[Pathomechanism of dyskinesia associated with treatment of Parkinson disease with levodopa].
The 5-HIAA/HVA ratio was determined in the cerebrospinal fluid in 5 patients with Parkinson's disease with L-DOPA preparations in which drug-induced dyskineses developed, in 5 patients treated with L-DOPA without dyskineses, and 10 controls. A decrease in the 5-HIAA/HVA ratio was observed in the group with dyskineses as compared with patients without dyskineses and in controls. The directions of further investigations on hte pathomechanism of drug-induced dyskineses are discussed.


You are never too old for a congenital disease!
Congenital diseases are sometimes overlooked by physicians because of their rarity or because of late onset of symptoms, which may delay treatment plans. This is illustrated in our patient who presented with dysphagia along with chest pain and who was found to have a congenital vascular anomaly, detected in her fifth decade of life.


Dismantling the relative effectiveness of core components of cognitive behavioural therapy in preventing depression in adolescents: protocol of a cluster randomized microtrial.
Both depressive disorder and subclinical depressive symptoms during adolescence are a major public health concern. Therefore, it is important that depression is detected at an early stage and is treated preventively. Prevention based on the principles of Cognitive Behavioural Therapy (CBT) has proven to be the most effective, however research has mainly focused on the effectiveness of "prevention packages" consisting of multiple CBT-components, rather than on the distinct CBT-components. This study will evaluate the relative effectiveness of four core components of CBT (cognitive restructuring (CR), behavioural activation (BA), problem solving (PS) and relaxation (RE)). In addition the relative (cost-)effectiveness of four different sequences of these components will be evaluated: (1) CR - BA - RE - PS, (2) BA - CR - RE - PS, (3) PS - GA - CR - RE and (4) RE - PS - BA - CR. We will perform a non-blinded multisite cluster randomized prevention microtrial with four parallel conditions consisting of the four sequences. The four sequences of components will be offered in groups of high school students with elevated depressive symptoms. For each CBT-component a module of three sessions is developed. Assessments will be conducted at baseline, after each CBT-component, prior to each session, at post-intervention and at 6-month follow-up. Potential moderators and mediators will be evaluated exploratively to shed light on for whom the (sequences of) CBT-components are most effective and how effects are mediated. The potential value of the study is insight in the relative effectiveness of the four most commonly used CBT-components and four different sequences, and possible moderators and mediators in the prevention of depression among adolescents. This knowledge can be used to optimize and personalize CBT-programs. The study is registered in the Dutch Trial Register (Trial NL5584 / NTR6176) on October 13, 2016.


Proteome dynamics of cold-acclimating Rhododendron species contrasting in their freezing tolerance and thermonasty behavior.
To gain a better understanding of cold acclimation in rhododendron and in woody perennials in general, we used the 2D-DIGE technique to analyze the rhododendron proteome during the seasonal development of freezing tolerance. We selected two species varying in their cold acclimation ability as well as their thermonasty response (folding of leaves in response to low temperature). Proteins were extracted from leaves of non-acclimated (NA) and cold acclimated (CA) plants of the hardier thermonastic species, R. catawbiense (Cata.), and from leaves of cold acclimated plants of the less hardy, non-thermonastic R. ponticum (Pont.). All three protein samples (Cata.NA, Cata.CA, and Pont.CA) were labeled with different CyDyes and separated together on a single gel. Triplicate gels were run and protein profiles were compared resulting in the identification of 72 protein spots that consistently had different abundances in at least one pair-wise comparison. From the 72 differential spots, we chose 56 spots to excise and characterize further by mass spectrometry (MS). Changes in the proteome associated with the seasonal development of cold acclimation were identified from the Cata.CA-Cata.NA comparisons. Differentially abundant proteins associated with the acquisition of superior freezing tolerance and with the thermonastic response were identified from the Cata.CA-Pont.CA comparisons. Our results indicate that cold acclimation in rhododendron involves increases in abundance of several proteins related to stress (freezing/desiccation tolerance), energy and carbohydrate metabolism, regulation/signaling, secondary metabolism (possibly involving cell wall remodeling), and permeability of the cell membrane. Cold acclimation also involves decreases in abundance of several proteins involved in photosynthesis. Differences in freezing tolerance between genotypes can probably be attributed to observed differences in levels of proteins involved in these functions. Also differences in freezing tolerance may be attributed to higher levels of some constitutive protective proteins in Cata. than in Pont. that may be required to overcome freeze damage, such as glutathione peroxidase, glutamine synthetase, and a plastid-lipid-associated protein.


Outcomes of COVID-19 in Kidney Transplant Recipients: The Sri Lankan Experience.
Coronavirus disease 2019 (COVID-19) causes severe illness in the immunocompromised. This study aimed to describe the severity and outcomes of kidney transplant recipients (KTRs) treated for COVID-19 during the first 16 months of the pandemic in Sri Lanka. We conducted a cross-sectional survey of all nephrology centers in Sri Lanka using a self-administered electronic data collection sheet. All practicing nephrologists were invited. KTRs who had been treated/were under treatment for COVID-19 between March 1, 2020 and June 30, 2021 were included. Data on patient demographics, management practices, and outcomes were collected. Outcomes included graft loss, requirement of kidney replacement therapy (KRT), duration of hospital stay, highest level of treatment setting, highest level of respiratory support, and mortality. Fifteen nephrologists (12 centers) responded with data regarding 58 KTRs with COVID-19, 10 of whom were receiving ongoing treatment; 47/58 (81%) were male. Forty (69%) were between 30 and 59 years of age and 15 (25.9%) were aged 60 years or above. Fourteen (24.1%) were within 1 year of transplantation. Fifty-three (91.4%) were on triple immunosuppression. Antiproliferative was reduced/withheld in 89.1% and calcineurin inhibitor was reduced/withheld in 42.1%. Overall mortality was 16/48 (33.3%). Seventeen (29.3%) required intensive care. Six (10.3%) received noninvasive ventilation, and 11 (19.0%) received invasive ventilation. Ten of the ventilated patients died. Six needed acute KRT, five of whom died. One patient survived with a loss of graft. There was no association between modifications to the immunosuppression and outcomes. COVID-19 causes poor outcomes and severe illness in KTRs. Special preventive and therapeutic strategies are urgently required.


An exceptional case of myelodysplastic syndrome with myelofibrosis following combination chemotherapy for squamous cell lung cancer.
A 60-year-old woman with squamous cell carcinoma in the right lung was successfully treated with four cycles of combination chemotherapy after surgery, and complete remission was achieved. However, the patient developed myelodysplastic syndrome (MDS) RAEB-2 with myelofibrosis after remission, possibly because of chemotherapy or DNA methylation. The patient responded well to dacitabine (Dacogen), suggesting that DNA hypomethylation agents can be a promising therapy to retard the progression of a second tumor or carcinoma.


Percolation analysis in electrical conductivity of Madin-Darby canine kidney and Caco-2 cells by permeation-enhancing agents.
The control of permeability through the paracellular route has been paid great attention to for enhanced bioavailability of macromolecular and hydrophilic drugs. The paracellular permeability is controlled by tight junctions (TJ), and claudins are the major constituents of TJ. Despite numerous studies on TJ modulation, the dynamics is not well understood, although it could be crucial for clinical applications. Here, we studied the time (t) course of electrical conductivity (Σ) in a monolayer of Madin-Darby canine kidney (MDCK) and Caco-2 cells upon treatment with modulators, the C-terminus fragments of Clostridium perfringens enterotoxin (C-CPE) and sodium caprate (C10). For C-CPE treatment, Σ remains approximately constant, then starts increasing at t=tc (percolation threshold). For C10, on the other hand, Σ increases to 1.6-2.0 fold of the initial value, stays constant, and then starts increasing again for both MDCK and Caco-2 cells at t=tc. We find that this behavior can be explained within a framework of percolation, where Σ shows a logarithmic dependence on t-tc with the power of μ; μ denotes the critical exponent. We obtain μ=1.1-1.2 regardless of cell type or modulator. Notably, μ depends only on the dimensionality (d) of the system, and these values correspond to those for d=2. Percolation is thus the operative mechanism for the increase in Σ through TJ modulation. The findings provide fundamental knowledge, not only on controlled drug delivery, but also on bio-nanotechnologies including the fabrication of biological devices.


Prolonged occurrence of Moraxella bovis infection on a restricted heifer farm.
An epizootiologic study was conducted for infectious bovine keratoconjunctivitis (IBK) on a large grassland farm rearing a total of 1,300-1,400 heifers during May to October in both 1991 and 1992. Heifers were examined for infection with Moraxella bovis, and isolation of M. bovis from the affected eyes and from Asian face flies (Musca bezzii Patton et Cragg) swarming on the heifer face was carried out. During the observation period, 10.7% of the heifers in 1991 and 5.3% of the heifers in 1992 were affected with IBK. Eight M. bovis isolates were isolated from the ocular swabs of affected heifers with IBK for 2 years and identified by biochemical examinations and Southern DNA-DNA hybridization, but no M. bovis was obtained from 331 Asian face flies tested. Plasmid profile analysis showed that two plasmids (35-kb and 4.0-kb) were commonly found in all 8 M. bovis isolates. This indicates that M. bovis isolates with the same plasmid profile were widely disseminated on this farm for 2 years.


Coherent field transients below 15 THz from phase-matched difference frequency generation in 4H-SiC.
We experimentally demonstrate tunable, phase-matched difference frequency generation covering the spectral region below 15 THz using 4H-SiC as a nonlinear crystal. This material combines a non-centrosymmetric lattice and strong birefringence with broadband transparency at low optical frequencies. Thorough refractive index measurements in the terahertz spectral range allow us to calculate phase-matching conditions for any near-infrared pump laser source. 4H-SiC is also exploited as a detector crystal for electro-optic sampling. The results allow us to estimate the effective second-order nonlinear coefficient.


