Multi-lipase gene knockdown in Chinese hamster ovary cells using artificial microRNAs to reduce host cell protein mediated polysorbate degradation.
A large number of companies observe polysorbate (PS) degradation and associated (sub-)visible particle formation in biological drug formulations, which compromise the stability of the drug product, ultimately posing a risk toward delivering innovative medicines to patients. The main culprits of PS degradation are hydrolytic host cell proteins (HCPs) originating from the production cell lines, which are mostly Chinese hamster ovary (CHO) cell derived. Here, a small portion of particularly difficult-to-remove HCPs-mainly lipases-cause hydrolytic cleavage of PS resulting in the accumulation of free fatty acid aggregates/particles. One possible mitigation strategy is the removal of such critical HCPs in the production cell line. Multigene regulation can be achieved via microRNAs (miRNAs) thereby serving as a smart tool to reduce the expression of different target genes using a single miRNA. To enable a tailored gene regulation of multiple specific target lipases self-designed and non-naturally occurring artificial miRNAs (amiRNA) can be designed. Based on micro-conserved regions in the mRNA sequence of two sets of target HCPs, we provide a proof-of-concept for a simultaneous multi-lipase knockdown in CHO cells using single amiRNAs. By this, we were not only able to reduce PS degradation but laid the foundation to expand this tool to other areas of cell line phenotype engineering.


Cesarean deliveries and maternal weight retention.
Cesarean delivery accounts for nearly one-third of all births in the U.S. and contributes to an additional $38 billion in healthcare costs each year. Although Cesarean delivery has a long record of improving maternal and neonatal mortality and morbidity, increased utilization over time has yielded public health concerns and calls for reductions. Observational evidence suggests Cesarean delivery is associated with increased maternal postpartum weight, which may have significant implications for the obesity epidemic. Previous literature, however, typically does not address selection biases stemming from correlations of pre-pregnancy weight and reproductive health with Cesarean delivery. We used fetal malpresentation as a natural experiment as it predicts Cesarean delivery but is uncorrelated with pre-pregnancy weight or maternal health. We used hospital administrative data (including fields used in vital birth record) from the state of Wisconsin from 2006 to 2013 to create a sample of mothers with at least two births. Using propensity score methods, we compared maternal weight prior to the second pregnancy of mothers who delivered via Cesarean due to fetal malpresentation to mothers who deliver vaginally. We found no evidence that Cesarean delivery in the first pregnancy causally leads to greater maternal weight, BMI, or movement to a higher BMI classification prior to the second pregnancy. After accounting for correlations between pre-pregnancy weight, gestational weight gain, and mode of delivery, there is no evidence of a causal link between Cesarean delivery and maternal weight retention.


Chasms in Achievement of Recommended Diabetes Care among Geographic Regions in Korea.
Although effective care for type 2 diabetes (T2DM) is well known, considerable inadequate care has been still existed. Variations in achievement of the recommended quality indicators inT2DM care among small areas are not well known in Korea. This study examined the quality of care T2DM care and its geographical variations. We used the national health insurance database and national health screening database. Seven quality indicators were used to evaluate continuity of care (medication possession ratio), process of care (hemoglobin A1c test, lipid profile, microalbuminuria test, and eye examination), and intermediate outcome (blood pressure control, and low-density lipoprotein control). Crude and age-standardized proportions were calculated for each 252 districts in Korea. All quality indicators failed to achieve the recommended level. Only about 3% and 15% of the patients underwent eye examination and microalbuminuria test, respectively. Other indicators ranged from 48% to 68%. Wide variation in the quality existed among districts and indicators. Eye examination and microalbuminuria test varied the most showing tenfold (0.9%-9.2%) and fourfold (6.3%-28.9%) variation by districts, respectively. There were 32.4 and 42.7 percentage point gap between the best and the worst districts in hemoglobin A1c test and blood pressure control, respectively. Considerable proportion of T2DM patients were not adequately managed and quality of care varied substantially district to district. To improve the quality of diabetes care, it is necessary to identify the poor performance areas and establish a well-coordinated care system tailored to the need of the district.


