Dry Bean Preferences and Attitudes among Midwest Hispanic and Non-Hispanic White Women.
Bean (Phaseolus vulgaris L.) intakes in the United States (US) lag behind dietary recommendations despite their positive nutrition profile, health benefits for reducing chronic disease risk, and inclusion in nutrition assistance programs. Low-income groups, including Hispanics, have an increased risk of cardiovascular disease, type 2 diabetes, obesity, and some cancers. Hispanic dietary quality and bean consumption may decline with increasing acculturation. Intakes at recommended levels could improve health in all vulnerable low-income populations. The study objectives were to describe dry and canned bean preferences, consumption frequency, and attitudes among low-income Hispanic and non-Hispanic white women, and to assess if these characteristics differed by ethnicity and acculturation level among the Latinas. A convenience sample of 158 women, aged 18⁻65 years, completed a written survey in English or Spanish at two healthcare clinics, one Special Supplemental Nutrition Program for Women, Infants and Children office, and five County Extension nutrition education and outreach programs in Iowa. Less acculturated Latinas consumed beans more often, preferred dry to canned, bought in bulk, valued color and shape in dry bean selection, and held less positive attitudes toward canned beans in contrast to bicultural/more acculturated and non-Hispanic white women. Ethnicity and acculturation level have a role in varying purchase patterns and attitudes regarding dry and canned beans. Culturally-held differences should be considered in nutrition programs and leveraged to increase consumption and improve health.


Broadband terahertz heterodyne spectrometer exploiting synchrotron radiation at megahertz resolution.
A new spectrometer allowing both high resolution and broadband coverage in the terahertz (THz) domain is proposed. This instrument exploits the heterodyne technique between broadband synchrotron radiation and a quantum-cascade-laser-based molecular THz laser that acts as the local oscillator. Proof of principle for exploitation for spectroscopy is provided by the recording of molecular absorptions of hydrogen sulfide (H2S) and methanol (CH3OH) around 1.073 THz. Ultimately, the spectrometer will enable to cover the 1-4 THz region in 5 GHz windows at Doppler resolution.


Stimulation of aflatoxin biosynthesis by lipophilic epoxides.
Epoxy fatty acids added to the culture media either with the inoculum or at the end of exponential growth phase stimulated aflatoxin production by toxigenic strains of Aspergillus flavus and Aspergillus parasiticus. This effect did not appear when the unsaturated fatty acids used for the synthesis of the epoxides and the polyhydroxyacids (which can be considered to be derived from the opening of the oxirane ring) replaced the epoxides in the culture media. No significant differences were detected in the lipid fractions (diglycerides, sterols, triglycerides, free fatty acids, sterol esters) extracted from the mycelia grown in the presence of any of the fatty acid derivates.


Plasma-derived proteins in airway defence, disease and repair of epithelial injury.
One significant characteristic of the airway mucosa in vivo, that cannot easily be mimicked in vitro, is its microcirculation, which generates a highly dynamic, biologically active milieu of plasma-derived molecules that may pass to the airway lumen in vivo. New data on the mechanisms of airway mucosal exudation indicate that the protein systems of circulating plasma may contribute significantly to the biology and immunology of the lamina propria, its surface epithelium and the luminal surface, not only in injured airways, but also in airways that are activated but display no sign of oedema, epithelial disruption, or increased absorption capacity. We suggest that present knowledge of the mechanisms of plasma exudation, together with rapidly emerging information (not detailed herein) on receptors, target cells and cellular responses to the plasma-derived molecules, must be considered in any realistic model that investigates "immuno-inflammatory" mechanisms of the airway mucosa.


Antithrombin III Attenuates AKI Following Acute Severe Pancreatitis.
Antithrombin III (ATIII), the predominant coagulation factor inhibitor, possesses anti-inflammatory properties and exerts renoprotective effects on renal ischemia-reperfusion injury in animal models. However, the ATIII's protective effects of ATIII on acute kidney injury (AKI) following severe acute pancreatitis (SAP) need to be confirmed. We assessed the association between ATIII activities and the incidence of AKI in patients with SAP, and explored therapeutic effects and potential mechanisms of ATIII on kidney injury in sodium taurocholate induced SAP rat model. Rats were intravenously injected with ATIII (500 μg/kg) before or after the induction of SAP. The results demonstrated ATIII did not attenuate pancreatic injury, but significantly ameliorate renal dysfunction and renal histological injury. ATIII administration alleviated renal inflammation response, oxidative stress, and cell apoptosis. Moreover, ATIII attenuated tumor necrosis factor α (TNFα)-stimulated intercellular cell adhesion molecule 1(ICAM-1) and monocyte chemotactic protein 1 (MCP-1) upregulation in cultured renal tubular epithelial cells. ATIII appears to ameliorate SAP-induced kidney injury by inhibiting inflammation, oxidative stress, and apoptosis. ATIII supplementation may have a potential prophylactic and therapeutic effect on SAP induced AKI.


Functional disconnection of axonal fibers generated by high frequency stimulation in the hippocampal CA1 region in-vivo.
High frequency stimulation (HFS) applied in the brain has been shown to be efficient for treating several brain disorders, such as Parkinson's disease and epilepsy. But the mechanisms underlying HFS are not clear. In particular, the effect of HFS on axons has been intriguing since axonal propagation plays an important role in the functional outcome of HFS. In order to study the potential effect of axonal block by HFS in-vivo, both orthodromic- and antidromic-HFS (O-HFS, A-HFS) with biphasic pulses were applied to the hippocampal CA1 region in anaesthetized rats. Changes in the amplitude and latency of orthodromic- and antidromic-population spikes within 1-min long period of stimulation at 50, 100 and 200 Hz HFS were analyzed. The results show that except for a short onset period, activity evoked by O-HFS with a frequency over 100 Hz could not be sustained. For A-HFS at frequencies over 100 Hz, the amplitudes and the latencies of antidromic population spike (APS) greatly decreased and increased respectively. Significantly larger changes in APS latency were observed in HFS than those generated at low frequency, suggesting a suppression of axon conduction by HFS. Furthermore, the CA1 somata remained excitable while failing to respond to excitation from orthodromic or antidromic HFS. Taken together, these results show that HFS produces an axonal block of both afferent and efferent fibers localized to the area of stimulation since it does not affect the excitability of CA1 somata. This effect of HFS on axons causes a functional disconnection of axonal pathways that is reversible and temporary. The reversible disconnection or temporary deafferentation between putative therapeutic targets could have extensive implication for various clinical applications of HFS to treat brain diseases.


Comparison of Proximal and Remote Sensing for the Diagnosis of Crop Status in Site-Specific Crop Management.
The presented paper deals with the issue of selecting a suitable system for monitoring the winter wheat crop in order to determine its condition as a basis for variable applications of nitrogen fertilizers. In a four-year (2017-2020) field experiment, 1400 ha of winter wheat crop were monitored using the ISARIA on-the-go system and remote sensing using Sentinel-2 multispectral satellite images. The results of spectral measurements of ISARIA vegetation indices (IRMI, IBI) were statistically compared with the values of selected vegetation indices obtained from Sentinel-2 (EVI, GNDVI, NDMI, NDRE, NDVI and NRERI) in order to determine potential hips. Positive correlations were found between the vegetation indices determined by the ISARIA system and indices obtained by multispectral images from Sentinel-2 satellites. The correlations were medium to strong (r = 0.51-0.89). Therefore, it can be stated that both technologies were able to capture a similar trend in the development of vegetation. Furthermore, the influence of climatic conditions on the vegetation indices was analyzed in individual years of the experiment. The values of vegetation indices show significant differences between the individual years. The results of vegetation indices obtained by the analysis of spectral images from Sentinel-2 satellites varied the most. The values of winter wheat yield varied between the individual years. Yield was the highest in 2017 (7.83 t/ha), while the lowest was recorded in 2020 (6.96 t/ha). There was no statistically significant difference between 2018 (7.27 t/ha) and 2019 (7.44 t/ha).


First report: Robotic pelvic exenteration for locally advanced rectal cancer.
The aim of this study was to present the feasibility and surgical outcome of robotic en bloc resection of the rectum and with prostate and seminal vesicle invaded by rectal cancer. The details of three consecutive cases involving male patients in their forties, with locally invasive low rectal cancers are presented. The da Vinci robotic system was used by experienced colorectal and urological surgeons to perform en bloc resection of the rectum, prostate and seminal vesicles. In the first case, coloanal and vesico-urethral anastomoses were performed, and the second included an end colostomy and vesico-urethral anastomosis. The bladder and bulbar urethra were also removed en bloc in the third case, with robotic intracorporeal ileal conduit formation and end colostomy. There was no major complication postoperatively. In the second patient there was a minor leakage at the vesico-urethral anastomosis. The third was readmitted the following week with a urinary infection which settled with intravenous antibiotics. In the first case, the circumferential resection margin was microscopically positive but the patient is currently free of recurrence after 14 months. In the second and third cases, all margins were clear. This the first report of the use of the da Vinci robotic system for pelvic exenteration in patients with locally advanced rectal cancer invading the prostate and seminal vesicles. The robot may have a potential role in selected patients requiring exenterative pelvic surgery particularly in men.


Functional dissociation of pre-SMA and SMA-proper in temporal processing.
The ability to assess temporal structure is crucial in order to adapt to an ever-changing environment. Increasing evidence suggests that the supplementary motor area (SMA) is involved in both sensory and sensorimotor processing of temporal structure. However, it is not entirely clear whether the structural differentiation of the SMA translates into functional specialization, and how the SMA relates to other systems that engage in temporal processing, namely the cerebellum and cortico-striatal circuits. Anatomically, the SMA comprises at least two subareas, the rostral pre-SMA and the caudal SMA-proper. Each displays a characteristic pattern of connections to motor and non-motor structures. Crucially, these connections establish a potential hub among cerebellar and cortico-striatal systems, possibly forming a dedicated subcortico-cortical temporal processing network. To further explore the functional role of each SMA subarea, we performed a meta-analysis of functional neuroimaging studies by contrasting activations according to whether they linked with either sensory, sensorimotor, sequential, non-sequential, explicit, non-explicit, subsecond, or suprasecond temporal processing. This procedure yielded a set of functional differences, which mirror the rostro-caudal anatomical dimension. Activations associated with sensory, non-sequential, and suprasecond temporal processing tend to locate to the rostral SMA, while the opposite is true for the caudal SMA. These findings confirm a functional dissociation of pre-SMA and SMA-proper in temporal processing.