Novel ¹⁸F-labeled benzoxazole derivatives as potential positron emission tomography probes for imaging of cerebral β-amyloid plaques in Alzheimer's disease.
Two radiofluoro-pegylated phenylbenzoxazole derivatives, 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N-methylaniline ([(18)F]24) and 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N,N-dimethylaniline ([(18)F]32), were synthesized and evaluated as probes for imaging cerebral β-amyloid (Aβ) plaques in living brain tissue by PET. [(18)F]24 and [(18)F]32 displayed high affinity for Aβ(1-42) aggregates (K(i) = 9.3 and 3.9 nM, respectively). In vitro autoradiography with sections of post-mortem AD brain and transgenic mouse brain confirmed the affinity of these tracers. Initial high uptake into and rapid washout from the brain in normal mice were observed. [(18)F]24 also displayed excellent binding to Aβ plaques in ex vivo autoradiographic experiments with Tg2576 mice. Furthermore, small-animal PET studies demonstrated significant differences in the clearance profile after the administration of [(18)F]24 between Tg2576 and wild-type mice. The results suggest [(18)F]24 to be a useful PET agent for detecting Aβ plaques in the living human brain.


Radioimmunoassay of flurazepam in human plasma.
A radioimmunoassay for the determination of the hypnotic flurazepam in plasma was developed. Plasma levels of intact flurazepam were measured following oral administration of therapeutic doses to humans. The procedure employs an antiserum obtained from a rabbit immunized with 3-hemisuccinyloxyfluorazepam covalently coupled to bovine serum albumin and tritium-labeled flurazepam as the radioligand. Assay specificity was achieved by chromatographic isolation of flurazepam from plasma extracts on Sephadex LH-20 prior to analysis. The method has a sensitivity limit of 0.1 ng of flurazepam/ml using a 1-ml plasma sample, and the intra- and interassay coefficients of variation did not exceed 9% over a range of 0.1-5 ng/ml. In eight subjects who received a single 30-mg dose of flurazepam, peak plasma concentrations of 0.5-3.0 ng of intact drug/ml were reached after 0.5-1 hr, except in one subject where the peak occurred at 4 hr. The plasma concentrations of flurazepam declined with a harmonic mean apparent half-life of 2.3 hr.


Prevalence, social acceptance, and awareness of waterpipe smoking among dental university students: a cross sectional survey conducted in Jordan.
Waterpipe tobacco smoking is increasing in popularity especially among young adults. This spread could be related to limited knowledge of the negative health effects of waterpipe smoking. In this study, prevalence, social acceptance, and awareness of waterpipe smoking were examined among dental university students. This is a cross-sectional survey study, where a self-administered questionnaire was completed by a sample of dental university students in Jordan. Students (n=547) reported current tobacco use of 54.3% for males versus 11.1% for females (P<0.005). Among current smokers, 3.5% used only cigarettes (22.0% males, 2.3% females), 12.6% used only waterpipe (36.6% males, 88.6% females), and 6.9% used both (41.5% males, 9.1% females). Approximately, 70% of males and 42.5% of females who used waterpipe reported smoking mostly at a café. Nearly half of the females reported that they smoke at home in the presence of parents. Among participants, 33.3% of males and 62.5% of females reported indifferent parents' reaction regarding their waterpipe smoking. Approximately one third of students agreed with the statement that waterpipe smoking is less harmful to oral health than cigarette smoking. About 50-70% of students agreed that waterpipe smoking causes halitosis, delays wound healing time, is associated with dental implant failure, and increases the risk of dental decay. In this sample, waterpipe tobacco smoking was more common than cigarette smoking among dental students, especially females. This could be an implication of social acceptance of waterpipe leading to its predominance, and thus, the gradual replacement of cigarette smoking with waterpipe smoking. Additionally, dental students' awareness about the harms of waterpipe is not optimal, and steps are needed to ensure providing such knowledge to students.


[A new method of studying blood aggregation in geriatric surgical patients].
A new technique of nephelometry based on the determination of optic radius of platelets and their aggregates has been tested in surgical patients of very advanced age with abdominal pathology. The technique in question makes it possible to use subthreshold inducer doses compatible with their real concentration in vivo. The nature of changes in platelet aggregation at preoperative stage has been described, postoperative course of hyperaggregation syndrome has been followed and qualitative disorders in aggregate forming processes have been specified. It has been shown that intravascular blood irradiation with low-intensive laser is effective for the correction of high platelet sensitivity.


Idiopathic recurrence of diffuse lamellar keratitis after LASIK.
To report a case of late recurrence of bilateral diffuse lamellar keratitis (DLK) after LASIK. A 39-year-old woman presented in the early postoperative period with bilateral DLK after hyperopic LASIK and was treated with topical steroids. One year after and with no obvious cause (idiopathic), recurrence of the same stage (stage III) of disease was observed. Slit-lamp examination revealed diffuse, multifocal, and granular haze in the interface. The microbiology culture was negative. Confocal microscopy demonstrated multiple activated keratocytes, debris, and inflammatory cells adjacent to the flap interface. After intense treatment with topical corticosteroids, DLK resolved and corneal transparency was achieved with complete restoration of visual acuity. Diffuse lamellar keratitis may recur in LASIK patients with previous episodes without an obvious cause (idiopathic). Early diagnosis and treatment with topical corticosteroids can achieve complete resolution without visual loss--even in advanced stages of DLK.


Using genetics to examine the overall and sex-specific associations of branch-chain amino acids and the valine metabolite, 3-hydroxyisobutyrate, with ischemic heart disease and diabetes: A two-sample Mendelian randomization study.
Branch-chain amino acids (BCAAs) are linked to higher risk of diabetes, whilst the evidence on ischemic heart disease (IHD) is limited. Valine metabolite, 3-hydroxyisobutyrate (3-HIB), also plays an important role in metabolism, whilst its effect has been rarely examined. At the situation of no evidence from large trials, we assessed the role of BCAAs and 3-HIB in IHD and diabetes using Mendelian randomization to minimize confounding. Given their potential role in sex hormones, we also examined sex-specific associations. We used genetic variants to predict BCAAs and 3-HIB, and obtained their associations with IHD and diabetes in large consortia and cohorts, as well as sex-specific association in the UK Biobank and DIAGRAM. We obtained and combined the Wald estimates using inverse variance weighting, and different analytic methods robust to pleiotropy. Genetically predicted BCAAs were associated with higher risk of IHD (odds ratio (OR) 1.19 per standard deviation (SD) increase in BCAAs, 95% confidence interval (CI) 1.05 to 1.35) and diabetes (OR 1.20, 95% CI 1.08 to 1.34). The associations with IHD were stronger in women (OR 1.23, 95% CI 1.03 to 1.48) than men (OR 0.96, 95% CI 0.83 to 1.10). 3-HIB was associated with higher risk of IHD (OR 1.43, 95% CI 1.17 to 1.73) but not diabetes, with no sex disparity. BCAAs and 3-HIB are potential targets for prevention in IHD and/or diabetes. BCAAs may exert a sex-specific role in IHD. Consideration of the sex disparity and exploration of the underlying pathways would be worthwhile.


Colonization Potential to Reconstitute a Microbe Community in Pseudo Germ-Free Mice After Fecal Microbe Transplant From Equol Producer.
Human intestinal microbiota plays a crucial role in the conversion of isoflavones into equol. Usually, human microbiota-associated (HMA) animal models are used, since it is difficult to establish the mechanism and causal relationship between equol and microbiota in human studies. Currently, several groups have successfully established HMA animal models that produce equol through germ-free mice or rats; however, the HMA model of producing equol through pseudo germ-free mice has not been established. The objective of this study is to establish an HMA mice model for equol production through pseudo germ-free mice, mimicking the gut microbiota of an adult human equol producer. First, a higher female equol producer was screened as a donor from 15 volunteers. Then, mice were exposed to vancomycin, neomycin sulfate, metronidazole, and ampicillin for 3 weeks to obtain pseudo germ-free mice. Finally, pseudo germ-free mice were inoculated with fecal microbiota of the equol producer for 3 weeks to establish HMA mice of producing equol. The results showed that (i) the ability to produce equol was partially transferred from the donor to the HMA mice. (ii) Most of the original intestinal microbiota of mice were eliminated after broad-spectrum antibiotic administration. (iii) The taxonomy data from HMA mice revealed similar taxa to the donor sample, and the species richness returned to the level close to the donor. (iv) The family Coriobacteriaceae and genera Collinsella were successfully transferred from the donor to HMA mice. In conclusion, the HMA mice model for equol production, based on pseudo germ-free mice, can replace the model established by germ-free mice. The model also provides a basis for studying microbiota during the conversion from isoflavones into equol.


Association study of the 5-HT6 receptor gene in schizophrenia.
Serotonergic (5-hydroxytryptamine; 5-HT) transmission may play an important role in the treatment and/or pathogenesis of schizophrenia. Previous studies reported that several atypical antipsychotic agents have high affinities for the 5-HT6 receptor. The 5-HT6 receptor gene polymorphism might contribute to the genetic background of this disorder. One hundred and fifty unrelated patients with schizophrenia and 150 unrelated healthy controls were genotyped for a biallelic polymorphism (267C/T) at the 5-HT6 receptor gene. No significant positive association between the 5-HT6 receptor genotype and schizophrenia was observed. Our results suggests that the 267C/T polymorphism of the 5-HT6 receptor gene may not be involved in the susceptibility to schizophrenia.