Predictors of response to intra-articular steroid injection in psoriatic arthritis.
To assess the effectiveness of IA corticosteroid (IAS) injections in PsA and to determine the association between macrophage migration inhibition factor (MIF) gene polymorphism and response to IAS injections. A cohort analysis of PsA patients who were followed prospectively was performed. Clinical response was defined as no tenderness or effusion in the injected joint at 3 months. Relapse was defined as re-occurrence of joint pain or effusion. MIF 173C > G genotyping (rs755622) was performed. Two hundred and twenty patients with 245 IAS injections were included in the study. The probability of responding at 3 months was 41.6%. Within 12 months, 25.5% of the joints relapsed. Clinical factors that were associated with response included duration of psoriasis [Odds ratio (OR) 1.03] and the use of MTX or anti-TNF agents at the time of injection (OR 2.68). Factors that were associated with relapse included injection into large joints (OR 4.58) and elevated sedimentation rate (OR 15.0), whereas absence of clinical and/or radiographic damage (OR 0.23) and duration of PsA (OR 0.92) reduced risk of relapse. MIF polymorphism was not associated with clinical response, but was associated with relapse (OR 3.2). On multivariate analysis including clinical covariates, the association between MIF polymorphism and relapse was lost. IAS injections are effective in PsA. MIF gene polymorphism is associated with relapse. However, this effect is explained by clinical variables that reflect disease activity, suggesting that MIF gene polymorphism influences inflammatory activity.


Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans.
Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.


HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma.
Promoter DNA hypermethylation with gene silencing is a common feature of human cancer, and cancer-prone methylation is believed to be a landmark of tumor suppressor genes (TSG). Identification of novel methylated genes would not only aid in the development of tumor markers but also elucidate the biological behavior of human cancers. We identified several epigenetically silenced candidate TSGs by pharmacologic unmasking of esophageal squamous cell carcinoma (ESCC) cell lines by demethylating agents (5-aza-2'-deoxycitidine and trichostatin A) combined with ESCC expression profiles using expression microarray. HOP/OB1/NECC1 was identified as an epigenetically silenced candidate TSG and further examined for (a) expression status, (b) methylation status, and (c) functional involvement in cancer cell lines. (a) The HOP gene encodes two putative promoters (promoters A and B) associated with two open reading frames (HOPalpha and HOPbeta, respectively), and HOPalpha and HOPbeta were both down-regulated in ESCC independently. (b) Promoter B harbors dense CpG islands, in which we found dense methylation in a cancer-prone manner (55% in tumor tissues by TaqMan methylation-specific PCR), whereas promoter A does not harbor CpG islands. HOPbeta silencing was associated with DNA methylation of promoter B in nine ESCC cell lines tested, and reactivated by optimal conditions of demethylating agents, whereas HOPalpha silencing was not reactivated by such treatments. Forced expression of HOP suppressed tumorigenesis in soft agar in four different squamous cell carcinoma cell lines. More convincingly, RNA interference knockdown of HOP in TE2 cells showed drastic restoration of the oncogenic phenotype. In conclusion, HOP is a putative TSG that harbors tumor inhibitory activity, and we for the first time showed that the final shutdown process of HOP expression is linked to promoter DNA hypermethylation under the double control of the discrete promoter regions in cancer.


Organic-inorganic hybrid zeolites containing organic frameworks.
Organic-inorganic hybrid zeolite materials containing an organic framework have been synthesized by partially superseding a lattice oxygen atom by a methylene group. The use of methylene-bridged organosilane as a silicon source gives zeolite materials containing an organic group as lattice (ZOL), with several zeolitic phases such as the MFI and the LTA structures. Through various characterization methods, the presence of methylene frameworks (Si-CH2-Si) that replace siloxane bonds (Si-O-Si) has been verified, although the Si-C bonds are partly cleaved to give rise to terminal methyl groups. The shape-selective lipophilicity of a ZOL material indicates that it is not a physical mixture of conventional zeolite and amorphous organic-containing material but contains a genuine organic-inorganic hybrid zeolite.


On the Very-Long-Term Effect of Managing One's Own Memory: The Intention to Forget Improves Recognition After a Year's Delay.
While such factors as demand characteristics, encoding, and retrieval inhibition were shown to be significant in producing the directed forgetting effect, no attention was paid to whether the intention to manage one's own memory, per se, matters. In the present article, we addressed this important gap in the literature. To control the quality of encoding we ensured that both the to-be-remembered (TBR) and to-be-forgotten (TBF) items were genuinely learned before the manipulation. We used extremely long delays between the memory instructions and testing to release inhibition associated with the content of instructions. 98 participants demonstrated flawless recall of 12 Russian - made up language word pairs. They then viewed each Russian word from a pair once, with randomized instructions "Forget", "Remember", "Repeat", or a short cognitive task. Self-reports on the mnemonic strategies were collected. Free recall and recognition tests were administered three times - 45 minutes, a month and a year (N = 58) later. Despite a strong incentive to recall all word pairs, fewer TBF pairs were recalled in comparison with TBR pairs, both after 45 minutes and after one month's delay. Recognition among all conditions was equally high. A year later free recall was close to zero. In contrast, the TBR and TBF pairs were recognized equally better than pairs presented in "Repeat" and "Task" conditions. Thus, our results show that the intention to manage one's own memory enhances the accessibility of memories at a very long time delay, no matter what type of instruction is issued.


