Neuroprotective properties of statins.
Treatment with statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) reduces the risk of ischemic stroke among patients with increased risk of vascular disease. Recent experimental data point to neuroprotective properties of statins in acute cerebral ischemia. There is a proven link between bioavailability of nitric oxide and the activity of statins and ischemic stroke. Due to their ability to up-regulate nitric oxide synthase, statins have been considered in the therapy of a number of the central nervous system disorders, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, tumors, and trauma. It has been claimed that they suppress inflammatory response and secondary injury after acute ischemia.


Monoclonal anti-cardiolipin antibodies from New Zealand Black x New Zealand White F1 mice react to thrombomodulin.
The reactivity with and affinity for thrombomodulin (TM) of monoclonal anti-cardiolipin Abs (MoaCL), derived from a New Zealand Black x New Zealand White F1 (NZB/W F1) mouse, were studied to investigate the pathogenicity of anti-cardiolipin Abs (aCL). Four of eighteen MoaCL were found to react with rabbit TM when examined using ELISA. These four MoaCL also reacted with synthetic peptide that included the epidermal growth factor-like domain of human TM, a binding site for thrombin. The reaction with TM of these four MoaCL was inhibited by bovine thrombin. When the affinity for TM of the MoaCL was determined, the dissociation constants (Kd) ranged from 4.8 x 10(-9) to 4.7 x 10(-8) M. By contrast, examination of the affinity for cardiolipin (CL) gave values from 8.3 x 10(-6) to 7.4 x 10(-5) M. Thus, these MoaCL reacted to TM with a higher affinity than to CL. Moreover, these MoaCL also bound to TM on HUVEC and down-regulated the expression level of TM on the surface of HUVEC due to internalization of TM. The binding of thrombin to TM is known to initiate rapid protein C activation, and complexes of activated protein C and protein S show anticoagulatory activity. Thus, the present studies suggest that certain pathogenic aCL cross-react with TM and induce down-regulation of TM on endothelial cells, followed by induction of thrombosis.


A study of the types and manifestations of physicians' unintended behaviors in the DRG payment system.
In recent years, China has implemented the Diagnosis Related Groups (DRG) payment system as part of its healthcare insurance reimbursement policy. Numerous studies have focused on the effectiveness of DRG payment system in controlling unreasonable growth in medical expenses. However, there has been no systematic report on the types of unintended behaviors exhibited by doctors under the DRG payment system. The study first utilized interrupted time series analysis to analyze medical records and insurance data from eight hospitals. It investigated the data changes in MDC and ADRG groups before and after the implementation of the DRG payment system. Subsequently, a semi-structured interview method was employed to conduct qualitative research on the unintended behaviors of physicians, aiming to gain a more accurate understanding of specific changes in physician behavior after the implementation of the DRG payment system. This study discovered that doctors engage in unintended behaviors within the framework of the DRG payment system. In the early implementation of the DRG payment system in China, the contradictions between the flawed DRG payment methods and supporting systems and the actual diagnostic and treatment work manifested in the form of unintended doctor behaviors. Most of these unintended behaviors can be considered reasonable feedback from doctors to cope with the existing system flaws. They are conducive to identifying the deficiencies in China's DRG payment system and suggesting directions for improvement.


Bilateral epidiymal cysts in an alpaca male used for breeding.
A 4-year-old alpaca stud was presented for examination of his reproductive tract. Ultrasonographic examination of the gonads revealed 2 cystic structures associated with the head of each epididymis. Biopsies of each testicle evidenced mild testicular degeneration. Histopathologic examination of the gonads revealed cystic efferent ductules in the head of each epididymis.


Restoration of reaching and grasping movements through brain-controlled muscle stimulation in a person with tetraplegia: a proof-of-concept demonstration.
People with chronic tetraplegia, due to high-cervical spinal cord injury, can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as functional electrical stimulation (FES). Users typically command FES systems through other preserved, but unrelated and limited in number, volitional movements (eg, facial muscle activity, head movements, shoulder shrugs). We report the findings of an individual with traumatic high-cervical spinal cord injury who coordinated reaching and grasping movements using his own paralysed arm and hand, reanimated through implanted FES, and commanded using his own cortical signals through an intracortical brain-computer interface (iBCI). We recruited a participant into the BrainGate2 clinical trial, an ongoing study that obtains safety information regarding an intracortical neural interface device, and investigates the feasibility of people with tetraplegia controlling assistive devices using their cortical signals. Surgical procedures were performed at University Hospitals Cleveland Medical Center (Cleveland, OH, USA). Study procedures and data analyses were performed at Case Western Reserve University (Cleveland, OH, USA) and the US Department of Veterans Affairs, Louis Stokes Cleveland Veterans Affairs Medical Center (Cleveland, OH, USA). The study participant was a 53-year-old man with a spinal cord injury (cervical level 4, American Spinal Injury Association Impairment Scale category A). He received two intracortical microelectrode arrays in the hand area of his motor cortex, and 4 months and 9 months later received a total of 36 implanted percutaneous electrodes in his right upper and lower arm to electrically stimulate his hand, elbow, and shoulder muscles. The participant used a motorised mobile arm support for gravitational assistance and to provide humeral abduction and adduction under cortical control. We assessed the participant's ability to cortically command his paralysed arm to perform simple single-joint arm and hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralysed arm with that of a virtual three-dimensional arm. This study is registered with ClinicalTrials.gov, number NCT00912041. The intracortical implant occurred on Dec 1, 2014, and we are continuing to study the participant. The last session included in this report was Nov 7, 2016. The point-to-point target acquisition sessions began on Oct 8, 2015 (311 days after implant). The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80-100% accuracy), using first a virtual arm and second his own arm animated by FES. Using his paralysed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session 463 days after implant) and feed himself (717 days after implant). To our knowledge, this is the first report of a combined implanted FES+iBCI neuroprosthesis for restoring both reaching and grasping movements to people with chronic tetraplegia due to spinal cord injury, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoration of reaching and grasping after paralysis. National Institutes of Health, Department of Veterans Affairs.


An evaluative case study of online learning for healthcare professionals.
This evaluation study assessed the pedagogical and instructional design (e-pedagogy) effectiveness of online continuing professional education (CPE) courses offered by a large Australian CPE provider. A naturalistic theory approach and a multilevel evaluation were used to examine the impact of web-based learning on more than 300 healthcare professionals. Participant satisfaction, learning achievement, self-reported practice performance change, and e-pedagogical courseware characteristics were assessed by various qualitative and quantitative data collection methods. Findings revealed that learning online was an effective means for increasing CPE knowledge (p < .05) and improving self-reported practice performance change (p < .05). Courses containing a clinical tool resulted in an increased self-reported practice performance change over courses that did not (Zobs = 3.757). Online CPE offers a convenient format for healthcare professionals from educationally and geographically diverse populations to update their knowledge and view best practice.


Label-free non-linear microscopy to measure myelin outcome in a rodent model of Charcot-Marie-Tooth diseases.
Myelin sheath produced by Schwann cells covers and nurtures axons to speed up nerve conduction in peripheral nerves. Demyelinating peripheral neuropathies result from the loss of this myelin sheath and so far, no treatment exists to prevent Schwann cell demyelination. One major hurdle to design a therapy for demyelination is the lack of reliable measures to evaluate the outcome of the treatment on peripheral myelin in patients but also in living animal models. Non-linear microscopy techniques which include second harmonic generation (SHG), third harmonic generation (THG) and coherent anti-stokes Raman scattering (CARS) were used to image myelin ex vivo and in vivo in the sciatic nerve of healthy and demyelinating mice and rats. SHG did not label myelin and THG required too much light power to be compatible with live imaging. CARS is the most reliable of these techniques for in vivo imaging and it allows for the analysis and quantification of myelin defects in a rat model of CMT1A disease. This microscopic technique therefore constitutes a promising, reliable and robust readout tool in the development of new treatments for demyelinating peripheral neuropathies.


Dinitrogen Reduction: Interfacing the Enzyme Nitrogenase with Electrodes.
Potential for nitrogenase: Milton, Minteer, and co-workers report the first evidence for the bioelectrochemical reduction of N2 to ammonia by nitrogenase. This complex enzyme could be wired to an electrode by using the soluble mediator methyl viologen; this very simple approach makes it possible to develop a variety of biotechnological devices.


Hetero blood types and breeding performance.
The phenomenon of hybrid vigor apparently depends to some extent upon the degree of diversity between the genes of the two parents. Results are presented which suggest that diversity of cellular antigens might be used as an indicator of general genetic diversity between mates.


[The clinical significance of glycosylated ferritin in iron overloads and hematopoietic malignancies].
Serum ferritin concentration had been known to represent the amount of total body iron and has been clinically used as a parameter to evaluate the iron storage pool in a whole body. Glycosylated (secreted) and non-glycosylated (non-secreted) forms of serum ferritin (sFt) have been reported by others based on the difference in their affinity to concanavalin-A binding. In this report, we assessed the amount of glycosylated serum ferritin (Glyco-sFt) and the ratio (%) of Glyco-sFt/in hematopoietic disorders including iron overloads (n = 10), leukemias (n = 36), malignant lymphomas (n = 10), multiple myelomas (n = 3) and myelodysplastic syndromes (n = 12). A high percentage of Glyco-sFt was observed in normal healthy controls (n = 18, 78.1 +/- 7.4%) and iron-overloads (61.1 +/- 17.8%) as compared with that in hematopoietic malignancies (43.8 +/- 23.4%, p < 0.001). The amount of Glyco-sFt in iron-overloads was higher than that in hematopoietic malignancies with hyperferritinemia (p < 0.005). These data demonstrated that the same part of serum ferritin in hematopoietic malignancies was the non-secreted form and appeared to be derived from tumor cell lysis. We conclude that assessment of Glyco-Ft is a useful parameter to distinguish iron-overloads from malignant hematopoietic disorders both displaying hyperferritinemia.