Time trends in myopia and high myopia prevalence in young university adults in China.
To investigate time trends in myopia and high myopia prevalence over 6y among young university adults in China. This is a 6-year series cross-sectional study from 2016 to 2021. Totally 4910 freshmen were enrolled and completed a questionnaire concerning age, gender, and disease history. Students with eye diseases were excluded after a detailed eye examination. The refractive status was measured by non-cycloplegic objective refraction and ocular parameters were measured by Lenstar 900. The examination followed the same protocol each year. Trends over time in myopia and high myopia prevalence, as well as ocular biometry parameters, were analyzed. From 2016 to 2021, the axial length (AL) and corneal radius (CR) increased significantly (P=0.002 for AL; P=0.04 for CR). However, the spherical equivalent (SE) and the ratio of axial length to the corneal radius (AL/CR) did not change significantly (P=0.59 for SE; P=0.24 for AL/CR). The frequency of AL ≥26.0 mm increased from 26.6% in 2016 to 29.3% in 2021 (P=0.05 for trend). The prevalence of myopia and high myopia did not change significantly in our study (P≥0.18). Compared to a similar cross-sectional study conducted 10 years ago, the prevalence of myopia decreased significantly (94.9% vs 91.8%, P<0.001). Whereas the prevalence of high myopia increased largely (18.12% vs 27.6%, P<0.001). The prevalence of high myopia increases in young university adults during 10y period. Myopia control should begin earlier in childhood. However, these interventions are still needed for high myopia even in young adulthood.


Studies on the salivary secretion induced by substance P in perfused submandibular gland of rat.
The purpose of these experiments was to clarify the effects of substance P (SP) on the salivary secretion in comparison with those of autonomic agents. Salivary secretion from rat submandibular gland (SMG) was induced by intravenous infusion into the femoral vein or partial perfusion of SMG with isotonic solution containing SP or autonomic stimulants. Blood and salivary flow rates, and electrolyte concentrations of saliva were measured. The relationship between electrolyte concentrations and salivary flow rate after intravenous infusion of SP was similar to that obtained using parasympathomimetic agents. Salivary flow rates induced by phenylephrine and isoproterenol were significantly increased by the further addition of SP, while the pilocarpine-induced flow rate was not affected. SP alone caused a significant increase in blood flow rate of perfused rat SMG. SP with atropine or phentolamine somewhat increased the blood flow. However, concomitant perfusion of atropine and phentolamine completely inhibited the SP effect. Salivary secretion induced by SP perfusion was reduced by atropine or phentolamine. Both blood flow elevation and salivary secretion induced by SP were reduced with increasing doses of a SP-antagonist. Also blood and salivary flow responses induced by phenylephrine were severely reduced by the SP-antagonist. On the other hand, the salivary secretion induced by pilocarpine was moderately reduced by the SP-antagonist. These results indicate that the salivation and especially the glandular vasodilation induced by SP were partially modified by the autonomic agents.


Structural properties of non-traditional drug targets present new challenges for virtual screening.
Traditional drug targets have historically included signaling proteins that respond to small molecules and enzymes that use small molecules as substrates. Increasing attention is now being directed toward other types of protein targets, in particular those that exert their function by interacting with nucleic acids or other proteins rather than small-molecule ligands. Here, we systematically compare existing examples of inhibitors of protein-protein interactions to inhibitors of traditional drug targets. While both sets of inhibitors bind with similar potency, we find that the inhibitors of protein-protein interactions typically bury a smaller fraction of their surface area upon binding to their protein targets. The fact that an average atom is less buried suggests that more atoms are needed to achieve a given potency, explaining the observation that ligand efficiency is typically poor for inhibitors of protein-protein interactions. We then carried out a series of docking experiments and found a further consequence of these relatively exposed binding modes is that structure-based virtual screening may be more difficult: such binding modes do not provide sufficient clues to pick out active compounds from decoy compounds. Collectively, these results suggest that the challenges associated with such non-traditional drug targets may not lie with identifying compounds that potently bind to the target protein surface, but rather with identifying compounds that bind in a sufficiently buried manner to achieve good ligand efficiency and, thus, good oral bioavailability. While the number of available crystal structures of distinct protein interaction sites bound to small-molecule inhibitors is relatively small at present (only 21 such complexes were included in this study), these are sufficient to draw conclusions based on the current state of the field; as additional data accumulate it will be exciting to refine the viewpoint presented here. Even with this limited perspective however, we anticipate that these insights, together with new methods for exploring protein conformational fluctuations, may prove useful for identifying the "low-hanging fruit" among non-traditional targets for therapeutic intervention.


The relationship between soluble L-selectin and the development of diabetic retinopathy.
Diabetic retinopathy is a leading cause of adult vision loss and blindness. Earlier studies have shown that polymorphonuclear neutrophils play an important role in the pathogenesis of diabetic vascular complications. Stimulation of these cells is associated with the desquamation of L-selectin. The aim of the study was to evaluate the relationship between the serum concentration of L-selectin and the development of retinopathy in Type 2 diabetic patients. The study comprised 51 Type 2 diabetic patients, aged 65.2 +/- 7.5 years, with a diabetes duration of 10.1 +/- 8.9 years and HbA1c of 8.2 +/- 1.4. The study subjects were divided into two groups: Group A diabetic patients with retinopathy (n = 28) and Group B diabetic patients without retinopathy (n = 23). Twenty age- and sex-matched nondiabetic healthy subjects were enrolled as the control group. Patients with any inflammatory disease were excluded. Retinopathy was assessed by centrally graded retinal photographs. The serum concentration of sL-selectin was estimated using an ELISA test. We observed significantly higher serum concentrations of sL-selectin in Type 2 diabetic patients with retinopathy than in healthy subjects (36.5 +/- 18.1 vs. 11.4 +/- 7.5 ng/ml, p < 0.001). There was also a significant difference between Group A and Group B (36.5 +/- 18.1 vs. 24.2 +/- 13.5 ng/ml, p < 0.05) as well as between Group B and the controls (24.2 +/- 13.5 vs. 11.4 +/- 7.5 ng/ml, p < 0.01) with regard to sL-selectin levels. sL-selectin was significantly correlated with HbA1c (r = 0.93, p < 0.001) and with diabetes duration (r = 0.44, p < 0.001). These results suggest that there was a strong relationship between sL-selectin and diabetic retinopathy. The strong correlation between sL-selectin and HbA1c levels supports the concept that the sL-selectin level is increased with poor glycemic control, which may affect endothelial cell activity and cause subsequent microvascular complications.


Respiratory management of motor neurone disease: a review of current practice and new developments.
Motor neurone disease is a neurodegenerative condition with a significant morbidity and shortened life expectancy. Hypoventilatory respiratory failure is the most common cause of death and respiratory function significantly predicts both survival and quality of life in patients with motor neurone disease. Accordingly, supporting and maintaining respiratory function is important in caring for these patients. The most significant advance in motor neurone disease care of recent years has been the domiciliary provision of non-invasive ventilation for treating respiratory failure. Neuromuscular respiratory weakness also leads to ineffective cough and retained airways secretions, predisposing to recurrent chest infections. In this review, we discuss current practice and recent developments in the respiratory management of motor neurone disease, in terms of ventilatory support and cough augmentation.


A curious serendipitous finding: Spitz naevus combined with a syringoma.
Combined tumours are often a serendipitous finding. Among the spectrum of melanocytic tumours, the co-existence of different cell populations of the same lineage is a well-recognised phenomenon. Less commonly documented, but still well documented is the event of a melanocytic tumour in collision with an epithelial benign or malignant neoplasm. Exceptionally infrequent is however the collision of a Spitz naevus with an epithelial tumour. Here we report the clinical-dermoscopic and histopathological findings of a Spitz naevus occurring in collision with a syringoma.


Strategies used by dairy family farmers in the south of Brazil to comply with organic regulations.
The aims of this study were to investigate the environmental, feeding, and health management of organic (ORG) family dairy farms in the south of Brazil in comparison with conventional (CONV) farms, and to assess their degree of compliance with Brazilian organic legislation and the strategies they adopt to accomplish this (n=17 per group). During 2 visits to each farm in March and September, 2010, observations were made on the environment, feed, and health management, followed by bulk milk testing, clinical evaluation, and breed assessment of each individual cow, and an evaluation of diseases and treatments reported within the period. Additional data were collected directly from the farmers through direct interviews. The number of lactating cows was, on average, 11 (range 5 to 19) in the ORG and 16 (range 7 to 42) in the CONV herds. The ORG herds presented a lower percentage of the Holstein breed; whereas CONV herds were predominantly Holstein, in the ORG herds, only 2 herds were 100% Holstein and the remaining herds were crosses of Holstein, Jersey, and Gir (Bos indicus) cattle. Milk production per cow was lower (10.2 vs. 15.1 ± 1.22 L/cow, respectively) in ORG than in the CONV farms. The ORG farms offered less concentrate feed than CONV farms and had better pasture management. Organic farmers reported using phytotherapic and homeopathic products, and pasture management as a strategy to keep infection levels of endo- and ectoparasites low, whereas CONV farmers regularly used anthelmintics and acaricides. Milk production was lower in ORG than in CONV farms, but cow health and condition scores were broadly similar, indicating that the with these strategies ORG farms were able to secure levels of animal welfare comparable with CONV farms while complying with organic regulation, although at the cost of lower cow productivity.


Detection of K-Ras oncogene using magnetic beads-quantum dots in microfluidic chip.
Recently quantum dots (QDs) have been extensively used in the field of biotechnology. QDs have merits of wide selection of emission wavelength and exceptional stability against photo bleaching over conventional organic fluorophores and are used in cell imaging, biomarker, and fluorescence resonance energy transfer (FRET) sensor. Magnetic beads have been used as solid support in microfluidic devices to trace bio-molecules. In this study, Polydimethylsiloxane (PDMS) based microfluidic chips were prepared for the detection of K-Ras oncogene by using QDs-DNA conjugate. K-Ras oncogene can be detected by fluorescence quenching in microfluidic chip. Carboxylated CdSe/ZnS QDs (emission wavelength: 605 nm) could bind to magnetic beads of polystyrene/divinyl benzene via EDC/NHS crosslinking reaction. The fluorescence from QDs could be quenched by intercalating dye (thiazol orange dimers: TOTO-3) after hybridization with target DNA and probe DNA in the channel of microfluidic chip. The fluorescence intensity change of QDs after hybridization in microfluidic chip has been studied.


Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence.
Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) β-cell mass and pancreatic insulin content. Studies in humans with T2DM have indicated improvement of islet-cell function, both in the fasted state and under postprandial conditions and these beneficial effects were sustained in studies with a duration up to 2 years. However, there is at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on β-cell function after cessation of therapy. Long-term, large-sized trials using an active blood glucose lowering comparator followed by a sufficiently long washout period after discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably preserve pancreatic islet-cell function in patients with T2DM.


Investigating visual effects of a disgust nocebo with fMRI.
There is growing evidence that placebos are able to influence visual perception. A previous functional magnetic resonance imaging study on the processing of disgust images demonstrated that a ''disgust placebo'' (inert pill administered with the verbal suggestion of an anti-nausea medication) reduced visual cortex activity and connectivity. In the present functional magnetic resonance imaging investigation, visual effects corresponding to a ''disgust nocebo'' (an odorless substance introduced as an aversive smell that enhances disgust feelings) were examined. Data from 29 females were reanalyzed. They viewed disgusting, fear-eliciting, and neutral images once with and once without the nocebo. In the nocebo condition with disgusting images disgust experienced that significantly increased fusiform gyrus activation, which also showed enhanced coupling with the amygdala and several (extra)striate cortex regions. The nocebo changed the affective value and motivational relevance of the stimuli as well the perception of basic visual features. These findings demonstrate that nocebo-related expectations can have a strong influence on the experience of sensory input.


Direct observation of period-doubled nonspherical states in single-bubble sonoluminescence.
We present direct observations of period doubling in the flash to flash pulse heights in single-bubble sonoluminescence. States involved are stable, spherically symmetry broken. Observations are made using seven detectors distributed in the equatorial plane of the bubble. Contrary to earlier experiments by Holt et al. [Phys. Rev. Lett. 72, 1376 (1994)], where period doubling was observed in the time intervals between flashes but not in the pulse heights, we observe period doubling in pulse heights, but no corresponding period doubling is seen in the time intervals. In parameter space the period doubling is observed below the n=2 shape instability boundary line where extinction is shown to take place.


Medication adherence in pediatric renal transplant patients: The role of family functioning and parent health locus of control.
Children and adolescents with renal disease experience daily social, emotional, and medical challenges. Renal transplantation can help to improve quality of life but requires a lifelong regimen of immunosuppressant medication to maintain health. Adherence to a daily complex regimen can be difficult, particularly for adolescents who are beginning to develop autonomy from caregivers and are faced with a unique set of socio-emotional challenges. This study examines two factors that have shown to influence adherence in other pediatric populations, namely family functioning and parent health locus of control, from mothers' perspectives, in predicting medication non-adherence for adolescents (ages 12-19 years) 1 year post-transplant. Non-adherence was defined as the percentage of missed doses and late doses of the weekly immunosuppressant doses prescribed. Regression results demonstrated that mothers' perceptions of poorer overall family functioning predicted missed medication doses (ΔR2 = 0.383, F(7, 21) = 2.570, P = 0.044) with significant contributions in the domains of problem-solving (β = -0.795, t(21) = -2.927, P = 0.008) and affective involvement (β = 0.872, t(21) = 3.370, P = 0.003). Moreover, mothers who perceived that their adolescent had control over his/her health also predicted more missed medication doses (ΔR2 = 0.133, F(1, 27) = 5.155, P = 0.031). Important implications for these findings include implementation of family-based interventions that promote developmentally appropriate skills for adolescents and cultivate emotional involvement within the family.


Alkynes From Furans: A General Fragmentation Method Applied to the Synthesis of the Proposed Structure of Aglatomin B.
Furans are versatile synthons in organic chemistry. Described is a general method for transforming furans into alkynes by dual C-C double-bond cleavage. The reaction is proposed to proceed by sequential [4+2] cycloaddition between furan and singlet oxygen and a formal retro-(3+2) fragmentation of the endoperoxide intermediate. A wide array of furans, including those derived from sapogenins, are amenable to this reaction, thus providing the corresponding alkynoic acids in up to 88 % yields. The synthetic utility was demonstrated by a seven-step synthesis of the proposed structure of a pregnane natural product, aglatomin B, from a known intermediate.


Home training experience in peritoneal dialysis patients.
The objective of nursing is to increase health and well being, prevent morbidity and obtain the best physical and social rehabilitation. The nurse's role in Peritoneal Dialysis (PD) consists of promoting and supporting patients to perform self-care. In the'Text Book of Peritoneal Dialysis, published in 2000,the chapter dedicated to the nurses' role says:"Regular home visits are an important part of follow-up care, as the family and patient need to realize that continuing support is available... It is advisable that the first exchange after discharge from hospital is in the presence of a nurse... Early recognition and management of problems will assist in keeping the patient healthy and well rehabilitated, and will hopefully reduce hospital visits and inpatient stays" (1). Home care in Hospital Universitario La Paz has been developed with varying dedication over the years. Firstly, it was offered if significant problems appeared (1979-1990), later, home visits were started for some new PD patients (1990-1994) and follow up visits then ensued (1995-1996). In 1997, a project was undertaken which included home training for the first time in our unit, as well as periodic follow up visits. This project was shown to the Hospital Nurse Direction, and approved immediately. It started during the first term of 1997. There were several reasons which led us to undertake this project including the importance of providing PD at home and making it lifelong and it was felt that the hospital was an unfriendly environment in which to learn PD. The main objective was to establish early on, the patient's social environment and psychological status, and to assess how these influenced aspects of learning and adapting to PD. Most patients expressed a very good opinion about the home training. Only one patient rejected the presence of the nurse at home. The nursing team was very satisfied because early knowledge about the patient's psychosocial conditions and family environment was established. The incidence of peritonitis decreased.


Toll-Like Receptor 2 and Its Relationship With Streptococcus in Psoriasis.
The authors present the immunopathologic findings of Toll-like receptor 2 in psoriasis. This novel work shows positive staining within the dermal capillaries in psoriatic lesions. Neither normal skin nor lesional skin in eczema showed similar staining. The authors postulate how the activation of this innate immune system reactant plays a significant role in psoriasis and show how it may be associated with a cascade of events that begins with streptococcus and ends with psoriasis.


Progressive structuring of a branched antimicrobial peptide on the path to the inner membrane target.
In recent years, interest has grown in the antimicrobial properties of certain natural and non-natural peptides. The strategy of inserting a covalent branch point in a peptide can improve its antimicrobial properties while retaining host biocompatibility. However, little is known regarding possible structural transitions as the peptide moves on the access path to the presumed target, the inner membrane. Establishing the nature of the interactions with the complex bacterial outer and inner membranes is important for effective peptide design. Structure-activity relationships of an amphiphilic, branched antimicrobial peptide (B2088) are examined using environment-sensitive fluorescent probes, electron microscopy, molecular dynamics simulations, and high resolution NMR in solution and in condensed states. The peptide is reconstituted in bacterial outer membrane lipopolysaccharide extract as well as in a variety of lipid media mimicking the inner membrane of Gram-negative pathogens. Progressive structure accretion is observed for the peptide in water, LPS, and lipid environments. Despite inducing rapid aggregation of bacteria-derived lipopolysaccharides, the peptide remains highly mobile in the aggregated lattice. At the inner membranes, the peptide undergoes further structural compaction mediated by interactions with negatively charged lipids, probably causing redistribution of membrane lipids, which in turn results in increased membrane permeability and bacterial lysis. These findings suggest that peptides possessing both enhanced mobility in the bacterial outer membrane and spatial structure facilitating its interactions with the membrane-water interface may provide excellent structural motifs to develop new antimicrobials that can overcome antibiotic-resistant Gram-negative pathogens.


[On the galenical development of a nose spray from N-(2-imidazolin-2-yl)-N-(4-indanyl)amine monohydrochloride (indanazoline) (author's transl)].
An account if given of the aim of the galenical development of the new remedy, indanazolin nose-spray. The description of the quality of the active ingredient N-(2-imidazolin-2-yl)-N-(4-indanyl)amine monohydrochloride (indanazoline, Farial) and the dosage form allows a pharmaceutical evaluation. The descriptions of the organoleptic, physical and chemical properties of the active substance are given in detail. The formulation, the procedures for manufacturing, and the specifications for the packaging materials give some idea of the galenical aspects. The quality of the finished dosage form is defined by means of product specifications relating to the identity, purity, and potency, and is proved by suitably designed stability studies. Finally a detailed summary is made of the analytical methods which were used.


Setting the stage for bench-to-bedside movement of anti-HIV RNA inhibitors-gene therapy for AIDS in macaques.
Despite significant progress over the last two decades, treatment of HIV infection remains a tremendous challenge. Although antiretroviral therapy has proved quite effective in most HIV-infected patients, increasing recognition of toxicity and the emergence of multidrug resistant HIV strains has fueled the development of alternative therapeutic approaches. Introduction of genes to inhibit HIV replication into CD4+ T lymphocytes or hematopoietic stem cells represents a potentially attractive but still unproven strategy. Despite the availability of a diverse range of molecular strategies that are able to provide potent inhibition of HIV replication in the laboratory, translation of these in vitro successes to in vivo therapies has been difficult. Fundamental challenges facing AIDS gene therapy at the present time includes the need to increase the efficiency of gene transfer in vivo, to confer upon genetically-modified T cells the ability to have a selective growth advantage in vivo, and the development of additional techniques to decrease the probability of emergence of resistant viruses. As one of the leading animal models for AIDS and for hematopoietic stem cell gene therapy, nonhuman primates are ideally suited to help address many of these basic questions. This review will provide a general overview of RNA-based genetic strategies for inhibition of HIV and SIV replication, criteria to be considered in the selection of promising inhibitory strategies for in vivo use, and key questions that can be addressed in the macaque model.