Testing the Multiple Pathways of Residential Greenness to Pregnancy Outcomes Model in a Sample of Pregnant Women in the Metropolitan Area of Donostia-San Sebastián.
Residential greenness may positively impact diverse human health indicators through the reduction of air pollution, the improvement of psychological health, and the promotion of physical activity. Previous studies indicate a weak but positive association with pregnancy outcomes. Our aim was to test the multiple pathways from residential greenness to pregnancy outcomes model, using residential NO2 concentrations, psychological health, and moderate-to-vigorous physical activity (MVPA) during the first trimester of pregnancy, in a sample of 440 pregnant women residing in Donostia, Spain. Three metrics of residential greenness were calculated around each participant's home address: normalized difference vegetation index (NDVI) within 300 m, and green space (>5000 m2) availability within 300 and 500 m. Residential NO2 concentrations, psychological health, and MVPA were explored as mediators of the associations between these metrics and the following pregnancy outcomes: birth weight (BW), low birth weight (LBW), prematurity, small for gestational age (SGA), and large for gestational age (LGA). Educational attainment, parity, and body mass index (BMI) were treated as covariates. Counterfactual mediation analyses showed very low to null statistical support for an association between any of the greenspace metrics and pregnancy outcomes in the full sample. Green space availability (300 m) was associated with lower BW and showed a marginal protective effect against LGA.


Endoscopic versus histological characterisation of polyps during screening colonoscopy.
As screening colonoscopy becomes more widespread, the costs for histopathological assessment of resected polyps are rising correspondingly. Reference centres have published highly accurate results for endoscopic polyp classification. Therefore, it has been proposed that, for smaller polyps, the differential diagnosis that guides follow-up recommendations could be based on endoscopy alone. The aim was to prospectively assess whether the high accuracy for endoscopic polyp diagnosis as reported by reference centres can be reproduced in routine screening colonoscopy. Ten experienced private practice endoscopists had initial training in pit patterns. Then they assessed all polyps detected during 1069 screening colonoscopies. Patients (46% men; mean age 63 years) were randomly assigned to colonoscopy with conventional or latest generation HDTV instruments. The main outcome measure was diagnostic accuracy of in vivo polyp assessment (adenomatous vs hyperplastic). Secondary outcome measures were differences between endoscopes and reliability of image-based follow-up recommendations; a blinded post hoc analysis of polyp photographs was also performed. 675 polyps were assessed (461 adenomatous, 214 hyperplastic). Accuracy, sensitivity and specificity of in vivo diagnoses were 76.6%, 78.1% and 73.4%; size of adenomas and endoscope withdrawal time significantly influenced accuracy. Image-based recommendations for post-polypectomy surveillance were correct in only 69.5% of cases. Post hoc analysis of polyp photographs did not improve accuracy. In everyday practice, endoscopic classification of polyp type is not accurate enough to abandon histopathological assessment and use of latest generation colonoscopes does not improve this. Image-based surveillance recommendations after polypectomy would consequently not meet guideline requirements. NCT01297712.


Mutagenicity and safety evaluation of the water extract of Camellia oleifera Abel.
The purpose of this study was to evaluate the mutagenicity and safety of water extract of the fruit hull of Camellia oleifera Abel (WECO), which was prepared using hot-reflux method. The oral maximum tolerated dose (MTD) of WECO was above 20 g/kg body weight both in rats and in mice, which can be regarded as virtually nontoxic. No mutagenicity was found in Ames test, mouse bone marrow cell micronucleus test and mouse sperm abnormality test. In the subacute study, the SD rats were administered orally at 0.5, 1, or 2 g/kg/BW for 30 d. There were no treatment-related toxic effects from WECO. No significant differences were found in parameters of body weight, hematology value, clinical chemistry value, and organ/body weight ratio. The level of no observed adverse effect level (NOAEL) for WECO was 2 g/kg/BW for subacute toxicity study. With the gradual increase in tea oil production, it was in urgent need of dealing with Camellia fruit hull, which was always discarded because of low economic benefits. Camellia fruit hull has been shown to have significant antioxidant effects including DPPH radical-scavenging ability and ferric-reducing antioxidant power (Zhang and others 2010). Toxicological evaluation of WECO provided a safety assurance of WECO for developing dietary supplements and functional foods.


Considerations for conducting group intervention with adults who stutter.
With recent changing trends in healthcare delivery and reimbursement, the focus on more efficient and cost-effective intervention has become increasingly important. A summary of desired clinician skills and responsibilities reported in the literature are presented along with information on structuring group intervention. Preliminary findings and a rationale for conducting speech therapy in a group environment with several adults who suffer are presented. In addition, findings and perceptions gleaned from the authors' experience in conducting group treatment with persons who stutter are also discussed.


GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism.
GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.


