from a Theoretical-Experimental Strategy.
Potential biomedical applications of gold nanoparticles have increasingly been reported with great promise for diagnosis and therapy of several diseases. However, for such a versatile nanomaterial, the advantages and potential health risks need to be addressed carefully, as the available information about their toxicity is limited and inconsistent. Atomically precise gold nanoclusters (AuNCs) have emerged to overcome this challenge due to their unique features, such as superior stability, excellent biocompatibility, and efficient renal clearance. Remarkably, the elucidation of their structural and physicochemical properties provided by theory-experiment investigations offers exciting opportunities for site-specific biofunctionalization of the nanoparticle surface, which remains a significant concern for most of the materials in the biomedical field. This concept highlights the advantages conferred by atomically precise AuNCs for biomedical applications and the powerful strategy combining computational and experimental studies towards finding an optimal biocompatible AuNCs-based nanosystem.


Recent advances in inhalation anesthesia.
Both desflurane and sevoflurane offer theoretical and practical advantages over other inhalation anesthetics for horses. The lower solubility of both agents provides improved control of delivery and helps to counteract the confounding influence of the voluminous patient breathing circuit commonly used for anesthetizing horses. The lower solubility should account for faster rates of recovery compared with the older agents; whether or not the quality of recovery differs remains to be objectively evaluated in a broad range of circumstances. The pharmacodynamic effects are, in large part, similar to those of isoflurane (e.g., low arrhythmogenicity) but with some differences. For example, desflurane may be overall more sparing to cardiovascular function (especially during controlled ventilation) compared with isoflurane and sevoflurane, which are roughly similar. Respiratory depression with both new agents is equal to or more depressing than isoflurane, suggesting the use of mechanical ventilation, especially in circumstances of prolonged management (i.e., hours of anesthesia). Both new anesthetics, not surprisingly, are expensive. From this point there are some agent-unique considerations. The anesthetic potency of both agents is less than that of isoflurane, which influences the cost of anesthesia, but also places an upper limit on inspired oxygen concentration (of particular concern with desflurane). Both agents require new vaporizers, but because of the high boiling point and steep vapor-pressure curve of desflurane, new technology was required. This translates into more costly equipment, adding to the cost of desflurane use. In addition, electricity is necessary for the new desflurane vaporizer to function, which limits its portability and adds additional practical considerations in its clinical use. On the other hand, desflurane strongly resists degradation both in vitro and in vivo, but in vitro degradation of sevoflurane by CO2 absorbents may produce renal injury. This may be true especially in association with low fresh-gas inflow rates (used to reduce the cost of using the new agent), and university based practices, where prolonged anesthesia is common.


Plasma biomarkers improve prediction of diabetic kidney disease in adults with type 1 diabetes over a 12-year follow-up: CACTI study.
The objective of the study was to determine whether plasma biomarkers of kidney injury improve the prediction of diabetic kidney disease (DKD) in adults with type 1 diabetes (T1D) over a period of 12 years. Participants (n = 527, 53% females) in the Coronary Artery Calcification in T1D (CACTI) Study were examined during 2002-04, at a mean (± standard deviation) age of 39.6 ± 9.0 years with 24.8 years as the median duration of diabetes. Urine albumin-to-creatinine (ACR) and estimated glomerular filtration rate (eGFR) by CKD-EPI (chronic kidney disease epidemiology collaboration) creatinine were measured at the baseline and after mean follow-up of 12.1 ± 1.5 years. Albuminuria was defined as ACR ≥30 mg/g and impaired GFR as eGFR <60 mL/min/1.73 m2. Kidney injury biomarkers (Meso Scale Diagnostics) were measured on stored baseline plasma samples. A principal component analysis (PCA) identified two components: (i) kidney injury molecule-1, calbindin, osteoactivin, trefoil factor 3 and vascular endothelial growth factor; and (ii) β-2 microglobulin, cystatin C, neutrophil gelatinase-associated lipocalin and osteopontin that were used in the multivariable regression analyses. Component 2 of the PCA was associated with increase in log modulus ACR [β ± standard error (SE): 0.16 ± 0.07, P = 0.02] and eGFR (β ± SE: -2.56 ± 0.97, P = 0.009) over a period of 12 years after adjusting for traditional risk factors (age, sex, HbA1c, low-density lipoprotein cholesterol and systolic blood pressure and baseline eGFR/baseline ACR). Only Component 2 of the PCA was associated with incident-impaired GFR (odds ratio 2.08, 95% confidence interval 1.18-3.67, P = 0.01), adjusting for traditional risk factors. The addition of Component 2 to traditional risk factors significantly improved C-statistics and net-reclassification improvement for incident-impaired GFR (ΔAUC: 0.02 ± 0.01, P = 0.049, and 29% non-events correctly reclassified, P < 0.0001). Plasma kidney injury biomarkers can help predict development of DKD in T1D.