The use of telemedicine in the care of the pediatric trauma patient.
Telemedicine is increasingly becoming an important part of the health care system as it has the potential to help deliver quality medical care to underserved areas. When implemented correctly, it can be a cost-effective way of expanding access to excellent medical care. However, because it is a relatively new and quickly changing field, there are multiple issues and challenges that need to be addressed. This article reviews the current literature on various modalities of telemedicine, evidence for teletrauma, and challenges and barriers related to telemedicine.


Anthelmintic activity of Cymbopogon citratus against Haemonchus contortus.
Parasitic nematodes are of major economic importance in livestock. An alternative for the control of parasites is phytotherapy. This study evaluated the efficacy of Cymbopogon citratus decoction (CcD), C. citratus essential oil (CcEo) and citral against Haemonchus contortus using in vitro egg hatch test (EHT) and larval development test (LDT) and an in vivo test using a Meriones unguiculatus (gerbil) model. The effect of 800 mg/kg CcEo was evaluated in gerbils that had been artificially infected with 5,000 third-stage H. contortus larvae. The effective concentrations required to inhibit 50% (EC50) of egg hatching were 0.46, 0.14 and 0.13 mg/mL for CcD, CcEo and citral, respectively. The EC50 values in the LDT were 5.04, 1.92 and 1.37 mg/mL for CcD, CcEo and citral, respectively. H. contortus population in the group treated with C. citratus essential oil was reduced by 38.5% (P< 0.05) in comparison to the control group. These results suggest that it may be possible to use C. citratus essential oil to control of H. contortus parasite of small ruminant.


Green nanotechnology of MGF-AuNPs for immunomodulatory intervention in prostate cancer therapy.
Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.


[Analysis of migration of screwed acetabular components following revision arthroplasty of the hip joint. Results of single-image roentgen analysis].
Out of 57 revised acetabular components, which were regularly checked, 47 had been replaced by a cemented Müller's acetabular reinforcement ring resp. a cementless Müller's Sl-shell with flange. Both types of cups are anchored in the acetabular roof with cancellous bone screws (tab. 1). 42 cases with radiograph series permitted a detailed analysis with the EBRA-method, a computer aided method for the evaluation of acetabular spatial migration based on standard radiographs of the pelvis. The clinical results were very satisfying (tab. 6). The screwed acetabular components migrated little, although, some essential displacements of the center of rotation (in relation to the anatomical position) had to be accepted. As was recognizable with today's inaccurate methods of measuring the center of the head, the displacement too far towards cranial influenced the migration tendency less than an excessive lateralisation. Especially satisfying is the fact, that no increased migration was observed after reconstruction bone grafting of severe acetabular defects, provided that at least a partly direct contact between the acetabular component and the original bone stock was obtained. For the first time EBRA shall be introduced here as a method which shows the migration and the spatial inclination of the acetabular cup in a vector chart.


Muscle Activation Differs Between Partial and Full Back Squat Exercise With External Load Equated.
Changes in range of motion affect the magnitude of the load during the squat exercise and, consequently, may influence muscle activation. The purpose of this study was to evaluate muscle activation between the partial and full back squat exercise with external load equated on a relative basis between conditions. Fifteen young, healthy, resistance-trained men (age: 26 ± 5 years, height: 173 ± 6 cm) performed a back squat at their 10 repetition maximum (10RM) using 2 different ranges of motion (partial and full) in a randomized, counterbalanced fashion. Surface electromyography was used to measure muscle activation of the vastus lateralis, vastus medialis, rectus femoris, biceps femoris (BF), semitendinosus, erector spinae, soleus (SL), and gluteus maximus (GM). In general, muscle activity was highest during the partial back squat for GM (p = 0.004), BF (p = 0.009), and SL (p = 0.031) when compared with full-back squat. There was no significant difference for rating of perceived exertion between partial and full back squat exercise at 10RM (8 ± 1 and 9 ± 1, respectively). In conclusion, the range of motion in the back squat alters muscle activation of the prime mover (GM) and stabilizers (SL and BF) when performed with the load equated on a relative basis. Thus, the partial back squat maximizes the level of muscle activation of the GM and associated stabilizer muscles.


Identification of the lymphocytic choriomeningitis virus (LCMV) proteins required to rescue LCMV RNA analogs into LCMV-like particles.
We have used a reverse genetic approach to identify the viral proteins required for packaging and assembly of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). Plasmids encoding individual LCMV proteins under the control of an RNA polymerase II promoter were cotransfected with a plasmid containing an LCMV minigenome (MG). Intracellular synthesis of the LCMV MG was driven by T7 RNA polymerase whose expression was also mediated by a Pol II promoter. The supernatant from transfected cells was passaged onto fresh cells that were subsequently infected with LCMV to provide the minimal viral trans-acting factors, NP and L, that are required for LCMV MG RNA replication and expression. Reconstitution of LCMV-specific packaging and passage was detected by expression of the chloramphenicol acetyl transferase (CAT) reporter gene present in the MG. NP and L did not direct detectable levels of MG passage. Addition of Z and GP resulted in high levels of passage of CAT activity, which could be prevented by LCMV neutralizing antibodies. Passage of LCMV MG was inhibited by omission of either GP or Z.


Obstructive sleep apnoea and anaesthesia.
Upper airway obstruction is common during both anaesthesia and sleep, as a result of loss of muscle tone present during wakefulness. Patients with obstructive sleep apnoea (OSA) are vulnerable during anaesthesia and sedation as the effects of loss of wakefulness are compounded by drug-induced depression of muscle activity and of arousal responses, so that they cannot respond to asphyxia. Conversely, those with 'difficult' airways during anaesthesia, either because of problems with maintenance of airway patency without tracheal intubation or because intubation itself is problematic, are at increased risk of OSA. These relationships have clinical importance. On the one hand identification of patients with OSA forewarns the anaesthetist of potential difficulty with airway maintenance intra- and postoperatively, influencing choice of anaesthetic technique and postoperative nursing environment. On the other hand difficulty with airway maintenance during anaesthesia should prompt further investigation for the possibility of OSA.


Role of radiology in occupational medicine.
This review discusses the contribution of radiology to occupational medicine as well as work-related problems in radiology departments. Research issues are emphasized. Radiology has been used especially when diagnosing occupational respiratory and locomotive system problems and solvent-induced encephalo- and hepatopathy. The aim of research in these areas is usually to characterize occupational diseases and to identify physico-chemical hazards in the work place by comparing between groups of workers and non-exposed controls. Radiological imaging allows an objective characterization of the disease, and it may clarify the pathogenesis of the process and provide a useful epidemiological tool. Advanced statistical methods are often needed to adjust analyses for confounding variables. As the diagnostic requirements are increasing, more sensitive and sophisticated radiological methods, such as high-resolution computed tomography, magnetic resonance imaging and magnetic resonance spectroscopy, may be required for the early recognition of occupational health risks. This necessitates good cooperation between occupational health units and well-equipped imaging departments. Considering occupational problems in radiology departments, the increasing use of digital radiology requires ergonomic measures to control and prevent locomotive problems caused by work with computers. Radiation protection measures are still worth concern, especially in interventional radiology.


Virus-mimicking nano-constructs as a contrast agent for near infrared photoacoustic imaging.
We report the first proof-of-principle demonstration of photoacoustic imaging using a contrast agent composed of a plant virus protein shell, which encapsulates indocyanine green (ICG), the only FDA-approved near infrared chromophore. These nano-constructs can provide higher photoacoustic signals than blood in tissue phantoms, and display superior photostability compared to non-encapsulated ICG. Our preliminary results suggest that the constructs do not elicit an acute immunogenic response in healthy mice.


Synthesis of MCM-41-Supported Metal Catalysts in Deep Eutectic Solvent for the Conversion of Carbohydrates into 5-Hydroxymethylfurfural.
A series of MCM-41 supported metal catalysts (denoted M/D41) were prepared by using the deep eutectic solvent (DES)-mediated ionothermal synthesis strategy. Al/D41 was found to have excellent performance in the conversion of carbohydrates into 5-hydroxymethylfurfural (HMF). Furthermore, the production of HMF from glucose could be performed at high concentrations in choline chloride aqueous solution (CAS; 32 wt %, relative to the reaction phase) and as a result, CAS is a more promising solvent than water and DES for HMF production.


Atezolizumab for the treatment of non-small cell lung cancer.
The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1). Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay. Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.


Paraneoplastic subacute sensory neuronopathy in association with adenocarcinoma of the prostate.
Paraneoplastic syndromes arise infrequently in prostate cancer and paraneoplastic subacute sensory neuronopathy has not previously been reported in association with prostate cancer. When paraneoplastic syndromes occur, it is usually in the setting of small-cell carcinoma of the prostate or advanced, hormone-resistant disease. Here the authors report a 64- year-old man who developed a progressive, severe, sensory neuronopathy in the setting of a recently diagnosed stage T4 hormone-responsive prostate adenocarcinoma. Anti-Hu antibodies were positive and screening for a concurrent neoplasm at another site was negative. Sensory neuronopathy progressed, despite hormone responsiveness of his prostate adenocarcinoma, and resulted in a severe level of disability. His symptoms did not respond to intravenous corticosteroid therapy but there was a partial response to intravenous immunoglobulin.