Laser applications to chemical and environmental analysis: an introduction.
This issue of Applied Optics features papers on the application of laser technology to chemical and environmental analysis. Many of the contributions to this issue, although not all, result from papers presented at the 1996 OSA Topical Meeting on Laser Applications to Chemical and Environmental Analysis, which was held in Orlando, Florida, in March 1996. This successful meeting, with nearly 100 participants, continued the tradition of earlier Laser Applications to Chemical Analysis (LACA) meetings. The title change reflects an expended scope and an even greater emphasis on environmental analysis than the previous four LACA meetings.


Developments in the field of allergy in 2008 through the eyes of Clinical & Experimental Allergy.
In 2008, many thousands of articles were published on the subject of allergic disease with over 200 reviews, editorials and original papers in Clinical & Experimental Allergy alone. These represent a considerable amount of data and even the most avid reader could only hope to assimilate a small fraction of this knowledge. There is therefore a pressing need for the key messages that emerge from a journal such as Clinical & Experimental Allergy to be summarized by experts in the field in a form that highlights the significance of the developments and sets them in the context of important findings in the field published in other journals. This also has the advantage of making connections between new data in conditions such as asthma, where articles often appear in different sections of the journal. As can be seen from this review, the body of work is diverse both in terms of the disease of interest and the discipline that has been used to investigate it. However, taken as a whole, we hope that the reader will gain a flavour of where the field is mature, where there remain controversies and where the cutting edge is leading.


Epidemiological background to diabetes.
Earlier seasonal inoidence studies indicated that juvenile diabetes is acquired mainly in the autumn and winter months, and more recent and extensive further studies conducted throughout Great Britain have confirmed these earlier findings. Studies relating the incidence of the disease to age among juveniles suggest that an initiating factor, probably viral in origin, is operative in early childhood and that after a latent period, a precipitating factor may then uncover the disease. This might explain the peak of juvenile diabetes which appears at age 11, in Britain. Studies on families in which diabetes has appeared almost simultaneously in two or more members, lends some support to the view that the disease may be precipitated by some infective process.


Proline isomerase Pin1 represses terminal differentiation and myocyte enhancer factor 2C function in skeletal muscle cells.
Reversible proline-directed phosphorylation at Ser/Thr-Pro motifs has an essential role in myogenesis, a multistep process strictly regulated by several signaling pathways that impinge on two families of myogenic effectors, the basic helix-loop-helix myogenic transcription factors and the MEF2 (myocyte enhancer factor 2) proteins. The question of how these signals are deciphered by the myogenic effectors remains largely unaddressed. In this study, we show that the peptidyl-prolyl isomerase Pin1, which catalyzes the isomerization of phosphorylated Ser/Thr-Pro peptide bonds to induce conformational changes of its target proteins, acts as an inhibitor of muscle differentiation because its knockdown in myoblasts promotes myotube formation. With the aim of clarifying the mechanism of Pin1 function in skeletal myogenesis, we investigated whether MEF2C, a critical regulator of the myogenic program that is the end point of several signaling pathways, might serve as a/the target for the inhibitory effects of Pin1 on muscle differentiation. We show that Pin1 interacts selectively with phosphorylated MEF2C in skeletal muscle cells, both in vitro and in vivo. The interaction with Pin1 requires two novel critical phospho-Ser/Thr-Pro motifs in MEF2C, Ser(98) and Ser(110), which are phosphorylated in vivo. Overexpression of Pin1 decreases MEF2C stability and activity and its ability to cooperate with MyoD to activate myogenic conversion. Collectively, these findings reveal a novel role for Pin1 as a regulator of muscle terminal differentiation and suggest that Pin1-mediated repression of MEF2C function could contribute to this function.


Effects on cerebral hemodynamics of resuscitation from endotoxic shock with hypertonic saline versus lactated Ringer's solution.
This study was carried out to determine whether 7.5% hypertonic saline (HSS) and lactated Ringer's solution restore cerebral hemodynamics comparably when used for resuscitation from endotoxic shock. Endotoxic shock was produced in 13 dogs by the iv administration of 1.5 mg/kg Escherichia coli endotoxin. After 90 min of shock, seven animals were resuscitated with lactated Ringer's solution, 60 ml/kg iv, and six with 7.5% HSS, 6 ml/kg iv. Both solutions increased cardiac output and mean arterial pressure. With HSS, intracranial pressure was lower immediately after resuscitation (p less than .001) and one hour later (p less than .01). However, cerebral blood flow was not increased by either fluid and, due to hemodilution, cerebral oxygen transport decreased during resuscitation in both groups of animals. Thus, HSS restored systemic hemodynamics and maintained a lower intracranial pressure during resuscitation from endotoxic shock, but failed, as did lactated Ringer's solution, to restore cerebral blood flow and oxygen transport.


Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C→T polymorphism.
The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F(2α) and 11-dehydro-thromboxane (TX)B(2) (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF(2α) (p<0.0001) and 11-dehydro-TXB(2) (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 C→T polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF(2α) excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF(2α) and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 C→T polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.


Evolution of spliceosomal introns following endosymbiotic gene transfer.
Spliceosomal introns are an ancient, widespread hallmark of eukaryotic genomes. Despite much research, many questions regarding the origin and evolution of spliceosomal introns remain unsolved, partly due to the difficulty of inferring ancestral gene structures. We circumvent this problem by using genes originated by endosymbiotic gene transfer, in which an intron-less structure at the time of the transfer can be assumed. By comparing the exon-intron structures of 64 mitochondrial-derived genes that were transferred to the nucleus at different evolutionary periods, we can trace the history of intron gains in different eukaryotic lineages. Our results show that the intron density of genes transferred relatively recently to the nuclear genome is similar to that of genes originated by more ancient transfers, indicating that gene structure can be rapidly shaped by intron gain after the integration of the gene into the genome and that this process is mainly determined by forces acting specifically on each lineage. We analyze 12 cases of mitochondrial-derived genes that have been transferred to the nucleus independently in more than one lineage. Remarkably, the proportion of shared intron positions that were gained independently in homologous genes is similar to that proportion observed in genes that were transferred prior to the speciation event and whose shared intron positions might be due to vertical inheritance. A particular case of parallel intron gain in the nad7 gene is discussed in more detail.


Measuring progress against cancer in Europe: has the 15% decline targeted for 2000 come about?
Against a background of increasing cancer rates in the mid-1980s, Europe Against Cancer launched an ambitious programme aiming to reduce cancer mortality by 15% by the year 2000. A programme of activities and research, focussing on three major themes [prevention (particularly tobacco control), screening, and education and training], was developed together with the European Code Against Cancer. To evaluate the outcome of the programme, all cancer mortality data were abstracted for each member state of the European Union (EU) until the most recent year available. For each gender group in each member state, age-specific rates were estimated for 2000. For each country-gender grouping, the standardized mortality rate (SMR) and expected numbers of deaths in 2000 were calculated based on the age-specific rates for 1985 and the population estimates for 2000. The ratio of the SMR in 2000 to that of 1985, was used as the measure to compare mortality rates. In 1985, there were 850 194 cancer deaths in the EU. Based solely on demographic considerations, this number was expected to rise to 1 033 083 in the year 2000. Between 1985 and 2000, the number of cancer deaths increased in both men (+12%) and women (+9%). The target of a 15% reduction in the expected numbers of cancer deaths in the EU was not met, although the 10% reduction in number of deaths expected in men and 8% in women, along with a 11% reduction in risk of cancer death in men and a 10% reduction in women, was noteworthy. Only Austria and Finland achieved the 15% reductions in deaths in both men and women. The UK and Luxembourg (where the small population and annual number of deaths make interpretation difficult) came close to meeting these targets, as did Italy. Portugal and Greece had the poorest performance, with increases in each gender group. Cancer deaths in the EU were expected to rise from 850 194 in 1985 to 1 033 083 in 2000. It is estimated that there will be 940 510 cancer deaths that year, due to the decline in risk observed since 1985. The Europe Against Cancer programme appears to have been associated with the avoidance of 92 573 cancer deaths in the year 2000. With few exceptions, most countries are experiencing declining trends in cancer death rates, which seem set to continue, at least in the near future. Renewed tobacco control efforts are clearly needed for women, and there is a strong case for the introduction of organized breast and cervix screening programmes in all member states. Continuing to emphasize prevention within cancer control will help to promote the continuing decline in death rates in the future.


CTLA-4 regulates induction of anergy in vivo.
The requirement for CTLA-4 during the induction of peripheral T cell tolerance in vivo was investigated using naive TCR transgenic T cells lacking CTLA-4. CTLA-4(-/-) T cells are resistant to tolerance induction, as demonstrated by their proliferative responses, IL-2 production, and progression into the cell cycle. Following exposure to a tolerogenic stimulus in vivo and restimulation in vitro, wild-type T cells are blocked at the late G1 to S restriction point of the cell cycle. In contrast, CTLA-4(-/-) T cells enter into the S phase of the cell cycle, as shown by downregulation of p27(kip1), elevated cdk2 kinase activity, and Rb hyperphosphorylation. Thus, CTLA-4 has an essential role in determining the outcome of T cell encounter with a tolerogenic stimulus.


The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis.
Obesity is characterized by excessive fat mass and is associated with serious diseases such as type 2 diabetes. Targeting excess fat mass by sustained lipolysis has been a major challenge for anti-obesity therapies due to unwanted side effects. TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity-associated diseases. The molecular mechanism is still largely uncharacterized. We used a combination of pharmacological and genetic gain and loss of function approaches. 3T3-L1 and mature murine adipocytes were used for in vitro experiments. Chronic in vivo experiments were conducted on diet-induced obese wild type, β1, β2, β3-adrenergic receptor (AR) deficient and C3aR1 knockout mice. Acute in vivo lipolysis experiments were conducted on Sprague Dawley rats. We demonstrated that TLQP-21 does not possess lipolytic properties per se. Rather, it enhances β-AR activation-induced lipolysis by a mechanism requiring Ca2+ mobilization and ERK activation of Hormone Sensitive Lipase (HSL). TLQP-21 acutely potentiated isoproterenol-induced lipolysis in vivo. Finally, chronic peripheral TLQP-21 treatment decreases body weight and fat mass in diet induced obese mice by a mechanism involving β-adrenergic and C3a receptor activation without associated adverse metabolic effects. In conclusion, our data identify an alternative pathway modulating lipolysis that could be targeted to diminish fat mass in obesity without the side effects typically observed when using potent pro-lipolytic molecules.