[Effects of weight-bearing exercise on bone metabolism in college women].
This study was done to identify the effects of weight-bearing exercise(WBE) on bone metabolism. WBE was performed for 12 weeks by healthy college women. Bone-related parameters were measured four times during this period by evaluating the immunoradiometric assay and enzyme immunoassay. Bone mineral densities (BMDs) were measured by dual energy x-ray absorptiometry before and after the WBE program. Data was analyzed using t-test, paired t-test, x2-test, and repeated measures ANOVA. Osteocalcin, a bone formation marker, increased more in the experimental group than in the control group based on the interaction between time and group (F=3.29 p=.024). Little difference between the two groups was found for the other parameters: urinary deoxypyridinoline, insulin-like growth factor I, parathormone, serum calcium, and serum phosphorus without showing any time interaction between the groups. The femoral trochanter BMD rose in the experimental group while that of the control group fell, showing a significant difference for BMD (t=3.06 p=.005). However, there was no significant difference between the two groups for changes in BMD of the forearm, lumbar spine, femoral neck, and femoral ward's triangle. These findings supported the WBE is beneficial for increasing bone formation in college women and long-term application is needed to substantiate the effects of WBE as a intervention in promotion of bone-health.


The inactivation and reactivation of an expression-linked gene copy for a variant surface glycoprotein in Trypanosoma brucei.
We have previously shown that the gene for variant surface glycoprotein 118 of Trypanosoma brucei (strain 427) is activated by a duplicative transposition to a telomeric expression site. In chronically-infected animals, this expression-linked copy is lost when the 118 gene is replaced at the expression site by another variant surface glycoprotein gene. We show here that expression of the 118 gene can also be switched off without loss of the extra expression-linked copy. In two variants, called 1.8b and 1.8c, we find expression of the variant surface glycoprotein 1.8 gene, notwithstanding the continued presence of the 118 expression-linked copy. The 1.8 gene activated has a telomeric location, like the 118 expression-linked copy. In variant 1.8b, activation is accompanied by duplication of the 1.8 gene, resulting in an extra telomeric gene copy; in variant 1.8c it is not. Variants 1.8b and 1.8c both switch back preferentially to expression of the 118 gene. The 5'-flanking regions of the active, inactive and reactivated versions of the 118 expression-linked copy are indistinguishable by restriction mapping up to 28 kb. We conclude that there are at least two separate telomeric expression sites in our T. brucei strain. How these are switched on and off is unclear. The ability to retain expression-linked copies in inactive form may allow the trypanosome to re-programme the order in which variant surface glycoprotein genes are expressed.


