Bioinspired All-Polyester Diblock Copolymers Made from Poly(pentadecalactone) and Poly(3-hydroxycinnamate): Synthesis and Polymer Film Properties.
A bioinspired diblock copolymer was synthesized from pentadecalactone and 3-hydroxy cinnamic acid. Poly(pentadecalactone) (PPDL) with a molar mass of up to 43,000 g mol-1 was obtained by ring-opening polymerization initiated propargyl alcohol. Poly(3-hydroxy cinnamate) (P3HCA) was obtained by polycondensation and end-functionalized with 3-azido propanol. The two functionalized homopolymers were connected via 1,3-dipolar Huisgen addition to yield the block copolymer PPDL-triazole-P3HCA. The structure the block copolymer was confirmed by proton NMR, FTIR spectroscopy and GPC. By analyzing the morphology of polymer films made from the homopolymers, from a 1:1 homopolymer blend, and from the PPDL-triazole-P3HCA block copolymer, clearly distinct micro- and nanostructures were revealed. Quantitative nanomechanical measurements revealed that the block copolymer PPDL-triazole-P3HCA had a DMT modulus of 22.3 ± 2.7 MPa, which was lower than that of the PPDL homopolymer (801 ± 42 MPa), yet significantly higher than that of the P3HCA homopolymer (1.77 ± 0.63 MPa). Thermal analytics showed that the melting point of PPDL-triazole-P3HCA was similar to PPDL (89-90 °C), while it had a glass transition was similar to P3HCA (123-124 °C). Thus, the semicrystalline, potentially degradable all-polyester block copolymer PPDL-triazole-P3HCA combines the thermal properties of either homopolymer, and has an intermediate elastic modulus.


Simon effects in change detection and change blindness.
Responses to centrally presented target stimuli are faster when they are accompanied by a task-irrelevant lateral accessory stimulus that corresponds spatially with the response hand (accessory variant of the Simon effect). In four experiments, we tested whether this effect depends on the awareness of the accessory stimulus. In a change blindness task, participants were asked to respond to a central letter that was accompanied by a lateral background change on some trials. Change blindness describes the phenomenon that even large changes may remain unnoticed when they occur simultaneously with another visual disruption, e.g., a blank screen. In a series of four experiments, a significant Simon effect was observed both when the accessory stimulus reached awareness and when it remained unnoticed. These results indicate that, based on the spatial location of an accessory stimulus, a spatial code is generated. This code interferes with the response code on the response-selection stage.


The effect of oxidative environment on immunosuppressive properties of human seminal plasma.
Human seminal plasma (SP) has an important immunosuppressive function that enables sperm survival in the female reproductive tract. The aim of this study was to evaluate how oxidized proteins, by oxidative stress, may influence seminal plasma immunosuppressive properties in male infertility. Human SP immunosuppressive ability was evaluated by a lymphocyte proliferation assay. We used phytohemagglutinin mitogen to induce lymphocyte proliferation in the presence of human SP from infertile and fertile men, and under in vitro oxidizing conditions. Human SP-oxidized proteins (MDA-protein) were determined by the thiobarbituric acid test. Significant high levels of oxidized proteins were found in SP from asthenozoospermic patients. There was a significant difference (P < 0.05) between lymphocyte proliferation in the presence of SP from normozoospermic and asthenozoospermic group compared to the fertile donor group. Oxidized human SP in vitro allows for higher lymphocyte proliferation than non-oxidized SP. Human SP proteins have an inhibitory ability on lymphocyte proliferation, but under oxidative stress conditions, these proteins lose their immunosuppressive function.


Homeostatic model assessment indices in evaluation of insulin resistance and secretion in hemodialysis patients.
Some previous observations suggest that insulin resistance and glucose metabolism disturbances are frequent complications of chronic kidney disease. However, there are no conclusive studies on other indices of the effectiveness of insulin action in end-stage renal disease (ESRD) patients, including chronically hemodialysed (HD) ones. The groups comprised 33 non-diabetic ESRD hemodialysed patients and 33 healthy controls matched for age, sex, and body mass index (BMI). In both groups, HOMA-%B, HOMA-%S, HOMA-IR indices, and DI were calculated using HOMA1 and HOMA2 as measures of insulin resistance. The indices were also assessed in subgroups divided according to BMI. Mean fasting plasma glucose concentrations were lower in ESRD patients than in healthy persons (82.4±10.4 vs. 93.9±11.6, p=0.001). Fasting serum insulin concentrations were similar in both groups (median 6.8 vs. 6.0 mU/l, p=0.698). HOMA1-%B values were higher in ESRD patients than controls (median 137.1 vs. 81.6, p=0.002). HOMA1-%S (median 75.6 vs. 71.5) and HOMA1-IR (median 1.3 vs. 1.4) values were not significantly different (p=0.264 and p=0.189, respectively). DI1 levels were higher for HD patients than for healthy subjects (median 1.16 vs. 0.53, p<0.001). In subgroup analysis, all statistically significant differences were restricted mainly to persons with BMI <25 kg/m2. Similar results as for the HOMA1 model were obtained for HOMA2. 1. HOMA beta-cell function is strongly correlated with HOMA insulin resistance in HD patients. 2. In non-diabetic ESRD hemodialysed patients, the HOMA indices and DI may be useful and important models in interpretation of glucose metabolism disturbances.


[Nutrition and bone health. Dietary sodium intake and bone health].
Dietary sodium (Na) intake has been known to influence urinary calcium (Ca) excretion. High Na intake has been reported to increase urinary Ca excretion and bone resorption markers, and to be associated with bone loss. In these studies, however, the effect of high Na intake is small, and also affected by other nutrients intakes such as Ca or potassium intakes. Therefore, the association of Na intake and bone health could not be studied alone, but should be studied with full consideration of its interaction with other nutrients.


Effects of solar ultraviolet radiation on engineered human skin equivalent containing both Langerhans cells and dermal dendritic cells.
Exposure of human skin to solar ultraviolet (UV) light induces local and systemic immune suppression. It is known that alterations of immune functions of Langerhans cells (LCs) and dermal dendritic cells (DDCs) mediate this phenomenon. The purpose of this study was to mimic in vitro the early UV-induced skin disruption to better understand the involvement of the skin micro-environment in triggering this immunosuppressive state. We therefore developed skin equivalents (SEs) integrating LCs and DDCs derived from monocytes (mo-LCs and mo-DDCs, respectively). First, we showed that Langerin(+) mo-LC and dendritic cell (DC)-specific ICAM-3 grabbing nonintegrin (SIGN)(+) mo-DDCs were immunolocalized in situ in epidermal and dermal compartments of SEs, respectively. The SE micro-environment without immune cells displayed full cytokine profile that may ensure and maintain differentiation, localization, and immaturity of LCs and DDCs in situ, as shown by secretion of granulocyte-macrophage colony-stimulating factor, transforming growth factor beta (beta)-1, interleukin (IL)-4, IL-13, and IL-15 involved in cell differentiation; presence of complete chemokine network as macrophage inflammatory protein 3 alpha (alpha); low secretion of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), IL-1 beta, IL-6, and IL-8; and surprising secretion of immunosuppresive cytokine IL-10. Second, we demonstrated that skin micro-environment homeostasis was greatly disrupted under solar UV irradiation of SEs. In fact, we showed a pro-inflammatory state characterized by high secretion of TNF-alpha, IL-1 beta, IL-6, and IL-8 and low secretion of IL-10. This breakdown of immune homeostasis was visualized at the same time as in situ migration of mo-LCs and mo-DDCs into the dermal equivalent of SEs. Moreover, this tissue migration of mo-LCs and mo-DDCs into SEs was in accordance with the chemokine (C-C motif) receptor 7 expression and the DC-lysosome-associated membrane glycoprotein acquisition only on mo-LCs. Our results highlighted major participation of the skin micro-environment in the triggering and modulating of UV-induced skin immune responses. In addition, it could be concluded that these SEs are reliable tools for modeling biological events inaccessible in humans.


EPFFECT OF PROPRanolol on plasma renin level and angiotensin sensitivity in man.
The effect of 160 mg oral propranolol daily for a week on angiotensin sensitivity and plasma renin activity has been studied in ten patients with Kaplan's test and by determining renin with the radioimmunoassay. Propranolol was found to increase angiotensin activity and to reduce the plasma renin level. The results are compared with the respective effects of other antihypertensive drugs tested under identical conditions.


The effects of replacing the water model while decoupling water-water and water-solute interactions on computed properties of simple salts.
The effects of decoupling the water-water and water-solute interactions are studied with selected mono-valent ions as the solute. Using the ion-water cross terms developed for the BLYPSP-4F water model, we replaced the water potential with WAIL, TIP4P, and TIP3P without changing the ion-water parameters. When the adaptive force matching (AFM) derived BLYPSP-4F model is replaced by the other AFM derived WAIL model, the difference in ion properties, such as hydration free energies, radial distribution functions, relative diffusion constants, is negligible, demonstrating the feasibility for combining AFM parameters from different sources. Interestingly, when the AFM-derived ion-water cross-terms are used with a non-AFM based water model, only small changes in the ion properties are observed. The final combined models with TIP3P or TIP4P water reproduce the salt hydration free energies within 6% of experiments. The feasibility of combining AFM models with other non-AFM models is of significance since such combinations allow more complex systems to be studied without specific parameterization. In addition, the study suggests an interesting prospect of reusing the cross-terms when a part of a general force field is replaced with a different model. The prevailing practice, which is to re-derive all cross-terms with combining rules, may not have been optimal.


Mercury speciation by CE: a review.
CE methods for the speciation of inorganic and organomercury compounds are reviewed. Sample preparation, separation conditions and detection modes are discussed. Efficient separation and sensitive determination of mercury species by CE typically involves complexation with various thiols, chromogenic and other chelating agents; however, some methods do not require complexation. Spectrophotometric detection based on UV-visible absorption is by far the most commonly used. Hyphenated techniques, such as CE/inductively coupled plasma (ICP)-MS, hydride generation coupled to ICP-MS or atomic fluorescence spectrometry and CE/atomic absorption spectrometry are gaining popularity due to their high sensitivity and selectivity. Last, but not least, the potential and applications of electrochemical methods for detection of separated mercury species are outlined.