Ritanserin and alcohol abuse and dependence.
Ritanserin is a potent long-acting 5-HT2 antagonist that acts centrally. In humans, ritanserin increases deep slow wave sleep, improved liveliness in a variety of psychiatric disorders and facilitated participation in behaviour therapy. During clinical trials unexpected observations indicated that ritanserin may be of value in treating drug addicts. Furthermore, initial clinical observations confirmed the efficacy of ritanserin in the chronic withdrawal phase after detoxification from ethanol. In the present paper, four experiments which support the potential of ritanserin as a pharmacological treatment for alcohol abuse and dependence are described. Firstly, ritanserin has been demonstrated to lack abuse potential and any direct interaction with ethanol. Secondly, in various models ritanserin has been shown to reduce alcohol intake and preference. The level of activity varies to some degree depending on the test and treatment procedure, as well as on the animal strain used. Long term ritanserin-related efficacy was illustrated by the gradual increase in alcohol drinking after cessation of the ritanserin treatment. Thirdly, the dopaminergic pathway and the nucleus accumbens have been shown to play a role in the effects of ritanserin. Finally, ritanserin reduces some alcohol withdrawal signs. Based on these findings, a clinical development plan started. After safety-interactions studies, ritanserin was demonstrated to influence the desire to drink in normal volunteers who display heavy social drinking. Currently, three major trials in 900 alcohol-dependent patients with different levels of dependence are running.


Tissue distribution of Na+/H+ exchanger isoforms NHE2 and NHE4 in rat intestine and kidney.
We present evidence that tissue distribution of two highly conserved Na+/H+ exchanger isoforms, NHE2 and NHE4, differs significantly from previously published reports. Riboprobes unique to each of these antiporters, from 5' (noncoding and coding) and 3' coding regions, were used to analyze mRNA from adult rat kidney and intestine by ribonuclease protection assay and in situ hybridization. In contrast to earlier work that concluded that both NHE2 and NHE4 were expressed throughout the intestine and in the kidney, our data show that there is no NHE2 message in the kidney and NHE4 is not expressed in small or large intestine. Analyses of intestinal epithelial and kidney membrane proteins by an NHE2-specific antibody identified a doublet at < 90 kDa in intestine but not in kidney. NHE2 is highly expressed in the Na(+)-absorptive epithelium of jejunum, ileum, and ascending and descending colon. NHE4 mRNA message is found in the inner medulla of the kidney as previously reported (C. Bookstein, M. W. Musch, A. DePaoli, Y. Xie, M. Villereal, M. C. Rao, and E. B. Chang. J. Biol. Chem. 269: 29704-29709, 1994) and not in the intestine. From these data, we speculate that neither NHE2 nor NHE4 has a role in renal Na+ absorption. NHE2 is likely involved in gut Na+ absorption, whereas NHE4 may have a specialized role in cell volume rectification of inner medullary collecting duct cells. Knowledge of the correct tissue and cell-specific distribution of these two antiporters should help significantly in understanding their physiological roles.


How intramolecular hydrogen bonding (IHB) controls the C-ON bond homolysis in alkoxyamines.
Recent amazing results (Nkolo et al., Org. Biomol. Chem., 2017, 6167) on the effect of solvents and polarity on the C-ON bond homolysis rate constants kd of alkoxyamine R1R2NOR3 led us to re-investigate the antagonistic effect of intramolecular hydrogen-bonding (IHB) on kd. Here, IHB is investigated both in the nitroxyl fragment R1R2NO and in the alkyl fragment R3, as well as between fragments, that is, the donating group on the alkyl fragment and the accepting group on the nitroxyl fragment, and conversely. It appears that IHB between fragments (inter IHB) strikingly decreases the homolysis rate constant kd, whereas IHB within the fragment (intra IHB) moderately increases kd. For one alkoxyamine, the simultaneous occurrence of IHB within the nitroxyl fragment and between fragments is reported. The protonation effect is weaker in the presence than in the absence of IHB. A moderate solvent effect is also observed.


Effects of gamma-aminobutyric acid on neural regulation of the canine sinus node.
The direct effects of gamma-aminobutyric acid (GABA) on the sinus node and its neural regulation were studied by selective perfusion of the sinus node artery (SNA) in 26 open-chest pentobarbital-anesthetized dogs. GABA (1-1,000 micrograms/ml, 2 ml, SNA) produced no direct effect on intrinsic sinus rate, but in several experiments (at 1 microgram/ml) it produced an inconsistent augmentation of the sinus tachycardia due to right stellate stimulation. At all other concentrations tested (10-1,000 micrograms/ml), GABA did not significantly alter the sinus node response to stellate stimulation. Local alpha-receptor blockade with phentolamine or muscarinic receptor blockade with atropine through the SNA prior to the perfusion of GABA did not change the sinus node responses. GABA (10-1,000 micrograms/ml, 2 ml, SNA) significantly attenuated (by 45-80% of control) the sinus bradycardia due to stimulation of the right vagosympathetic trunk. The sinus node response to selective perfusion of norepinephrine or acetylcholine (0.01 micrograms/ml, 2 ml, SNA) was not affected by GABA. The stellate augmentation (when present) and vagal attenuation were both antagonized by perfusion of picrotoxin (1,000 micrograms/ml, 2 ml, SNA). It is concluded that GABA does not exert any direct effect on the sinus node but may indirectly influence sinus rate by an effect on local nerves or ganglia.


25-Hydroxyvitamin D serum level in Hashimoto's thyroiditis, but not Graves' disease is relatively deficient.
Vitamin D is a modulator of both the innate and adaptive immune system. As vitamin D deficiency was a risk factor for some autoimmune diseases, we aimed to evaluate the serum vitamin D levels in autoimmune thyroid diseases (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) and investigated the association between serum vitamin D levels and AITD. 175 AITD patients including 51 GD, 61 euthyroid HT (mild HT), 63 euthyroid HT patients with hypothyroidism receiving hormone therapy (treated HT) were recruited from the outpatient department. 51 controls were from the physical checkup center of the hospital. 25-Hydroxyvitamin D levels, thyroid function, antithyroid antibodies, IL-4, IL-17, and TNF-α were determined. Compared with the controls, treated and mild HT patients had significantly lower 25(OH)D levels (45.77±3.48 vs. 83.49±6.24 nmol/L, p<0.001) and (55.25±3.88 vs. 83.49±6.24 nmol/L, p<0.001), respectively. However, GD patients had similar 25(OH)D levels (81.77±5.60 vs. 83.49±6.24 nmol/L, p=0.808). Compared to 24.1% controls with prevalent vitamin D deficiency, mild HT and treated HT patients were significantly different (55.4%, p<0.001) and (70.3%, p<0.001), respectively; no difference was seen in the GD patients (22.9%, p=0.797). Serum 25(OH)D levels were not associated with thyroid function, antithyroid antibodies, and serum cytokines IL-4, IL-17, and TNF-α in patients with AITD. We observed relatively low vitamin D level in mild and treated HT patients, while GD patients had similar 25(OH)D levels to those of healthy individuals. Further studies are imperative to explore the complex etiology of vitamin D deficiency in AITD.


The use of irradiated embryos of Chrysomya bezziana for the detection of the Old World screw-worm fly.
Irradiation of Chrysomya bezziana embryos 1 h before hatching with doses less than or equal to 7 kilorad (kr) had a significant effect on percentage egg hatch, weights and survival of larvae. Doses greater than or equal to 1 kr allowed larval development to the end of the 3rd instar stage in vitro, but prevented normal pupal development. Cattle with wounds infested with 1st instar larvae derived from irradiated embryos had 3rd instar larvae present after 3 d but these failed to pupate. Thus it would be feasible to use such larvae for wound infestation for the enhanced detection of screw-worm fly in areas where the release of fertile flies is undesirable.


Total hip replacement in high riding developmental dysplasia of the hip: cementless total hip arthroplasty with femoral shortening using a subtrochanteric resection.
Total hip arthroplasty in younger patients with high riding dislocations is a challenging procedure. Although many procedures have been proposed, our preferred technique for this is to insert a small sized cementless acetabular component in the native acetabulum, a small sized cementless femoral component and perform a subtrochanteric oblique cylindrical resection of 4 centimeters. The femur is fixed with a plate using unicortical screw fixation. This technique is preferred to avoid stretching the neurovascular structures. This procedure was performed on 91 hips of 83 patients with a mean age of 45 years, between 1990 and 2005. After 8 years we observed a 10% failure with a good clinical outcome. The Merle d'Aubigne Hip Scores were improved from 10.65 preoperatively to 34.95 postoperatively. Despite a high complication and failure rate the patients were pleased with the final outcome. We continue to recommend this procedure in this unique patient population.


Inkless microcontact printing on SAMs of Boc- and TBS-protected thiols.
We report a new inkless catalytic muCP technique that achieves accurate, fast, and complete pattern reproduction on SAMs of Boc- and TBS-protected thiols immobilized on gold using a polyurethane-acrylate stamp functionalized with covalently bound sulfonic acids. Pattern transfer is complete at room temperature just after one minute of contact and renders sub-200 nm size structures of chemically differentiated SAMs.