The application of a frequency oscillation method for tooth extraction in dogs.
A tooth-grasping forceps with a gas-driven oscillating headpiece was designed for dental extractions in the dog, Compared with the conventional method, the extraction time was shortened considerably, and preliminary results indicate it may cause less trauma to alveolar bone and periodontal ligament.


Shape Theory Applied to Molecular Docking and Automatic Localization of Ligand Binding Pockets in Large Proteins.
Automatic search of cavities and binding mode analysis between a ligand and a 3D protein receptor are challenging problems in drug design or repositioning. We propose a solution based on a shape theory theorem for an invariant coupled system of ligand-protein. The theorem provides a matrix representation with the exact formulas to be implemented in an algorithm. The method involves the following results: (1) exact formulae for the shape coordinates of a located-rotated invariant coupled system; (2) a parameterized search based on a suitable domain of van der Waals radii; (3) a scoring function for the discrimination of sites by measuring the distance between two invariant coupled systems including the atomic mass; (4) a matrix representation of the Lennard-Jones potential type 6-12 and 6-10 as the punctuation function of the algorithm for a molecular docking; and (5) the optimal molecular docking as a solution of an optimization problem based on the exploration of an exhaustive set of rotations. We apply the method in the xanthine oxidase protein with the following ligands: hypoxanthine, febuxostat, and chlorogenic acid. The results show automatic cavity detection and molecular docking not assisted by experts with meaningful amino acid interactions. The method finds better affinities than the expert software for known published cavities.


The causes of stroke in the young.
In a group of 75 patients under the age of 45 years with stroke, ischaemic cerebral infarction was diagnosed in 60 patients and primary intracerebral haemorrhage in 15. Trauma was found to be the commonest identifiable predisposing factor to cerebral infarction, being present in 13 cases (22%). Migraine was the second most commonly identified predisposing factor while atheroma and hypertension were infrequent. Such a high frequency of preceding trauma has not previously been described, perhaps because it is not generally appreciated that the delay between the traumatic event and subsequent stroke may be considerable. The diagnostic management of young stroke patients is considered with particular reference to the indications for specialized cardiac and neuroradiological investigations.


The Challenges and Successes of Dealing with the COVID-19 Pandemic in India.
As the infectivity of the SARS-CoV-2 virus is higher compared with other coronaviruses reported so far, so effective therapeutics and vaccines are the best way to control the proliferation of this infection The COVID-19 mortality rate is lower compared with other similar viral diseases such as severe acute respiratory Ssndrome (SARS) and Middle East respiratory syndrome (MERS). However, due to the evolution of SARS-CoV-2 mutants that are responsible for the subsequent waves, mortality due to COVID-19 has increased across the globe. Currently, the magnitude of SARS-CoV-2 infection is highly severe and is leading to a tremendously increased number of deaths globally. Scientists expect that SARS-CoV-2 has the potential to become a seasonal disease like influenza and may persist with humanity in the future. Currently, preventive strategies such as sanitation, social distancing, use of masks, potential chemotherapies (pathogen-centric and host-centric), and vaccines are the only option to fight against COVID-19. Many groups of Indian government-public private consortia had set up different strategies (development of multiple vaccines) for combat of this unique threat through stepssuch as an increase in vaccinations and sample testing per day. In this focused review, we have discussed the challenges faced and success stories employed to manage COVID-19.


[The use of liposomal form of phenylimide of cis-aconitic acid in herpes therapy].
The results of study of the antiviral activity and pharmacokinetics of phenylimide of cis-aconitic acid (PCAA) is presented. The 20% increase of the antiviral activity of PCAA incorporated into liposomes in comparison with the antiviral activity of the pure substance was shown. Liposomes with PCAA were tropic to lymphocytes and macrophages with maximum fluorescence being observed in the spleen, while empty liposomes were accumulated mainly in the liver. After the treatment with liposomal PCAA the symptoms of herpetic meningoencephalitis became less severe with 100% survival of the experimental animals. In the control group of rabbits 50% of the animals died, and in the surviving animals blindness or paralysis developed.


[Effect of insulin of dehydrogenases of pentosephosphate pathway and content of free fatty acids in rat kidney].
After administration of insulin into rats activity of dehydrogenases of pentosephosphate pathway was not altered in cortex and medulla of kidney as distinct from the liver tissue. Concentration of free fatty acids was slightly lower in soluble fraction of kidney cortex than in blood plasma and higher than in preparation from kidney medulla. Alterations in content of free fatty acids were not observed in the preparations of kidney of rats with alloxan diabetes.