Planet earth calling: unveiling the brain's response to awe and driving eco-friendly consumption.
Eco-friendly consumption is important for solving climate crisis and moving humanity toward a better future. However, few consumers are willing to pay premiums for eco-friendly products. We investigated the psychological and neural factors that can increase eco-friendly consumption. We propose an experience of awe, in which the individual self is temporarily attenuated as the importance of beings other than oneself increases. Behavioral (Study 1) and functional magnetic resonance imaging (fMRI; Study 2) experiments were conducted to explore the awe mechanisms through which climate crisis messages lead to eco-friendly consumption. In Study 1, we found participants felt awe when exposed to climate crisis messages, and their choice of eco-friendly consumption increased. In Study 2, we found that when individuals were exposed to messages depicting the climate crisis (as opposed to a control stimulus), their brains exhibited a lower level of activation in the self-awareness processing and a higher level of activation in external attention processing areas. These results suggest that the awe experience plays an important role in promoting eco-friendly consumption. Marketing must evolve from satisfying basic individual needs to a high level for the well-being of humanity, the planet, and the biosphere. This study sheds light on our understanding of human perceptions of the climate crisis and suggests an effective communication strategy to increase individuals' eco-friendly actions.


Proteasome inhibitor treatment of antibody-mediated allograft rejection.
Bortezomib is a first-in-class proteasome inhibitor that was originally Food and Drug Administration approved for the treatment of multiple myeloma. In the past few years, off-label use in solid organ transplant recipients has demonstrated its ability to provide plasma cell-targeted therapy in humans. The purpose of this review is to provide an update of recent basic science and clinical results with bortezomib in treating antibody-mediated rejection (AMR) that occurs in solid organ transplant recipients. Proteasome inhibitor therapy for AMR in kidney transplant recipients is effective both as primary and as rescue therapy. Optimal responses with proteasome inhibitor therapy are obtained when AMR is diagnosed promptly and early in the posttransplant period. However, proteasome inhibitor therapy for late AMR (i.e., occurring 6 months or later posttransplant) provides less predictable results, likely due to the existence of a substantial bone marrow niche-resident long-lived plasma cell population. Proteasome inhibitor therapy has also recently been shown to provide effective therapy for AMR in heart, and also, transplant recipients. Proteasome inhibitor therapy with bortezomib provides effective treatment for AMR in solid organ transplant recipients. As the first plasma cell-targeted therapy, proteasome inhibitor therapy provides the additional advantage of opening new possibilities for biologically defined plasma cell-targeted therapies.


Cytotoxic T cells recognize a peptide from the circumsporozoite protein on malaria-infected hepatocytes.
Irradiated malaria sporozoites can induce CD8+ T cells that are required for protection against infection. However, the parasite antigens targeted by this immune response are unknown. We have discovered a 16-amino acid epitope from the Plasmodium yoelii circumsporozoite (CS) protein that is recognized by cytotoxic T cells from immune mice. Lymphocytes stimulated with this peptide can kill P. yoelii liver stage parasites in vitro in an MHC-restricted, antigen-specific manner. Thus, epitopes from the CS protein are presented on the surface of infected hepatocytes and can be targets for T cells, even though intact CS protein has not been detected on the surface of the infected hepatocyte. A vaccine that induced CTL to parasite antigens might protect humans against malaria by eliminating liver stage parasites.


C band variation in polytene chromosomes of Chironomus riparius (Diptera, Chironomidae) from a polluted Piedmont station (Italy).
C banding in polytene chromosomes of Chironomus riparius from a Santena polluted station of the river Po, Italy was described. A large variation in the appearance of C bands was established. The process involved the transformation of euchromatin into heterochromatin. Activation of all chromosomes at telomeres was found. A structural modification of telomeric heterochromatin may exist. The centromeric heterochromatin was rarely observed. A high percentage of an amplification (88%) in arm F, B3h, was recorded. These changes in the appearance of heterochromatin in the population studied could be considered as a type of polymorphic system, existing in the polluted population. For the first time in C. riparius two types of position effect variegation are reported. In arm E the euchromatin near to the centromere became inactive due to a heterozygous inversion and in arms D and F the opposite phenomenon was observed in which a heterozygous inversion partly suppressed the inactivation of heterochromatin.


Temporal relationship between cancers of the lung and upper aerodigestive tract.
We retrospectively reviewed the chart records at the Veterans General Hospital-Taipei for the period between January 1985 and December 1994 to examine the temporal relationship between cancers of the lung and upper aerodigestive tract. A total of 56 patients (54 males, 2 females) with histocytologically proven double primary cancers, with either lung cancer or upper aerodigestive tract cancers appearing first, were found. Squamous cell carcinoma was the most frequent histologic type of lung cancer (squamous 57%, adenocarcinoma 27%, poorly differentiated carcinoma 9%, small cell lung cancer 7%). The incidence of lung cancer patients with upper aerodigestive tract cancer was 0.9% (56/6412). There was no significant difference in the occurrence of upper aerodigestive tract cancer between non-small cell and small cell lung cancer (P > 0.05). However, the incidence of squamous cell lung cancer with upper aerodigestive tract cancer was higher than that of non-squamous cell lung cancer (P < 0.05). With regard to the location of lung cancer, the right lung was more commonly affected than the left (P < 0.001). The locations of upper aerodigestive tract cancers in these lung cancer patients were as follows: larynx 24, nasopharynx 11, esophagus 10, hypopharynx 4, pharyngeal tonsils 2, oral cavity 5. Most upper aerodigestive tract cancers were diagnosed before lung cancer (36/56, 64%), and lung cancer was diagnosed within 3 years in more than half of cases after the diagnosis of upper aerodigestive tract cancer (58.3%). Most lung cancers that preceded upper aerodigestive tract cancer were at an early stage at diagnosis (stage I 4, stage Illa 1), whereas the others, appearing either synchronously or after the diagnosis of upper aerodigestive tract cancer, were mostly at the late stage. There was no difference in survival between lung cancer patients with upper aerodigestive tract cancer and those without (P > 0.05).


Cell cycle synchronization of canine ear fibroblasts for somatic cell nuclear transfer.
Cycle synchronization of donor cells in the G0/G1 stage is a crucial step for successful somatic cell nuclear transfer. In the present report, we evaluated the effects of contact inhibition, serum starvation and the reagents - dimethyl sulphoxide (DMSO), roscovitine and cycloheximide (CHX) - on synchronization of canine fibroblasts at the G0/G1 stage. Ear fibroblast cells were collected from a beagle dog, placed into culture and used for analysis at passages three to eight. The population doubling time was 36.5 h. The proportion of G0/G1 cells was significantly increased by contact inhibition (77.1%) as compared with cycling cells (70.1%); however, extending the duration of culture did not induce further synchronization. After 24 h of serum starvation, cells were effectively synchronized at G0/G1 (77.1%). Although synchronization was further increased gradually after 24 h and even showed significant difference after 72 h (82.8%) of starvation, the proportion of dead cells also significantly increased after 24 h. The percentage of cells at the G0/G1 phase was increased (as compared with controls) after 72 h treatment with DMSO (76.1%) and after 48 h treatment with CHX (73.0%) or roscovitine (72.5%). However, the rate of cell death was increased after 24 and 72 h of treatment with DMSO and CHX, respectively. Thus, we recommend the use of roscovitine for cell cycle synchronization of canine ear fibroblasts as a preparatory step for SCNT.


Physical activity and stroke risk: the Framingham Study.
The authors prospectively examined the influence of increased levels of physical activity on risk of stroke in members of the Framingham Study cohort. Two separate analyses were performed, one during midlife in 1,897 men (mean age = 49.7 years) and 2,299 women (mean age = 49.9 years) and another when the cohort was older (1,361 men (mean age = 63.0) and 1,862 women (mean age = 63.7)). A structured questionnaire administered at two separate examinations was used to estimate the amount of metabolic work done during a typical 24-hour period. Physical activity was categorized into tertiles, and medium and high levels of physical activity were compared with a low level of physical activity, which was used as the referent group. Cox proportional hazards, life table, and time-dependent covariate analyses were used to examine the relation between level of physical activity and stroke risk over a follow-up period of up to 32 years. In men, adjusted analyses revealed that increased levels of physical activity were protective. The strongest effect was obtained from an analysis involving older cohort members in the medium tertile (risk ratio = 0.41, 95% confidence interval 0.24-0.69). High levels of physical activity did not confer an additional benefit over medium levels. Adjusted analyses showed no significant protective effect in women. These results indicate that medium and high levels of physical activity among men are protective against stroke relative to low levels.


Diagnosis and Treatment of Vaginal Discharge Syndromes in Community Practice Settings.
Although vaginal symptoms are common, diagnosis of bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and Trichomonas vaginalis (TV) is not standardized. Diagnostic approaches and appropriateness of treatment were evaluated for women with symptoms of vaginitis who were seeking care at community practice sites. Three hundred three symptomatic women, across 8 University of Pittsburgh Medical Center-affiliated clinics, were evaluated per standard office-based practice. Four of 5 vaginal swabs (1 cryopreserved) were collected for a US Food and Drug Administration-authorized nucleic acid amplification test (NAAT) for vaginitis/vaginosis diagnosis; Nugent scoring (BV); yeast culture (VVC); and a second NAAT (for TV). Two hundred ninety women had evaluable samples. Medical record extraction facilitated verification of treatments prescribed within 7 days of the index visit and return visit frequency within 90 days. Women had a mean age of 29.4 ± 6.5 years, 90% were not pregnant, 79% were of white race, and 38% reported vaginitis treatment within the past month. Point-of-care tests, including vaginal pH (15%), potassium hydroxide/whiff (21%), and wet mount microscopy (17%), were rarely performed. Of the 170 women having a laboratory-diagnosed cause of vaginitis, 81 (47%) received 1 or more inappropriate prescriptions. Of the 120 women without BV, TV, or VVC, 41 (34%) were prescribed antibiotics and/or antifungals. Among women without infectious vaginitis, return visits for vaginitis symptoms were more common among women treated empirically compared to those not receiving treatment (9/41 vs 5/79, P = .02). Within a community practice setting, 42% of women having vaginitis symptoms received inappropriate treatment. Women without infections who received empiric treatment were more likely have recurrent visits within 90 days. NCT03151928.