Cystic Echinococcosis in Turkana, Kenya: The Role of Cross-Sectional Screening Surveys in Assessing the Prevalence of Human Infection.
Cystic echinococcosis (CE) is a neglected zoonotic disease caused by Echinococcus granulosus. Infection leads to formation of cysts within the viscera of the human host. In the 1980s, the transhumant population of northwest Turkana, Kenya, was found to have the highest prevalence of CE in the world. In 1983, AMREF Health Africa and the Kenya Medical and Research Institute launched a CE Control Program in northwest Turkana, screening and treating the local people. This epidemiological study of CE in Turkana analyses approximately 30 years of surveillance and surgical data. Cyst data were categorized using the World Health Organization CE ultrasound classification system before being analyzed for cyst, patient, and population characteristics, and surveillance data from 1985 are compared with more recent surveillance data to assess changes in prevalence in the control region since the commencement of control activities. In 1985, the prevalence of CE among the Turkana was 5.6%. In 2010-2011 and 2011-2012, calculated CE prevalence rates were 1.9% and 3.8%, respectively. Since the 1980s, the age distribution of people with CE in Turkana has shifted: initially, cases of CE appeared predominantly within younger age groups, but recent data reveal a higher prevalence within older age groups. The frequency of infection in females also significantly decreased. The reduction in CE prevalence from 5.6% in the 1980s to 1.9-3.8% in 2010-2012 and the shift in age distribution of CE-infected individuals over time indicate that the prevalence of CE in Turkana has decreased since the control program began.


Age-specific findings on lifestyle and trajectories of cognitive function from the Korean Longitudinal Study of Aging.
Few longitudinal studies have explored age-related differences in the relationship between lifestyle factors and cognitive decline. This study investigated lifestyle factors at baseline that slow the longitudinal rate of cognitive decline in young-old (55-64 years), middle-old (65-74 years), and old-old (75+ years) individuals. We conducted an 11-year follow-up that included 6,189 older adults from the Korean Longitudinal Study of Aging, which is a cohort study of community-dwelling older Koreans. Lifestyle factors, including physical activity, social activity (SA), smoking, and alcohol consumption were assessed at baseline. Cognitive function was measured at 2-year intervals over 11 years. Latent growth modeling and multi-group analysis were performed. The influence of lifestyle factors on the rate of cognitive decline differed by age. Smoking at baseline (-0.05; 95% confidence interval [CI], -0.11 to -0.00, per study wave) accelerated cognitive decline in young-old individuals, whereas frequent participation in SA at baseline (0.02; 95% CI, 0.01 to 0.03, per study wave) decelerated cognitive decline in middle-old individuals. None of the lifestyle factors in this study decelerated cognitive decline in old-old individuals. Cognitive strategies based on modifiable lifestyle factors such as smoking cessation in young-old individuals and frequent SA participation in middle-old age individuals may have great potential for preventing cognitive decline. Because the influence of lifestyle factors varied by age group, age-specific approaches are recommended to promote cognitive health.


Redundant and selective roles for erythropoietin receptor tyrosines in erythropoiesis in vivo.
Cytokine receptors have been shown in cell culture systems to use phosphotyrosine residues as docking sites for certain signal transduction intermediates. Studies using various cellular backgrounds have yielded conflicting information about the importance of such residues. The present studies were undertaken to determine whether or not tyrosine residues within the erythropoietin receptor (EPOR) are essential for biologic activity during hematopoiesis in vivo. A variant of the EPOR was constructed that contains both a substitution (R129C) causing constitutive receptor activation as well as replacement of all eight cytoplasmic tyrosines by phenylalanines (cEPORYF). A comparison between animals exposed to recombinant retroviruses expressing cEPOR and cEPORYF showed that efficient red blood cell (RBC) development in vivo is dependent on the pressence of tyrosine residues in the cytoplasmic domain of the EPOR. In addition, an inefficient EPOR tyrosine independent pathway supporting RBC development was detected. Tyrosine add-back mutants showed that multiple individual tyrosines have the capacity to restore full erythropoietic potential to the EPOR as determined in whole animals. The analysis of primary erythroid progenitors transduced with the various cEPOR tyrosine mutants and tyrosine add-backs showed that only tyrosine 343 (Y1) and tyrosine 479 (Y8) were capable of supporting immature burst-forming unit-erythroid progenitor development. Thus, this receptor is characterized by striking functional redundancy of tyrosines in a biologically relevant context. However, selective tyrosine residues may be uniquely important for early signals supporting erythroid development.


Coping strategies of family carers for older relatives in Finland.
As the population continues to age, it is important that older people and their family carers get all the help and support they need with coping. This requires knowledge and understanding of the factors that foster and promote coping strategies, and on the other hand that complicate coping. Conducted as part of a major international research project on carers' work and coping in four countries, the purpose of this study was to explore the coping strategies of family carers looking after older relatives in their own home and to identify related factors. A survey involving 290 family carers from three towns in Finland. The data were collected with a questionnaire including the Carers' Assessment of Managing Index developed by Nolan et al. (1995). The most helpful coping strategy was to establish one's priorities and concentrate on them. Other strategies that over 80% of the respondents regarded as helpful were believing in oneself and one's ability to handle the situation, taking life 1 day at a time, looking for positive things in each situation and relying on one's own expertise and experience. The 10 most helpful coping methods included five problem-solving strategies, four emotional-cognitive strategies and one managing stress strategy. The age and gender of the family carers were found to correlate with the results. Our findings lend further support to earlier results according to which there are both similarities and differences in the coping strategies of family carers in different countries. Nurses who meet family carers of ageing individuals in their work will be able to use these results in assessing how these carers are coping and whether they need support, as well as in developing services for family carers.


Novel nuclear localization signal between the two DNA-binding zinc fingers in the human vitamin D receptor.
The human vitamin D receptor (hVDR) possesses a unique array of five basic amino acids positioned between the two DNA-binding zinc fingers that is similar to well-characterized nuclear localization sequences in other proteins. When residues within this region are mutated to nonbasic amino acids, or when this domain is deleted, the receptor is still well expressed, but it no longer associates with the vitamin D-responsive element in DNA, in vitro, and hVDR-mediated transcriptional activation is abolished in transfected cells. Concomitantly, the mutated hVDRs exhibit a significant shift in hVDR cellular distribution favoring cytoplasmic over nuclear retention as assessed by subcellular fractionation and immunoblotting. Independent immunocytochemical studies employing a VDR-specific monoclonal antibody demonstrate that mutation or deletion of this basic domain dramatically attenuates hVDR nuclear localization in transfected COS-7 cells. Although wild-type hVDR is partitioned predominantly to the nucleus in the absence of the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) hormone, treatment with ligand further enhances nuclear translocation, as it does to some degree in receptors with the basic region altered. The role of 1,25(OH)2D3 may be to facilitate hVDR heterodimerization with retinoid X receptors, stimulating subsequent DNA binding and ultimately enhancing nuclear retention. Taken together, these data reveal that the region of hVDR between Arg-49 and Lys-55 contains a novel constitutive nuclear localization signal, RRSMKRK.


Fungal endophytes of aquatic macrophytes: diverse host-generalists characterized by tissue preferences and geographic structure.
Most studies of endophytic symbionts have focused on terrestrial plants, neglecting the ecologically and economically important plants present in aquatic ecosystems. We evaluated the diversity, composition, host and tissue affiliations, and geographic structure of fungal endophytes associated with common aquatic plants in lentic waters in northern Arizona, USA. Endophytes were isolated in culture from roots and photosynthetic tissues during two growing seasons. A total of 226 isolates representing 60 putative species was recovered from 9,600 plant tissue segments. Although isolation frequency was low, endophytes were phylogenetically diverse and species-rich. Comparisons among the most thoroughly sampled species and reservoirs revealed that isolation frequency and diversity did not differ significantly between collection periods, among species, among reservoirs, or as a function of depth. However, community structure differed significantly among reservoirs and tissue types. Phylogenetic analyses of a focal genus (Penicillium) corroborated estimates of species boundaries and informed community analyses, highlighting clade- and genotype-level affiliations of aquatic endophytes with both sediment- and waterborne fungi, and endophytes of proximate terrestrial plants. Together these analyses provide a first quantitative examination of endophytic associations in roots and foliage of aquatic plants and can be used to optimize survey strategies for efficiently capturing fungal biodiversity at local and regional scales.


Physical Activity as Moderator of the Association Between APOE and Cognitive Decline in Older Adults: Results from Three Longitudinal Cohort Studies.
Previous studies have suggested that the association between APOE ɛ 4 and dementia is moderated by physical activity (PA), but the results remain inconclusive and longitudinal data on cognitive decline are missing. In this study, we examine whether there is a gene-environment interaction between APOE and PA on cognitive decline in older adults using 9-year follow-up data of three cohort studies. We followed 7,176 participants from three longitudinal cohort studies: Longitudinal Aging Study Amsterdam (LASA), InCHIANTI, and Rotterdam Study for 9 years. PA was assessed with self-reported questionnaires and was categorized in low, moderate, and high PA. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and cognitive decline was defined as a decrease of three points or more on the MMSE during 3 years follow-up. We fitted logistic regression models using generalized estimating equations adjusting for age, sex, education, depressive symptoms, and number of chronic disease. Interaction between APOE and PA was tested on multiplicative and additive scale. Cohorts were similar in most aspects but InCHIANTI participants were on average older and had lower education. APOE ɛ 4 carriers had higher odds of cognitive decline (odds ratio [OR] = 1.46, 95% confidence interval [CI]: 1.29-1.64) while PA was not significantly associated with cognitive decline overall (moderate PA: OR = 0.87, 0.67-1.13; high PA: OR = 0.71, 0.36-1.40). There was no evidence for an interaction effect between PA and APOE ɛ 4 in cognitive decline in older adults (APOE × moderate PA: p = .83; APOE × high PA: p = .90). Previous claims of a gene-environment interaction between APOE ɛ 4 and PA in cognitive decline are not supported by our results.