A 13.56-mbps pulse delay modulation based transceiver for simultaneous near-field data and power transmission.
A fully-integrated near-field wireless transceiver has been presented for simultaneous data and power transmission across inductive links, which operates based on pulse delay modulation (PDM) technique. PDM is a low-power carrier-less modulation scheme that offers wide bandwidth along with robustness against strong power carrier interference, which makes it suitable for implantable neuroprosthetic devices, such as retinal implants. To transmit each bit, a pattern of narrow pulses are generated at the same frequency of the power carrier across the transmitter (Tx) data coil with specific time delays to initiate decaying ringing across the tuned receiver (Rx) data coil. This ringing shifts the zero-crossing times of the undesired power carrier interference on the Rx data coil, resulting in a phase shift between the signals across Rx power and data coils, from which the data bit stream can be recovered. A PDM transceiver prototype was fabricated in a 0.35- μm standard CMOS process, occupying 1.6 mm(2). The transceiver achieved a measured 13.56 Mbps data rate with a raw bit error rate (BER) of 4.3×10(-7) at 10 mm distance between figure-8 data coils, despite a signal-to-interference ratio (SIR) of -18.5 dB across the Rx data coil. At the same time, a class-D power amplifier, operating at 13.56 MHz, delivered 42 mW of regulated power across a separate pair of high-Q power coils, aligned with the data coils. The PDM data Tx and Rx power consumptions were 960 pJ/bit and 162 pJ/bit, respectively, at 1.8 V supply voltage.


Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Italian Group of Antiemetic Research.
Differences in pharmacodynamic and pharmacokinetic characteristics among serotonin-receptor antagonists have been reported in preclinical studies. This prompted us to carry out a study to determine whether such differences are important in terms of clinical efficacy or tolerability. 973 consecutive cancer patients scheduled to receive cisplatin for the first time (at doses > or = 50 mg2), entered a double-blind multicenter randomized study comparing intravenous ondansetron 8 mg versus granisetron 3 mg. Dexamethasone 20 mg was added to both serotonin antagonists. On days 2 to 4 after chemotherapy all patients received oral metoclopramide plus intramuscular dexamethasone as antiemetic prophylaxis for delayed emesis. Nausea and vomiting were assessed daily until day 6 after chemotherapy. We evaluated 966 patients (483 receiving ondansetron and 483 granisetron). Complete protection from acute vomiting/nausea was obtained in 79.3%/72.0% of patients receiving ondansetron and in 79.9%/71.8% of those receiving granisetron. Complete protection from delayed vomiting/nausea as obtained in 69.7%/52.9% and 70.0%/49.6% of patients receiving the ondansetron or granisetron regimens, respectively. Adverse effects were mild and not significantly different between the two antiemetic regimens. Ondansetron 8mg and granisetron 3 mg, both combined with dexamethasone, showed similar efficacy and tolerability in the prevention of cisplatin-induced emesis. The choice between the two regimens can be dictated by their respective purchase prices.


To predict or not to predict: age-related differences in the use of sentential context.
Older adults (as a group) are less likely than younger adults to engage in an anticipatory mode of language comprehension, failing to successfully preactivate information about upcoming likely (predictable) words during online processing. To assess (within one set of materials) age-related changes in the use of sentential context to affect processing of predictable words and in the consequences of violating predictions, event-related brain potentials were recorded while older adults read sentences that varied in sentence-level constraint and expectancy of sentence-final words. Strongly constraining sentences were completed by their most expected, predictable words and weakly constraining sentences were completed by their most expected, less predictable words. Both types of sentences also were completed by unexpected (but plausible) words. Older adults showed reduced and delayed effects of sentential context on processing predictable words. Whereas younger adults elicit an enhanced positive ERP (starting around 500 ms poststimulus onset, largest over prefrontal electrode sites), specifically for unexpected words that violate strong expectancies for a different word, older adults as a group did not exhibit this neural consequence of disconfirmed predictions. Older adults were instead more likely to show a left-lateralized frontal negativity for predictable items. This ERP response has been attributed to processes needed to revisit contextual material in forming an interpretation of message-level meaning, which may be more likely when anticipatory modes of comprehension are not engaged. Taken together, the results suggest that normal aging can affect allocation of resources to different cognitive and neural pathways in achieving comprehension outcomes.


The osteotome technique: Part 4--Future site development.
Previous articles in the Compendium (February 1944, April 1944, and June 1944) described the use of osteotome hand instruments for maxillary implant surgery. The osteotome procedures that were introduced compressed soft maxillary bone, widened narrow ridge segments (ridge expansion osteotomy [REO] technique), and elevated the sinus floor for immediate implant insertion (osteotome sinus floor elevation [OSFE] and bone-added osteotome sinus floor elevation [BAOSFE] surgery). This article presents an improved method of creating sites with osteotomes under a low sinus when there is insufficient bone for immediate fixation of implants. In addition, a new means of intruding the ridge crest with larger osteotomes to create broader areas of sinus floor elevation, known as the future site development (FSD) procedure, is outlined. A comparison of FSD with current types of sinus floor surgery is detailed. The advantages of combining FSD with periodontal surgery, other regenerative procedures, and tooth extraction is presented. The author concludes that FSD surgery is a suitable means of altering the ridge to create implant sites for staged implant placement.