The challenge of embracing a smoke-free lifestyle: a neglected area in smoking cessation programs.
Relapse prevention theory and practice has focussed on teaching coping skills to deal with withdrawal and temptations to relapse with the result that treatments appear to be effective in reducing relapse over the short term, but not over the longer term. Once cravings subside ex-smokers face a further task of adjusting to a smoke-free lifestyle that involves learning to think and act like a non-smoker. To highlight this task, we operationalized a new conceptual framework that describes three tasks of quitting (the 3Ts): (i) making a quit attempt; (ii) learning to effectively deal with cravings and withdrawal; and (iii) adapting to a smoke-free lifestyle. This was introduced to the Quitline service in Victoria, Australia, in preparation for a randomized controlled trial aimed at testing whether a program of four to six extra callbacks could help ex-smokers with the third task and as a result reduce rates of relapse compared with Quitline's standard callback program. This paper describes the conceptual framework (focussing on the third task) and initial reactions to it from both Quitline advisors and callers. The conceptual framework is now integrated in the service and appears to have changed the way Quitline operates and the apparent expectations of its clients.


Solid Phase Mesh Enhanced Sorption from Headspace (SPMESH) Coupled to DART-MS for Rapid Quantification of Trace-Level Volatiles.
Quantitation of trace-level (μg/L to ng/L) volatile compounds is routinely performed in a broad range of applications, including analyses of odorants, pesticide residues, or toxins in foodstuffs and related matrices. Conventional analyses based on gas chromatography-mass spectrometry (GC-MS) are limited by low throughput, and ambient approaches to sample introduction have typically had poor sensitivity. We prepared polydimethylsiloxane-coated stainless steel meshes for extraction and preconcentration of volatiles (Solid Phase Mesh Enhanced Sorption from Headspace, SPMESH), which could then be analyzed by Direct Analysis in Real Time (DART)-MS. The SPMESH cards were characterized by electron microscopy, and figures of merit for the approach were determined using two representative volatiles: 2-isobutyl-3-methoxypyrazine (IBMP) and linalool. Using DART-MS/MS and isotopically labeled internal standards, we achieved detection limits of 21 ng/L and 71 μg/L for IBMP and linalool in water. Good accuracy and precision could also be achieved for IBMP spikes in grape macerate, although accuracy for linalool was compromised by the presence of interferences. Detection limits could be further improved by an order of magnitude through the use of high resolution (HR) MS. Because extraction can be performed inexpensively in parallel and because it requires short data acquisition times (<1 min), SPMESH-DART-MS may be appropriate for high throughput trace level volatile analyses.


Evaluation of Health Literacy and Associated Factors Among Adults Living in Saudi Arabia: A Cross-Sectional Study.
In this westernized culture, maintaining a healthy lifestyle has become a major health concern internationally. Health literacy is an emerging concept and requires effective measures and reform to improve the health status and health of individuals at both national and international levels, and has become one of the important determinants of individual health and healthcare service. This study aimed to assess health literacy among adults in Saudi Arabia. A cross-sectional study was conducted among a randomly selected population using a structured validated questionnaire over 4 months in 2021. The questionnaires designed for the study included 26 items divided into 5 domains assessed on a five-point Likert scale. Data were analyzed using IBM SPSS Statistics 26 (IBM Inc., Chicago, IL, USA) and IBM SPSS 26 (IBM Inc.). The mean score for reading, access to information, understanding, appraisal, and decision-making was 12.01 ± 4.37, 20.16 ± 7.17, 24.84 ± 8.37, 11.85 ± 4.90, and 36.94 ± 10.41 respectively. The mean scores of reading and understanding domains were found to have significant differences concerning gender (P < .05). Additionally, participants' age was significantly associated with the mean score of reading and decision-making (P < .006 and P < .049). The findings reported a prevalence of inadequate HL in the population of Saudi Arabia was 54.4%, and the determinants associated with the scores of HL were age, gender, and education.


Photodynamic therapy for cutaneous leishmaniasis: the effectiveness of topical phenothiaziniums in parasite eradication and Th1 immune response stimulation.
Photodynamic therapy (PDT) is emerging as a therapeutic modality in the clinical management of cutaneous leishmaniasis (CL). The efficacy of PDT against CL has been demonstrated previously with aminolevulinic acid, although the prolonged terms of therapy were less than ideal, and the search for new photosensitizers (PS) is ongoing. However, phenothiaziniums have demonstrated high parasiticidal effects in vitro. The subject of our investigation is the in vivo activity of two PS, 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium chloride (EtNBSe) and (3,7-Bis(N,N-dibutylamino) phenothiazinium bromide (PPA904). The results of our comparative analysis of the efficacy of these two phenothiazinium analogues demonstrated a high antiparasitic activity of EtNBSe in vitro, and the higher efficacy of PPA904 in a mouse model of CL. The kinetics of photodestruction are different in parasite and mammalian cells, and with both dyes, the macrophages are more susceptible to photodynamic effects than L. major parasites. As the number of parasites in the lesions undergoes a biphasic change, temporarily increasing on days 2-4 and decreasing on days 5-7, more than one treatment is required within an interval of 5 to 7 days. We have also shown that PPA904-PDT can provide an immunomodulating, dose-dependent efflux on IL-12p70 production. This mechanism could be responsible for promoting a more rapid healing in PPA904-PDT treated mice. Our initial data indicate that phenothiaziniums exhibit a high parasiticidal effect in vivo against CL; this finding may be of use in establishing curative PDT regimens for future clinical trials.


The effect of chronic ethanol administration on nitric oxide-mediated responses in rat isolated trachea preparation.
1. In the present study, we investigated the effect of chronic ethanol administration on nitric oxide (NO)-mediated responses in rat isolated trachea preparation. 2. Ethanol was given to rats in a modified liquid diet for 21 days. Isolated tracheal rings were then used to obtain responses to electrical field stimulation (EFS) after precontraction with 100 microM histamine. The parameters of field stimulation were as follows: supramaximal voltage of 50 V, 0.5 ms duration, 10-s train; 0.5, 1, 3, 5, 10, 20, 30 and 50 Hz at 2-min intervals. The effects of L-and D-arginine (10(-6) M) on the responses to field stimulation (10-20 Hz) were studied. In other experiments, we tested the effects of N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-6)-10(-5) M) and SIN-1 (10(-6)-10(-5) M) on the responses to field stimulation. 3. Electrical field stimulation induced relaxation responses in the tracheal rings precontracted with histamine from control- and ethanol-treated rats. The relaxation responses induced by EFS were significantly reduced in the tracheal rings precontracted with histamine from ethanol dependent group. The responses induced by EFS in both groups were completely abolished by tetrodotoxin (1 microM), but unaffected by hexamethonium (1 microM). Incubation with D-arginine did not cause statistically significant increases in relaxation responses to EFS in both groups. L-Arginine (10(-6) M) caused statistically significant increases in relaxation responses to EFS in control rats, but not in ethanol dependent rats. Incubation with L-NAME (10(-6)-10(-5) M) caused statistically significant inhibition of the relaxation responses to EFS in both groups. SIN-1 (10(-6)-10(-5) M) induced significantly increase in relaxation responses to EFS in both groups. 4. Our results suggest that the possible mechanism responsible for inhibition of tracheal inhibitory responses to EFS in ethanol-dependent rats may be a reduction in production of NO and in the uptake of L-arginine.


Morphological structure and variations of lumbar plexus in human fetuses.
The objective of this study is to study the anatomy of lumbar plexus on human fetuses and to establish its morphometric characteristics and differences compared with adults. Twenty lumbar plexus of 10 human fetal cadavers in different gestational ages and genders were dissected. Lumbar spinal nerves, ganglions, and peripheral nerves were exposed. Normal anatomical structure and variations of lumbar plexus were investigated and morphometric analyses were performed. The diameters of lumbar spinal nerves increased from L1 to L4. The thickest nerve forming the plexus was femoral nerve, the thinnest was ilioinguinal nerve, the longest nerve through posterior abdominal wall was iliohypogastric nerve, and the shortest nerve was femoral nerve. Each plexus had a single furcal nerve and this arose from L4 nerve in all fetuses. No prefix or postfix plexus variation was observed. In two plexuses, L1 nerve was in the form of a single branch. Also, in two plexuses, genitofemoral nerve arose only from L2 nerve. Accessory obturator nerve was observed in four plexuses. According to these findings, the morphological pattern of the lumbar plexus in the fetus was found to be very similar to the lumbar plexus in adults.


"It's hard for everyone" systemic barriers to home confinement to prevent community spread of COVID-19.
Rapid identification and isolation/quarantine of COVID-19 cases or close contacts, respectively, is a vital tool to support safe, in-person learning. However, safe isolation or quarantine for a young child also necessitates home confinement for at least one adult caregiver, as well as rapid learning material development by the teacher to minimize learning loss. The purpose of this study is to better understand barriers and supports to student home confinement. We conducted a mixed-methods study using focus group discussions and a self-administered online survey with parents and staff members from 12 elementary schools and childcare sites across San Diego County serving low-income and socially vulnerable families. Focus group participants reported that mental distress and loneliness, learning loss, childcare, food, income loss, and overcrowded housing were major barriers related to home confinement. The experiences described by FGD participants were prevalent in a concurrent community survey: 25% of participants reported that isolation would be extremely difficult for a household member who tested positive or was exposed to COVID-19, and 20% were extremely concerned about learning loss while in isolation or quarantine. Our findings suggest that there are serious structural impediments to safely completing the entire recommended course of isolation or quarantine, and that the potential for isolation or quarantine may also lead to increased hesitancy to access diagnostic testing.


Na4MgM2Se6 (M = Si, Ge): The First Noncentrosymmetric Compounds with Special Ethane-like [M2Se6](6-) Units Exhibiting Large Laser-Damage Thresholds.
Two new noncentrosymmetric compounds, Na4MgM2Se6 (I, M = Si; II, M = Ge), that contain special ethane-like [M2Se6](6-) units were reported for the first time. Remarkably, they exhibit high laser-damage thresholds [9 (I) and 7 (II) × benchmark AgGaS2] and moderate second-harmonic-generation responses with type I phase matching.