Triterpene betulin may be involved in the acute effects of pulp and paper mill effluent on testis physiology in zebrafish.
Pulp and paper mill effluent can cause changes in the morphology and energy metabolism in the zebrafish (Danio rerio) testis. Betulin, a naturally occurring triterpene is commonly present in this type of effluent and is suspected of being involved in these effects. The aim of this study was to compare the effects pulp and paper mill effluent and betulin on various aspects of testicular physiology in the zebrafish. This included the in vitro effects of effluent and betulin on testicular lactate content and lactate dehydrogenase (LDH) activity. In addition, the effects of betulin on glucose uptake, glycogen, alanine aminotransferase (ALT), reactive oxygen and nitrogen species formation and oxidative damage in the testes were determined. Furthermore, we compared the effects and mechanism of action of betulin and effluent on calcium homeostasis in testes. In vitro exposure to both effluent and betulin decreased lactate and calcium influx, possibly due to the activation of the sodium‑calcium exchanger (NCX) pump. Additionally, betulin-treated testes had higher reactive oxygen species (ROS) and reduced glutathione (GSH) content, as well as increased glutathione transferase (GST) activity and a tendency towards decreased catalase (CAT) activity. Thus, this study shows that alterations in testis physiology caused by the pulp and paper mill effluent in the testis may be due in part to the actions of betulin.


Parallax Attention for Unsupervised Stereo Correspondence Learning.
Stereo image pairs encode 3D scene cues into stereo correspondences between the left and right images. To exploit 3D cues within stereo images, recent CNN based methods commonly use cost volume techniques to capture stereo correspondence over large disparities. However, since disparities can vary significantly for stereo cameras with different baselines, focal lengths and resolutions, the fixed maximum disparity used in cost volume techniques hinders them to handle different stereo image pairs with large disparity variations. In this paper, we propose a generic parallax-attention mechanism (PAM) to capture stereo correspondence regardless of disparity variations. Our PAM integrates epipolar constraints with attention mechanism to calculate feature similarities along the epipolar line to capture stereo correspondence. Based on our PAM, we propose a parallax-attention stereo matching network (PASMnet) and a parallax-attention stereo image super-resolution network (PASSRnet) for stereo matching and stereo image super-resolution tasks. Moreover, we introduce a new and large-scale dataset named Flickr1024 for stereo image super-resolution. Experimental results show that our PAM is generic and can effectively learn stereo correspondence under large disparity variations in an unsupervised manner. Comparative results show that our PASMnet and PASSRnet achieve the state-of-the-art performance.


Spinally administered dynorphin A produces long-lasting allodynia: involvement of NMDA but not opioid receptors.
The endogenous opioid peptide dynorphin A has non-opioid effects that can damage the spinal cord when given in high doses. Dynorphin has been shown to increase the receptive field size of spinal cord neurons and facilitate C-fiber-evoked reflexes. Furthermore, endogenous dynorphin levels increase following damage to the spinal cord, injury to peripheral nerves, or inflammation. In this study, sensory processing was characterized following a single, intrathecal injection of dynorphin A (1-17) in mice. A single intrathecal injection of dynorphin A (1-17) (3 nmol, i.t.) induced mechanical allodynia (hind paw, von Frey filaments) lasting 70 days, tactile allodynia (paint brush applied to flank) lasting 14 days, and cold allodynia (acetone applied to the dorsal hind paw) lasting 7 days. Similarly, dynorphin A (2-17) (3 nmol, i.t.), a non-opioid peptide, induced cold and tactile allodynia analogous to that induced by dynorphin A (1-17), indicating the importance of non-opioid receptors. Pretreatment with the NMDA antagonists, MK-801 and LY235959, but not the opioid antagonist, naloxone, blocked the induction of allodynia. Post-treatment with MK-801 only transiently blocked the dynorphin-induced allodynia, suggesting the NMDA receptors may be involved in the maintenance of allodynia as well as its induction. We have induced a long-lasting state of allodynia and hyperalgesia by a single intrathecal injection of dynorphin A (1-17) in mice. The allodynia induced by dynorphin required NMDA receptors rather than opioid receptors. This result is consistent with results in rats and with signs of clinically observed neuropathic pain. This effect of exogenously administered dynorphin raises the possibility that increased levels of endogenous dynorphins associated with spinal cord injuries may participate in the genesis and maintenance of neuropathic pain.


Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb.
We have previously shown that monocytes adhere to the vascular wall during collateral vessel growth (arteriogenesis) and capillary sprouting (angiogenesis). In this study we investigated the association of monocyte accumulation with both the production of the cytokines-basic fibroblast growth factor (bFGF) and TNF-alpha-and vessel proliferation in the rabbit after femoral artery occlusion. In particular, we studied the effects of an increase in monocyte recruitment by LPS on capillary density as well as collateral and peripheral conductance after 7 d of occlusion. Monocytes accumulated around day 3 in collateral arteries when maximal proliferation was observed, and stained strongly for bFGF and TNF-alpha. In the lower limb where angiogenesis was shown to be predominant, macrophage accumulation was also closely associated with maximal proliferation (around day 7). LPS treatment significantly increased capillary density (424+/-26.1 n/mm2 vs. 312+/-20.7 n/mm2; P < 0.05) and peripheral conductance (109+/-33.8 ml/min/100 mmHg vs. 45+/-6.8 ml/min/100 mmHg; P < 0.05) as compared with untreated animals after 7 d of occlusion. These results indicate that monocyte activation plays a major role in angiogenesis and collateral artery growth.


Effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression in a large cohort of HIV-1-positive persons in Uganda.
The effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression was investigated in 1045 adults in Uganda. At enrollment and every 6 months, a clinical history, examination, and laboratory investigations that included CD4 cell counts were done. HIV-1 envelope subtype was assessed mainly by peptide serology supplemented by heteroduplex mobility assay and DNA sequencing. A multivariate analysis of survival was performed to assess the prognostic value of HIV-1 subtype on death. A marginal general linear model also determined the effect of subtype on CD4 cell count during follow-up. Subtype D was associated with faster progression to death (relative risk, 1.29; 95% confidence interval, 1.07-1.56; P=.009) and with a lower CD4 cell count during follow-up (P=.001), compared with subtype A, after adjusting for CD4 cell count at enrollment. In Africa, envelope subtype D is associated with faster disease progression, compared with subtype A.


Fe3+ coordination and redox properties of a bacterial transferrin.
The Fe(3+) binding site of recombinant nFbp, a ferric-binding protein found in the periplasmic space of pathogenic Neisseria, has been characterized by physicochemical techniques. An effective Fe(3+) binding constant in the presence of 350 microm phosphate at pH 6.5 and 25 degrees C was determined as 2.4 x 10(18) m(-1). EPR spectra for the recombinant Fe(3+)nFbp gave g' = 4.3 and 9 signals characteristic of high spin Fe(3+) in a strong ligand field of low (orthorhombic) symmetry. (31)P NMR experiments demonstrated the presence of bound phosphate in the holo form of nFbp and showed that phosphate can be dialyzed away in the absence of Fe(3+) in apo-nFbp. Finally, an uncorrected Fe(3+/2+) redox potential for Fe-nFbp was determined to be -290 mV (NHE) at pH 6.5, 20 degrees C. Whereas our findings show that nFbp and mammalian transferrin have similar Fe(3+) binding constants and EPR spectra, they differ greatly in their redox potentials. This has implications for the mechanism of Fe transport across the periplasmic space of Gram-negative bacteria.


Dependence of subarachnoid hemorrhage on climate conditions: a systematic meteorological analysis from the dusseldorf metropolitan area.
A number of publications suggest that there are seasonal influences on the incidence of subarachnoid hemorrhage (SAH). Most series agree on a peak incidence during springtime. Meteorological influences have been assumed to be obvious explanations for seasonal variations. Furthermore, the perceived clustering of the incidence of subarachnoid hemorrhage is also intuitively related to meteorological influences. The present study was initiated to determine whether specific meteorological conditions are related to the occurrence of SAH in the mild climatic zone of North Rhine Westphalia. We retrospectively examined 183 patients (107 women and 76 men) treated at our department between January 2003 and June 2005 for SAH that had occurred within the Düsseldorf metropolitan area. We correlated the date of SAH (Day 0) and of the week preceding the incident (Days -1, -3, -5, and -7) with the meteorological key parameters from Düsseldorf International Airport. Parameters analyzed were mean daily temperature (7C), relative humidity (%), barometric pressure (hPa), and weather condition (divided into 6 groups: clear, cloudy, rain, thunderstorms, snow, and not available). A relative peak incidence of SAH was found for the month of April. In addition, a diurnal rhythm with two peaks during morning and in the evening, and a statistically significant nadir during forenoon and midday was evident (P <0.002). None of the average meteorological key parameters of the day of SAH differed from the annual average, and no general trends during the days preceding hemorrhage could be identified. Apparent clustering of the occurrence of SAH could not be related to short-term meteorological trends. The results of the present study demonstrate a trend toward a seasonal distribution in the incidence of SAH with a peak during spring in the metropolitan area of Düsseldorf. Furthermore, weather variables, such as temperature, barometric pressure, and humidity, were shown to be without influence on aneurysm rupture within the patient population. Therefore, the result indicates the need to validate further parameters in detail to isolate risk circumstances to achieve a risk pattern for patients with SAH.


Strong improvement of apolipoprotein E/low-density lipoprotein receptor signals by telmisartan in poststroke spontaneously hypertensive stroke resistant.
Telmisartan, an angiotensin receptor blocker also called metabosartan, is a promising solution for preventing cognitive decline or the incidence of dementia. We examined the effects of telmisartan on cholesterol transport-related proteins (apolipoprotein E [ApoE]/low-density lipoprotein receptor [LDL-R]) and microtubule-associated protein 2 (MAP2) in the brain of spontaneously hypertensive stroke resistant (SHR-SR). SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes at 12 weeks of age and then was divided into 3 experiment groups including a vehicle, low-dose telmisartan (.3 mg/kg/day), and high-dose telmisartan (3 mg/kg/day). The low dose served to improve the metabolic syndrome of SHR-SR without lowering the blood pressure (BP) whereas the high dose was used to improve metabolic syndrome while lowering BP. Immunohistologic analysis showed that ApoE expression of cortical neurons was strong in the vehicle group at 6, 12, and 18 months of age, and that this ApoE expression pattern was very similar between the ipsilateral and contralateral sides of cerebral ischemia. On the other hand, LDL-R expression of cortical neurons was transiently increased at 6 months of age only on the ipsilateral side. Telmisartan dramatically suppressed the expression of ApoE/LDL-R at both doses. There was no remarkable difference in neuronal MAP2 staining between the 3 groups. These findings suggest that both low and high doses of telmisartan prevented the activation of ApoE/LDL-R in SHR-SR after tMCAO, and that the antimetabolic effect was regarded as the most important mechanism with few additional benefits by lowering BP in this transient stroke model.