Measuring inflammatory cell migration in the zebrafish.
A key feature of inflammatory cells is the ability to migrate to a site of injury or infection quickly and efficiently. Infectious agents can then be taken up by these inflammatory cells, preventing established infection. Inflammatory cell migration is driven by a complex interaction between inflammatory cells and their environment. In order to maintain health, inflammation needs to resolve, allowing the surrounding tissues to recover and heal. These processes are not fully understood and have been difficult to study in cell culture due to the complex interactions between cell types. We therefore use a range of techniques in near-transparent zebrafish (Danio rerio) larvae to study these migration events in a whole-organism, in vivo model. Using a transgenic zebrafish line that specifically marks neutrophils with green fluorescent protein, Tg(mpx:GFP)i114, we are able to follow neutrophil behaviour at a single cell level. Using these methods, the cellular processes involved in all phases of inflammation can be studied and better understood.


Assessing innovations: what is the optimal approach for healthcare organizations?
Innovations in healthcare may improve patient outcomes and create economic benefits for healthcare organizations. The information available when an innovation is introduced to the market, however, may be insufficient to provide a compelling rationale for an institution to invest in the innovation. Generating the data required for an effective decision-making process involves assessing current performance indicators for an individual institution and the projected impact of adopting the innovation. The benefits of the innovation are verified after implementation. This article explores some of the issues and processes in evaluating healthcare innovations.


Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene.
A good correlation was observed between enhanced lung cancer risk and restriction fragment length polymorphisms (RFLPs) of the P450IA1 gene with the restriction enzyme MspI. Genotype frequencies of 0.49 for the predominant homozygote, 0.40 for the heterozygote, and 0.11 for the homozygous rare allele were observed in a healthy population. Among lung cancer patients, the frequency of homozygous rare allele of P450IA1 gene was found to be about 3-fold higher than that among healthy population, and this difference was statistically significant. This is the first report to identify the genetically high risk individuals to lung cancer at the gene level.


Vascular response to modified Widman flap surgery in monkeys.
Revascularization of the periodontal tissues was studied after flap surgery. Modified Widman flap procedures were performed in four young Rhesus monkeys. All premolars and molars were involved. Experimental periods covered from 1 day to 90 days. The animals were sacrificed by exsanguination and perfused through the carotid arteries with a combined solution of equal parts of India ink and 10% buffered formalin solution. After fixation and decalcification, part of the blocks were processed to obtain cleared specimens following the Spalteholtz method. The remaining blocks were processed for routine histologic examination. The findings, mainly from the cleared specimens, showed that 1 day after surgery the supraperiosteal vessels in the flap demonstrated an overt hyperemic response. Patency of the vessels in the periodontal membrane and cancellous bone was evident; however, vessels were not depicted in the exposed cortical bone, nor in the clot. Vascular continuity apical to the surgical detachment was observed. In 3 to 4 days vascular proliferation within the organizing clot was observed and anastomosis between the gingiva and cancellous bone or periodontal membrane started to develop. At 7 days anastomoses were evident and vasodilation was present throughout the tissues. At 15 days and thereafter, vascular organization started to decrease, and the only hyperemic foci remaining were associated with areas of delayed bone remodeling, cementum remodeling or persistent marginal inflammation.


Influence of the Treatment of Nonbonded Interactions on the Thermodynamic and Transport Properties of Pure Liquids Calculated Using the 2016H66 Force Field.
The effect of different treatments of the nonbonded interactions in simulations employing the recently introduced GROMOS-compatible 2016H66 force field is evaluated based on calculations carried out with the GROMACS software. This is done considering four thermodynamic and transport properties (pure liquid density, vaporization enthalpy, surface-tension coefficient, and self-diffusion constant) of 58 organic liquids representative of the chemical groups alcohol, ether, aldehyde, ketone, carboxylic acid, ester, amine, amide, thiol, sulfide, disulfide, and aromatic compounds, also including water (SPC model). A dipalmitoylphosphatidylcholine bilayer system is considered as well. The simulated properties are found to be very sensitive to the treatment of the long-range dispersion interactions, notably for the least polar systems. In general, the treatment of the long-range electrostatic or Lennard-Jones interactions using homogeneous correction terms or lattice-sum approaches yield similar results, with punctual discrepancies. The combination of a lattice-sum approach for the electrostatic interactions with a straight-cutoff truncation of the Lennard-Jones interactions at a distance of at least 1.2 nm is found to represent a good compromise setup within GROMACS for achieving compatibility with the reference results obtained using GROMOS as well as a comparable level of agreement with the experimental data. This study also reveals two potential issues with the GROMACS software, related to an incorrect calculation of the pressure when using LINCS in version 4.0.7 and an inadequate implementation of the twin-range scheme in version 5.1.2.


Optimal ventricular pacing rate in fetal lambs with complete atrioventricular block.
This study was undertaken to determine the optimum ventricular pacing rate at which the optimal cardiac function can be attained in fetal lambs with complete atrioventricular block. Complete atrioventricular block was created by cryosurgery in 12 fetal lambs, and the ventricle was paced randomly at rates of 60, 90, 120, 150, 180, 210, 240, and 270 beats/min. The aortic pressure, central venous pressure, and right ventricular cardiac output were measured before cryosurgery and during ventricular pacing. Complete atrioventricular block was created in 9 of 12 fetal lambs. Systolic aortic pressure significantly decreased at pacing rates of 60, 90 and 240 beats/min (P <.01), and central venous pressure was increased significantly at a pacing rate of 60 beats/min (P <.01) compared with the control. Right ventricular cardiac output significantly decreased at pacing rates of 60, 90, 120, 180, 210, 240, and 270 beats/min (P <.01), although no significant difference was found at the pacing rate of 150 beats/min compared with control. Ventricular pacing at a rate of 150 beats/min gave the highest aortic pressure, the lowest central venous pressure, and the highest right ventricular cardiac output in fetal lambs with complete atrioventricular block.


Acromegaly in Carney complex.
Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by mucocutaneous pigmentation, cardiac, cutaneous myxomas and endocrine overactivity. It is generally caused by inactivating mutations in the PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) gene. Acromegaly is an infrequent manifestation of CNC, reportedly diagnosed in 10% of patients. We here report the case of a patient who was concomitantly diagnosed with Carney complex, due to a new mutation in PRKAR1A ((NM_002734.3:c.80_83del, p.(Ile27Lysfs*101 in exon 2), and acromegaly. In parallel, we conducted an extensive review of published case reports of acromegaly in the setting of CNC. The 43-year-old patient was diagnosed with an acromegaly due to a GH-secreting pituitary microadenoma resistant to somatostatin analogs. He underwent transsphenoidal surgery in our tertiary referral center, which found a pure GH-secreting adenoma. In the literature, we identified 57 cases (24 men, 33 women) of acromegaly in CNC patients. The median age at diagnosis was 28.8 ± 12 year and there were 6 cases of gigantism. Acromegaly revealed CNC in only 4 patients. 24 patients had a microadenoma and two carried pituitary hyperplasia and/or multiple adenomas, suggesting that CNC may result in a higher proportion of microadenoma as compared to non-CNC acromegaly. Although it rarely reveals CNC, acromegaly is diagnosed at a younger age in this setting, with a higher proportion of microadenomas.


Changes in the Serum Hepcidin-to-ferritin Ratio with Erythroferrone after Hepatitis C Virus Eradication Using Direct-acting Antiviral Agents.
Objective Hepcidin is a master iron regulator hormone produced by the liver, but precise mechanism underlying its involvement in iron overload in hepatitis C virus (HCV) infection remains unclear. We investigated the serum hepcidin levels against iron overload before and after HCV eradication. Methods We prospectively investigated the iron metabolism characteristics in 24 patients with HCV genotype 1b infection before and after treatment. We also assessed the serum erythroferrone (ERFE) levels to investigate its association with iron metabolism changes. Patients were treated with Ledipasvir 90 mg and Sofosbuvir 400 mg once daily for 12 weeks and observed for 12 more weeks in order to evaluate their sustained virological response. Results Serum hepcidin levels at baseline were in the normal range, although serum ferritin levels were increased. After HCV eradication, both serum ferritin and hepcidin levels were significantly decreased at 24 weeks from baseline (p<0.001, p=0.006, respectively). However, the serum hepcidin-to-ferritin ratios were significantly increased (p<0.001). In addition, the serum ERFE levels were significantly decreased (p<0.001). Increases in the serum hepcidin-to-ferritin ratios were correlated with decreases in the serum ERFE levels (ρ=-0.422, p=0.039). Conclusion Serum hepcidin levels were relatively low against ferritin levels in HCV infection. However, after HCV eradication, the serum hepcidin-to-ferritin ratios were increased. These results indicate the improvement of inadequate hepcidin secretion against iron overload after HCV eradication. Downregulation of ERFE may have affected the improvement of iron metabolism.


The vagus.
The surgical physiology of the vagus is reviewed with respect to vagotomy in the treatment of duodenal ulcer. All types of vagotomy (truncal, selective gastric, or proximal gastric) produce similar reduction in acid secretion and comparable elevation in serum gastrin. The evidence is mounting that the vagus may have opposing influences on gastrin release: stimulation and inhibition. Division of only the extragastric vagal branches leads to withdrawal of an inhibitory mechanism rendering the denervated stomach more sensitive to the action of gastrin. The loss of this vagally controlled inhibitory mechanism, rather than more meticulous dissection, may explain the higher incidence of more complete vagotomies in selective than in truncal vagotomy. Proximal gastric vagotomy may be the ideal elective operation yet devised for duodenal ulcer. It does, however, cause elevation in serum gastrin and more than 90 per cent of patients after this operation will have positive insulin test in two to four years. This is higher than the positivity seen with truncal vagotomy. Results of controlled trials are needed before this operation becomes fully established.