Association between sleep deficiency and cardiometabolic disease: implications for health disparities.
Cardiometabolic diseases, which include obesity, diabetes, hypertension, and cardiovascular disease, are associated with reduced quality of life and reduced life expectancy. Unfortunately, there are racial/ethnic and socioeconomic disparities associated with these diseases such that minority populations, such as African Americans and Hispanics, and those of lower socioeconomic status, experience a greater burden. Several reports have indicated that there are differences in sleep duration and quality that mirror the disparities in cardiometabolic disease. The goal of this paper is to review the association between sleep and cardiometabolic disease risk because of the possibility that suboptimal sleep may partially mediate the cardiometabolic disease disparities. We review both experimental studies that have restricted sleep duration or impaired sleep quality and examined biomarkers of cardiometabolic disease risk, including glucose metabolism and insulin sensitivity, appetite regulation and food intake, and immune function. We also review observational studies that have examined the association between habitual sleep duration and quality, and the prevalence or risk of obesity, diabetes, hypertension, and cardiovascular disease. Many experimental and observational studies do support an association between suboptimal sleep and increased cardiometabolic disease risk.


The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer.
During the last 2 decades there has been an increase in the number of men with prostate cancer placed on luteinizing hormone releasing hormone (LH-RH) agonist therapy. In addition, the duration of individual therapy has extended from what was once only a few months to, in many cases, several years. As a result there has been an increase in the incidence of side effects, including osteoporosis, decreased cognitive abilities, vascular stiffness and fatigue. We explored the use of estrogen in the form of diethylstilbestrol (DES) as an alternative treatment for men with prostate cancer, and introduce the concept of androgen deprivation without estrogen deprivation. In doing so we hope to elucidate some of the nonhormonal nonsteroidal effects of DES. Furthermore, we hope to define the mechanisms by which DES can be useful when LH-RH agonist therapy or orchiectomy has failed. We comprehensively reviewed the literature from 1935 to the present regarding estrogen and antiandrogen therapy. Our search focused on issues pertaining to side effects, efficacy and nonsteroidal effects of antiandrogens and estrogens. It is readily apparent from the literature that androgen deprivation with DES can achieve effective prostate cancer control with demonstrable benefits compared to conventional LH-RH agonist therapy. In particular, rates of bone resorption and osteoporosis are less with the use of estrogen therapies. Estrogen has a clear beneficial effect on cognitive function. The estrogen metabolite 2-methoxyestradiol has significant antiangiogenic and pro-apoptotic effects. These effects give estrogens an added anticancer effect not otherwise seen in conventional LH-RH agonist therapy. The efficacy of 1 mg DES extends well beyond its androgen suppressive effects. Androgen deprivation without estrogen deprivation is a concept that deserves further attention in the urological community.


Enhanced factor H binding to sialylated Gonococci is restricted to the sialylated lacto-N-neotetraose lipooligosaccharide species: implications for serum resistance and evidence for a bifunctional lipooligosaccharide sialyltransferase in Gonococci.
We isolated serologically identical (by serovar determination and porin variable region [VR] typing) strains of Neisseria gonorrhoeae from an infected male and two of his monogamous female sex partners. One strain (termed 398078) expressed the L1 (Galalpha1 --> 4 [corrected] Galbeta1 --> 4Glcbeta1 --> 4HepI) lipooligosaccharide (LOS) structure exclusively; the other (termed 398079) expressed the lacto-N-neotetraose (LNT; Galbeta1 --> 4GlcNAcbeta1 --> 3Galbeta1 --> 4Glcbeta1 --> 4HepI) LOS structure. The strain from the male index case expressed both glycoforms and exhibited both immunotypes. Nuclear magnetic resonance analysis revealed that sialic acid linked to the terminal Gal of L1 LOS via an alpha2 --> 6 linkage and, as expected, to the terminal Gal of LNT LOS via an alpha2--> 3 linkage. Insertional inactivation of the sialyltransferase gene (known to sialylate LNT LOS) abrogated both L1 LOS sialylation and LNT LOS sialylation, suggesting a bifunctional nature of this enzyme in gonococci. Akin to our previous observations, sialylation of the LNT LOS of strain 398079 enhanced the binding of the complement regulatory molecule, factor H. Rather surprisingly, factor H did not bind to sialylated strain 398078. LOS sialylation conferred the LNT LOS-bearing strain complete (100%) resistance to killing by even 50% nonimmune normal human serum (NHS), whereas sialylation of L1 LOS conferred resistance only to 10% NHS. The ability of gonococcal sialylated LNT to bind factor H confers high-level serum resistance, which is not seen with sialylated L1 LOS. Thus, serum resistance mediated by sialylation of gonococcal L1 and LNT LOS occurs by different mechanisms, and specificity of factor H binding to sialylated gonococci is restricted to the LNT LOS species.


Coverage is the key for effective screening of Chlamydia trachomatis in Australia.
The rate of diagnosis of Chlamydia trachomatis (chlamydia) infection has risen dramatically in Australia. In response, the Australian government is planning to implement systematic screening and testing. Several decisions must be made, including whom to screen. To inform decisions surrounding screening, a dynamic transmission model of the chlamydia epidemic was developed and parameterized with Australian sexual behavior and epidemiology data. A range of screening strategies and coverage rates were evaluated targeting various groups based on age and sex. Rigorous uncertainty and sensitivity analyses were undertaken. The model predicts that even moderate screening coverage in young adults (<25 years old) will reduce prevalence rapidly. The absolute numbers of people screened, rather than the sex targeted, is the key determinant in reducing prevalence. Sensitivity analysis determined that chlamydia transmission is strongly related to 2 biological parameters (the proportion of infections that are asymptomatic in women and the duration of infection in men) and 2 behavioral parameters (the frequency of sex acts for 20-24-year-olds and the level of condom usage). The model predicts that routine annual screening can significantly reduce the prevalence of chlamydia within 10 years, provided that adequate screening coverage is achieved. The most effective screening strategies will be those that target 20-24-year-olds.


Morphologic, phenotypic and functional characteristics of endothelial cells derived from human hepatic cavernous hemangioma.
The pathogenesis of cavernous hemangiomas is largely unknown, and it is speculated that abnormal vasculogenesis and angiogenesis may be involved. In this study, the characteristics of cavernous hemangioma endothelial cells (CHECs) derived from the human liver were analyzed in terms of morphology, phenotype and function and compared with human liver sinusoidal endothelial cells (LSECs). By transmission electron microscopy, abnormally expanded endoplasmic reticulum (ER) and similarly arranged cytoplasmic vacuoles were only found in CHECs. Phenotypic analysis showed that the expression of alphavbeta3 was significantly increased in CHECs. mRNA expression of vascular endothelial growth factor A, and angiopoietins 1 and 2 was significantly increased in CHECs compared to LSECs. The functional analysis indicated that CHECs released more vascular endothelial growth factor A, produced significantly more pro-matrix metalloproteinase 2 (pro-MMP2) and activated MMP2, and exhibited higher procoagulant and fibrinolytic activities compared with LSECs. Confocal microscopy revealed that MMP2 was concentrated in some cytoplasmic granules of CHECs and was consistent with the distribution of expanded ER. CHECs exhibited more activated angiogenesis capacity and formed abnormal capillary-like structures in vitro. These results suggested that endothelial cells (ECs) derived from human cavernous hemangiomas differ from normal ECs in morphology, phenotype and function.


Novel design of hollow g-C3N4 nanofibers decorated with MoS2 and S, N-doped graphene for ternary heterostructures.
Herein, we newly design a ternary structure of 1-dimensional hollow g-C3N4 nanofibers (HGCNF) decorated with molybdenum disulfide (MoS2) and sulfur/nitrogen-doped graphene (SNG) via a one-pot hydrothermal treatment at relatively low temperature. The firstly presented HGCNF are fabricated using electrospinning followed by the thermal sintering method. After that, MoS2 is grown onto HGCNF, while SNG covered the structures during the hydrothermal method. We observed the morphological structures, chemical composition and optical absorbance of this ternary HGCNF/SNG/MoS2 structure. Of the as-prepared catalysts, HGCNF/SNG/MoS2 exhibited a good possibility to produce hydrogen as an electrocatalyst. Furthermore, we evaluated its stability performance using chronoamperometry for 48 hours, as well as by 3000 cycles of cyclic voltammetry. From the double-layer capacitance measurement, HGCNF/SNG/MoS2 proved itself as an electrocatalyst due to the higher value of electrocatalytically active sites to be 6.97 × 10-3 F cm-2 than that of only HGCNF (0.18 × 10-5 F cm-2) and the binary structure of HGCNF/MoS2 (2.54 × 10-3 F cm-2). We believe that our novel 1-dimensional ternary HGCNF/SNG/MoS2 structure has expedited the electron pathways by reducing the resistance at interfaces among HGCNF, SNG and MoS2, to be potentially useful for the hydrogen evolution reaction.


Temporal and spatial expression of major histocompatibility complex class I H-2K in the early mouse embryo.
The pattern of expression of major histocompatibility complex class I H-2K in early mouse embryos was determined through reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization methods. H-2K transcripts were detected in all stages of preimplantation embryos from oocyte to blastocyst. In the blastocyst, transcripts were found in both trophectoderm and inner cell mass. Quantitative RT-PCR revealed that in CD-1 mice H-2Kq transcript levels per oocyte/embryo were 71 +/- 13 in oocyte, 150 +/- 9 in 2-cell embryos, 220 +/- 22 in 8-cell embryos, and 560 +/- 86 in blastocysts. By RT-PCR, H-2Kq mRNA was also detected in postimplantation staged (7.5-, 8.5-, and 9.5-day) embryos. Examination of components of the 7.5-day conceptus revealed the highest levels in the ectoplacental cone (EPC), followed by the decidua, and finally the embryo. The spatial distribution of H-2K transcripts in decidua was very heterogeneous, whereas the low levels in the embryo were found to be uniform throughout. Both cell types of the EPC contained H-2K transcripts. In the 9.5-day embryo, high transcript levels were observed over the developing liver above a background of constitutive expression everywhere else.