A radio frequency single-electron transistor based on an InAs/InP heterostructure nanowire.
We demonstrate radio frequency single-electron transistors fabricated from epitaxially grown InAs/InP heterostructure nanowires. Two sets of double-barrier wires with different barrier thicknesses were grown. The wires were suspended 15 nm above a metal gate electrode. Electrical measurements on a high-resistance nanowire showed regularly spaced Coulomb oscillations at a gate voltage from -0.5 to at least 1.8 V. The charge sensitivity was measured to 32 microe rms Hz(-1/2) at 1.5 K. A low-resistance single-electron transistor showed regularly spaced oscillations only in a small gate-voltage region just before carrier depletion. This device had a charge sensitivity of 2.5 microe rms Hz(-1/2). At low frequencies this device showed a typical 1/f noise behavior, with a level extrapolated to 300 microe rms Hz(-1/2) at 10 Hz.


Androgens and coronary artery disease.
A significant and independent association between endogenous testosterone (T) levels and coronary events in men and women has not been confirmed in large prospective studies, although cross-sectional data have suggested coronary heart disease can be associated with low T in men. Hypoandrogenemia in men and hyperandrogenemia in women are associated with visceral obesity; insulin resistance; low high-density lipoprotein (HDL) cholesterol (HDL-C); and elevated triglycerides, low-density lipoprotein cholesterol, and plasminogen activator type 1. These gender differences and confounders render the precise role of endogenous T in atherosclerosis unclear. Observational studies do not support the hypothesis that dehydroepiandrosterone sulfate deficiency is a risk factor for coronary artery disease. The effects of exogenous T on cardiovascular mortality or morbidity have not been extensively investigated in prospective controlled studies; preliminary data suggest there may be short-term improvements in electrocardiographic changes in men with coronary artery disease. In the majority of animal experiments, exogenous T exerts either neutral or beneficial effects on the development of atherosclerosis. Exogenous androgens induce both apparently beneficial and deleterious effects on cardiovascular risk factors by decreasing serum levels of HDL-C, plasminogen activator type 1 (apparently deleterious), lipoprotein (a), fibrinogen, insulin, leptin, and visceral fat mass (apparently beneficial) in men as well as women. However, androgen-induced declines in circulating HDL-C should not automatically be assumed to be proatherogenic, because these declines may instead reflect accelerated reverse cholesterol transport. Supraphysiological concentrations of T stimulate vasorelaxation; but at physiological concentrations, beneficial, neutral, and detrimental effects on vascular reactivity have been observed. T exerts proatherogenic effects on macrophage function by facilitating the uptake of modified lipoproteins and an antiatherogenic effect by stimulating efflux of cellular cholesterol to HDL. In conclusion, the inconsistent data, which can only be partly explained by differences in dose and source of androgens, militate against a meaningful assessment of the net effect of T on atherosclerosis. Based on current evidence, the therapeutic use of T in men need not be restricted by concerns regarding cardiovascular side effects. Available data also do not justify the uncontrolled use of T or dehydroepiandrosterone for the prevention or treatment of coronary heart disease.


Enhanced expression of DNA topoisomerase II by recombinant human granulocyte colony-stimulating factor in human leukemia cells.
The effect of recombinant human granulocyte colony-stimulating factor (G-CSF) on DNA topoisomerase II (topo II) expression was studied in two human acute myelogenous leukemia cell lines, NKM-1 and NOMO-1, which express G-CSF receptor and proliferate in response to exogenous G-CSF. Northern blot analysis revealed that the level of topo II mRNA in 16-h stimulated cells in serum-free medium with G-CSF (10 ng/ml) was approximately 2-fold higher than that in cells without G-CSF. Enhanced topo II mRNA expression was detectable within 3 h after the addition of G-CSF. Topo II activity in crude nuclear extracts from 16-h G-CSF-stimulated cells was also found to be approximately 2-fold greater than that from unstimulated cells. According to in vitro cytotoxic assay, the sensitivity of G-CSF-stimulated cells to intercalating (daunorubicin) and nonintercalating (etoposide) topo II-targeting drugs increased significantly, whereas no enhancement of sensitivity was observed with an alkylating agent (4-hydroperoxycyclophosphamide). The augmented drug sensitivity observed was not due to the increased level of drug transport, as suggested by the similar extent of [3H]etoposide uptake between G-CSF-stimulated and unstimulated cells. By measuring the topo II mRNA and the cytotoxicity of the above mentioned drugs, we obtained essentially the same results in G-CSF-responsive leukemia cells isolated from three acute myeloblastic leukemia patients, as observed in the cultured cell lines. These findings strongly suggest that the sensitivity to "topo II-targeting drugs" could be augmented by exogenous G-CSF through elevated topo II activity in G-CSF-responsive leukemia cells.