[Relationship between alveolar epithelial type II cells and pulmonary surfactant protein A levels in young rats with acute lung injury].
This study examined the relationship between the ultrastructural alterations of alveolar epithelial cells type II (AEC-II) and pulmonary surfactant protein A (SP-A) levels in the lung tissue of young rats with acute lung injury (ALI) in order to explore the possible mechanism of ALI. Forty-eight young Sprague-Dawley rats were randomly divided into control and ALI groups. The rats in the ALI group were intraperitoneally injected with 4 mg/kg of lipopolysaccharide (LPS) in order to induce ALI. The control subjects were injected with the same volume of normal saline. Rats were sacrificed at 24, 48 and 72 hrs after LPS or NS injection. Lung samples were obtained from the lower parts of the left lung and fixed with 2.5% glutaraldehyde for transmission electron microscope examination and for Western blot test of SP-A. The microvilli of AEC-II disappeared 24 hrs after LPS injection. After 24 and 48 hrs of LPS injection, lamellar body (Lb) increased in number, enlarged in size and reduced in density, and the ring-like arrangement of Lb was present. By 48 hrs after LPS injection, giant Lb with vacuole-like deformity appeared. The contents of lung SP-A in the ALI group 24 hrs (6.52+/-0.62 vs 5.02+/-0.35; P<0.01) and 48 hrs (6.65+/-0.62 vs 5.01+/-0.36; P<0.01) after LPS injection were significantly higher than those in the control group. By 72 hrs after LPS injection, Lbs ruptured and were reduced in number. The shape of the nuclei was irregular and the border was blurred. The content of lung SP-A was greatly reduced in the ALI group 72 hrs after LPS injection compared with that in the control group (3.87+/-0.50 vs 5.22+/-0.36; P<0.01). The alterations of AEC-II and lung SP-A were time-dependent in young rats with ALI induced by LPS. In the early stage of ALI, the lung SP-A content showed a compensatory increase. With the increasing injury of AEC-II cells, the secretion of SP-A presented with a decompensation and the lung SP-A content decreased. This may be one possible mechanism for the development of ARD.


The use of microRNAs as reference genes for quantitative polymerase chain reaction in soybean.
Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is a robust and widely applied technique used to investigate gene expression. However, for correct analysis and interpretation of results, the choice of a suitable gene to use as an internal control is a crucial factor. These genes, such as housekeeping genes, should have a constant expression level in different tissues and across different conditions. The advances in genome sequencing have provided high-throughput gene expression analysis and have contributed to the identification of new genes, including microRNAs (miRNAs). The miRNAs are fundamental regulatory genes of eukaryotic genomes, acting on several biological functions. In this study, miRNA expression stability was investigated in different soybean tissues and genotypes as well as after abiotic or biotic stress treatments. The present study represents the first investigation into the suitability of miRNAs as housekeeping genes in plants. The transcript stability of 10 miRNAs was compared to those of six previously reported housekeeping genes for the soybean. In this study, we provide evidence that the expression stabilities of miR156b and miR1520d were the highest across the soybean experiments. Furthermore, these miRNAs genes were more stable than the most commonly protein-coding genes used in soybean gene expression studies involving RT-qPCR.


Risk of Endometriosis and Subsequent Ovary and Breast Cancers in Nurses: A Population-Based Cohort Study in Taiwan.
Endometriosis has been associated with the subsequent development of ovarian and breast cancers. This study evaluated whether nurses were at increased risks of developing endometriosis and subsequent ovarian and breast cancers. From Taiwan National Health Insurance Research Database during 2000 to 2011, we established 3 study cohorts, consisting of 23,801 nurses, 11,973 other hospital employees, and 143,096 general women free of endometriosis and cancer. Women in all cohorts were followed to the end of 2011 to measure the occurrences of endometriosis and subsequent ovarian and breast cancers. The incident endometriosis cases and related hazard ratio (HR) and 95% confidence interval (CI) were calculated. The incident cases of ovarian cancer and breast cancer and related odds ratio were calculated. The incidence of endometriosis was the highest in the nurse cohort (4.23 per 100, n = 966) followed by other health professionals (3.74 per 100, n = 427) and control cohort (3.06 per 100, n = 4193), with adjusted hazard ratios of 1.28 (95% CI = 1.20-1.38) and 1.13 (95% CI = 1.02-1.25), respectively, comparing to controls. Among those who developed endometriosis, nurses had higher subsequent ovarian cancer and lower breast cancer, but not significant. Nurses are at a higher risk of developing endometriosis. However, the link between endometriosis and subsequent cancers is weak.