[Clinical pharmacology and aging].
Clinicians must be aware that aging can lead to changes in the pharmacokinetics and pharmacodynamics of many drugs. Drug distribution may be modified with aging secondarily to the decrease of serum albumin and to modifications of body composition (increase in the proportion of fat mass and decrease of lean mass). Hepatic metabolism of several drugs is reduced with age, especially drugs which depend of hepatic blood flow or P450 cytochroms. The incidence of renal failure increase largely with age. Glomerular filtration rate should be systematically estimated in older patients and, when needed, the doses of those drugs having significant renal elimination should be adjusted. In older patients, changes in the response to drugs can also develop, concerning specially the central nervous system (increased sensibility to any neurological effect of drugs), the cardiovascular system and the renal management of water and electrolytes. In many cases, the pharmacological changes associated to age are mild and requires no dose adjustment. However, many drugs should be adapted depending on the individual situation of each patient, particularly his renal function and nutritional state. Finally, some drugs should be avoided in older patients because of a bad effectiveness/tolerance ratio compared to alternatives.


Spontaneous calf haematoma in severe dengue.
We report a case of spontaneous calf muscle haematoma, formed during the recovery phase of dengue haemorrhagic fever, which, to the best of our knowledge, has never been encountered before. A 45-year-old man presented with features of severe dengue and got admitted to our intensive care unit. He was treated with intravenous fluid therapy and supportive measures, and gradually improved, initially. However, during the recovery phase, he suddenly developed painful left calf, which was found tender, hot and swollen on physical examination. Colour Doppler ultrasound revealed left calf haematoma. As the patient rapidly developed local compartmental syndrome, surgical evacuation of the haematoma followed by urgent fasciotomy was performed. He recovered without further complication and was discharged home. At follow-up after 2 months, he remained well.


Frontal Release Signs and Their Relationship With the Initiation and Perseveration Component of the Mattis Dementia Rating Scale in Persons With Dementia.
As part of a longitudinal study of dementia, 35 elderly patients with dementia were studied, correlating frontal release signs and performance on components of the Mattis Dementia Rating Scale. A frontal release score was developed using glabellar, palmar grasp, plantar grasp, and palmomental signs. There was a direct relationship between the frontal release score and the Initiation and Perseveration component of the Mattis Dementia Rating Scale. This relationship persisted between isolated glabellar sign findings and the Initiation and Perseveration component of the Mattis Dementia Rating Scale. These findings are highly preliminary. Refining frontal release sign testing and frontal lobe mental status testing may strengthen their relationship and lead to a better understanding of dementia and its progression.


Sesquiterpene lactones: adverse health effects and toxicity mechanisms.
Sesquiterpene lactones (STLs) present a wide range of biological activities, mostly based on their alkylating capabilities, which underlie their therapeutic potential. These compounds are the active constituents of a variety of plants, frequently used as herbal remedies. STLs such as artemisinin and its derivatives are in use as first-line antimalarials while others, such as parthenolide, have recently reached cancer clinical trials. However, the toxicological profile of these compounds must be thoroughly characterized, since the same properties that make STL useful medicines can also cause severe toxicity. STL-containing plants have long been known to induce a contact dermatitis in exposed farm workers, and also to cause several toxic syndromes in farm animals. More recently, concerns are been raised regarding the genotoxic potential of these compounds and the embryotoxicity of artemisinins. A growing number of STLs are being reported to be mutagenic in different in vitro and in vivo assays. As yet no systematic studies have been published, but the genotoxicity of STLs seems to depend not so much on direct DNA alkylation as on oxidative DNA damage and other partially elucidated mechanisms. As the medicinal use of these compounds increases, further studies of their toxic potential are needed, especially those focusing on the structural determinants of genotoxicity and embryotoxicity.


Influence of the water activity of a solid substrate on the growth rate and sporogenesis of filamentous fungi.
The water activity (a(w)) of substrates has been related to the mycelial growth and the sporogenesis of two molds. In the absence of other limiting factors, optimal a(w) values were determined for growth and sporogenesis as 0.99 and 0.98, respectively, for Trichoderma viride TS and 0.97 and 0.96 for Penicillium roqueforti. In all cases, the accuracy of the optimal value would justify the regulation of this parameter. A model was proposed which establishes a relationship between the mycelial growth and the water activity value of the substrate.


Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration.
The rd3 mouse is one of the oldest identified models of early-onset retinal degeneration. Using the positional candidate approach, we have identified a C-->T substitution in a novel gene, Rd3, that encodes an evolutionarily conserved protein of 195 amino acids. The rd3 mutation results in a predicted stop codon after residue 106. This change is observed in four rd3 lines derived from the original collected mice but not in the nine wild-type mouse strains that were examined. Rd3 is preferentially expressed in the retina and exhibits increasing expression through early postnatal development. In transiently transfected COS-1 cells, the RD3-fusion protein shows subnuclear localization adjacent to promyelocytic leukemia-gene-product bodies. The truncated mutant RD3 protein is detectable in COS-1 cells but appears to get degraded rapidly. To explore potential association of the human RD3 gene at chromosome 1q32 with retinopathies, we performed a mutation screen of 881 probands from North America, India, and Europe. In addition to several alterations of uncertain significance, we identified a homozygous alteration in the invariant G nucleotide of the RD3 exon 2 donor splice site in two siblings with Leber congenital amaurosis. This mutation is predicted to result in premature truncation of the RD3 protein, segregates with the disease, and is not detected in 121 ethnically matched control individuals. We suggest that the retinopathy-associated RD3 protein is part of subnuclear protein complexes involved in diverse processes, such as transcription and splicing.


Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications.
Metabolic reprogramming of cells, from the normal mode of glucose metabolism named glycolysis, is a pivotal characteristic of impending cancerous cells. Pyruvate kinase M2 (PKM2), an important enzyme that catalyzes the final rate-limiting stage during glycolysis, is highly expressed in numerous types of tumors and aids in development of favorable conditions for the survival of tumor cells. Increasing evidence has suggested that PKM2 is one of promising targets for innovative drug discovery, especially for the developments of antitumor therapeutics. Herein, we systematically summarize the recent advancement on PKM2 modulators including inhibitors and activators in cancer applications. We also discussed the classifications of pyruvate kinases in mammals and the biological functions of PKM2 in this review. We do hope that this review would provide a comprehensive understanding of the current research on PKM2 modulators, which may benefit the development of more potent PKM2-related drug candidates to treat PKM2-associated diseases including cancers in future.


Ventricular assist device support for management of sustained ventricular arrhythmias.
We describe herein the cases of 2 patients who had ventricular arrhythmias. In one, a short-term biventricular assist device, the ABIOMED BVS 5000, was placed because the patient had sustained ventricular tachycardia and could not be weaned from cardiopulmonary bypass. Excellent hemodynamic support was maintained for several days while the antiarrhythmic therapy was maximized. Sinus rhythm was restored, and the patient was successfully weaned from the ventricular assist device. However, the substrate for the arrhythmia persisted, and a recurrence, 1 week later, resulted in the patient's death. In the 2nd patient, the use of an implantable left ventricular assist device was successful in temporarily alleviating the ventricular tachycardia associated with ischemic cardiomyopathy. However, after 2 days of device assistance, the patient experienced a recurrence of the tachycardia, which degenerated into ventricular fibrillation with a marked deterioration in the patient's hemodynamics. The arrhythmia persisted despite multiple attempts at external cardioversion, and internal cardioversion and placement of an automatic implantable cardioverter-defibrillator were necessary. This treatment, along with repeated boluses of amiodarone, led to successful suppression of the arrhythmias, and the patient eventually underwent transplantation. The mechanical hemodynamic support of the circulation by ventricular assist devices was effective in supporting these 2 patients who had sustained ventricular arrhythmias.


Twelve tips for optimising medical student retention of anatomy.
Concern that many graduate medical students do not know sufficient anatomy to safely and effectively assess and treat patients is a frequent complaint by clinicians. Although downgrading of anatomy relative to newer basic sciences is often blamed, there is evidence students rapidly forget anatomy. However, there are a number of ways instructors can foster long-term retention of anatomy, the most powerful involving intertwining clinical and anatomical information and assessing in-depth processing. Assisting this process is 'triaging' the curriculum so it contains only clinically engaged anatomy. Students are far more likely to remember information which they consider to be relevant to their future vocation. Therefore, teaching only anatomy which is likely to be useful in a clinical context tends to improve long-term retention of anatomy by medical students. Other helpful techniques include incorporating surface and radiological anatomy in a vertically integrated curriculum, reciprocal peer teaching and employing clinically qualified instructors.


Pancreatic ductal adenocarcinoma showing iso-attenuation in early-phase contrast-enhanced CT: comparison with histopathological findings.
To clarify the CT characteristics and histopathological findings of pancreatic ductal adenocarcinomas that are not detected in early-phase contrast-enhanced CT images. The CT findings of eight patients with histopathologically proven pancreatic carcinomas that were not detected in early-phase images following the rapid injection of contrast material were reviewed. The examinations consisted of pre-contrast-enhanced CT and multi-phase contrast-enhanced CT, with thin-section scanning in each patient. The CT findings were compared with those of the resected specimens. In all cases but one, the lesion was in the pancreatic head. In seven cases, the tumor did not appear as a focal area of hypoattenuation compared with surrounding pancreatic parenchyma in early-phase images, and in the remaining case, small areas of poor enhancement were observed. In late-phase images, hyperattenuated and isoattenuated areas were seen in six and two cases, respectively. In all but one case, the lesion was less than 40 mm in size. All lesions were composed of acinar tissues and tumor cells, and contained small amounts of mucin, necrotic tissue, and pus. The fibrous tissues were not abundant and were interlobular and/or relatively loose. Pancreatic ductal adenocarcinomas showing isoattenuation in early-phase images tend to be relatively mild lesions with scirrhous and/or desmoplastic changes.


Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10.
The symptoms of severe early-onset obesity, adrenal insufficiency, and red hair define the proopiomelanocortin (POMC) deficiency syndrome as described so far in two children with complete loss-of-function mutations of the human POMC gene. In POMC deficiency, obesity reflects the lack of POMC-derived peptides as ligands at the melanocortin (MC) MC4 and MC3 receptors, which are expressed in the hypothalamic leptin-melanocortin pathway of body weight regulation. Hypocortisolism and alteration of pigmentation are caused by the lack of POMC-derived peptides at the adrenal MC2 receptor and the skin MC1 receptor, respectively. Here we describe three new cases of complete loss-of-function mutations of the POMC gene. Patients were diagnosed based on the clinical trials of red hair, adrenal insufficiency, and early-onset severe obesity. One previously described translation initiation mutation (C3804A) as well as one new nonsense (A6851T) and two new frame-shift mutations (6996del and 7100 + 2G) were found in homozygosity or compound heterozygosity. The heterozygous parents were found to have high normal or mildly elevated body weight, suggesting a dosage effect of the POMC gene product on weight regulation. To compensate for the lack of hypothalamic melanocortin function, we initiated a trial in the two previously published patients with intranasal ACTH4-10, a melanocortin fragment for which an anorexic effect has been described recently. During 3 months with increasing doses of ACTH4-10, no change of body weight or metabolic rate was observed, suggesting that at least in these two POMC-deficient patients ACTH4-10 is without any compensatory effect. In the same two patients, further investigation revealed a mildly elevated TSH. However, a 1-yr treatment with thyroid hormone did not result in a significant reduction of body weight.


Involvement of apolipoprotein E in excess fat accumulation and insulin resistance.
Although apolipoprotein E (apoE) is well known to play a major role in lipid metabolism, its role in glucose and energy homeostasis remains unclear. Herein, we established apoE-deficient genetically obese Ay (apoE(-/-);Ay/+) mice. ApoE deficiency in Ay mice prevented the development of obesity, with decreased fat accumulation in the liver and adipose tissues. ApoE(-/-);Ay/+ mice exhibited better glucose tolerance than apoE(+/+);Ay/+ mice. Insulin tolerance testing and hyperinsulinemic-euglycemic clamp study revealed marked improvement of insulin sensitivity, despite increased plasma free fatty acid levels. These metabolic phenotypes were reversed by adenoviral replenishment of apoE protein, indicating circulating apoE to be involved in increased adiposity and obesity-related metabolic disorders. Uptake of apoE-lacking VLDL into the liver and adipocytes was markedly inhibited, but adipocytes in apoE(-/-);Ay/+ mice exhibited normal differentiation, suggesting that apoE-dependent VLDL transport is involved in the development of obesity, i.e., surplus fat accumulation. Interestingly, apoE(-/-);Ay/+ mice exhibited decreased food intake and increased energy expenditure. Pair-feeding experiments indicate these phenomena to both contribute to the obesity-resistant phenotypes associated with apoE deficiency. Thus, apoE is involved in maintaining energy homeostasis. ApoE-dependent excess fat accumulation is a promising therapeutic target for the metabolic syndrome.


Evaluating Whole Grain Intervention Study Designs and Reporting Practices Using Evidence Mapping Methodology.
Consumption of whole grains have been associated with reduced risk of chronic diseases in many observational studies; yet, results of intervention studies are mixed. We aimed to use evidence mapping to capture the methodological and reporting variability in whole grain intervention studies that may contribute to this inconsistency. We conducted a reproducible search in OVID Medline for whole grain human intervention studies (published 1946 to February 2018). After screening based on a priori criteria, we identified 202 publications describing a total of 213 unique trials. Over half (55%) were acute trials, lasting ≤1 day, 30% were moderate duration studies (up to 6 weeks) and 15% were of longer duration (more than 6 weeks). The majority of acute trials (75%) examined measures of glycaemia and/or insulinemia, while most of the longer trials included measures of cardiometabolic health (71%), appetite/satiety (57%) and weight/adiposity (56%). Among the moderate and long duration trials, there was a wide range of how whole grains were described but only 10 publications referenced an established definition. Only 55% of trials reported the actual amount of whole grains (in grams or servings), while 36% reported the amount of food/product and 9% did not report a dose at all. Of the interventions that provided a mixture of whole grains, less than half (46%) reported the distribution of the different grain types. Reporting of subject compliance also varied and only 22% used independent biomarkers of whole grain intake. This evidence map highlights the need to standardize both study protocols and reporting practices to support effective synthesis of study results and provide a stronger foundation to better inform nutrition scientists and public health policy.


Experimental study of the POP technique: focus on the physical basis of the process.
Central or peripheral vascular access devices have been in use for many decades. However, despite adequate care and maintenance, complete occlusion may occur, and its impact cannot be overlooked. A new procedure using a percussion technique has been published and referred as 'the POP technique'. A hydrodynamic bench was used permitting both the recording of the movement of the piston with a fast camera and the pressure variations in the polyurethane and silicone catheters while connected to 2- and 3-piece syringes. The results are twofold. First the upward movement of the piston leads to the installation of a saturation vapour pressure in the body of the syringe. During this sequence, the clot is submitted to a force of aspiration. Then the release of the plunger leads to a pulse pressure whose dynamics and intensity are dependent of the types of syringes and catheters. The experiments bring to light the importance of practical features such as the orientation of the syringe and the nature of the polyurethane or silicone catheters. Then the analysis enables the definition of practical rules for safe practice of the POP technique. This study will impact clinicians as many may be tempted to use the technique in hope to resolve the occlusion safely, in a timely manner.


Somatic Mutations of TSC2 or MTOR Characterize a Morphologically Distinct Subset of Sporadic Renal Cell Carcinoma With Eosinophilic and Vacuolated Cytoplasm.
The differential diagnosis of renal cell neoplasms with solid or nested architecture and eosinophilic cytoplasm has become increasingly complex. Despite recent advances in classifying a number of entities exhibiting this morphology, some tumors remain in the unclassified category. Here we describe a morphologically distinct group of sporadic renal cell carcinoma (RCC) with predominantly nested architecture, eosinophilic, and remarkably vacuolated cytoplasm retrospectively identified from a cohort of previously unclassified tumors. We examined the clinicopathologic and immunohistochemical features of these tumors and investigated their mutational and copy number alterations using a targeted next-generation sequencing platform. The study included 7 patients with a mean age of 54 years (range: 40 to 68 y) and a male to female ratio of 3:4. All patients presented with a solitary renal mass and had no prior medical or family history raising concern for syndromic conditions. Tumors were well-circumscribed, unencapsulated, and comprised of nests of eosinophilic cells in a hypocellular and often edematous stroma. Tumor cells had round nuclei with prominent nucleoli and granular cytoplasm with striking vacuolization. Thick-walled vessels and calcifications were also frequently present, whereas increased mitotic activity, necrosis, foamy histiocytes or lymphocytic infiltrates were not identified. All cases were positive for PAX8, had retained expression of SDHB and FH, and exhibited a CK7-/CK20- phenotype. While cathepsin-K was positive in 5 cases, none exhibited immunoreactivity to HMB45 or Melan A, or TFE3 immunostaining. Next-generation sequencing identified somatic inactivating mutations of TSC2 (3/5 tumors tested) or activating mutations of MTOR (2/5) as the primary molecular alterations, consistent with hyperactive mTOR complex 1 signaling which was further demonstrated by phospho-S6 and phospho-4E-BP1 immunostaining. Copy number analysis revealed a loss of chromosome 1 in both cases with MTOR mutation. These tumors represent a novel subset of sporadic RCC characterized by alterations in TSC1-TSC2 complex or the mTOR complex 1 pathway. Recognition of their characteristic morphologic and immunophenotypic features will allow them to be readily identified and separated from the unclassified RCC category.


Long-term survival in a cat with pancreatic adenocarcinoma treated with surgical resection and toceranib phosphate.
Primary pancreatic adenocarcinoma is an uncommon neoplasm seen in cats and often has a poor prognosis. We report a case of an 8-year-old male neutered domestic shorthair cat weighing 5.8 kg diagnosed with pancreatic adenocarcinoma treated with surgical resection and toceranib phosphate, which had a progression-free interval of 1148 days and survived for more than 1436 days. The treatment was well tolerated; however, the cat developed generalised coat hypopigmentation. To our knowledge, the cat in our report has the longest progression-free interval and survival time post-surgical resection of pancreatic carcinoma treated with toceranib. Hypopigmentation as a side effect of toceranib has been reported in dogs, but this is the first case reported in cats.


Synthesis and Preliminary Biological Evaluations of Fluorescent or 149Promethium Labeled Trastuzumab-Polyethylenimine.
Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. The results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.


Patterns of drug use by young people in the rural community of Spain.
The patterns of drug use were studied in 1886 14-30-year-olds in rural (less than 10,000 inhabitants) Spain in 1987. Cannabis was the most frequently consumed drug. For the 'past month', the frequency of drug consumption was 10.07% of the population for cannabis, and ranged between 1.01% for amphetamines and 0.11% for inhalants. Drug consumption was more frequent among males than among females. The earlier start in consumption was among inhalants (15.3 years) whereas cocaine consumers started later (20 years). 'New sensations and curiosity' was the most frequently reported reason for the initial consumption of the various drugs, whereas the 'search for pleasure and happiness', and 'to relax' (for tranquillizers) were the principal reasons given for continuing use. 'Euphoria' and 'well-being' were the principal effects felt under the influence of the different drugs. The present data show that drug consumption is common among young people in Spanish rural communities.