Cytokines, chaperones and neuroinflammatory responses in heroin-related death: what can we learn from different patterns of cellular expression?
Heroin (3,6-diacetylmorphine) has various effects on the central nervous system with several neuropathological alterations including hypoxic-ischemic brain damage from respiratory depressing effects and neuroinflammatory response. Both of these mechanisms induce the release of cytokines, chemokines and other inflammatory mediators by the activation of many cell types such as leucocytes and endothelial and glial cells, especially microglia, the predominant immunocompetent cell type within the central nervous system. The aim of this study is to clarify the correlation between intravenous heroin administration in heroin related death and the neuroinflammatory response. We selected 45 cases among autopsies executed for heroin-related death (358 total cases); immunohistochemical studies and Western blotting analyses were used to investigate the expression of brain markers such as tumor necrosis factor-α, oxygen-regulated protein 150, (interleukins) IL-1β, IL-6, IL-8, IL-10, IL-15, cyclooxygenase-2, heat shock protein 70, and CD68 (MAC387). Findings demonstrated that morphine induces inflammatory response and cytokine release. In particular, oxygen-regulated protein 150, cyclooxygenase-2, heat shock protein 70, IL-6 and IL-15 cytokines were over-expressed with different patterns of cellular expression.


Neuromusculoskeletal conditions of the upper extremity: are they due to repetitive occupational trauma?
The significance of neuromusculoskeletal conditions in the workplace is the subject of much discussion among occupational medicine professionals. There are differing philosophies as to what constitutes appropriate diagnostic criteria for identification of these conditions. The traditional diagnostic model requires the presence of objective pathology. An emerging symptom-based model accepts that symptoms by themselves can constitute a diagnostic entity. The extent to which these conditions are considered to be associated with occupational activity depends greatly upon which of the two models is employed. This chapter presents an overview of each diagnostic model and a discussion of the impact each has on the prevalence of identified conditions and the manner in which the various diagnostic requirements can affect treatment, prevention, and disability rating protocols.


[Psychological aspects and essential arterial hypertension].
In addition to organic and hereditary factors, psychological variations among individuals are also known to play an important role in the etiology of essential arterial hypertension. To investigate in detail the psychological processes possibly involved in the etiology of essential arterial hypertension. A group of 20 subjects, all of whom where diagnosed as suffering from essential arterial hypertension, was studied using psychological interviews and the Rorschach Test. The results obtained were compared with those gathered from normal (non-hypertensive) individuals represented by the Rorschach Test for the Brazilian population. In terms of personality structure, the hypertensive group presented signs of subjective and immature mechanics which prevailed over more mature and adult traits. These characteristics lead the patients to emotional withdrawal as a defense inadequate affectivity. The blocking of emotional expression, as well as simultaneous anxiety, may affect the autonomic nervous system and lead to periodic transitory hypertensive crises which, with time assume a permanent nature.


[Airway management of COVID-19 patients: a survey on the experience of 1125 physicians in Spain].
We explored the experience of clinicians from the Spanish Society of Anesthesiology in airway management of COVID-19 patients. An software-based survey including a 32-item questionnaire was conducted from April 18 to May 17, 2020. Participants who have been involved in tracheal intubations in patients with suspected or confirmed COVID-19 infection were included anonymously after obtaining their informed consent. The primary outcome was the preferred airway device for tracheal intubation. Secondary outcomes included the variations in clinical practice including the preferred video laryngoscope, plans for difficult airway management, and personal protective equipment. 1125 physicians completed the questionnaire with a response rate of 40,9%. Most participants worked in public hospitals and were anesthesiologists.The preferred device for intubation was the video laryngoscope (5.1/6), with the type of device in decreasing order as follows: Glidescope, C-MAC, Airtraq, McGrath and King Vision. The most frequently used device for intubation was the video laryngoscope (70,5%), using them in descending order as follow: the Airtraq, C-MAC, Glidescope, McGrath and King Vision.Discomfort of intubating wearing personal protective equipment and the frequency of breaching a security step was statistically significant, increasing the risk of cross infection between patients and physicians. The opinion of senior doctors differed from younger physicians in the type of video-laryngoscope used, the number of experts involved in tracheal intubation and the reason that caused more stress during the airway management. Most physicians preferred using a video-laryngoscope with remote monitor and disposable Macintosh blade, using the Frova guide.