Theoretical conformational analysis of a family of alpha-helical immunocytokines.
According to the results of the theoretical conformation analysis and available experimental data, the known immunocytokines can be divided into two groups: alpha-helical (IFNs-alpha, beta, gamma, omega; IL-2, 3, 4, 5, 6, 7; G-, M-, GM-CSFs; cMGF, PDGF) and beta-pleated proteins (ILs-1 alpha, beta; TNFS-alpha, beta). IFNs-alpha, beta, gamma, omega, IL-6, G-CSF, cMGF were shown to form a family of alpha-helical globular proteins characterized by a statistically significant homology in amino acid sequences and by common features of the secondary structure formation. Comparison of the sequences of 72 IFNs-alpha, beta, omega reveals three clusters of conservative amino acid positions. Their participation in the formation of active sites of IFN-alpha, beta, omega is supposed.


Recombinant human erythropoietin attenuates renal tubulointerstitial injury in murine adriamycin-induced nephropathy.
Erythropoietin (EPO) has been found to provide cytoprotection against acute ischemic and toxic renal tubulointerstitial injury. This study aimed to elucidate the mechanism(s) underlying EPO protection while examining whether EPO provides tubulointerstitial protection in a mouse model with adriamycin (ADR)-induced tubulointerstitial injury. Adriamycin nephropathy (AN) was induced by a single injection of ADR in the 2 experimental groups on day 0. The saline-control group and the AN-saline group were administered saline at days 7, 14, and 21, while the EPO-control group and the AN-EPO group were administered EPO at days 7, 14, and 21. Kidneys were harvested at days 14 and 28 after ADR injection to measure the expression levels of the EPO receptor (EPO-R), CD34, and phosphorylated Akt by immunohistochemistry; to determine the extent of apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and active caspase-3 staining; and to map the hypoxic area by pimonidazole staining. EPO-R was detected in glomerular, tubular epithelial, and endothelial cells. EPO administration significantly improved tubulointerstitial injury, decreased the number of TUNEL-positive and active caspase-3-positive cells, and increased the phosphorylated-Akt-positive area in the tubulointerstitial area without increasing the hemoglobin or hematocrit levels. EPO provides renoprotection against AN by reducing apoptotic cell death and preserving peritubular capillaries, possibly by exerting pleiotropic effects independently of its hemopoietic effects.


Transformation of terahertz vibrational modes of cytosine under hydration.
Cytosine and cytosine monohydrate are representative biomolecules for investigating the effect of hydrogen bonds in deoxyribonucleic acid. To better understand intermolecular interactions, such as hydrogen bonds, between nucleobases it is necessary to identify the low-frequency vibrational modes associated with intermolecular interactions and crystalline structures. In this study, we investigated the characteristic low-frequency vibrational modes of cytosine and cytosine monohydrate using terahertz time-domain spectroscopy (THz-TDS). The crystal geometry was obtained by the powder X-ray diffraction technique. The optimized atomic positions and the normal modes in the terahertz region were calculated using density functional theory (DFT), which agreed well with the experimental results. We found that overall terahertz absorption peaks of cytosine and cytosine monohydrate consist of collective vibrations mixed with intermolecular and intramolecular vibrations in mode character analysis, and that the most intense peaks of both samples involve remarkable intermolecular translational vibration. These results indicate that THz-TDS combined with DFT calculations including mode character analysis can be an effective method for understanding how water molecules contribute to the characteristics of the low-frequency vibrational modes by intermolecular vibrations with hydrogen bonding in biological and biomedical applications.


Atrioventricular Nodal Reentrant Tachycardia in Very Elderly Patients: A Single-center Experience.
We present a series of elderly patients older than 80 years who had recurrent palpitations for decades and who were subsequently diagnosed with atrioventricular (AV) nodal reentrant tachycardia (AVNRT). Through a retrospective chart analysis, we identified 12 patients (nine females and three males) aged 88 years ± 3.7 years (range: 80-92 years) seen at our center from 2015 to 2016 for recurrent palpitations and supraventricular tachycardia (SVT) who were ultimately diagnosed with AVNRT. These patients had palpitations and had been treated for anxiety and panic attacks for decades. They underwent electrophysiology (EP) study and successful ablation of the slow pathway. The demographic data, symptoms, and EP characteristics during the EP studies of the patients were evaluated. All 12 patients experienced palpitations and all but three had documented SVT on a loop recorder or an event monitor. During EP study, all patients displayed slow-pathway conduction. Nine patients demonstrated discontinuous AV nodal conduction curves, while three showed continuous AV nodal conduction curves. The observed tachycardia rates were 496.7 ms ± 25.7 ms. Three patients had atrial fibrillation (AF), which was noted during monitoring with the implanted loop recorders. Tachycardia was induced with both burst atrial pacing and atrial extrastimuli in five patients and with extrastimuli only in two patients. In five patients, no tachycardia induction was noted, but these individuals showed evidence of dual AV node physiology. Successful elimination of residual slow-pathway conduction postablation and/or noninducibility of tachycardia in the postablation period were achieved in all patients. All patients remained symptom-free over a period of one year. The patients who had AF in addition to AVNRT also did not present any recurrent AF following AVNRT ablation but are being monitored for recurrence. AVNRT in elderly people is often confused with panic attacks; hence, reports of panic attacks in elderly people should be properly evaluated for an arrhythmic etiology.


Development and Implementation of Team-Based Panel Management Tools: Filling the Gap between Patient and Population Information Systems.
Effective team-based models of care, such as the Patient-Centered Medical Home, require electronic tools to support proactive population management strategies that emphasize care coordination and quality improvement. Despite the spread of electronic health records (EHRs) and vendors marketing population health tools, clinical practices still may lack the ability to have: (1) local control over types of data collected/reports generated, (2) timely data (eg, up-to-date data, not several months old), and accordingly (3) the ability to efficiently monitor and improve patient outcomes. This article describes a quality improvement project at the hospital system level to develop and implement a flexible panel management (PM) tool to improve care of subpopulations of patients (eg, panels of patients with diabetes) by clinical teams. An in-depth case analysis approach is used to explore barriers and facilitators in building a PM registry tool for team-based management needs using standard data elements (eg, laboratory values, pharmacy records) found in EHRs. Also described are factors that may contribute to sustainability; to date the tool has been adapted to 6 disease-focused subpopulations encompassing more than 200,000 patients. Two key lessons emerged from this initiative: (1) though challenging, team-based clinical end users and information technology needed to work together consistently to refine the product, and (2) locally developed population management tools can provide efficient data tracking for frontline clinical teams and leadership. The preliminary work identified critical gaps that were successfully addressed by building local PM registry tools from EHR-derived data and offers lessons learned for others engaged in similar work. (Population Health Management 2016;19:232-239).


[Factors affecting stroke patients' motivations for rehabilitation].
Factors correlated to the motivation for rehabilitation in stroke patients were studied. Thirty patients who had had only one stroke were recruited between December 1991 and April 1992 for our study. Several assessment tools including the Motivational scale, the Health Locus of Control scale and a questionnaire were used. According to the results of the assessment, the stroke patients' motivation remained stable when assessed two to three times during the hospital stay, whereas their UE/LE Brunnstrom stage scores and activities of daily living skill (ADL) improved significantly. The motivation of the patients was closely correlated with the degree of education, the internal scores and ADL performance: patients with education level higher than primary school, higher internal scores, or better ADL performance had stronger motivation for rehabilitation. On the other hand, motivational assessments between the nursing staff and the therapists were not completely in agreement. The ADL performance was better correlated with the degree of motivation on the nursing assessment, whereas the Brunnstrom stage scores of UE/LE were more closely correlated with the therapists' assessment. Items on the motivational questionnaire such as "eagerness to recover earlier", "recognition of the effectiveness of rehabilitation", "support of spouse" and "homesickness" were commonly considered to be positive factors. However, the other factors such as "being in bad mood", "lack of family cooperation", "worrying about things other than finances" and "lack of family support" were commonly considered to be negative factors on motivation. In the comparison between high and low motivation groups, the high motivation group payed more attention to the positive factors such as "eagerness to be independent" and such negative factors as "lack of understanding of illness" as well as "poor appetite and fatigue". The low motivation group was considered to be more affected by such negative factors as "worrying about things other than finances", "not good enough facilities" and "homesickness" which resulted in lessening the motivation for rehabilitation.


Longitudinal outcomes after endovascular repair of abdominal aortic aneurysms.
Endovascular abdominal aneurysm repair (EVAR) is increasingly used, but there is insufficient evaluation of long-term outcomes. Retrospective cohort study using the linked Washington State hospital discharge database. 3,350 patients underwent elective repair of AAA (1181 EVAR) between 2000 and 2005. EVAR patients were older and had higher comorbidity scores. The 30-day readmission rate after EVAR was 11.6%. The 30-day readmissions included cardiac complications (18.5%) and device complications (10.4%). 46% of the 30-day readmissions after EVAR underwent procedures: abdominal/ iliac angiography (7.4%), angioplasty (8.9%), and device revision (8.2%). Mean time to late interventions was 611 days. Readmission, reintervention, and complication rates after EVAR occur more commonly than previously described. Cardiac complications were the most common readmission. Almost half of the 30-day readmissions required a secondary intervention. Long-term complications after EVAR occurred before two years. Population-based assessment may be more reflective of "real world" complication rates after EVAR.