Selective botulinum toxin injection in the treatment of recurrent deformity following surgical correction of club foot: a preliminary report of 3 children.
Management of a child with club foot deformity that recurs after an apparently successful posteromedial soft tissue release remains a challenge. Revision surgery is often attempted, but this carries a high risk of significant scarring or neurovascular complications. We have treated 3 children (3 feet) with relapsed club foot and fixed deformities, using Botulinum toxin A (BTX-A) injection into muscle groups clinically thought to be responsible for recurrent deformity, followed by moulded plaster casts. Two cases have maintained a good foot position with an minimum follow-up of 18 months, and one other is also doing well having had a tibialis anterior tendon transfer as well as the BTX-A therapy. In our limited experience, targeted BTX-A injection with plaster casting has been safe, and may obviate the need for major revision surgery in a proportion of cases with recurrent club foot deformity following previous posteromedial soft tissue release.


A study of family carers of people with a life-threatening illness 1: the carers' needs analysis.
This study examines the educational and supportive requirements of carers of people with a life-threatening illness. Responses would indicate the content and format of an educational or supportive programme of material that might then be developed. Twenty-four carers known to a Macmillan team in a national health service trust in the north of England were targeted for participation and quantitative data collected were analysed manually. Qualitative data arising from the carer interviews were subjected to a simple content analysis exercise that led to the identification of some overarching themes. In both strands of the research, similar emergent themes of physical, emotional and social stress were identified. Findings suggest that consideration of carers' age, length of caring experience and gender may be helpful in understanding their experience of stress and in developing support strategies.


Experiment and Simulation of Non-Reactive Solute Transport in Porous Media.
To more accurately predict the migration behavior of pollutants in porous media, we conduct laboratory scale experiments and model simulation. Aniline (AN) is used in one-dimensional soil column experiments designed under various media and hydrodynamic conditions. The advection-dispersion equation (ADE) and the continuous-time random walk (CTRW) were used to simulate the breakthrough curves (BTCs) of the solute transport. The results show that the media and hydrodynamic conditions are two important factors affecting solute transport and are related to the degree of non-Fickian transport. The simulation results show that CTRW can more effectively describe the non-Fickian phenomenon in the solute transport process than ADE. The sensitive parameter in the CTRW simulation process is β , which can reflect the degree of non-Fickian diffusion in the solute transport. Understanding the relationship of β with velocity and media particle size is conducive to improving the reactive solute transport model. The results of this study provide a theoretical basis for better prediction of pollutant transport in groundwater.


Global patterns in lake ecosystem responses to warming based on the temperature dependence of metabolism.
Climate warming is expected to have large effects on ecosystems in part due to the temperature dependence of metabolism. The responses of metabolic rates to climate warming may be greatest in the tropics and at low elevations because mean temperatures are warmer there and metabolic rates respond exponentially to temperature (with exponents >1). However, if warming rates are sufficiently fast in higher latitude/elevation lakes, metabolic rate responses to warming may still be greater there even though metabolic rates respond exponentially to temperature. Thus, a wide range of global patterns in the magnitude of metabolic rate responses to warming could emerge depending on global patterns of temperature and warming rates. Here we use the Boltzmann-Arrhenius equation, published estimates of activation energy, and time series of temperature from 271 lakes to estimate long-term (1970-2010) changes in 64 metabolic processes in lakes. The estimated responses of metabolic processes to warming were usually greatest in tropical/low-elevation lakes even though surface temperatures in higher latitude/elevation lakes are warming faster. However, when the thermal sensitivity of a metabolic process is especially weak, higher latitude/elevation lakes had larger responses to warming in parallel with warming rates. Our results show that the sensitivity of a given response to temperature (as described by its activation energy) provides a simple heuristic for predicting whether tropical/low-elevation lakes will have larger or smaller metabolic responses to warming than higher latitude/elevation lakes. Overall, we conclude that the direct metabolic consequences of lake warming are likely to be felt most strongly at low latitudes and low elevations where metabolism-linked ecosystem services may be most affected.


Ultrastructural evidence for calcium phosphate deposition by isolated corn shoot mitochondria.
This study demonstrates that isolated corn (Zea mays L. Wf9 xM14) shoot mitochondria will accumulate calcium phosphate crystals in vitro that are comparable to those observed in both in vivo and in vitro animal mitochondria. The intensity of deposition, as observed by electron microscopy, increased with incubation time, substrate concentration, and concentration of calcium and inorganic phosphate. Calcium phosphate deposits were initially observed as amorphous, nearly spherical areas that lacked sharp or clear edges, but which were crystalline in nature under heavier loading conditions and longer incubation times.