Control of SRC molecular dynamics encodes distinct cytoskeletal responses by specifying signaling pathway usage.
Upon activation by different transmembrane receptors, the same signaling protein can induce distinct cellular responses. A way to decipher the mechanisms of such pleiotropic signaling activity is to directly manipulate the decision-making activity that supports the selection between distinct cellular responses. We developed an optogenetic probe (optoSRC) to control SRC signaling, an example of a pleiotropic signaling node, and we demonstrated its ability to generate different acto-adhesive structures (lamellipodia or invadosomes) upon distinct spatio-temporal control of SRC kinase activity. The occurrence of each acto-adhesive structure was simply dictated by the dynamics of optoSRC nanoclusters in adhesive sites, which were dependent on the SH3 and Unique domains of the protein. The different decision-making events regulated by optoSRC dynamics induced distinct downstream signaling pathways, which we characterized using time-resolved proteomic and network analyses. Collectively, by manipulating the molecular mobility of SRC kinase activity, these experiments reveal the pleiotropy-encoding mechanism of SRC signaling.


Who are the high hospital users? A Canadian case study.
Researchers have taken two different approaches to understanding high use of hospital services, one focusing on the large proportion of services used by a small minority and a second focusing on the poor health status and high hospital use of the poor. This work attempts to bridge these two widely researched approaches to understanding health care use. Administrative data from Winnipeg, Manitoba covering all hospitalizations in 1995 were combined with public use Census measures of socio-economic status (neighbourhood household income). High users were defined as the 1% of the population who spent the most days in hospital in 1995 (n = 6487 hospital users out of population of 648715 including non-users). One per cent of the Winnipeg population consumed 69% of the hospital days in 1995. Thirty-one per cent of the highest users were among the 20% of residents of neighbourhoods with the lowest household incomes, and 10% of the highest users were among the 20% from neighbourhoods with the highest household incomes. However, on most other dimensions, including gender, age, average days in hospital, average admissions, percentage who died in hospital and diagnostic reasons for being hospitalized, the similarities between high users, regardless of their socio-economic group, were striking. The lower the socio-economic status, the more likely an individual is to make high demands on hospitals. However, patterns of use as well as the diseases and accidents that produce high use among residents of low income neighbourhoods are not much different from those that produce high use among residents of high income neighbourhoods.


Polymeric micelles with π-π conjugated moiety on glycerol dendrimer as lipophilic segments for anticancer drug delivery.
Polymeric micelles are important nanovehicles for anticancer drug delivery. The lipophilic segment in polymeric micelles is an important factor to affect the drug loading properties. In our previous work, we found that small molecules with π-π conjugated structures could be used to replace hydrophobic polymeric chains as lipophilic segments for anticancer drug delivery. Herein, we report a novel polymeric micelle with π-π conjugated cinnamate moiety on glycerol dendrimer as lipophilic segment, the modified dendritic segment was connected to poly(ethylene glycol) (PEG) via click chemistry. The received amphiphiles self-assembled into micelles in aqueous medium. The properties of the polymeric micelles such as critical micelle concentration (CMC), mean size and morphology were investigated. Anticancer drug doxorubicin (DOX) was loaded in the polymeric micelles. The π-π interaction, drug release profile and in vitro anticancer efficiency of the DOX loaded micelles were studied. The results showed that the micelles with more cinnamate moieties exhibited a lower CMC. The drug loading content and release rate of the micelles increased with increasing generation of glycerol dendrimer. Strong π-π stacking interaction was detected between DOX and carriers. The DOX loaded polymeric micelles exhibited efficient anticancer activity in vitro.


LncRNA WEE2-AS1 knockdown inhibits the proliferation, migration and invasion of glioma cells via regulating miR-29b-2-5p/TPM3 axis.
Glioma is a general malignant tumor with a dismal prognosis. Long noncoding RNAs (lncRNAs) have been implicated in the initiation and processes of tumors. An investigation of the GEPIA database revealed that long noncoding RNA WEE2 antisense RNA 1 (WEE2-AS1) is upregulated in glioma tissues compared to normal brain tissues, and validation with quantitative real-time polymerase chain reaction (qRT-PCR) revealed that WEE2-AS1 expression was consistent with the database prediction. Fluorescence in situ hybridization (FISH) assays revealed that WEE2-AS1 was localized primarily in the cytoplasm. Clone formation experiment and EDU assay were used to detect cell proliferation ability, and Transwell assay was used to detect cell migration and invasion ability, Western-blot assay and immunofluorescence were used to determine TPM3 protein level. Functional experiments revealed that the downregulation of WEE2-AS1 impeded cell proliferation, migration, and invasion in glioma cell lines. Furthermore, downregulation of WEE2-AS1 suppressed tumor growth in vivo. Bioinformatics predictions and integrated experiments indicated that WEE2-AS1 promoted tropomyosin 3 (TPM3) expression by sponging miR-29b-2-5p. A dual-luciferase reporter assay was conducted to uncover the binding of WEE2-AS1 and miR-29b-2-5p and that of miR-29b-2-5p and TPM3. Additionally, a series of rescue assays showed that WEE2-AS1 promotes proliferation, migration, and invasion by targeting miR-29b-2-5p to regulate TPM3 expression. Ultimately, the results of this study indicate that WEE2-AS1 plays an oncogenic role in glioma and may promote further investigations of the diagnostic and prognostic value of WEE2-AS1 in glioma.


A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue therapy: 48 weeks' observational data.
Dolutegravir (DTG) plus darunavir/ritonavir (DRV/r) is a simple combination of drugs that has the best genetic barrier to HIV-1 resistance and may be fit for salvage therapy. All HIV-1-infected subjects treated with DTG plus DRV/r between March 2014 and September 2015 in eight Italian centres were included in the analysis. The main metabolic data, efficacy parameters and safety data routinely collected were provided. This observational study is aimed to assess the efficacy of such approach. The primary end-point was the proportion of subjects achieving or maintaining virologic suppression <50 copies/mL at week 24. Secondary end points were maintaining virologic suppression in the follow-up (weeks 48 and 96) and safety. One hundred and thirty subjects were followed for a median of 56 months. Reasons for switching were simplification (44.6%), viral failure (30%), toxicity (16.9%), non-adherence (4.6%), persistent low-level viremia (3.1%), and drug-drug interaction (0.8%). At baseline, 118 subjects had documented resistance to 1 to 5 antiretroviral classes while 12 had viral rebound at a time when genotypic tests were not yet available. Seventeen and 14 subjects took DRV/r and DTG twice daily, respectively. One subject was lost to follow-up, one discontinued for liver enzymes' elevation, one died of illicit drug abuse and one of cancer-related complications. The proportion of subjects with ongoing HIV replication dropped from 40% to 6.1%. Those with undetectable viral load increased from 38.5% to 76.2%. At week 48, 17.7% had HIV RNA between 1 and 49 copies/mL. The number of subjects with altered serum glucose, creatinine, ALT, AST, total-, HDL- and LDL-cholesterol, triglycerides and MDRD <90 mL/min decreased by week 48, while those having MDRD <60 mL/min remained 4.6%. Overall 90/283 baseline laboratory alterations returned to normality. Switching to DTG plus DRV/r proved to be safe, suppressing viral replication without metabolic impact.


Disparities in the treatment and outcomes of vascular disease in Hispanic patients.
The Hispanic population represents the fastest growing minority in the United States. As the population grows and ages, the vascular surgery community will be providing increasing amounts of care to this diverse group. To appropriately administer preventive and therapeutic care, it is important to understand the incidence, risk factors, and natural history of vascular disease in Hispanic patients. We analyzed hospital discharge databases from New York and Florida to determine the rate of lower extremity revascularization (LER), carotid revascularization (CR), and abdominal aortic aneurysm (AAA) repair in Hispanics relative to the general population. The rates of common comorbidities, the indications for the procedures, and outcomes during the same hospitalization as the index procedure were determined. Multivariate logistic regression analysis was used to determine the differences between Hispanics and white non-Hispanics with respect to rate of procedure, symptoms at presentation, and outcome after procedure. Demographic variables and length of stay were also analyzed. The rate of LER, CR, and AAA repair was significantly lower in Hispanic patients than in white non-Hispanics. Despite this lower rate of intervention, Hispanics were significantly more likely than whites to present with limb-threatening lower extremity ischemia (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.91 to 2.29), symptomatic carotid artery disease (OR, 1.57; 95% CI, 1.4 to 1.75), and ruptured AAA (OR, 1.26; 95% CI, 1.04-1.52) than white non-Hispanics These differences were maintained after controlling for the presence of diabetes mellitus and other comorbidities. Hispanic patients had higher rates of amputation during the same hospitalization after LER (6.2% vs 3.4%, P < .0001) and higher mortality after elective AAA repair (5% vs 3.4%, P = .0032). Length of stay after LER, CR, and AAA repair was longer for Hispanic patients than white non-Hispanics. Significant disparities in the rate of utilization of three common vascular surgical procedures exist between Hispanic patients and the general population. In addition, Hispanics appear to present with more advanced disease and have worse outcomes in some cases. Reasons for these disparities must be determined to improve these results in the fastest growing segment of our society.


Peritoneal metastases: detection with spiral CT in patients with ovarian cancer.
To determine the accuracy of spiral computed tomography (CT) in the depiction of peritoneal metastases by using surgical findings in patients with ovarian cancer as the standard of reference. Three independent readers reviewed the preoperative CT scans obtained in 64 patients who underwent primary surgery for ovarian cancer. Readers rated the likelihood of peritoneal metastases on a five-point scale and recorded the presence or absence of ascites, parietal peritoneal thickening or enhancement, and small-bowel wall thickening or distortion. Peritoneal metastases were identified as nodular, plaquelike, or infiltrative soft-tissue lesions in the peritoneal fat or on the peritoneal surface. Area under the receiver operating characteristic curve was calculated for each reader. Interreader agreement was evaluated with the kappa statistic. Descriptive statistical data were determined with dichotomized ratings (1-3 = absent; 4-5 = present). Areas under the receiver operating characteristic curves for the three readers were 0.95, 0.93, and 0.89. Paired kappa values ranged from 0.75 to 0.91. Reader sensitivity for metastases 1 cm or smaller in maximum diameter (25%-50%) was significantly (P <.05) lower than overall sensitivity (85%-93%). Ascites, parietal peritoneal thickening or enhancement, and small-bowel wall thickening or distortion demonstrated positive predictive values of 72%-93%, with kappa values of 0.12-0.80. Spiral CT is accurate in the depiction of peritoneal metastases from ovarian cancer, although sensitivity is reduced in patients with tumor implants 1 cm or smaller. Ancillary signs of peritoneal malignancy are limited by low interobserver agreement.