Role of B cells in host defense against primary Coxiella burnetii infection.
Despite Coxiella burnetii being an obligate intracellular bacterial pathogen, our recent study demonstrated that B cells play a critical role in vaccine-induced immunity to C. burnetii infection by producing protective antibodies. However, the role of B cells in host defense against primary C. burnetii infection remains unclear. In this study, we investigated whether B cells play an important role in host defense against primary C. burnetii infection. The results showed that peritoneal B cells were able to phagocytose virulent C. burnetii bacteria and form Coxiella-containing vacuoles (CCVs) and that C. burnetii can infect and replicate in peritoneal B1a subset B cells in vitro, demonstrating a potential role for peritoneal B cells in host defense against C. burnetii infection in vivo. In addition, the results showing that B1a cells secreted a high level of interleukin-10 (IL-10) in response to C. burnetii infection in vitro suggest that B1a cells may play an important role in inhibiting the C. burnetii infection-induced inflammatory response. The observation that adoptive transfer of peritoneal B cells did not significantly affect the severity of C. burnetii infection-induced diseases in both severe combined immunity-deficient (SCID) and μMT mice indicates that peritoneal B cells alone may not be able to control C. burnetii infection. In contrast, our finding that C. burnetii infection induced more-severe splenomegaly and a higher bacterial burden in the spleens of B1a cell-deficient Bruton's tyrosine kinase x-linked immunity-deficient (BTK(xid)) mice than in their wild-type counterparts further suggests that B1a cells play an important role in host defense against primary C. burnetii infection.


[Ethacizin: pharmacologic properties and prospects for clinical application].
The study of the regularities between the chemical structure and pharmacologic action of phenathiazine dialkylaminoacyl derivatives led to the identification and investigation of a new drug called ethacizine-phenothiazin-2-carbethoxyamino-10 (beta-diethylamino-propionyl) hydrochloride. Ethacizine exceeds its structural analogue ethmozin by two times in terms of intensity and by 4-5 times in terms of the duration of antiarrhythmic effect. Ethacizine has marked antianginal properties. It shows a prolonged inhibitory effect on the average elevation of the ST interval at multiple leads of the epicardial electrogram during coronary occlusion, increases the threshold of myocardial ischemia development, and reduces the size of experimental infarction. The combination of potent antiarrhythmic activity, already confirmed by clinical observations, with antianginal properties and a capacity to limit the size of infarction makes in possible to consider ethacizine a promising means for treating coronary heart disease.


Injuries caused by freshwater stingrays in the Tapajós River Basin: a clinical and sociodemographic study.
Freshwater stingray envenomations are an important cause of morbidity in riverine populations living in various regions of Brazil. The sequelae include temporary or permanent disability. This study aimed to identify sociodemographic, clinical, and therapeutic aspects related to stingray injuries in such populations. This cross-sectional study was conducted in the Extractive Reserve of Tapajos-Arapiuns, located in the municipalities of Santarém and Aveiro (Pará State). A convenience sample comprising 300 local adults was used to obtain data by means of a questionnaire/ interview. Overall, 19 (6.3%) participants reported having sustained a stingray injury in the 12 months prior to the study. All 19 were injured either while fishing (n=13 [68.4%]) or engaging in other riverine activities. Most injuries [n=14 (73.7%)] occurred from September through November, and most injured respondents [n=15 (78.9%)] reported seeing stingrays at beaches. Severe pain and the appearance of ulcers in the later stages of envenomation were described by 18 (94.7%) and 12 (63.2%) participants, respectively. Freshwater stingray injuries, which should be considered occupational injuries, are common in the study area, especially in places like beaches or in the lakes that form during the dry season, when stingrays are routinely observed. A significant proportion of respondents was unaware of the correct first aid measures and had insufficient resources to treat the complications of these injuries in the locality where they reside. Interactive activities involving local residents - such as lectures and the distribution of simple pamphlets providing information about stingray injuries - are needed.


Coordinated peripheral neuronal activities among the different regions of the digestive tract in Aplysia.
Peripheral neuronal somata are scattered throughout the enteric nervous system (ENS) in Aplysia. We found that somata on the outer surface of the digestive tract were more densely distributed on the stomatogastric ring and the posterior gizzard than on other regions. In preparations with or without the central nervous system, two types of synchronous bursting activity were recorded from the nerves of the ENS. Some of the synchronous bursts were recorded from nerves on the crop and stomatogastric ring, whereas others were recorded from nerves on the crop, stomatogastric ring, and gizzard. Experiments using preparations in which the different regions were separated suggested that the former bursts originated in neurons on the crop and the latter originated in neurons on the gizzard. Axonal projections of neurons on the different regions were examined by backfilling and analysis of the direction of impulse conduction. Blocking chemical synapses in separated gizzards depressed EPSP-like potentials and eliminated the bursting activities. When chemical synapses on the crop and stomatogastric ring but not on the gizzard were blocked in a whole digestive tract preparation, bursting activity recorded from nerves on all the regions was decreased, although the frequency of the bursting rhythm did not change. Stimulation of a neuron on the crop elicited bursts in nerves on the gizzard. These results suggest that chemical synaptic connections and a feedback loop along the digestive tract coordinate the synchrony of bursting activity originating in the gizzard.


Shape dependence of all-dielectric terahertz metasurface.
All-dielectric metasurfaces have been attracting attention in the terahertz spectral range for low-loss planar optical elements such as lenses, beam splitters, waveplates, vortex plates, and magnetic mirrors. Various shapes of meta-atoms have been used in many studies; however, no systematic comparative study of each shape has been reported. The optical properties of various shapes of metasurfaces are reported in this work using finite difference time domain simulation. The phase of a pillar-type all-dielectric metasurface is mainly determined by the cross-sectional area, rather than its detailed shape. Consequently, in the square lattice geometry, the square shape meta-atom performs best in terms of full phase control at the lowest pillar height with negligible polarization dependence. Furthermore, we compare the transmission, phase, and polarization dependence of the hexagonal and square lattices. Square-shape metasurface successfully realizes subwavelength focusing metalens and vortex plate.


Perillaldehyde Alleviates Spinal Cord Ischemia-Reperfusion Injury Via Activating the Nrf2 Pathway.
Spinal Cord ischemia-reperfusion injury (SCII) is one of the most destructive complications in thoracic-abdominal aortic surgery, which can cause physical abnormalities, paralysis and even brain death. Evidence has shown that perillaldehyde (PAH) can ameliorate rat's cerebra ischemia-reperfusion injury. However, the effect of PAH on SCII remains unknown. The current study established SCII rat models and oxygen and glucose deprivation/reoxygenation-induced BV2 microglia models to explore whether PAH could alleviate SCII symptoms and to investigate underlying mechanism. SCII rats underwent severe neurologic motor dysfunction and histopathologic injury compared with the normal rats, which are exhibited by loss of motor neurons and decrease of nissl bodies. Treatment with PAH significantly ameliorated motor dysfunction and neuron damage. PAH downregulated the expression of NLR family pyrin domain containing 3, cleaved/pro caspase-1, interleukin-1β and interleukin-18 in spinal cord tissues of SCII rats. Besides, the contents of oxidative stress-related factors superoxide dismutase, manganese-dependent superoxide dismutase, catalase and glutathione peroxidase were significantly increased and malondialdehyde content was decreased after PAH treatment. PAH treatment upregulated the expression of nuclear factor-E2-related factor 2 and heme oxygenase-1 in spinal cord tissues of SCII rats. Our in vitro study confirmed that PAH inhibited microglial activation by activating the nuclear factor-E2-related factor 2/heme oxygenase-1 pathway, exhibited by alleviated inflammation and oxidative stress. This study elucidates that PAH has the potential value for treating SCII, which provides an experimental basis for clinical trials in the future.


Relative loss of oncogenic potency of mouse leukemia virus (Gross) after prolonged propagation in tissue culture.
Since the initial development of the "passage A" mouse leukemia virus in 1957, this virus has been propagated in our laboratory by serial passage in newborn C3H(f) mice. At the present time, 10(-2)-10(-3) dilutions in physiological saline solution of this mouse-passaged virus induce lymphatic leukemia in practically all inoculated mice after a latency of 3-5 months. On the other hand, when the same virus was propagated on NIH 3T3 mouse embryo cells in tissue culture for more than 10 years, its leukemogenic potency became considerably reduced. Recent bioassay experiments carried out in our laboratory demonstrated that after such prolonged propagation in tissue culture this virus now induced leukemia in less than 15% of the inoculated suckling C3H(f) mice; only undiluted or 10% dilutions of the tissue culture fluid (very occasionally 10(-2) or 10(-3) dilutions) induced leukemia after a prolonged latency varying from 5.5 to 18 months. The passaged and the tissue-culture-grown virus strains are identical immunologically and indistinguishable in their morphology when examined by electron microscopy. The tissue-culture-grown virus, attenuated in its leukemogenic potency, does not, however, confer immunity against a challenge with the mouse-passaged virus.


Peanut allergy in-flight.
An unknown but probably significant number of airline passengers are allergic to peanuts. Reactions can be mild, moderate, or severe (life threatening). Because peanuts are sometimes dispensed by flight attendants on commercial flights, there is public concern that passengers are at risk of an in-flight allergic reaction. Although there is little in the medical literature to substantiate this concern, there are anecdotal cases of inflight allergic reactions to peanuts from ingestion, dermal contact, and inhalation of airborne peanut particles. Consequently, there are several options among which the airlines must choose in order to satisfy passenger concerns.


HIV incidence in Ethiopian immigrants to Israel.
The HIV incidence in recent adult Ethiopian immigrants to Israel is estimated through the use of snapshot estimators based on percentage of CD4 progression with time since infection, whereas the preimmigration incidence experienced by this population is estimated using an epidemic model applied to HIV prevalence data obtained from immigrants on arrival in Israel. The snapshot estimators place incidence in adult Ethiopian immigrants in Israel between 3 and 11 infections/1000 uninfected persons/year around May 1995. In contrast, the epidemic model suggests that the incidence experienced by this population before immigration was between 12 and 22 infections/1000 uninfected persons/year. Although the drop in incidence postimmigration is good news, in the aggregate, we estimate that between 50 and 190 new infections have occurred annually in adult Ethiopians who have immigrated to Israel.