Polyphenol estimated intake and dietary sources among older adults from Mallorca Island.
The aim was the assessment of the polyphenol estimated intake and dietary sources among older adults from Mallorca Island. The study was carried out (2013-2014) in 211 participants dwelling women (n = 112) and men (n = 99). Polyphenol intake was calculated from two non-consecutive 24-h recall diets using the Polyphenol Explorer. The mean daily intake of polyphenol was 332.7 mg/d (SD: 237.9; median: 299 mg/d). Highest polyphenol intake was observed among females, 64-67 y.o. people, higher income and educational level, alcohol consumers, and physically active people. Most polyphenols consumed were flavonoids, and among them the major subclass was flavanols. Alcoholic beverages were the major contributors to the total polyphenol intake (118.3 mg/d, SD: 127.5), and red wine contributed 17.7% of total polyphenols consumed. Polyphenol intake was highest among alcohol drinkers, high educational level, high income, and physical active people. Flavonoids were the highest ingested polyphenols. Alcoholic beverages were the major contributors to the total polyphenol intake, mainly red wine.


New fluorimetric determination of hemoglobin used as a substitute of mimietic peroxidase.
Hemoglobin (Hb) could be used as a substitute of peroxidase in the catalytic oxidation of tetra-substituted amino aluminum phthalocyanine (TAA1Pc) by H2O2. We found that the fluorescence of TAA1Pc (a red-region fluorescent dye with a maximum excitation wavelength at 606 nm and a maximum emission wavelength at 673 nm) could significantly be quenched by H2O2 in the presence of Hb. The value of F0/F (where the relative fluorescence intensity of blank solution and that of the sample solution containing Hb were given by F0 and F, respectively) is linearly related to the concentration of Hb. Based on this, a novel fluorimetric method was developed for the determination of Hb in aqueous solution. Under optimal conditions, Hb could be determined in the concentration range of 5 x 10(-11) - 12 x 10(-8) mol L(-1) with a detection limit of 1.5 x10(-11) mol L(-1). The relative standard deviation of ten replicate measurements was 1.95% for solution containing 1 x10(-9 ) mol L(-1) Hb. The proposed method has been applied to the analysis of Hb in human blood and the results were in good agreement with those reported by a hospital laboratory. So this is a new, high sensitive and precise fluorescence quenching method to determine Hb.


Direct observations of muscle arterioles and venules following contraction of skeletal muscle fibres in the rat.
Direct observations have been made of responses of individual arterioles and venules of rat spinotrapezius muscle to contraction of the skeletal muscle fibres. Stimuli of 4-6 V intensity, 0.1 ms duration, delivered via a micro-electrode inserted into the spinotrapezius, evoked contraction of a small bundle of skeletal muscle fibres, followed by vasodilatation which was limited to all those arterioles and venules which crossed or ran alongside activated muscle fibres. Since venules outside the region of contraction, but supplied by dilating arterioles, were not passively distended by the attendant rise in intravascular pressure, it is concluded that both the arterioles and venules dilated actively in response to muscle contraction. All arterioles responded to a single twitch contraction, the terminal arterioles (7-13 micron i.d.) showing the largest increase in diameter. Collecting venules (9-18 micron i.d.) responded to just two twitches in 1 s and larger venules to five twitches in 1 s. When twitch contractions were continuously evoked for 10 s, the responses in individual arterioles and venules were graded with twitch frequency, the fastest and largest response occurring at 6-8 Hz. Tetanic contraction, at 40 Hz for 1 s, produced faster responses in all vessels, a maximum 55% increase from resting internal diameter being attained in only 8 s in some terminal arterioles. In all vessels the responses to tetanic contraction were equal to the maximal dilatation induced by papaverine. These results, in contrast with conclusions drawn from indirect estimates of venous responses, show that venules, like arterioles, dilate actively in response to muscle contraction. Venule dilatation may reduce the rise in capillary hydrostatic pressure, thereby limiting the outward filtration of fluid.


Frequency Of Undiagnosed Chronic Obstructive Pulmonary Disease In Patients With Coronary Artery Disease.
Chronic obstructive airway disease (COPD) is considered as risk factor for coronary artery disease (CAD) along with other risk factors. This study was conducted to determine the frequency of undiagnosed chronic obstructive pulmonary disease in patients with coronary artery disease. This cross-sectional study was conducted in the Pulmonology and Cardiology wards/OPD's of Khyber Teaching Hospital Peshawar. Patients more than 35 years of age, diagnosed with CAD of either gender were included. Patients already diagnosed with COPD, recent myocardial infarction (within 7 days), left ventricular impairment, pneumothorax, bronchiectasis, comatose patient, asthmatic and those with chest trauma were excluded. All the patients underwent spirometry examination before and after administration of salbutamol (5 mg for 5 minutes) via nebulizer. FEV1/FVC less than 70% confirmed the presence of COPD. Out of 151 patients, 57 (37.7%) were found to have COPD. Among them, 39 (68.42%) were male and 18 (31.57%) were female. Among male patients with COPD, 82.05% (n=32) were smokers and 17.94% (n=7) were nonsmokers while in females with COPD no one was smoker. COPD is an under-diagnosed progressive disease in patients with high risk patients with coronary artery disease.


Clinical and Demographic Factors Associated With Receipt of Non Guideline-concordant Initial Therapy for Nonmetastatic Prostate Cancer.
To determine the extent to which initial therapy for nonmetastatic prostate cancer was concordant with nationally recognized guidelines using supplemented cancer registry data and what factors were associated with receipt of nonguideline-concordant care. Initial therapy for 8229 nonmetastatic prostate cancer cases diagnosed in 2004 from cancer registries in 7 states was abstracted as part of the Centers for Disease Control's Patterns of Care Breast and Prostate Cancer study conducted during 2007 to 2009. The National Comprehensive Cancer Network clinical practice guidelines version 1.2002 was used as the standard of care based on recurrence risk group and life expectancy (LE). A multivariable model was used to determine risk factors associated with receipt of nonguideline-concordant care. Nearly 80% with nonmetastatic prostate cancer received guideline-concordant care for initial therapy. Receipt of nonguideline-concordant care (including receiving either less aggressive therapy or more aggressive therapy than indicated) was related to older age, African American race/ethnicity, being unmarried, rural residence, and especially to being in the high recurrence risk group where receiving less aggressive therapy than indicated occurred more often than receiving more aggressive therapy (adjusted OR=4.2; 95% CL, 3.5-5.2 vs. low-risk group). Compared with life table estimates adjusted for comorbidity, physicians tended to underestimate LE. Receipt of less aggressive therapy than indicated among high-risk group men with >5-year LE based on life table estimates adjusted for comorbidity was a concern. Physicians may tend to underestimate 5-year survival among this group and should be alerted to the importance of recommending aggressive therapy when warranted. However, based on more recent guidelines, among those with low-risk disease, the proportion considered to be receiving less aggressive therapy than indicated may now be lower because active surveillance is now considered appropriate.


Adsorption properties and vibrational spectra of propyne adsorbed on Rh(111). Comparison with other (111) metal surfaces.
We have studied the adsorption properties of propyne on the Rh(111) surface by means of the generalized gradient approach of density functional theory using periodic slab models. The simulation of the vibrational spectra has permitted us to corroborate and complete the experimental band assignment and to confirm the adsorption site preference. Propyne prefers to sit on a 3-fold hollow site, with the C[triple bond]C axis parallel to a Rh-Rh bond and the molecular plane tilted away from the surface normal. The comparison between the adsorption behaviour of propyne on Rh(111) and on other (111) metal surfaces allows one to provide an explanation for the different reactivity observed experimentally.


Five-Year Follow-up of a Coronally Advanced Flap Over Grafted Bone and Restorative Composite in Maxillary Recession Defect.
Periodontal plastic surgery has become a predictable method of managing gingival recession defects. In the current case report, a five-year follow-up of a coronally advanced flap surgery with bone graft along with endodontics and fixed prosthodontic rehabilitation is reported in the maxillary anterior sextant of a middle aged female. The present case demonstrates that deep and wide gingival defects can be treated with coronally positioned surgical flap without a connective tissue graft. Amultidisciplinary management approach was adopted in this case that yielded predictable outcome.


Methane, arsenic, selenium and the origins of the DMSO reductase family.
Mononuclear molybdoenzymes of the dimethyl sulfoxide reductase (DMSOR) family catalyze a number of reactions essential to the carbon, nitrogen, sulfur, arsenic, and selenium biogeochemical cycles. These enzymes are also ancient, with many lineages likely predating the divergence of the last universal common ancestor into the Bacteria and Archaea domains. We have constructed rooted phylogenies for over 1,550 representatives of the DMSOR family using maximum likelihood methods to investigate the evolution of the arsenic biogeochemical cycle. The phylogenetic analysis provides compelling evidence that formylmethanofuran dehydrogenase B subunits, which catalyze the reduction of CO2 to formate during hydrogenotrophic methanogenesis, constitutes the most ancient lineage. Our analysis also provides robust support for selenocysteine as the ancestral ligand for the Mo/W atom. Finally, we demonstrate that anaerobic arsenite oxidase and respiratory arsenate reductase catalytic subunits represent a more ancient lineage of DMSORs compared to aerobic arsenite oxidase catalytic subunits, which evolved from the assimilatory nitrate reductase lineage. This provides substantial support for an active arsenic biogeochemical cycle on the anoxic Archean Earth. Our work emphasizes that the use of chalcophilic elements as substrates as well as the Mo/W ligand in DMSORs has indelibly shaped the diversification of these enzymes through deep time.