Mitochondria-targeted Antioxidants as a Prospective Therapeutic Strategy for Multiple Sclerosis.
Multiple sclerosis (MS) is one of the most widespread chronic neurological diseases that manifests itself by progressive demyelination in the central nervous system. The study of MS pathogenesis begins with the onset of the relapsing-remitting phase of the disease, which becomes apparent due to microglia activation, neuroinflammation and demyelination/ remyelination in the white matter. The following progressive phase is accompanied by severe neurological symptoms when demyelination and neurodegeneration are spread to both gray and white matter. In this review, we discuss a possible role of mitochondrial reactive oxygen species (mtROS) in MS pathogenesis, mechanisms of mtROS generation and effects of some mitochondria-targeted antioxidants as potential components of MS therapy. In the early phase of MS, mtROS stimulate NLRP3 inflammasomes, which is critical for the formation of local inflammatory lesions. Later, mtROS contribute to blood-brain barrier disruption induced by mediators of inflammation, followed by infiltration of leukocytes. ROS generated by leukocytes and activated microglia promote mitochondrial dysfunction and oligodendrocyte cell death. In the progressive phase, neurodegeneration also depends on excessive mtROS generation. Currently, only a few immunomodulatory drugs are approved for treatment of MS. These drugs mainly reduce the number of relapses but do not stop MS progression. Certain dietary and synthetic antioxidants have demonstrated encouraging results in animal models of MS but were ineffective in the completed clinical trials. Novel mitochondria-targeted antioxidants could be promising components of combined programs for MS therapy considering that they can be applied at extremely low doses and concurrently demonstrate anti-inflammatory and neuroprotective activities.


Anatomical Closure of Left-to-Right Shunts in Premature Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension: A Cautionary Tale.
Closure of a systemic to pulmonary shunt in premature infants with bronchopulmonary dysplasia may be beneficial, but in the presence of pulmonary hypertension is controversial. Here, we discuss two premature infants with pulmonary hypertension who developed acute pulmonary hypertensive crisis after closure of these shunts and hence advise caution.


Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.
Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model. AAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP. Spatial learning memory of these mice was assessed in the Barnes maze, after which hippocampal tissues were isolated for downstream analysis. Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß 1-40 and Aß 1-42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation and microgliosis, which are increased in 5xFAD mice, were significantly reduced by dHc DUSP6 overexpression in both males and females. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulated expression of genes involved in inflammatory and extracellular signal-regulated kinase (ERK) pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. A limited number of differentially expressed genes (DEGs) (FDR<0.05) were identified in male mice; gene ontology analysis of DEGs (p<0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD. Notably, the msh homeobox 3 gene, Msx3 , previously shown to regulate microglial M1/M2 polarization and reduce neuroinflammation, was one of the most robustly upregulated genes in female and male wild type and 5xFAD mice overexpressing DUSP6. In summary, our data indicate that DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.


Perturbations in the Replication Program Contribute to Genomic Instability in Cancer.
Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due to aberrations in the temporal organization of the replication process. Here we review the mechanisms and impact of these major sources of error to the replication program.


Identification of cross-country skiing movement patterns using micro-sensors.
This study investigated the potential of micro-sensors for use in the identification of the main movement patterns used in cross-country skiing. Data were collected from four elite international and four Australian athletes in Europe and in Australia using a MinimaxX™ unit containing accelerometer, gyroscope and GPS sensors. Athletes performed four skating techniques and three classical techniques on snow at moderate velocity. Data from a single micro-sensor unit positioned in the centre of the upper back was sufficient to visually identify cyclical movement patterns for each technique. The general patterns for each technique were identified clearly across all athletes while at the same time distinctive characteristics for individual athletes were observed. Differences in speed, snow condition and gradient of terrain were not controlled in this study and these factors could have an effect on the data patterns. Development of algorithms to process the micro-sensor data into kinematic measurements would provide coaches and scientists with a valuable performance analysis tool. Further research is needed to develop such algorithms and to determine whether the patterns are consistent across a range of different speeds, snow conditions and terrain, and for skiers of differing ability.


Aluminum and zinc complexes based on an amino-bis(pyrazolyl) ligand: synthesis, structures, and use in MMA and lactide polymerization.
The coordination chemistry of bis[2-(3,5-dimethyl-1-pyrazolyl)ethyl]amine (1, LH) with aluminum- and zinc-alkyls has been studied. Reaction of 1 with AlR3 affords the adducts [LH] x AlR3 (R = Me, 2; Et, 3), which undergo alkane elimination upon heating to yield the amido complexes [L]AlR2 (R = Me, 4; Et, 5). Reaction of LiO(iPrO)C=CMe2 with 2 proceeds via N-H deprotonation to give Li[L]AlMe3 (6), while the former enolate adds to 4 to generate [Me2C=C(OiPr)OLi] x [L]AlMe2 (7). Similarly, the 1:1 reaction of ZnEt2 with 1 gives [LH] x ZnEt2 (9), which is transformed into [L]ZnEt (10) upon heating. When an excess of ZnEt2 was used in the latter reaction, the bimetallic complex [L]ZnEt x ZnEt2 (11) was isolated beside 10. Performing the same reaction in the presence of O2 traces yielded selectively the dinuclear ethyl-ethoxide complex [L]Zn2Et2(mu-OEt) (12), which was alternatively prepared from the reaction of 10 and ZnEt(OEt). Zinc chloride complexes [LH] x ZnRCl (R = Et, 13; p-CH3C6H4CH2, 14) and [L]ZnCl (15) were prepared in high yields following similar strategies. Ethyl abstraction from 10 with B(C6F5)3 yields [L]Zn+EtB(C6F5)3- (16). All complexes have been characterized by multinuclear nuclear magnetic resonance (NMR), elemental analysis, and single-crystal X-ray diffraction studies for four-coordinate Al complexes 2, 4, and 6 and Zn complexes 9-12 and 14. Aluminate species 6 and 7 initiate the polymerization of methyl methacrylate, and the monomer conversions are improved in the presence of neutral complexes 2 or 4, respectively; however, these methyl methacrylate (MMA) polymerizations are uncontrolled. Polymerization of rac-lactide takes place at 20 degrees C in the presence of zinc ethoxide complex 12 to yield atactic polymers with controlled molecular masses and relatively narrow polydispersities.


Does Subclinical Hypothyroidism Affect Hospitalization Outcomes and Mortality in Congestive Cardiac Failure Patients?
Objective This study aimed to determine the differences in hospitalization outcomes among patients admitted for congestive cardiac failure (CCF) with underlying subclinical hypothyroidism (SCH). Methods This retrospective case-control study used data from the nationwide inpatient sample (NIS) for the years 2012-2014. We identified cases with CCF as the primary diagnosis and SCH as the secondary diagnosis using validated ICD-9-CM codes and controls with CCF only. The differences in hospitalization outcomes and hospital characteristics were quantified using the multinomial logistic regression model (adjusted odds ratio (aOR)). Results A total of 143,735 CCF patients were enrolled in this study, and 73,440 cases had IH. About 31.8% of SCH patients were hospitalized for more than four days (median) compared to 44.7% patients without SCH (P < .001). The median hospitalization charges per admission for CCF was $20,312. CCF patients with SCH had lower odds of longer hospitalization (aOR = .709, 95% CI .660-.762, P < .001) and higher hospitalization charges (aOR = .783, 95% CI .728-.841, P < .001) compared to CCF patients without SCH. CCF patients with SCH had two times higher odds of minor morbidity (aOR = 2.276; 95% CI 2.105-2.462; P < .001) but lower odds of major morbidity (aOR = .783; 95% CI .728-.841; P < .001). Inpatient mortality with SCH patients (2%) compared to 3.6% patients without SCH (P < .001). CCF patients with SCH had lower odds of in-hospital mortality (aOR = .547; 95% CI .496-.604; P < .001). CCF patients with SCH had higher odds of being seen in rural non-teaching hospitals (aOR = 1.696; 95% CI 1.572-1.831; P < .001). Also, CCF patients with SCH had the highest likelihood of presence in the western region of the United States (aOR = 149.924; 95% CI 110.497-203.419; P < .001) followed by the southern region (aOR = 31.431; 95% CI 26.066-37.900; P < .001). Conclusions Among CCF with SCH patients during hospitalization, we observed a variation in hospitalization outcomes, including inpatient length of stay and cost, morbidity, and in-hospital mortality. We found no significant increase in mortality and major morbidity in CCF patients with SCH. There were differences in the hospital characteristics between CCF patients with and without SCH. Thus, hospital bed size, location, and teaching status act as predictors for a co-diagnosis of SCH in CCF. Further research is needed to guide the development of clinical care models for targeting early diagnosis and treatment to determine whether thyroid hormone replacement would be beneficial for CCF patients with SCH and improve quality of care in these patients.


Change in major amputation rate in a center dedicated to diabetic foot care during the 1980s: prognostic determinants for major amputation.
From 1990 to 1993, 115 diabetic patients were consecutively hospitalized in our diabetologic unit for foot ulcer and 27 (23.5%) major amputations were carried out. The major amputation rate of this series of cases was compared with that occurring in diabetic subjects taken into our hospital for foot ulcer in two previous periods: 1979-1981 (17 major amputations in 42 inpatients or 40.5%) and 1986-1989 (26 major amputations in 78 inpatients or 33.3%). The comparison shows a progressive reduction in major amputation rate [Odds ratio 0.66, 95% confidence interval (CI) 0.46-0.96]. Univariate and multivariate analysis, carried out in the population of the 1990-1993 period, in order to detect the independent factors associated with major amputation show the following prognostic determinants of major amputation: Wagner grade (odds ratio 7.69, CI 1.58-37.53), prior stroke (odds ratio 35.05, CI 3.14-390.53), prior major amputation (odds ratio 3.49, CI 1.26-9.38), transcutaneous oxygen level (odds ratio 1.06, CI 1.01-1.12), and ankle-brachial blood pressure index (odds ratio 4.35, CI 1.58-12.05), while an independent protective role was attributed to hyperbaric oxygen treatment (odds ratio 0.15, CI 0.03-0.64). In accordance with other studies, we, therefore, conclude that a comprehensive protocol as well as a multidisciplinary approach in a dedicated center can assure a decrease in major amputation rate. The parameters of limb perfusion were the modifiable prognostic determinants most strongly predictive for amputation.


FLUCTUATING SELECTION AND RESPONSE IN A POPULATION OF FRESHWATER COPEPODS.
The timing of springtime production of diapausing eggs by a population of the freshwater copepod, Diaptomus sanguineus, has been shown previously to be consistent with avoidance of seasonally intense fish predation. Natural selection acting on the timing of diapause fluctuates between years depending upon the population density of fish. Here we show that, in the field, the mean timing of diapause shifts between years in response to fluctuations in selection. Diapause is earlier in years following high predator density, and is later in years following low predator density. Although selection intensity in individual years may be large, the mean intensity over the decade of fluctuating selection investigated here is close to zero. Photoperiod sensitivity of the diapausetiming trait is heritable in the laboratory. The combination of fluctuating selection and multi-generation storage of genotypes as diapausing eggs in lake sediments may contribute to the maintenance of the genetic variation that permits the rapid selection response seen in the field.