Acidification of the intimal fluid: the perfect storm for atherogenesis.
Atherosclerotic lesions are often hypoxic and exhibit elevated lactate concentrations and local acidification of the extracellular fluids. The acidification may be a consequence of the abundant accumulation of lipid-scavenging macrophages in the lesions. Activated macrophages have a very high energy demand and they preferentially use glycolysis for ATP synthesis even under normoxic conditions, resulting in enhanced local generation and secretion of lactate and protons. In this review, we summarize our current understanding of the effects of acidic extracellular pH on three key players in atherogenesis: macrophages, apoB-containing lipoproteins, and HDL particles. Acidic extracellular pH enhances receptor-mediated phagocytosis and antigen presentation by macrophages and, importantly, triggers the secretion of proinflammatory cytokines from macrophages through activation of the inflammasome pathway. Acidity enhances the proteolytic, lipolytic, and oxidative modifications of LDL and other apoB-containing lipoproteins, and strongly increases their affinity for proteoglycans, and may thus have major effects on their retention and the ensuing cellular responses in the arterial intima. Finally, the decrease in the expression of ABCA1 at acidic pH may compromise cholesterol clearance from atherosclerotic lesions. Taken together, acidic extracellular pH amplifies the proatherogenic and proinflammatory processes involved in atherogenesis.


With hiccups and bumps: the development of a Rasch-based instrument to measure elementary students' understanding of the nature of science.
This research describes the development process, psychometric analyses and part validation study of a theoretically-grounded Rasch-based instrument, the Nature of Science Instrument-Elementary (NOSI-E). The NOSI-E was designed to measure elementary students' understanding of the Nature of Science (NOS). Evidence is provided for three of the six validity aspects (content, substantive and generalizability) needed to support the construct validity of the NOSI-E. A future article will examine the structural and external validity aspects. Rasch modeling proved especially productive in scale improvement efforts. The instrument, designed for large-scale assessment use, is conceptualized using five construct domains. Data from 741 elementary students were used to pilot the Rasch scale, with continuous improvements made over three successive administrations. The psychometric properties of the NOSI-E instrument are consistent with the basic assumptions of Rasch measurement, namely that the items are well-fitting and invariant. Items from each of the five domains (Empirical, Theory-Laden, Certainty, Inventive, and Socially and Culturally Embedded) are spread along the scale's continuum and appear to overlap well. Most importantly, the scale seems appropriately calibrated and responsive for elementary school-aged children, the target age group. As a result, the NOSI-E should prove beneficial for science education research. As the United States' science education reform efforts move toward students' learning science through engaging in authentic scientific practices (NRC, 2011), it will be important to assess whether this new approach to teaching science is effective. The NOSI-E can be used as one measure of whether this reform effort has an impact.


Pleural effusions: a new negative prognostic parameter for acute pancreatitis.
To evaluate the incidence, localization, and size of pleural effusions in 133 patients with acute pancreatitis. A contrast-enhanced computed tomographic scan was prospectively obtained within 72 h after admission. Patients with pleural effusions (66 = 50%) had significantly more severe morphological changes of the pancreas and necroses (independent of the size and localization of the effusions and etiology of the acute pancreatitis), more often had a pancreatic pseudocyst, and had a higher mortality rate than patients without this complication. Pleural effusions are indicative of severe acute pancreatitis and are a negative prognostic parameter for the course of the disease.


Heterogeneity of ICAM-1 expression, and cytokine regulation of ICAM-1 expression, in skin and oral keratinocytes.
Differences in expression of intercellular adhesion molecule-1 (ICAM-1) and ICAM-1 mRNA levels were studied in cultured skin and oral keratinocytes before and after stimulation with different pro-inflammatory cytokines. Basal expression of ICAM-1 was undetectable on skin keratinocytes but oral keratinocytes expressed ICAM-1 at high levels. Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) increased ICAM-1 expression on both cell types, although TNF-alpha had a greater effect on oral than skin keratinocytes (P<0.05) and IFN-gamma was more effective than TNF-alpha on both cell types (P<0.01). In combination, TNF-alpha and IFN-gamma synergistically increased ICAM-1 expression on skin keratinocytes only, although ICAM-1 mRNA was synergistically increased in both cell types. IL-1alpha and IL-1beta induced a small increase in ICAM-1 expression on oral keratinocytes but had no effect on skin keratinocytes.


Escape dynamics through a continuously growing leak.
We formulate a model that describes the escape dynamics in a leaky chaotic system in which the size of the leak depends on the number of the in-falling particles. The basic motivation of this work is the astrophysical process, which describes the planetary accretion. In order to study the dynamics generally, the standard map is investigated in two cases when the dynamics is fully hyperbolic and in the presence of Kolmogorov-Arnold-Moser islands. In addition to the numerical calculations, an analytic solution to the temporal behavior of the model is also derived. We show that in the early phase of the leak expansion, as long as there are enough particles in the system, the number of survivors deviates from the well-known exponential decay. Furthermore, the analytic solution returns the classical result in the limiting case when the number of particles does not affect the leak size.


Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence.
Although cisplatin has played a role in "standard-of-care" multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high-risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK-1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC.


The Presence of T Allele (rs35705950) of the MUC5B Gene Predicts Lower Baseline Forced Vital Capacity and Its Subsequent Decline in Patients with Hypersensitivity Pneumonitis.
Hypersensitivity pneumonitis (HP) is an exposure-related interstitial lung disease with two phenotypes-fibrotic and non-fibrotic. Genetic predisposition is an important factor in the disease pathogenesis and fibrosis development. Several genes are supposed to be associated with the fibrosing cascade in the lungs. One of the best-recognized and most prevalent is the common MUC5B gene promoter region polymorphism variant rs35705950. The aim of our study was to establish the frequency of the minor allele of the MUC5B gene in the population of patients with HP and to find the relationship between the MUC5B promoter region polymorphism and the development of lung fibrosis, the severity of the disease course, and the response to the treatment in patients with HP. Eighty-six consecutive patients with HP were tested for the genetic variant rs35705950 of the MUC-5B gene. Demographic, radiological, and functional parameters were collected. The relationship between the presence of the T allele and lung fibrosis, pulmonary function test parameters, and the treatment response were analyzed. The minor allele frequency in the study group was 17%, with the distribution of the genotypes GG in 69.8% of subjects and GT/TT in 30.2%. Patients with the GT/TT phenotype had significantly lower baseline forced vital capacity (FVC) and significantly more frequently had a decline in FVC with time. The prevalence of lung fibrosis in high-resolution computed tomography (HRCT) was not significantly increased in GT/TT variant carriers compared to GG ones. The patients with the T allele tended to respond worse to immunomodulatory treatment and more frequently received antifibrotic drugs. In conclusions: The frequency of MUC5B polymorphism in HP patients is high. The T allele may indicate a worse disease course, worse immunomodulatory treatment response, and earlier need for antifibrotic treatment.


Biochemical characterization of the Drosophila dpp protein, a member of the transforming growth factor beta family of growth factors.
The decapentaplegic (dpp) gene of Drosophila melanogaster is required for pattern formation in the embryo and for viability of the epithelial cells in the imaginal disks. The dpp protein product predicted from the DNA sequence is similar to members of a family of growth factors that includes transforming growth factor beta (TGF-beta). We have produced polyclonal antibodies to a recombinant dpp protein made in bacteria and used a metallothionein promoter to express a dpp cDNA in Drosophila S2 cells. Similar to other proteins in the TGF-beta family, the dpp protein produced by the Drosophila cells was proteolytically cleaved, and both portions of the protein were secreted from the cells. The amino-terminal 47-kilodalton (kDa) peptide was found in the medium and in the proteins adhering to the plastic petri dish. The carboxy-terminal peptide, the region with sequence similarity to the active ligand portion of TGF-beta, was found extracellularly as a 30-kDa homodimer. Most of the 30-kDa homodimer was in the S2 cell protein adsorbed onto the surface of the plastic dish. The dpp protein could be released into solution by increased salt concentration and nonionic detergent. Under these conditions, the amino-terminal and carboxy-terminal portions of dpp were not associated in a stable complex.


Spatial frequency specific interaction of dot patterns and gratings.
Adaptation to patterns of paired random dots produces loss of contrast sensitivity to sinusoidal luminance gratings oriented perpendicularly to the dot-pair direction. This adaptation loss is spatial frequency- and orientation-specific and varies with dot-pair separation in a manner predictable from the Fourier spectra of the stimuli and observed characteristics of the visual system. These results support the idea that the visual system acts as a periodicity analyzer with known restrictions and cannot be accounted for by a feature-detector model. When the bars of the test gratings are aligned in the dot-pair direction, there is no adaptational loss at any frequency despite the fact that the adaptation pattern contains significant spectral power at all frequencies in this orientation. This lack of adaptation may be due to inhibitory interactions among channels or to nonlinear effects within local receptive fields.


Airborne lidar measurements of smoke plume distribution, vertical transmission, and particle size.
Observations were made of a dense smoke plume downwind from a forest fire using the ALPHA-1 two-wavelength downward-looking airborne lidar system. Facsimile displays derived from lidar signatures depict plume dimensions, boundary layer height, and underlying terrain elevation. Surface returns are interpreted in terms of vertical transmission as function of cross-plume distance. Results show significantly greater plume attenuation at 0.53-microm wavelength than at 1.06-microm, indicating ~0.1-microm mean particle diameters or the presence of gaseous constituents that absorb the visible radiation. These results demonstrate the potential of multiple-wavelength airborne lidar for quantitative analysis of atmospheric particulate and gaseous constituents.