Quantitative GSL-glycome analysis of human whole serum based on an EGCase digestion and glycoblotting method.
Glycosphingolipids (GSLs) are lipid molecules linked to carbohydrate units that form the plasma membrane lipid raft, which is clustered with sphingolipids, sterols, and specific proteins, and thereby contributes to membrane physical properties and specific recognition sites for various biological events. These bioactive GSL molecules consequently affect the pathophysiology and pathogenesis of various diseases. Thus, altered expression of GSLs in various diseases may be of importance for disease-related biomarker discovery. However, analysis of GSLs in blood is particularly challenging because GSLs are present at extremely low concentrations in serum/plasma. In this study, we established absolute GSL-glycan analysis of human serum based on endoglycoceramidase digestion and glycoblotting purification. We established two sample preparation protocols, one with and the other without GSL extraction using chloroform/methanol. Similar amounts of GSL-glycans were recovered with the two protocols. Both protocols permitted absolute quantitation of GSL-glycans using as little as 20 μl of serum. Using 10 healthy human serum samples, up to 42 signals corresponding to GSL-glycan compositions could be quantitatively detected, and the total serum GSL-glycan concentration was calculated to be 12.1-21.4 μM. We further applied this method to TLC-prefractionated serum samples. These findings will assist the discovery of disease-related biomarkers by serum GSL-glycomics.


Nectar-living yeasts of a tropical host plant community: diversity and effects on community-wide floral nectar traits.
We characterize the diversity of nectar-living yeasts of a tropical host plant community at different hierarchical sampling levels, measure the associations between yeasts and nectariferous plants, and measure the effect of yeasts on nectar traits. Using a series of hierarchically nested sampling units, we extracted nectar from an assemblage of host plants that were representative of the diversity of life forms, flower shapes, and pollinator types in the tropical area of Yucatan, Mexico. Yeasts were isolated from single nectar samples; their DNA was identified, the yeast cell density was estimated, and the sugar composition and concentration of nectar were quantified using HPLC. In contrast to previous studies from temperate regions, the diversity of nectar-living yeasts in the plant community was characterized by a relatively high number of equally common species with low dominance. Analyses predict highly diverse nectar yeast communities in a relatively narrow range of tropical vegetation, suggesting that the diversity of yeasts will increase as the number of sampling units increases at the level of the species, genera, and botanical families of the hosts. Significant associations between specific yeast species and host plants were also detected; the interaction between yeasts and host plants impacted the effect of yeast cell density on nectar sugars. This study provides an overall picture of the diversity of nectar-living yeasts in tropical host plants and suggests that the key factor that affects the community-wide patterns of nectar traits is not nectar chemistry, but rather the type of yeasts interacting with host plants.


The Impact of Psychological Contract, Physical and Mental Health on Burnout in Grassroots Civil Servants: Evidence from China.
The report of the 20th Party Congress proposes to build a high-quality cadre capable of taking on the important task of national rejuvenation. Grassroots civil servants are facing great pressure and challenges, and alleviating burnout has become an important issue in the construction of grassroots civil servants. Empirically analysing the impact of psychological contract on burnout of grassroots civil servants in the Chinese context will help to build a high-quality grassroots civil service team. Using a sample of 1824 grassroots civil servants in China, this study empirically examined the effect of the psychological contract on burnout among grassroots civil servants using the OLS methodology, conducted a robustness test by way of substituting variables and research methods, and then discussed the mediating effect of physical and mental health in the psychological contract and burnout among grassroots civil servants. The study showed that grassroots civil servants' psychological contract had a significant negative impact on burnout; transactional psychological contract was positively related to burnout, and relational and developmental psychological contracts were negatively related to burnout in grassroots civil servants. The results of the heterogeneity analysis showed that the effect of psychological contract on burnout differed by age, gender, exercise frequency, and sleep status. The results of the mediation analysis showed that higher psychological contract scores were related to better physical and mental health, thus inhibiting burnout among grassroots civil servants. This indicates a significant mediation effect of physical and mental health in the relationship between psychological contract and burnout of grassroots civil servants. The psychological contract of grassroots civil servants has a significant negative effect on burnout, and physical and mental health mediate between the two. These conclusions are of great theoretical and practical significance for alleviating the stress of grassroots civil servants and improving their work performance.


Tumor metabolism: cancer cells give and take lactate.
Tumors contain well-oxygenated (aerobic) and poorly oxygenated (hypoxic) regions, which were thought to utilize glucose for oxidative and glycolytic metabolism, respectively. In this issue of the JCI, Sonveaux et al. show that human cancer cells cultured under hypoxic conditions convert glucose to lactate and extrude it, whereas aerobic cancer cells take up lactate via monocarboxylate transporter 1 (MCT1) and utilize it for oxidative phosphorylation (see the related article beginning on page 3930). When MCT1 is inhibited, aerobic cancer cells take up glucose rather than lactate, and hypoxic cancer cells die due to glucose deprivation. Treatment of tumor-bearing mice with an inhibitor of MCT1 retarded tumor growth. MCT1 expression was detected exclusively in nonhypoxic regions of human cancer biopsy samples, and in combination, these data suggest that MCT1 inhibition holds potential as a novel cancer therapy.


A new protocol to accurately determine microtubule lattice seam location.
Microtubules (MTs) are cylindrical polymers of αβ-tubulin that display pseudo-helical symmetry due to the presence of a lattice seam of heterologous lateral contacts. The structural similarity between α- and β-tubulin makes it difficult to computationally distinguish them in the noisy cryo-EM images, unless a marker protein for the tubulin dimer, such as kinesin motor domain, is present. We have developed a new data processing protocol that can accurately determine αβ-tubulin register and seam location for MT segments. Our strategy can deal with difficult situations, where the marker protein is relatively small or the decoration of marker protein is sparse. Using this new seam-search protocol, combined with movie processing for data from a direct electron detection camera, we were able to determine the cryo-EM structures of MT at 3.5 Å resolution in different functional states. The successful distinction of α- and β-tubulin allowed us to visualize the nucleotide state at the E-site and the configuration of lateral contacts at the seam.


[Assessment of the hygienic and sanitary conditions of housing in a sample in Chieti (central Italy)].
The study describes the housing conditions of 106 dwellings in the town of Chieti (Abruzzo region, central Italy), inspected by Local Health Authority, in the period between the 1st of January 2009 and the 28th of February 2011. In 59.4% of them lived Italians, while in the remaining 40.6% lived foreigners. 35.8% of the houses met minimum law requirements, 24.5% were anti-hygienic, 24.5% anti-hygienic and overcrowded, 13.2% overcrowded, 1.9% uninhabitable. The main issues were moisture and molds (52.8%). The second one was the inadequacy of floor area in relation with inhabitants (37.7%). Other problems were bedrooms (9.4%), baths (8.5%) and kitchens not complying minimum law requirements, but also not sufficient both ceiling hights (3.7%) and windows (2.8%) of rooms. Considering that human population in richest countries spend up to 90% of their lives in indoor environment, especially at home, the links between housing and health are really strong, and more must be done to improve general consideration of these themes both in general population and involved professionists (i.e. physicians, other health professionists, social workers, architects and engineers).


Fungal Endophthalmitis Masquerading as Sympathetic Ophthalmia.
To describe the ocular pathology of a patient with fungal endophthalmitis with features mimicking sympathetic ophthalmia. Review of medical records and histopathology of a single patient. A 72-year-old male who sustained penetrating injury to the left eye with an agave plant presented to our clinic 16 months after the initial injury. Prior to presentation, the patient had developed endophthalmitis and had undergone anterior chamber washout, vitrectomy, and intravitreal steroids, antibiotics, antifungals, and anti-vascular endothelial growth factor (VEGF) therapy. At presentation, the patient had a blind, painful eye and subsequently underwent enucleation. Histopathology demonstrated granulomatous inflammation with multinucleated giant cells in the iris and Dalen Fuchs nodules with CD68 positive epithelioid histiocytes associated with the retinal pigment epithelium (RPE) sparing the choriocapillaris. These findings were initially attributed to sympathetic ophthalmia. The fellow eye did not have any signs of inflammation, and additional fungal PAS stains were positive for filamentous fungal elements, leading to a diagnosis of fungal endophthalmitis. Fungal endophthalmitis may develop histopathologic features that are similar to those seen in sympathetic ophthalmia. Recognition of the overlap between the histopathologic features of these diseases may reduce the possibility of misdiagnosis and unnecessary treatment of the fellow eye.


Progesterone receptor gene variants and risk of endometrial cancer.
Prolonged excessive estrogen exposure unopposed by progesterone is widely accepted to be a risk factor for endometrial cancer development. The physiological function of progesterone is dependent upon the presence of its receptor [progesterone receptor (PGR)] and several studies have reported single nucleotide polymorphisms (SNPs) in the PGR gene to be associated with endometrial cancer risk. We sought to confirm the associations with endometrial cancer risk previously reported for four different PGR polymorphisms. A maximum of 2888 endometrial cancer cases and 4483 female control subjects from up to three studies were genotyped for four PGR polymorphisms (rs1042838, rs10895068, rs11224561 and rs471767). Logistic regression with adjustment for age, study, ethnicity and body mass index was performed to calculate odds ratios (ORs) and associated 95% confidence intervals (CIs) and P-values. Of the four SNPs investigated, only rs11224561 in the 3' region of the PGR gene was found to be significantly associated with endometrial cancer risk. The A allele of the rs11224561 SNP was associated with increased risk of endometrial cancer (OR per allele 1.31; 95% CI 1.12-1.53, P = 0.001, adjusted for age and study), an effect of the same magnitude and direction as reported previously. We have validated the endometrial cancer risk association with a tagSNP in the 3' untranslated region of PGR previously reported in an Asian population. Replication studies will be required to refine the risk estimate and to establish if this, or a correlated SNP, is the underlying causative variant.


Relationship between pressure-rate product and myocardial oxygen consumption of normal and hypertrophic right ventricles in open-chest dogs.
There are few reports on the relationship between right ventricular performance and its myocardial oxygen consumption (RVMVO2). The present study was conducted to investigate the relationship between RVMVO2 and the mechanical performance of normal and hypertrophic right ventricles in open-chest dogs. Right ventricular hypertrophy (RVH) was induced by producing chronic right ventricular pressure overload by banding the pulmonary arteries of 8 puppies for 6 months. The experiment was performed under basal conditions and after increasing the RVMVO2 in the eight dogs with RVH as well as in 20 normal dogs. The RVMVO2 showed significant positive relationships with right coronary (RCA) flow, right ventricular systolic pressure, and right ventricular pressure-rate product (PRP) in both the normal right ventricle and RVH hearts. However, the slope between the PRP and RVMVO2 was significantly steeper in the normal right ventricle (RV) than in the hypertrophic RV. When the PRP was normalized for the thickness of the right ventricular free wall, the slope of the two regression lines merged into a single line of fit. These results suggest that the pressure-rate product can be used to predict myocardial oxygen demand not only in the normal RV but also in well-compensated, hypertrophic RV. Isoproterenol induced smaller increases in cardiac output in the dogs with RVH than in those with normal RV. It also appears that the cardiac output of the hypertrophic RV is less sensitive to beta-adrenoceptor stimulation than that of the normal RV.