Nitrate, Nitrite, and Ammonium Variability in Drinking Water Distribution Systems.
Accurate assessments of exposure to nitrate in drinking water is a crucial part of epidemiological studies investigating long-term adverse human health effects. However, since drinking water nitrate measurements are usually collected for regulatory purposes, assumptions on (1) the intra-distribution system variability and (2) short-term (seasonal) concentration variability have to be made. We assess concentration variability in the distribution system of nitrate, nitrite, and ammonium, and seasonal variability in all Danish public waterworks from 2007 to 2016. Nitrate concentrations at the exit of the waterworks are highly correlated with nitrate concentrations within the distribution net or at the consumers' taps, while nitrite and ammonium concentrations are generally lower within the net compared with the exit of the waterworks due to nitrification. However, nitrification of nitrite and ammonium in the distribution systems only results in a relatively small increase in nitrate concentrations. No seasonal variation for nitrate, nitrite, or ammonium was observed. We conclude that nitrate measurements taken at the exit of the waterworks are suitable to calculate exposures for all consumers connected to that waterworks and that sampling frequencies in the national monitoring programme are sufficient to describe temporal variations in longitudinal studies.


Identification, molecular evolution of toll-like receptors in a Tibetan schizothoracine fish (Gymnocypris eckloni) and their expression profiles in response to acute hypoxia.
Hypoxia plays an important role in regulating a variety of physiological responses as well as in pathological situations, but to date the roles of Toll-like receptors (TLRs) in fish in response to hypoxia are still poorly understood. Here, we sequenced the transcriptome of G. eckloni and identified the members of TLR family by scanning transcriptome, and then investigated the expression profiles of a complete set of TLRs in G. eckloni in response to acute hypoxia (4 h at DO = 0.3 ± 0.1 mg/L). The de novo-assembled transcriptome consisted of a total of 162,235 transcripts, further clustered into 110,231 unigenes. Based on the transcriptome, a total of 18 TLRs were identified in G. eckloni, and of them three TLRs (TLR5, TLR8 and TLR22) possessed two distinct paralogous genes. The duplicated genes of TLR22 were discovered for the first time in cyprinid fish, but did not origin from a recent duplication event. Of them TLR22b may be specific for schizothoracine fish, at least for G. eckloni. Phylogenetic analysis supported the classification of TLRs into six families as in other vertebrates but was partly different from the previous study. The sliding window analysis showed strong signals of positive selection in TLR2, TLR 4, TLR 5a, TLR 7, TLR 19, TLR 20, TLR 21, TLR 22a and TLR 22b, but most codons under positive selection were located in the putative LRR regions. The mRNA expression of most TLRs in head kidney, spleen and gill decreased significantly or remained unchanged under acute hypoxia, whereas acute hypoxia increased expressions of TLR2 and TLR3 in head kidney, of TLR8a, TLR12 and TLR19 in spleen, and of TLR1 in gill, suggesting tissues-specific expressions of TLRs play important roles in mediating innate immune responses for host defense against tissue damages or physiological changes induced by hypoxia.


Neutral and cationic bismuth compounds supported by bis(amidodimethyl)disiloxane ligands.
Bis(amidodimethyl)disiloxane ligands derived from O{SiMe2N(H)R}2 (abbreviated as (NONR)H2) are a stable support for neutral and cationic bismuth compounds. Attempts to extend the series Bi(NONR)Cl (R = Ar = 2,6-iPr2C6H3; R = tBu) to include compounds where R = Ar' = 2,6-Me2C6H3 were complicated by concomitant formation of the bimetallic compound {Bi(NONAr')}2(μ-NONAr'). Compounds containing [Bi(NONR)]+ cations were obtained from reactions with group 13 chlorides MCl3 (M = Al, Ga). X-ray crystallographic analysis showed intermolecular interactions with the [MnCl(3n+1)] anion.


Organometallic Folate Gold Nanoparticles Ameliorate Lipopolysaccharide-Induced Oxidative Damage and Inflammation in Zebrafish Brain.
Synthesized organometallic gold-based folate nanoparticles (FAuNPs) were characterized, and its defense against lipopolysaccharide (LPS)-induced brain inflammation in Zebra fish was proven. Vitamin entrapment efficiency of these particles was found to be nearly 70%. The in vitro pH-dependent drug release dialysis study of FAuNPs confirmed a slow, sustained, and gradual release of folate for a period of 24 h. Both AuNPs and FAuNPs did not cause any marked changes in food intake, body weight, color, behavioral pattern, blood parameters, and hepatotoxicity. Histology of liver showed no changes between treated and control groups of fishes. The ex vivo study showed significant uptake of FAuNPs to free folate in folate receptor negative Hek293 cells, confirming a strategy to overcome folate deficiency in the brain. Antioxidant status and activities of few crucial brain enzymes were also measured to assess the brain function and found to be returned to the basal level, following FAuNP treatment. The transcription factor NRF2-Keap 1 expression pattern was also noted, and a prominent modulation was observed in the LPS-treated and FAuNP-administered group. Decisive brain enzymes like AChE and Na+K+ATPase were decreased significantly after LPS treatment, which is restored with FAuNP treatment. Caspases increased sharply after LPS treatment and diminished following FAuNP treatment. We conclude that FAuNP due to its high physical stability and uptake could be utilized against severe brain inflammation, leading to brain injury and neurodegeneration.


Combination Usage of AdipoCount and Image-Pro Plus/ImageJ Software for Quantification of Adipocyte Sizes.
In recent decades, the prevalence of obesity has been rising. One of the major characteristics of obesity is fat accumulation, including hyperplasia (increase in number) and hypertrophy (increase in size). After histological staining, it is critical to accurately measure the number and size of adipocytes for assessing the severity of obesity in a timely fashion. Manual measurement is accurate but time-consuming. Although commercially available adipocyte counting tools, including AdipoCount, Image-Pro Plus, and ImageJ were helpful, limitations still exist in accuracy and time consuming. In the present study, we introduced the protocol of combined usage of these tools and illustrated the process with histological staining slides from adipose tissues of lean and obese mice. We found that the adipocyte sizes quantified by the tool combination were comparable as manual measurement, whereas the combined methods were more efficient. Besides, the recognition effect of monochrome segmentation image is better than that of color segmentation image. Overall, we developed a combination method to measure adipocyte sizes accurately and efficiently, which may be helpful for experimental process in laboratory and also for clinic diagnosis.


Abrogation of CCL21 chemokine function by transgenic over-expression impairs T cell immunity to local infections.
The CC chemokine receptor 7 (CCR7) and its two ligands, CCL21 and CCL19, play an important role in migration of immune cells to lymphoid tissue. To analyze the function of CCR7 in T cell immunity to infectious agents in vivo, transgenic (tg) mice expressing CCL21 in an ubiquitous fashion were generated. These mice contained high amounts of CCL21 in the serum ( approximately 0.3 microg/ml that resulted in CCR7 down-regulation and in a strongly impaired migration of T cells toward CCL21 in vitro. Lymph nodes in CCL21-tg mice were reduced in size but with intact microanatomy and normal distribution of T and B cells. CCL21-tg mice showed a significantly decreased CD8 T cell response to lymphocytic choriomeningitis virus after footpad infection, whereas the response after systemic infection was not altered. Likewise, the CD4 T cell response to footpad infection with Leishmania major was considerably lowered and CCL21-tg mice failed to clear parasites from infected skin. Taken together, these data demonstrate the importance of CCR7 in mediating T cell immunity to viral and parasitic pathogens after local infection.


Time-dependent quasirelativistic density-functional theory based on the zeroth-order regular approximation.
A time-dependent quasirelativistic density-functional theory for excitation energies of systems containing heavy elements is developed, which is based on the zeroth-order regular approximation (ZORA) for the relativistic Hamiltonian and a noncollinear form for the adiabatic exchange-correlation kernel. To avoid the gauge dependence of the ZORA Hamiltonian a model atomic potential, instead of the full molecular potential, is used to construct the ZORA kinetic operator in ground-state calculations. As such, the ZORA kinetic operator no longer responds to changes in the density in response calculations. In addition, it is shown that, for closed-shell ground states, time-reversal symmetry can be employed to simplify the eigenvalue equation into an approximate form that is similar to that of time-dependent nonrelativistic density-functional theory. This is achieved by invoking an independent-particle approximation for the induced density matrix. The resulting theory is applied to investigate the global potential-energy curves of low-lying LambdaS- and omega omega-coupled electronic states of the AuH molecule. The derived spectroscopic parameters, including the adiabatic and vertical excitation energies, equilibrium bond lengths, harmonic and anharmonic vibrational constants, fundamental frequencies, and dissociation energies, are in good agreement with those of time-dependent four-component relativistic density-functional theory and ab initio multireference second-order perturbation theory. Nonetheless, this two-component relativistic version of time-dependent density-functional theory is only moderately advantageous over the four-component one as far as computational efforts are concerned.


Utilization of prenatal diagnosis and termination of pregnancies for the prevention of Down syndrome in Israel.
The national program for the prevention of Down syndrome includes screening (using the triple test) and invasive diagnostic tests in women at risk for a Down syndrome pregnancy. However, despite the program, the majority of Down syndrome infants are born alive (approximately 1/1000 live births). To determine whether the relatively high incidence of Down syndrome at birth in Israel is the result of failure of the preventive program or due to informed choices of the mothers. We conducted a retrospective study using the national registry of Down syndrome for the years 1997 and 2004, according to the mothers' religion and place of residence and the reasons for prenatal diagnosis. Most of the babies affected with Down syndrome are born in religious or traditional conservative communities where termination of pregnancy is usually not an option. In a pluralistic society like Israel with its diverse communities and dissimilar religious backgrounds and traditions, the different attitudes concerning utilization of the national program should be respected. It is necessary to tailor different approaches and solutions for the various ethnic and religious communities according to their need.