Rolling-circle amplification in DNA diagnostics: the power of simplicity.
Due to its robustness and simplicity, the rolling replication of circular DNA probes holds a distinct position in DNA diagnostics among other isothermal methods of target, probe or signal amplification. Major rolling-circle amplification approaches to DNA detection via posthybridization probe/signal turn-by-turn enhancement are briefly overviewed here with an emphasis on the new concepts and latest progress in the field, including the single-molecule and single-mutation detection assays as exemplary applications. Underlying mechanisms, current controversies and principal advantages of rolling-circle amplification are also considered. Possible future directions for the further advancement of this diagnostic methodology are outlined.


Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90.
Anaplastic large-cell lymphoma (ALCL) accounts for approximately 10% of pediatric non-Hodgkin lymphoma (NHL). Previous experience from NHL-Berlin-Frankfurt-Münster (BFM) trials indicated that the short-pulse B-NHL-type treatment strategy may also be efficacious for ALCL. The purpose of this study was to test the efficacy of this protocol for treatment of childhood ALCL in a large prospective multicenter trial and to define risk factors. From April 1990 to March 1995, 89 patients younger than 18 years of age with newly diagnosed ALCL were enrolled in trial NHL-BFM 90. Immunophenotype was T-cell in 40 patients, B-cell in 5, null in 31, and not determined in 13. Stages were as follows: I, n = 8; II, n = 20; III, n = 55; IV, n = 6. Extranodal manifestations were as follows: mediastinum, n = 28; lung, n = 13; skin, n = 16; soft tissue, n = 13; bone, n = 14; central nervous system, n = 1; bone marrow, n = 5. After a cytoreductive prephase, treatment was stratified into 3 branches: patients in K1 (stage I and II resected) received three 5-day courses (methotrexate [MTX] 0.5 g/m(2), dexamethasone, oxazaphorins, etoposide, cytarabine, doxorubicin, and intrathecal therapy); patients in K2 (stage II nonresected and stage III) received 6 courses; patients in K3 (stage IV or multifocal bone disease) received 6 intensified courses including MTX 5 g/m(2), high-dose cytarabine/etoposide. The Kaplan-Meier estimate for a 5-year event-free survival was 76% +/- 5% (median follow-up, 5.6 years) for all patients and 100%, 73% +/- 6%, and 79% +/- 11% for K1, K2, and K3, respectively. Events were as follows: progression during therapy, n = 2; progression or relapse after therapy, n = 20; second malignancy, n = 1. It was concluded that short-pulse chemotherapy, stratified according to stage, is effective treatment for pediatric ALCL. B symptoms were associated with increased risk of failure. (Blood. 2001;97:3699-3706)


Using economics alongside clinical trials: why we cannot choose the evaluation technique in advance.
When drafting protocols for the use of economic evaluation alongside clinical trials, it is common to have to specify which type of economic evaluation is going to be carried out. Will it be a cost-benefit analysis (CBA), cost-effectiveness analysis (CEA) or a cost-utility analysis (CUA)? It is our contention that prior specification of the appropriate economic technique is not possible, in the majority of cases, until data on effectiveness and cost are actually available. In this letter, we aim to demonstrate the thinking behind our contention and to illustrate this with two case studies; one of a recent randomised trial, the other of a trial currently in progress.


Cytogenetic research after accidental radiation exposure.
Currently, chromosome aberration analysis in peripheral lymphocytes is the most sensitive method to estimate individual doses in accidental radiation exposures. The assessment of dose is particularly reliable in cases with acute, uniform, whole-body exposure or after irradiation of large parts of the body. However, the scenarios of most radiation accidents largely result in partial-body exposures or a non-uniform dose distribution. This complicates dose estimation especially in cases with protracted or fractionated exposures. Problems exist also for the dose reconstruction of radiation exposures occurring a long time before sampling. To overcome these problems, the Qdr method or the "contaminated Poisson" method can be used to determine meaningful dose estimates from data based on conventional scoring of dicentrics. Scoring of so-called stable translocations by the newly developed technique of chromosome painting should be particularly useful for estimating doses of past exposures or of dose accumulation. After incorporation of radionuclides with largely localized depositions in certain organs or tissues, realistic individual dose estimates cannot be achieved. Exemplified by incidents involving larger groups of the population such as in Chernobyl and Goiania and by single cases with serious overexposures, chromosome dosimetry is evaluated in the present article.