E7 oncoprotein of human papillomavirus type 16 expressed constitutively in the epidermis has no effect on E7-specific B- or Th-repertoires or on the immune response induced or sustained after immunization with E7 protein.
A line of FVB (H-2q) mice transgenic for the E6/E7 open reading frames of Human Papillomavirus type 16 driven from the alpha-A crystallin promoter expresses E7 mRNA in lens and skin epithelium. E7 protein is detectable in adult skin, coinciding with the development of inflammatory skin disease, which progresses to papillomata and squamous carcinomata in some mice. By examining the outcome of parenteral immunization with E7 protein, we sought to determine whether endogenous expression of E7 in skin had induced a preexisting immune outcome, i.e., specific immunity or tolerance, or whether the mice remain naive ("ignorant") to E7. Our data show that the antibody response to defined E7 B-epitopes, the proliferative response to Th epitopes, and the delayed-type hypersensitivity (DTH) response to whole E7 did not differ between groups of young and old E6/E7 transgenic mice (likely having different degrees of lifetime exposure to E7 protein) or between E6/E7-transgenic and nontransgenic parental strain control mice. Although an E7-specific CTL response could not be induced in the H-2q background of these mice, incorporation of a Db allele into the genome allowed comparison of Db-restricted CTL responses in E6/E7 transgenic and nontransgenic mice. Experiments indicated that the E7-immunization-induced CTL response did not differ significantly between E6/E7 transgenic and nontransgenic mice. We interpret these results to indicate that in spite of expression of E7 protein in adult skin, E6/E7 transgenic mice remain immunologically naive (ignorant) of E7 epitopes presented by immunization.


Compensatory growth in runt pigs is not mediated by insulin-like growth factor I.
Runt pigs grow more slowly and never reach the same body weight as age-matched littermates. We hypothesized that IGF-I would be reduced in the runts and that postnatal nutrition would alter IGF-I concentration and tissue expression. Runt and control littermates were removed from 20 crossbred sows 20 to 28 h after birth. Tissues were collected from a baseline group (n = 4). The remaining pigs were fed porcine milk replacer at either 70 or 120 g/kg BW for 14 d (n = 8). Feed intake and body weight were measured daily, with plasma samples collected by jugular venipuncture throughout the experiment. Expression of IGF-I mRNA was measured in the liver and gastrocnemius with an RNase protection assay. At d 0, runts were significantly smaller than controls in all measurements, except brain weight. During the 14 d, the relative rate of growth was significantly faster and more efficient in runts than in controls; however, runts never attained the same absolute body weight as controls. Circulating IGF-I was significantly reduced at d 0 but was similar to that in controls by d 2 of feeding. The IGF-I mRNA expression in liver or gastrocnemius muscle was not different between control and runts at d 0 or 14 and was not affected by dietary intake. This study has shown that runt pigs grow in a compensatory manner for at least the first 2 wk of life. However, this growth response does not seem to be mediated by IGF-I.


IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning.
During social transmission of food preference (STFP), mice form long-term memory of food odors presented by a social partner. How does the brain associate a social context with odor signals to promote memory encoding? Here we show that odor exposure during STFP, but not unconditioned odor exposure, induces glomerulus-specific long-term potentiation (LTP) of synaptic strength selectively at the GABAergic component of dendrodendritic synapses of granule and mitral cells in the olfactory bulb. Conditional deletion of synaptotagmin-10, the Ca2+ sensor for IGF1 secretion from mitral cells, or deletion of IGF1 receptor in the olfactory bulb prevented the socially relevant GABAergic LTP and impaired memory formation after STFP. Conversely, the addition of IGF1 to acute olfactory bulb slices elicited the GABAergic LTP in mitral cells by enhancing postsynaptic GABA receptor responses. Thus, our data reveal a synaptic substrate for a socially conditioned long-term memory that operates at the level of the initial processing of sensory information.


Water fluoridation and the association of sugar-sweetened beverage consumption and dental caries in Australian children.
We examined demographic and socioeconomic differences in the consumption of sugar-sweetened beverages (SSBs), its association with dental caries in children, and whether exposure to water fluoridation modifies this association. In a cross-sectional study, we used a stratified, clustered sampling design to obtain information on 16 508 children aged 5 to 16 years enrolled in Australian school dental services in 2002 to 2005. Dental staff assessed dental caries, and parents completed a questionnaire about their child's residential history, sources of drinking water, toothbrushing frequency, socioeconomic status (SES), and SSB consumption. Children who brushed their teeth less often and were older, male, of low SES, from rural or remote areas consumed significantly more SSBs. Caries was significantly associated with greater SSB consumption after controlling for potential confounders. Finally, greater exposure to fluoridated water significantly reduced the association between children's SSB consumption and dental caries. Consumption of SSBs should be considered a major risk factor for dental caries. However, increased exposure to fluoridated public water helped ameliorate the association between SSB consumption and dental decay. These results reconfirm the benefits of community water fluoridation for oral health.


Electrochemical oxidation of trace organic contaminants in reverse osmosis concentrate using RuO2/IrO2-coated titanium anodes.
During membrane treatment of secondary effluent from wastewater treatment plants, a reverse osmosis concentrate (ROC) containing trace organic contaminants is generated. As the latter are of concern, effective and economic treatment methods are required. Here, we investigated electrochemical oxidation of ROC using Ti/Ru(0.7)Ir(0.3)O(2) electrodes, focussing on the removal of dissolved organic carbon (DOC), specific ultra-violet absorbance at 254 nm (SUVA(254)), and 28 pharmaceuticals and pesticides frequently encountered in secondary treated effluents. The experiments were conducted in a continuously fed reactor at current densities (J) ranging from 1 to 250 A m(-2) anode, and a batch reactor at J = 250 A m(-2). Higher mineralization efficiency was observed during batch oxidation (e.g. 25.1 ± 2.7% DOC removal vs 0% removal in the continuous reactor after applying specific electrical charge, Q = 437.0 A h m(-3) ROC), indicating that DOC removal is depending on indirect oxidation by electrogenerated oxidants that accumulate in the bulk liquid. An initial increase and subsequent slow decrease in SUVA(254) during batch mode suggests the introduction of auxochrome substituents (e.g. -Cl, NH(2)Cl, -Br, and -OH) into the aromatic compounds. Contrarily, in the continuous reactor ring-cleaving oxidation products were generated, and SUVA(254) removal correlated with applied charge. Furthermore, 20 of the target pharmaceuticals and pesticides completely disappeared in both the continuous and batch experiments when applying J ≥ 150 A m(-2) (i.e. Q ≥ 461.5 A h m(-3)) and 437.0 A h m(-3) (J = 250 A m(-2)), respectively. Compounds that were more persistent during continuous oxidation were characterized by the presence of electrophilic groups on the aromatic ring (e.g. triclopyr) or by the absence of stronger nucleophilic substituents (e.g. ibuprofen). These pollutants were oxidized when applying higher specific electrical charge in batch mode (i.e. 1.45 kA h m(-3) ROC). However, baseline toxicity as determined by Vibrio fischeri bioluminescence inhibition tests (Microtox) was increasing with higher applied charge during batch and continuous oxidation, indicating the formation of toxic oxidation products, possibly chlorinated and brominated organic compounds.


[SMALL BOWELL LIPOMA CAUSING INTUSSUSCEPTION IN AN ADULT]
Primary or metastatic neoplasms of the small bowel are rare. The most common cause of intestinal intussusceptionin adults are tumors of the small bowel. The intraluminal lesion alters the normal peristalsis of the intestine and permits the displacement of the proximal intestine to the interior of a segment of the distal intestine generally fixed. The preoperative diagnosis is difficult and computed tomography and intestinal barium are the most useful studies in order to define this entity. The management is surgical and consists in the reduction of the affected segment and the surgical resection with margin of mesentery. The prognosis correlates with the result of the histopathological study of the original tumor. The present study analyzes a case of lipoma of small bowel causing intussusception and intestinal occlusion. At laparotomy an ileocecal intussusception caused by an intraluminal tumor in the terminal ileon was evidenced, performing right hemicolectomy and end- to- end ileotransverse colostomy. The microscopic study revealed a lipoma of ileum.


Central pancreatectomy: an oncologically safe option to treat metastases of other neoplasms of the mid-portion of the pancreas?
Standard pancreatic resections are the current approach for patients with resectable, isolated pancreatic metastases of other neoplasms. However, the role of parenchyma-sparing pancreatectomies for such pathology is poorly investigated. The aim of the present study is to assess the oncological safety of central pancreatectomies for pancreatic metastases of other neoplasms. A literature search was performed in order to identify patients with central pancreatectomies for pancreatic metastases of other neoplasms. The available data of the patients were extracted and analyzed. A total number of 16 patients were identified. Renal carcinoma was the primary origin for the largest number of these patients (11 patients - 69%). The mean overall survival time was 109 months, with 1-, 5- and 10-year survival rates of 100%, 84%, and 60%, respectively. Although not often performed, a central pancreatectomy appears to be an oncologically safe surgical procedure in select patients with pancreatic metastases of other neoplasms of the pancreatic body and isthmus. However, no definitive conclusions should be drawn, based on the data provided in the present study, due to the limited number and heterogeneity of the patients.