The Incremental Role of Coronary Computed Tomography in Chronic Coronary Syndromes.
In the context of chronic coronary syndromes (CCS), coronary computed tomography angiography (CCTA) has gained broad acceptance as a noninvasive anatomical imaging tool with ability of excluding coronary stenosis with strong negative predictive value. Atherosclerotic plaque lesions are independent predictors of cardiovascular outcomes in high risk patients with known coronary artery disease (CAD). Calcium detection is commonly expressed through the coronary artery calcium score (CACS), but further research is warranted to confirm the powerness of a CACS-only strategy in both diagnosis and prognosis assessment. Recent studies evidence how defined plaque composition characteristics effectively relate to the risk of plaque instabilization and the overall ischemic burden. Fractional flow reserve from CCTA (FFR-CT) has been demonstrated as a reliable method for noninvasive functional evaluation of coronary lesions severity, while the assessment of perfusion imaging under stress conditions is growing as a useful tool for assessment of myocardial ischemia. Moreover, specific applications in procedural planning of transcatheter valve substitution and follow-up of heart transplantation have gained recent importance. This review illustrates the incremental role of CCTA, which can potentially revolutionize the diagnosis and management pathway within the wide clinical spectrum of CCS.


Antimicrobial resistance and biotechnological potential of plastic-associated bacteria isolated from an urban estuary.
Plastics have quickly become one of the major pollutants in aquatic environments worldwide and solving the plastic pollution crisis is considered a central goal of modern society. In this study, 10 different plastic samples, including high- and low-density polyethylene and polypropylene, were collected from a deeply polluted urban estuary in Brazil. By employing different isolation and analysis approaches to investigate plastic-associated bacteria, a predominance of potentially pathogenic bacteria such as Acinetobacter, Aeromonas, and Vibrio was observed throughout all plastic samples. Bacteria typically found in the aquatic environment harboured clinically relevant genes encoding resistance to carbapenems (blaKPC ) and colistin (such as mcr-3 and mcr-4), along with genetic determinants associated with potentially active gene mobilization. Whole genome sequencing and annotation of three plastic-associated Vibrio strains further demonstrated the carriage of mobile genetic elements and antimicrobial resistance and virulence genes. On the other hand, bacteria isolated from the same samples were also able to produce esterases, lipases, and bioemulsifiers, thus highlighting that the plastisphere could also be of special interest from a biotechnological perspective.


Overview of Therapeutic Inertia in Diabetes: Prevalence, Causes, and Consequences.
Many people with diabetes do not achieve individualized treatment targets. Therapeutic inertia, the underuse of effective therapies in preventing serious clinical end points, is a frequent, important contributor to this failure. Clinicians, patients, health systems, payors, and producers of medications, devices, and other products for those with diabetes all play a role in the development of therapeutic inertia and can all help to reduce it.


Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction.
Oxidative stress resulting from inflammatory responses that occur during acute lung injury and sepsis can initiate changes in mitochondrial function. Autophagy regulates cellular processes in the setting of acute lung injury, sepsis, and oxidative stress by modulating the immune response and facilitating turnover of damaged cellular components. We have shown that mesenchymal stromal cells (MSCs) improve survival in murine models of sepsis by also regulating the immune response. However, the effect of autophagy on MSCs and MSC mitochondrial function during oxidative stress is unknown. This study investigated the effect of depletion of autophagic protein microtubule-associated protein 1 light chain 3B (LC3B) and beclin 1 (BECN1) on the response of MSCs to oxidative stress. MSCs were isolated from wild-type (WT) and LC3B-/- or Becn1+/- mice. MSCs from the LC3B-/- and Becn1+/- animals had increased susceptibility to oxidative stress-induced cell death as compared with WT MSCs. The MSCs depleted of autophagic proteins also had impaired mitochondrial function (decreased intracellular ATP, reduced mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production) under oxidative stress as compared with WT MSCs. In WT MSCs, carbon monoxide (CO) preconditioning enhanced autophagy and mitophagy, and rescued the cells from oxidative stress-induced death. CO preconditioning was not able to rescue the decreased survival of MSCs from the LC3B-/- and Becn1+/- animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.


Preclinical in vivo assessment of a cell-free multi-layered scaffold prepared by 3D printing and electrospinning for small-diameter blood vessel tissue engineering in a canine model.
Tissue-engineered vascular grafts (TEVGs) are promising alternatives to existing prosthetic grafts. The objective of this study is to evaluate the clinical feasibility of a novel multi-layered small-diameter vascular graft that has a hierarchical structure. Vascular grafts with elaborately designed composition and architecture were prepared by 3D printing and electrospinning and were implanted into the femoral artery of 5 dogs. The patency of the grafts was assessed using Doppler ultrasonography. After 6 months, the grafts were retrieved and histological and SEM examinations were conducted. During implantation, the grafts exhibited resistance to kinking and no blood seepage thanks to the helical structure of the innermost and outermost layers. The grafts showed a high patency rate and remodelling ability. At 6 months post-implantation, the lumen was endothelialized and middle layers were regenerated by infiltration of smooth muscle cells (SMCs) and deposition of extracellular matrix (ECM). These results suggest that the multi-layered vascular graft may be a promising candidate for small-diameter blood vessel tissue engineering in clinical practice.


Dexamethasone can attenuate the pulmonary inflammatory response via regulation of the lncH19/miR-324-3p cascade.
To investigate lncRNAs and their roles in regulating the pulmonary inflammatory response under dexamethasone (Dex) treatment. IL-1β (10 ng/mL) and LPS (1 μg/mL) was used to construct inflammatory cell models with A549 cells; IL-1β performed better against LPS. Different concentrations of Dex were used to attenuate the inflammation induced by IL-1β, and its effect was assessed via RT-PCR to detect inflammatory cytokine-related mRNA levels, including those of IKβ-α, IKKβ, IL-6, IL-8, and TNF-α. Furthermore, ELISA was used to detect the levels of the inflammatory cytokines TNF-α, IL-6, and IL-8. RT-PCR was used to quantify the levels of lncRNAs, including lncMALAT1, lncHotair, lncH19, and lncNeat1. LncH19 was most closely associated with the inflammatory response, which was induced by IL-1β and attenuated by Dex. Among the lncRNAs, the level of lncH19 showed the highest increase following treatment with 1 and 10 μM Dex. Therefore, lncH19 was selected for further functional studies. LncH19 expression was inhibited by shRNA transduced with lentivirus. Cell assays for cell proliferation and apoptosis as well as RT-PCR, western blot, and ELISA for inflammatory genes were conducted to confirm the functions of lncH19. The predicted target miRNAs of lncH19 were hsa-miR-346, hsa-miR-324-3p, hsa-miR-18a-3p, hsa-miR-18b-5p, hsa-miR-146b-3p, hsa-miR-19b-3p, and hsa-miR-19a-3p. Following estimation via RT-PCR, hsa-miR-346, hsa-miR-18a-3p, and hsa-miR-324-3p showed consistent patterns in A549 NC and A549 shlncH19. An miRNA inhibitor was transfected into A549 NC and A549 shlncH19 cells, and the expression levels were determined via RT-PCR. hsa-miR-324-3p was inhibited the most compared with hsa-miR-346 and hsa-miR-18a-3p and was subjected to further functional studies. RT-PCR, ELISA, and western blotting for inflammatory gene detection were conducted to validate the functions of the target hsa-miR-324-3p. Treatment with 1 and 10 μM Dex could effectively attenuate the inflammatory response. During this process, lncH19 expression significantly increased (P < 0.05). Therefore, treatment with 1 μM Dex was used for further study. Under IL-1β treatment with or without Dex, lncH19 inhibition led to an increase in cell proliferation; a decrease in cell apoptosis; an increase in the protein levels of inflammatory genes; phosphorylation of P65, ICAM-1, and VCAM-1; and increase inflammatory cytokines. Prediction of the targets of lncH19 and validation via RT-PCR revealed that miR-346, miR-18a-3p, and miR-324-3p negatively correlate with lncH19. Additionally, Dex increased the lncH19 expression but reduced that of the miRNAs. Among the miRNAs, miR-324-3p was the most markedly downregulated miRNA following treatment of miRNA inhibitors. The MTS assay and cell apoptosis assay showed that the miR-324-3p inhibitor inhibited cell proliferation and induced cell apoptosis, thereby significantly attenuating the inflammatory response, which reversed the effect of lncH19 in regulating cell proliferation and the secretion of inflammatory cytokines (P < 0.05). Therefore, lncH19 might regulate miR-324-3p in pulmonary inflammatory response under Dex treatment. Dex can attenuate the pulmonary inflammatory response by regulating the lncH19/miR-324-3p cascade.


Congenital Deformities of the Upper Extremity.
Congenital deformities of the upper extremity are rare. They are often associated with other, more severe disorders of the cardiovascular, craniofacial, neurologic, and musculoskeletal systems. Most upper-extremity congenital anomalies are minor and cause no functional deficits, and surgical reconstruction is therefore unnecessary. If a severe cosmetic deformity is present or there is significant functional compromise, surgical treatment is indicated. The authors review the common congenital deformities of the upper extremity and offer treatment recommendations.