Growth hormone replacement therapy in pediatric brain tumor survivors.
Brain tumors are the most frequent type of solid neoplasms in children with a recognized 5-year survival rate between 57% and 65%. The survival rate progressively increased in the last few years, due to the improvements in their treatment based on chemotherapy, radiotherapy, and surgery. At the same time, at long term follow-up, clinicians should carefully evaluate comorbidities and long-term sequelae secondary to the disease and its treatment. Growth hormone deficiency (GHD) is an endocrinopathy commonly found among pediatric cancer survivors, with a negative effect on the child's final height and entire metabolism. GH replacement therapy (GHRT), with a synthetic hormone analog, may improve the growth rate and finally adult height, ameliorating the quality of life after cancer treatment. However, in clinical practice, GHRT is adopted with caution for fear of cancer recurrence or the onset of second malignancies. In our review, we perform a focus on the GH structure and function, comparing benefits and risks of GHRT, derived from the analysis of the data currently available in the literature.


COVID-19, physical (in-)activity, and dementia prevention.
Physical inactivity is one major modifiable risk factor for dementia (especially Alzheimer's disease). Due to contact restrictions and isolation measures in response to the current COVID-19 (coronavirus disease 2019) pandemic, physical inactivity levels have increased by up to 30%, which will likely have adverse consequences for primary and secondary dementia prevention. Therefore, new interdisciplinary prevention approaches (eg, outdoor exercise; app-based exercise with online partners) are urgently needed that account for the suspected long-term lifestyle changes that the current-and upcoming-pandemics are likely to entail (increased use of home office, social isolation, avoidance of fitness centers and club sports, and so on).


Late abscess formation caused by silk suture following hysterectomy in a female dog.
A 5-year-old female cross-breed dog was presented for a one-month history of lethargy, poor appetite and weight loss. A hysterectomy had been performed 2 years ago. Abdominal palpation revealed a mid-abdominal mass and haematological analysis showed leucocytosis with left shift. On abdominal radiographs, a 9 cm in diameter soft tissue opacity mass ventral to the colon and caudal to the left kidney was observed. The abdominal ultrasonography revealed a mass well circumscribed, with a hyperechoic capsule and hypoechoic center with echoic debris. The presumptive diagnosis was an abscess due to foreign body granuloma. Laparotomy was performed and a mass close to the left ovary was found. Adhesions and residues of the suture material were observed close to the right ovary and the uterine body stump. The mass, both ovaries and adhesions were removed. On cut section of the mass two cavities were observed. The small one contained three embedded silk suture residues. Histopathological examination confirmed the diagnosis of a chronic abscess caused by silk suture.


Evidence-based effectiveness of herbal treatment modality for recurrent aphthous ulcers - A systematic review and meta-analysis.
Recurrent Apthous Ulcers (RAU) has affected mankind through time immemorial. It is the most commonly prevalent oral mucosal lesion manifesting as painful ulcers involving non - keratinised oral mucosa. This review was done to assess herbal intervention in RAU patients for outcomes of ulcer size and pain intensity. Literature search of published articles in Medline, Scopus, Ovid and Journal of Web upto August 2020 were reviewed for the pre-described outcomes. Revman 5.4 software was used for study analysis. Total 9 articles were finally chosen for qualitative analysis. Meta analytic comparison demonstrated the ulcer reduction (CI = -2.22 to - 0.09; p <0.001) and pain intensity (CI = -4.60 to - 0.08; p <0.001) was reduced in the herbal group as compared to the controls. A definite evidence of herbal intervention was noted in alleviating RAU signs and symptoms.