The heritage of Bernardino Ramazzini.
Although the seminal work in what was to become the specialty of occupational medicine appeared in 1700 as written by the Italian physician, Bernardino Ramazzini and titled De Morbis Artificum Diatriba, it was through the English translation by Wilmer Cave Wright in 1940 and and the subsequent scholarship of Dr Pericle Di Pietro of Modena, Italy, that this monograph became widely known. Ramazzini has been cited by innumerable medical authors and his volume has undergone many translations from the mid-18th century to the present day. References to this early observations of persons and work and their subsequent disease patterns repeatedly infuse today's description of work-related illness. That his pioneering efforts continue to receive adulation is seen in the organizations bearing his name, many eponymous awards, the striking Ramazzini Hall in Japan, and the continuing appearance of new reprintings of Diseases of Workers world-wide. The name Ramazzini marks the beginning of society's concern with the well-being and physical and emotional health of its workers from the shops of the crafts to the offices of the executives.


Interference by new-generation mobile phones on critical care medical equipment.
The aim of the study was to assess and classify incidents of electromagnetic interference (EMI) by second-generation and third-generation mobile phones on critical care medical equipment. EMI was assessed with two General Packet Radio Service (GPRS) signals (900 MHz, 2 W, two different time-slot occupations) and one Universal Mobile Telecommunications System (UMTS) signal (1,947.2 MHz, 0.2 W), corresponding to maximal transmit performance of mobile phones in daily practice, generated under controlled conditions in the proximity of 61 medical devices. Incidents of EMI were classified in accordance with an adjusted critical care event scale. A total of 61 medical devices in 17 categories (27 different manufacturers) were tested and demonstrated 48 incidents in 26 devices (43%); 16 (33%) were classified as hazardous, 20 (42%) as significant and 12 (25%) as light. The GPRS-1 signal induced the most EMI incidents (41%), the GRPS-2 signal induced fewer (25%) and the UMTS signal induced the least (13%; P < 0.001). The median distance between antenna and medical device for EMI incidents was 3 cm (range 0.1 to 500 cm). One hazardous incident occurred beyond 100 cm (in a ventilator with GRPS-1 signal at 300 cm). Critical care equipment is vulnerable to EMI by new-generation wireless telecommunication technologies with median distances of about 3 cm. The policy to keep mobile phones '1 meter' from the critical care bedside in combination with easily accessed areas of unrestricted use still seems warranted.


Localisation of GABA(A) receptor epsilon-subunit in cholinergic and aminergic neurones and evidence for co-distribution with the theta-subunit in rat brain.
In situ hybridisation and immunohistochemical methodologies suggest the existence of a large diversity of GABA(A) receptor subtypes in the brain. These are hetero-oligomeric proteins modulated by a number of clinically important drugs, depending on their subunit composition. We recently cloned and localised the rat GABA(A) receptor epsilon-subunit by in situ hybridisation and immunohistochemical procedures. Here, in a dual-labelling immunohistochemical study in the rat brain, we used our affinity-purified antiserum to epsilon with antisera to markers of cholinergic, catecholaminergic, and serotonergic neurones. As far as cholinergic systems were concerned, epsilon-immunoreactivity was expressed in all forebrain cell-groups, as well as in the caudal lateral pontine tegmentum and dorsal motor nucleus of the vagus nerve. As far as dopaminergic systems were concerned, epsilon-immunoreactivity was found to be expressed in a great number of hypothalamic cell-groups (A15, A14 and A12) and in the substantia nigra pars compacta. The noradrenergic, and to a lesser extent, adrenergic cell-groups were all epsilon-immunoreactive. Also, epsilon-immunoreactivity was detected in all serotonergic cell-groups. We also revealed by in situ hybridisation in a monkey brain that epsilon mRNA was expressed in the locus coeruleus, as previously observed in rats. Finally, by using in situ hybridisation in rat brains, we compared the distribution of the mRNA of epsilon with that of the recently cloned theta-subunit of the GABA(A) receptor. Both subunits showed strikingly overlapping expression patterns throughout the brain, especially in the septum, preoptic areas, various hypothalamic nuclei, amygdala, and thalamus, as well as the aforementioned monoaminergic cell-groups. No theta-mRNA signals were detected in cholinergic cell-groups. Taken together with previously published evidence of the presence of the alpha3-subunit in monoamine- or acetylcholine-containing systems, our data suggest the existence of novel GABA(A) receptors comprising alpha3/epsilon in cholinergic and alpha3/theta/epsilon in monoaminergic cell-groups.


How to manage TB in children? Problems and solutions in four cases.
Children bear a substantial part of the tuberculosis (TB) epidemic worldwide, and it is estimated that there were ≅ 500.000 childhood TB cases globally in 2010, although accurate data are problematic to obtain given the many difficulties associated with TB diagnosis in children and the weaknesses of surveillance systems in countries where TB is endemic. The World Health Organization is working hard in order to reduce the TB prevalence rates and deaths by half by 2015. In this challenge, general practitioners and pediatricians play a key role in detecting early cases of suspected TB and sending them to experts in infectious diseases. This will reduce delayed diagnosis and the spread of disease, which is especially important now that the prevalence of multidrug resistant TB is increasing. For this reason, the purpose of this report was to delineate the characteristic clinical features of the most common forms of pediatric TB and to suggest a rational and practical approach to the disease underlining the role of patients and parents personal and clinical history.


[Subtype of HIV-1 strains: an epidemic study of 1157 samples in Henan Province, China].
To study the epidemic status of human immunodeficiency virus type 1 (HIV-1) subtypes and sequence variations in Henan province and to explore their epidemic characteristics and transmission sources and routes. HIV-1 env gene was amplified by nested PRC from uncultured peripheral blood mononuclear cells (PBMCs) obtained from 1157 HIV-1 carriers confirmed in Henan from 2005 to 2006. The C2-V3 region (about 350450 bp) of HIV-1 env was sequenced. Of 1157 samples, there were 4 HIV-1 strains including subtype B', C and recombinant subtype BC and AE, accounting for 96.456% (1116/1157), 0.346% (4/1157), 2.593% (30/1157) and 0.605% (7/1157), respectively. In comparison with the sequences of the international strains of RL42, C.95in21068, 07BC.CN.97.C54A and 01AE.TH.90.CM240, the genetic divergence was (8.971 +/- 3.182)%, (5.109 +/- 0.112)%, (3.568 +/- 0.254)% and (4.775 +/- 0.128)%, respectively. The phylogenetic tree analysis showed that 1116 Henan B' strain was closely related to those of Thailand B' and was far different from other international subtypes. The major transmit route in subtype B' strain was mainly found among former blood donators, while sexual transmission was the major route for BC spreading. For AE, the major transmission was sex and blood transfusion, and sex was defined as the major route for C. There are four HIV-1 strains including subtype B', C and recombinant subtype BC and AE identified in Henan province currently, and the dominant subtype B' is closely related to HIV-1 strains of Thailand B'. While, for non-B' subtype, there exists the aggregating phenomenon in some local areas. Therefore, it is necessary to attach importance and to strengthen the HIV test and surveillance on migrant populations.


BIOLUMINESCENT BEHAVIOR IN RENILLA. I. COLONIAL RESPONSES.
1. Some details are given of the external morphology of the autozooids and siphonozooids and of their distribution in the colony. It is estimated that a minimum of over 6 meters of nerve net would be required to conduct excitation across an average-size colony during the passage of a wave of luminescence. 2. An account is given of the localization of luminescence in the two types of polyp and of their apparently differing behaviors in colonies collected in summer and winter. 3. In summer colonies the sharp luminous waves induced by electrical stimulation are entirely due to siphonozooids. Under strong stimulation the autozooid calices produce a long lasting glow. 4. Neuroeffector facilitation takes place uniformly throughout the colonial conduction system. Decay of facilitation requires 10-36 seconds, by different tests. There are indications that sensory adaptation in the (hypothetical) net can be local. 5. Local recording shows that the response cycle in small areas of the colony is much shorter, and its frequency response much higher, than indicated by integrative recordings of the wave response as a whole. 6. Individual siphonozooid clusters can flash repetitively in successive waves, fail to participate in every wave and vary in intensity from wave to wave. The increase in light intensity during successive facilitating waves seems due to increase in the activity of individual clusters, not to recruitment of additional clusters. There were indications of individual differences in threshold, adaptation and autoexcitation between clusters. 7. During strong repetitive electrical stimulation there may arise extra siphonozooid waves of augmented brightness, running in the same direction as the "normal" waves ( i.e., centrifugally from the electrode) or in the reverse direction. The colony may then enter an autoexcitatory state ("frenzy"), independent of external stimulation and often involving development of several excitation centers, in which waves of irregular and constantly changing form course over the rachidial surface for up to an hour.


Studies on the mechanism of heterochromatic position effect at the rosy locus of Drosophila melanogaster.
Experiments are described that extend the characterization of position effect variants of the rosy locus and test possible mechanisms of heterochromatic position effect. Rosy position effect variants exhibit a variegated phenotype with respect to xanthine dehydrogenase activity in malpighian tubules. The breakpoints of the position effect mutations are located on the DNA map of the rosy region outside of the rosy locus DNA; ryps11136 is located in the DNA of the l(3)S12 gene immediately proximal to rosy, whereas ryps1149 is located some 15 kb distal to rosy in the pic locus. Southern blot experiments are described that test and reject the notion that heterochromatic position effect results from underreplication of the position-affected gene. Rather, the results of Northern blots serve to direct attention to position effect as a defect in transcription. Histone region deletion heterozygosity and butyrate-feeding experiments failed to exhibit specific suppression of position effect at the rosy locus.