Susceptibility of different breeds of goats in Kenya to experimental infection with Trypanosoma congolense.
To assess whether there was any evidence of genetic resistance to African trypanosomiasis, five breeds of goat (East African, Galla, and crossbreds between East African and Galla, Nubian or Toggenburg) were experimentally infected with Trypanosoma congolense either by needle inoculation or by tsetse-transmission. The goats had not been previously exposed to trypanosomiasis. With both methods of infection all breeds were found to be highly susceptible and suffered severe disease. Following tsetse-transmitted infection no significant differences were observed between breeds in the development, duration and size of the chancre reaction or in the degree and duration of parasitaemia. While Nubian goats developed anaemia more rapidly than the other breeds, all animals experienced a pronounced reduction in packed red cell volume. Similarly following needle inoculation no differences were found between breeds in the severity of anaemia or in the kinetics of parasitaemia. Immune responses against both metacyclic and bloodstream trypanosomes of the infecting serodeme were similar in all breeds as were the erythropoietic responses to the infection. No alterations in leucocyte parameters occurred.


Alloying and Structure of Ultrathin Gallium Films on the (111) and (110) Surfaces of Palladium.
Growth, thermal stability, and structure of ultrathin gallium films on Pd(111) and Pd(110) are investigated by low-energy ion scattering and low-energy electron diffraction. Common to both surface orientations are growth of disordered Ga films at coverages of a few monolayers (T = 150 K), onset of alloy formation at low temperatures (T ≈ 200 K), and formation of a metastable, mostly disordered 1:1 surface alloy at temperatures around 400-500 K. At higher temperatures a Ga surface fraction of ∼0.3 is slightly stabilized on Pd(111), which we suggest to be related to the formation of Pd2Ga bulk-like films. While on Pd(110) only a Pd-up/Ga-down buckled surface was observed, an inversion of buckling was observed on Pd(111) upon heating. Similarities and differences to the related Zn/Pd system are discussed.


Synergistic effects of p38 mitogen-activated protein kinase inhibition with a corticosteroid in alveolar macrophages from patients with chronic obstructive pulmonary disease.
Corticosteroids partially suppress cytokine production by chronic obstructive pulmonary disease (COPD) alveolar macrophages. p38 mitogen-activated protein kinase (MAPK) inhibitors are a novel class of anti-inflammatory drug. We have studied the effects of combined treatment with a corticosteroid and a p38 MAPK inhibitor on cytokine production by COPD alveolar macrophages, with the aim of investigating dose-sparing and efficacy-enhancing effects. Alveolar macrophages from 10 patients with COPD, six smokers, and six nonsmokers were stimulated with lipopolysaccharide (LPS) after preincubation with five concentrations of dexamethasone alone, five concentrations of the p38 MAPK inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB-796) alone, and all combinations of these concentrations. After 24 h, the supernatants were analyzed for interleukin (IL)-8, IL-6, tumor necrosis factor α (TNFα), granulocyte macrophage-colony-stimulating factor (GM-CSF), IL-1α, IL-1β, IL-1ra, IL-10, monocyte chemoattractant protein 3, macrophage-derived chemokine (MDC), and regulated on activation normal T cell expressed and secreted (RANTES). The effect of dexamethasone on p38 MAPK activation was analyzed by Western blotting. Dexamethasone and BIRB-796 both reduced LPS-induced cytokine production in a dose-dependent manner in all subject groups, with no differences between groups. Increasing the concentration of BIRB-796 in combination with dexamethasone produced progressively greater inhibition of cytokine production than dexamethasone alone. There were significant efficacy-enhancing benefits and synergistic dose-sparing effects (p < 0.05) for the combination treatment for IL-8, IL-6, TNFα, GM-CSF, IL-1ra, IL-10, MDC, and RANTES in one or more subject groups. Dexamethasone had no effect on LPS-induced p38 MAPK activation. We conclude that p38 MAPK activation in alveolar macrophages is corticosteroid-insensitive. Combining a p38 MAPK inhibitor with a corticosteroid synergistically enhances the anti-inflammatory effects on LPS-mediated cytokine production by alveolar macrophages from patients with COPD and controls.


Percutaneous absorption and model membrane variations of melatonin in aqueous-based propylene glycol and 2-hydroxypropyl-beta-cyclodextrin vehicles.
Percutaneous absorption and model membrane variations of melatonin (MT) in aqueous-based propylene glycol and 2-hydroxypropyl-beta-cyclodextrin vehicles were investigated. The excised hairless mouse skin (HMS) and two synthetic ethylene vinyl acetate (EVA) and microporous polyethylene (MPE) were selected as a model membrane. The solubility of MT was determined by phase equilibrium study. The vertical Franz type cell was used for diffusion study. The concentration of MT was determined using reverse phase HPLC system. The MT solubility was the highest in a mixture of PG and 2-HP beta CD. The percutaneous absorption of MT through excised HMS increased as the solubility increased. However, the permeability coefficient decreased and then slightly increased in a mixture of PG and 2-HP beta CD. On the other hand, both flux and permeability coefficient through EVA membrane decreased as the solubility increased. No MT was detected over 12 h after starting diffusion through MPE membrane. The flux of MT was dependent on the type of membrane selected. Flux of MT was greatest in excised HMS followed by EVA and MPE membrane. Flux of MT through EVA membrane was 5-20 times lower when compared to excised HMS. Interestingly, volumes of donor phase when MPE membrane was used, significantly increased during the study period. The HMS might be applicable to expect plasma concentration of MT in human subjects based on flux and pharmacokinetic parameters as studied previously. The current studies may be applied to deliver MT transdermally using aqueous-based vehicles and to fabricate MT dosage forms.


Ultrasound evaluation of the respiratory changes of the inferior vena cava and axillary vein diameter at rest and during positive pressure ventilation in spontaneously breathing healthy volunteers.
Ultrasound assessment of the inferior vena cava (IVC) has gained favour in aiding fluid management decisions for controlled, mechanically ventilated patients as well as in non-mechanically ventilated, spontaneously breathing patients. Its utility in spontaneously breathing patients during positive pressure non-invasive ventilation has not yet been determined. The use of the axillary vein, as an alternative option to the IVC due to its ease of accessibility and independence from intra-abdominal pressure, has also not been evaluated. The aim of this study was to assess respiratory variation in IVC and axillary vein diameters in spontaneously breathing participants (Collapsibility Index) and with the application of increasing positive end-expiratory pressure (PEEP) via positive pressure non-invasive ventilation (Distensibility Index). The IVC and axillary vein diameters of 28 healthy adult volunteers were measured, using ultrasound, at baseline and with increasing PEEP via non-invasive ventilation. The Collapsibility Index and Distensibility Index of these vessels were calculated and compared for each vessel. The association between increasing PEEP levels and the indices was evaluated. Positive pressure delivered via non-invasive ventilation produced a similar degree of diameter change in the IVC and the axillary vein, that is, the Distensibility Index was similar whether measured in the IVC or the axillary vein (P=0.21, 0.47 and 0.17 at baseline, 5 and 10 cmH2O PEEP, respectively). Individual study participants' IVC and axillary veins, however, had variable responses to PEEP; that is, there appeared to be no consistent relationship between PEEP and the diameter changes. While the axillary vein could potentially be used as an alternative vessel to the IVC to assess for volume responsiveness in controlled, mechanically ventilated patients as well as in non-mechanically ventilated, spontaneously breathing patients, neither vein should be used to guide fluid management decisions in spontaneously breathing patients during positive pressure non-invasive ventilation.


Association of polymorphisms in iNOS and NQO1 with bladder cancer risk in cigarette smokers.
quinine oxidoreductase (NQO1) plays an important role in the metabolism of several carcinogens contained in cigarettes. Inducible nitric oxide synthase (iNOS) expression had been detected in urinary bladder tumors. The aim of this study was to investigate the interaction of iNOS and NQO1 on bladder cancer (BC) risk stratified by cigarette smoking status. A total of 159 BC patients and 150 cancer-free controls were recruited from December 2003 to November 2004. Genotyping of NQO1 rs1800566 polymorphism and iNOS (CCTTT)n pentanucleotide repeat polymorphism was determined using the polymerase chain reaction-restricted fragment length polymorphism and sequencing method. The odds ratio and 95% confidence interval (CI) were calculated as a measure of the joint effect of NQO1 rs1800566 and iNOS (CCTTT)n polymorphisms on BC risk among cigarette smokers. Compared with study participants carrying the C/C genotype of NQO1 gene, those with C/T and T/T genotypes had a significantly increased BC risk of 1.8 (95% CI = 1.1-2.9). Among cigarette smokers, those who carried the 12-repeat allele of iNOS (CCTTT)n polymorphism had a significantly increased BC risk of 2.7 (95% CI = 1.0-6.7). Furthermore, a significant combined effect of the C/T and T/T genotypes of NQO1gene and the 12-repeat allele of iNOS (CCTTT)n repeat polymorphism on BC was found among cigarette smokers (odds ratio = 4.4, 95% CI = 1.3-14.9). Our findings suggest that a significant combined effect of NQO1 C/T and T/T genotypes and the 12-repeat allele of iNOS (CCTTT)n polymorphism on BC exists, especially in those with the habit of cigarette smoking.


Reasons for ordering laboratory tests and relationship with frequency of abnormal results.
Laboratory tests are ordered on a daily basis, even though disease probability is often very low. Abnormal results, especially mildly abnormal results, can be difficult to interpret in these circumstances. Further insights into the occurrence of abnormalities can help improve rational test ordering and test interpretation. The objective was therefore to examine the frequency of mildly and markedly abnormal results and their relationship with physicians' reasons for ordering tests. Prospective study. Participants. A total of 87 primary care physicians in the Netherlands collected data on 1775 patients. The physicians recorded the reason for ordering the tests, the most probable diagnosis and the pretest probability. The laboratories' reference values and specified "action limits" were used to assess the number of abnormal results and markedly abnormal results, respectively. Laboratory results were received for 1621 patients and 15,603 tests were reported (mean 9.6). The proportion of abnormal test results increased with increasing pretest probability (from 13.9% to 34.7%) and was 13.4% for tests ordered to reassure the patient and 13.3% for psychosocial diagnoses. The proportion of patients with at least one abnormal test result was high: 53.1% for tests ordered to reassure and 57.7% in patients with low pretest probability. Corresponding values for a marked abnormality were 11.1% and 12.4%, respectively. Abnormal laboratory test results were frequent, even when pretest probability was low. Physicians should therefore carefully consider when tests are necessary. Future research could explore physicians' interpretation of test results and its impact on diagnosis and management.