The Stimulated Glycolytic Pathway Is Able to Maintain ATP Levels and Kinetic Patterns of Bovine Epididymal Sperm Subjected to Mitochondrial Uncoupling.
Studies have reported the importance of mitochondria in sperm functionality. However, for some species, the glycolytic pathway appears to be as important as oxidative phosphorylation in ATP synthesis and sperm kinetics. These mechanisms have not been fully elucidated for bovine spermatozoa. Therefore, the aim of this study was to evaluate the role of mitochondria and the glycolytic pathway in ATP synthesis, sperm movement patterns, and oxidative homeostasis of epididymal spermatozoa in bovine specimens. We observed that mitochondrial uncoupling with protonophores significantly reduced ATP levels. However, these levels were reestablished after stimulation of the glycolytic pathway. We verified the same pattern of results for sperm kinetic variables and the production of reactive oxygen species (ROS). Thus, we suggest that, after its appropriate stimulation, the glycolytic pathway is capable of maintaining ATP levels, sperm kinetic patterns, and oxidative balance of bovine epididymal spermatozoa submitted to mitochondrial uncoupling.


Pediatric Liver Transplantation: Unique Concerns for the Critical Care Team.
Liver transplantation originated in children more than 50 years ago, and these youngest patients, while comprising the minority of liver transplant recipients nationwide, can have some of the best and most rewarding outcomes. The indications for liver transplantation in children are generally more diverse than those seen in adult patients. This diversity in underlying cause of disease brings with it increased complexity for all who care for these patients. Children, still being completely dependent on others for survival, also require a care team that is able and ready to work with parents and family in addition to the patient at the center of the process. In this review, we aim to discuss diagnoses of particular uniqueness or importance to pediatric liver transplantation. We also discuss the evaluation of a pediatric patient for liver transplant, the system for allocating them a new liver, and also touch on postoperative concerns that are unique to the pediatric population.


Qualitative confirmation of 9 synthetic cannabinoids and 20 metabolites in human urine using LC-MS/MS and library search.
Synthetic cannabinoids are an emerging illicit drug class. The variety of available substances is large and ever-changing, making it difficult for laboratories to remain current. We present a qualitative LC-MS/MS method identifying urinary metabolites of JWH-018, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, RCS-4, and AM2201 and the parent compounds JWH-018, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, RCS-4, AM2201, and MAM2201. After enzymatic hydrolysis, urinary proteins were precipitated with acetonitrile. Chromatography utilized a 10 min gradient on a Kinetex XB-C18 column with 0.1% formic acid in water and acetonitrile. Scheduled multiple reaction monitoring "survey scans" were followed by information-dependent acquisition-enhanced product ion scan experiments on an ABSciex 5500 QTRAP mass spectrometer. Analytes were identified by software-assisted library searching against reference spectra. The method was fully validated, including proof of selectivity (no exogenous or endogenous interferences were observed), assessment of matrix effects (95-122%) and recovery (53-95%), determination of limits of detection (0.5-10 ng/mL), carry-over studies (thresholds between 100 and 1000 ng/mL), and determination of autosampler stability (samples were stable for at least 3 days). Hydrolysis efficiency was thoroughly investigated for a wide range of glucuronides and for the reference standard, JWH-018 5-hydroxypentyl glucuronide.


Comparative sequence analysis of the eastern equine encephalitis virus pathogenic strains FL91-4679 and GA97 to other North American strains.
Eastern equine encephalitis (EEE) virus is a significant public health concern due to the high mortality rates observed in infected humans, equines and game birds. The EEE genomic sequences available prior to this report are based on laboratory strains with unknown passage histories that may contain an array of cell culture adaptations. Here we report the complete genomic sequences of two recently isolated EEE pathogenic strains with low passage histories. FL91-4697 was isolated in Florida from Aedes albopictus mosquitoes and GA97 was derived from brain tissue of a human fatality that occurred in 1997. Sequence alignment of these new genomes with the documented EEE's permitted us to generate a North American consensus sequence and identify regions of significant diversity. Sequence analysis of the FL91-4679 genome was essential to the production of an EEE infectious clone that is being used to create live attenuated vaccine candidates.


The principles of anatomical nomenclature revision: They're more like guidelines anyway.
Revision of the international standard anatomical terminology is required periodically to add names for new entities, delete archaic terms, and correct errors in existing terms. In addition to a small set of nomenclature rules, three principles have guided revisions: names should not be changed unless they are wrong; corrections of perceived errors should not be pedantic; and inclusion of every minor structure should not be attempted. These principles have served well, and are expected to continue to do so, but they have also proven to be subjective because their application through the history of the international terminology has varied. Specific efforts to deal with existing problems and new organizational initiatives to prevent future issues are presented. Clin. Anat. 33:327-331, 2020. © 2019 Wiley Periodicals, Inc.


Meta-analysis and its problems.
Including all relevant material--good, bad, and indifferent--in meta-analysis admits the subjective judgments that meta-analysis was designed to avoid. Several problems arise in meta-analysis: regressions are often non-linear; effects are often multivariate rather than univariate; coverage can be restricted; bad studies may be included; the data summarised may not be homogeneous; grouping different causal factors may lead to meaningless estimates of effects; and the theory-directed approach may obscure discrepancies. Meta-analysis may not be the one best method for studying the diversity of fields for which it has been used.


Renal norepinephrine content decreases after chronic flow probe implantation.
Electromagnetic flow probes were chronically implanted around the left renal artery in 6 female beagle dogs. 3-10 months after implantation, renal cortex norepinephrine contents of right and left kidneys were compared (liquid chromatography). In 4 out of the 6 dogs investigated 3-6 months after implantation, the norepinephrine content of the left kidney was reduced by 27-72%. In 2 dogs investigated 7 and 10 months after implantation, the difference between left and right kidney was not significant. These findings should be taken into consideration when interpreting results from chronically instrumented kidneys.


Use of narrowband imaging for the diagnosis and screening of laryngeal cancer: A systematic review and meta-analysis.
We evaluated the diagnostic accuracy of narrowband imaging (NBI) in terms of detecting laryngeal cancer compared to that of white light endoscopy (WLE). Two reviewers individually searched the six databases for studies published between the first record date and December 31, 2019. We recorded the numbers of true positives, true negatives, false positives, and false negatives. Quality Assessment of Diagnostic Accuracy Studies ver. 2 software was used to assess the studies. The extent of the inter-rater agreement was also measured. The diagnostic odds ratio (OR) associated with NBI was 87.463 (95% confidence interval [CI]: 46.968, 160.873). The area under the summary receiver operating characteristic curve was 0.954. NBI was more diagnostically accurate than WLE, which was associated with a diagnostic OR of 13.750. NBI affords high diagnostic accuracy, thus supporting a role for NBI in the diagnostic work-up of laryngeal cancer.


Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis.
Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) - extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity.


Pharmacological therapy of dysthymia.
For a number of years, dysthymia was considered to be non-responsive to antidepressant treatment. During the last decade, early studies with tricyclic antidepressants (TCAs) demonstrated the superiority of the TCAs over placebo. The side effect profile of the TCAs and the moderate degree of symptomatology resulted in reduced compliance and thus to the clinical impression of lack of efficacy. The newest generation of antidepressants, the SRRIs and the RIMAs, with their more acceptable side effect profiles, allowed for the adequate evaluation of pharmacotherapy in dysthymia. The initial open studies with SSRIs indicate a clear efficacy of this group of antidepressants. Likewise, a 5HT2 antagonist, ritanserin, has been shown to be superior to placebo. More recently, a large placebo-controlled study of moclobemide, a RIMA, clearly demonstrated the superiority of this drug over placebo. Based on this evidence, it is now appropriate to consider antidepressants as a clearly effective method of treating dysthymia.


Modes of action of poliovirus vaccines and relation to resulting immunity.
Parenteral inactivated poliovirus vaccine (IPV) chiefly induces formation of serum antibody. Infection, with oral poliovirus vaccine ( OPV ) or wild poliovirus, also induces development of secretory IgA antibody. In addition, infection results in virus shedding and, hence, in possible spread of virus to contacts (more likely with wild than with vaccine virus). IPV induces a high level (90%-95%) of protection against disease, which presumably is mediated by serum antibody that prevents CNS invasion resulting from viremia. IPV induces little protection against infection but does modify the related virus shedding--chiefly that from the oropharynx. Infection, whether by OPV or wild virus, induces a high level of protection against disease. It also results in appreciable prevention or modification of infection because of the development of secretory IgA antibody. This effect is directly protective for the vaccinee and also benefits the community, since the exposed vaccinee can play little or no part in the spread of wild virus. One major question remaining concerns the maintenance of immunity. Lifelong immunologic memory assures an enhanced serum antibody response to any infection that occurs, but will it be sufficiently rapid that when preinfection antibody cannot be detected newly formed antibody will block blood-borne viral invasion of the CNS? If not, booster doses of vaccine are indicated. OPV boosters might be indicated in any case to reinforce protection against infection and so maintain herd immunity.


Protease-catalyzed peptide synthesis using inverse substrates: the influence of reaction conditions on the trypsin acyl transfer efficiency.
Benzyloxycarbonyl-L-alanine p-guanidinophenyl ester behaves as a trypsin "inverse substrate," i.e., a cationic center is included in the leaving group instead of being in the acyl moiety. Using this substrate as an acyl donor, trypsin catalyzes the synthesis of peptide bonds that cannot be split by this enzyme. An optimal acyl transfer efficiency was achieved between pH 8 and 9 at 30 degrees C.The addition of as much as 50% cosolvent was shown to be of minor influence on the acyl transfer efficiency, whereas the reaction velocity decreases by more than one order of magnitude. The efficiency of H-Leu-NH(2) and H-Val-NH(2) in deacylation is almost the same for "inverse" and normal type substrates.


Reconstruction of stenotic external auditory canal with a postauricular chondrocutaneous flap.
A case of stenosis of the external auditory canal secondary to a burn injury was reconstructed with a chondrocutaneous postauricular flap. Advantages of this technique include the use of a single flap to reconstruct the whole circumference of the canal, the fact that a chondrocutaneous flap is more likely to prevent restenosis than a skin flap alone, and the fact that reconstruction with an axial-pattern flap is more reliable than reconstruction with a random-pattern flap.


[Examination of the Response Rate of Paclitaxel and Bevacizumab Therapy for Metastatic Advanced Breast Cancer According to the Lymphopenia Grade].
Bevacizumab is a well-established anti-VEGF monoclonal antibody that inhibits angiogenesis. Herein, we examined the response rates according to the grade of lymphopenia in metastatic breast cancer patients treated with bevacizumab+paclitaxel therapy. The objective responses were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guideline v1.1. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Twenty study patients were divided into group A (grade 2-4 lymphopenia) and group B (grade 1 lymphopenia or no decreased lymphocyte count) and compared. The mean progression-free survival (PFS)was 77.7 days in group A (n=7) and 56.8 days in group B (n=13). There was no significant difference between both groups (p=0.67, logrank test). The response rate (RR) was 14.3% (CR=0, PR=1, SD=3, PD=3) in group A, while in group B, it was 23.0% (CR=0, PR=3, SD= 6, PD=4). Furthermore, the clinical benefit rate (CBR) bwas 57.1% in group A and 69.2% in group B.


The applied value of public investments in biomedical research.
Scientists and policy-makers have long argued that public investments in science have practical applications. Using data on patents linked to U.S. National Institutes of Health (NIH) grants over a 27-year period, we provide a large-scale accounting of linkages between public research investments and subsequent patenting. We find that about 10% of NIH grants generate a patent directly but 30% generate articles that are subsequently cited by patents. Although policy-makers often focus on direct patenting by academic scientists, the bulk of the effect of NIH research on patenting appears to be indirect. We also find no systematic relationship between the "basic" versus "applied" research focus of a grant and its propensity to be cited by a patent.


Diabetes and Medicare competitive bidding: the "perfect storm" for patient harm.
A recent Diabetes Care study found flaws in Medicare's competitive bidding program for diabetes test strips. Two of that study's co-authors discuss the findings and why CMS should suspend the bidding program.


Gastric cancer-derived heat shock protein-gp96 peptide complex enhances dendritic cell activation.
To investigate the role of heat shock protein (HSP)-glycoprotein (gp)96 in dendritic cells (DCs) and lymphocytes induction in gastric cancer (GC). Human GC cell lines KATOIII, MKN-28 and SGC-7901 were infected with adenovirus gp96 at a multiplicity of infection of 100. gp96-GC antigen peptide complexes were purified. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, lactate dehydrogenase (LDH) release assay and enzyme-linked immunosorbent assay were used to determine allo-reactive T cell stimulation, natural killer (NK) cell activity and expression of cytokines (such as interleukin (IL)-10, IL-12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α), respectively. Effect of cytotoxic T lymphocyte (CTL) on DCs incubated with HSP-gp96 was also evaluated by LDH release. All assays were performed in triplicate and the average values were reported. Comparison between groups was conducted using Student's t test. T cells incubated with HSP-gp96 exhibited a marked increase in proliferation in a dose-dependent manner (P < 0.05). NK cell activity after gp96-GC peptide complex treatment was significantly higher than that after antigen peptide treatment (P < 0.05). The activity of CTLs incubated with DCs from three GC cells lines was obviously higher than that stimulated by GC antigen at ratios of 50: 1, 25: 1, 10: 1, and 5: 1 (P < 0.05). Furthermore, the secretion of TNF-α, IL-10, IL-12 (P70) and IFN-γ markedly increased after incubation with HSP-gp96 (P < 0.05). HSP-gp96 promotes T cell response, enhances DC antigen presentation and induces cytokine secretion, as well. HSP-gp96 has potential as immunotherapy for elimination of residual GC cells.


Variable tracheal stenosis related to body position.
We demonstrated a variable extrathoracic tracheal stenosis which developed after technically adequate tracheostomy and was worsened by changes in body position. When the patient's arms were above his head, minimal airway diameter was reduced 31 percent, and maximal inspiratory flow rate 37 percent below values measured with arms down, but expiratory flow rates were preserved. Tracheostomy may disrupt the integrity of tracheal support and allow airway collapse under circumstances of increased extratracheal or decreased intratracheal pressure.


Rationally Designed Transgene-Encoded Cell-Surface Polypeptide Tag for Multiplexed Programming of CAR T-cell Synthetic Outputs.
Synthetic immunology, as exemplified by chimeric antigen receptor (CAR) T-cell immunotherapy, has transformed the treatment of relapsed/refractory B cell-lineage malignancies. However, there are substantial barriers-including limited tumor homing, lack of retention of function within a suppressive tumor microenvironment, and antigen heterogeneity/escape-to using this technology to effectively treat solid tumors. A multiplexed engineering approach is needed to equip effector T cells with synthetic countermeasures to overcome these barriers. This, in turn, necessitates combinatorial use of lentiviruses because of the limited payload size of current lentiviral vectors. Accordingly, there is a need for cell-surface human molecular constructs that mark multi-vector cotransduced T cells, to enable their purification ex vivo and their tracking in vivo. To this end, we engineered a cell surface-localizing polypeptide tag based on human HER2, designated HER2t, that was truncated in its extracellular and intracellular domains to eliminate ligand binding and signaling, respectively, and retained the membrane-proximal binding epitope of the HER2-specific mAb trastuzumab. We linked HER2t to CAR coexpression in lentivirally transduced T cells and showed that co-transduction with a second lentivirus expressing our previously described EGFRt tag linked to a second CAR efficiently generated bispecific dual-CAR T cells. Using the same approach, we generated T cells expressing a CAR and a second module, a chimeric cytokine receptor. The HER2txEGFRt multiplexing strategy is now being deployed for the manufacture of CD19xCD22 bispecific CAR T-cell products for the treatment of acute lymphoblastic leukemia (NCT03330691).


Targeting Resident Memory T Cells for Cancer Immunotherapy.
A novel population of memory CD8+ T cells called resident memory T cells (TRM) has been identified based on their phenotype (CD103, CD69) and on their local tissue residency without recirculating in the blood. These cells have been implicated in protective immune response against pathogens in both animal models and humans. Their role in cancer is just emerging as a key player in tumor immunosurveillance. Many properties of these cells suggest that they could control tumor growth: (i) they respond much faster to reexposure to cognate antigen than circulating memory cells, (ii) they express high levels of cytotoxic molecules, and (iii) they are enriched in tumor-specific T cells in close contact with tumor cells. TRM are present in many human cancers and are associated with a good clinical outcome independently of the infiltration of CD8+ T cells. It has been recently shown that the efficacy of cancer vaccines depends on their ability to elicit TRM. In adoptive cell therapy, the transfer of cells with the ability to establish TRM at the tumor site correlates with the potency of this approach. Interestingly, TRM express immune checkpoint molecules and preliminary data showed that they could expand early during anti-PD-1 treatment, and thus be considered as a surrogate marker of response to immunotherapy. Some cues to better expand these cells in vivo and improve the success of cancer immunotherapy include using mucosal routes of immunization, targeting subpopulations of dendritic cells as well as local signal at the mucosal site to recruit them in mucosal tissue.


Transcription factor Sox10 regulates oligodendroglial Sox9 levels via microRNAs.
During development of myelin-forming oligodendrocytes in the central nervous system the two closely related transcription factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct transcriptional targets of Sox10. The two microRNAs in turn recognize the 3'-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels posttranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.


Diffusion of Carbon Dioxide and Nitrogen in the Small-Pore Titanium Bis(phosphonate) Metal-Organic Framework MIL-91 (Ti): A Combination of Quasielastic Neutron Scattering Measurements and Molecular Dynamics Simulations.
The diffusivity of CO2 and N2 in the small-pore titanium-based bis(phosphonate) metal-organic framework MIL-91(Ti) was explored by using a combination of quasielastic neutron scattering measurements and molecular dynamics simulations. These two techniques were used to determine the loading dependence of the self-diffusivity, corrected and transport diffusivities of these two gases to complement our previously reported thermodynamics study, which revealed that this material was a promising candidate for CO2 /N2 separation. The calculated and measured diffusivities of both gases were shown to be of an order of magnitude sufficiently high, from 10-9 to 10-10 m2 s-1 , and N2 diffused faster than CO2 through the small channel of MIL-91(Ti). Consequently, the separation process does not involve any kinetic-driven limitations. This study further revealed that the global diffusion mechanism involves motions of gases along the channels by a jump sequence, and the residence times for CO2 in the region close to the specific PO⋅⋅⋅H⋅⋅⋅N zwitterionic sites are much higher than those for N2 , which explains the faster diffusivity observed for N2 .


24-epibrassinolide confers tolerance against deep-seeding stress in Zea mays L. coleoptile development by phytohormones signaling transduction and their interaction network.
Coleoptile/mesocotyl elongation influence seedling emergence and establishment, is major causes of maize deep-seeding tolerance (DST). Detailed analyses on molecular basis underlying their elongation mediated by brassinosteroid under deep-seeding stress (DSS) could provide meaningful information for key factors controlling their elongation. Here we monitored transcriptome and phytohormones changes specifically in elongating coleoptile/mesocotyl in response to DSS and 24-epibrassinolide (EBR)-signaling. Phenotypically, contrasting maize evolved variant organs to positively respond to DST, longer coleoptile/mesocoty of K12/W64A was a desirable organ for seedling under DSS. Applied-EBR improved maize DST, and their coleoptiles/mesocotyls were further elongated. 15,607/20,491 differentially expressed genes (DEGs) were identified in W64A/K12 coleoptile, KEGG analysis showed plant hormone signal transduction, starch and sucrose metabolism, valine, leucine, and isoleucine degradation were critical processes of coleoptile elongation under DSS and EBR signaling, further highly interconnected network maps including 79/142 DEGs for phytohormones were generated. Consistent with these DEGs expression, interactions, and transport, IAA, GA3, ABA, and Cis-ZT were significantly reduced while EBR, Trans-ZT, JA, and SA were clearly increased in coleoptile under DSS and EBR-signaling. These results enrich our knowledge about the genes and phytohormones regulating coleoptile elongation in maize, and help improve future studies on corresponding genes and develop varieties with DST.