The effects of a heating pad on anxiety, pain, and distress during urodynamic study in the female patients with stress urinary incontinence.
Although generally well tolerated, a urodynamic study is an unpleasant and stressful procedure for some patients. This study evaluated the effects of a heating pad on anxiety, pain, and distress during urodynamic studies in female patients with stress urinary incontinence. A total of 74 female patients with stress urinary incontinence who underwent a urodynamic study between May 2015 and October 2015 were randomized to either the experimental group using a heating pad (n = 37) or control group (n = 37). In the experimental group, a heating pad was applied on the patient's sacrum during the urodynamic study. All patients completed the State-Trait Anxiety Inventory (20-80) before and after the procedure and assessed their degree of pain and distress after the procedure by the visual analog scale (0-10). Systolic and diastolic blood pressure and pulse rate were also checked before and after the procedure. Demographic characteristics, mean age, procedure duration, pre and post-procedural systolic, and diastolic blood pressures, and pulse rate were statistically similar between the experimental and control groups. The mean State-Trait Anxiety Inventory was significantly lower in the experimental group than in the control group (30.9 ± 7.5 vs 42.5 ± 10.1, P < 0.001). The experimental group showed significantly lower pain and distress scores (Visual Analog Scale, 2.7 ± 1.5, 3.0 ± 1.5) compared with the control group (4.0 ± 1.6, 4.7 ± 2.0, both P < 0.001). Using a heating pad for female patients with stress urinary incontinence during a urodynamic study is a simple, economical, and effective therapy that enhances patient comfort and decreases anxiety, pain, and distress.


Refractive error and ocular biometry in Jordanian adults.
The aim of this study was to establish the prevalence of refractive errors in Jordanian adults of working age, and to study the ocular biometric correlates of refractive error in this population. Refractive error and ocular biometry were measured in 1093 Jordanian adult subjects aged 17-40 years to determine the prevalence of refractive error, and explore structural correlations of ametropia. Refractive error was measured using a Grand-Seiko GR-3100K closed-view infrared autorefractor. Ocular component measurements were made using A-scan ultrasonography and autokeratometry. The prevalence of myopia [spherical equivalent refraction (SER) less than -0.50 DS] and hyperopia (SER greater than +0.50 DS) was 53.71 and 5.67% respectively; 40.62% of the sample was emmetropic (refraction between +0.50 D and -0.50 D inclusive in both principal meridians). The distribution of SER was found to show marked leptokurtosis, exhibiting a peak between plano and 1 D of myopia. Corneal radius, anterior chamber depth, crystalline lens thickness, vitreous chamber depth and axial length (AL) parameters were normally distributed in the population studied. AL to corneal curvature ratio was not normally distributed, and showed marked leptokurtosis. Linear regression analysis showed that AL correlated most closely with spherical equivalent refractive error. This study has established a database of refractive error prevalence and ocular biometric correlates of ametropia in a Middle Eastern population of working age.


Significance of the reductase-dependent pathway for the beta-oxidation of unsaturated fatty acids with odd-numbered double bonds. Mitochondrial metabolism of 2-trans-5-cis-octadienoyl-CoA.
The beta-oxidation of unsaturated fatty acids with odd-numbered double bonds proceeds by reduction of the double bond (reductase-dependent pathway) in addition to the well established isomerization of the double bond (isomerase-dependent pathway). The metabolic significance of the reductase-dependent pathway was assessed with 2-trans-5-cis-octadienoyl-CoA (2,5-octadienoyl-CoA) and its products, all of which are metabolites of alpha-linolenic acid. A kinetic evaluation of beta-oxidation enzymes revealed that the presence of a 5-cis double bond in the substrate most adversely affected the activity of 3-ketoacyl-CoA thiolase although not enough to become rate-limiting. Concentration-dependent and time-dependent measurements indicated that most (80%) of 2,5-octadienoyl-CoA is metabolized via the isomerase-dependent pathway. The reason for the greater flux through the isomerase-dependent pathway is the higher activity of L-3-hydroxyacyl-CoA dehydrogenase as compared with Delta3,Delta2-enoyl-CoA isomerase. These two enzymes catalyze the rate-limiting steps in the isomerase-dependent and reductase-dependent pathways, respectively. Once 2,5-octadienoyl-CoA is converted to 3,5-octadienoyl-CoA (perhaps fortuitously because of the presence of Delta3,Delta2-enoyl-CoA isomerase), the only effective route for its degradation is via the reductase-dependent pathway. It is concluded that the reductase-dependent pathway assures the degradation of 3,5-dienoyl-CoA intermediates, thereby preventing the depletion of free coenzyme A and a likely impairment of mitochondrial oxidative function.


Functional impairments among adults with ADHD: A comparison with adults with other psychiatric disorders and links to executive deficits.
The aim of the present study was to investigate daily life functioning in adults with ADHD and adults with other psychiatric disorders and to compare ADHD subgroups with or without executive deficits. Daily life functioning was assessed using self-ratings covering the following domains: academic/occupational functioning, social relations, daily life problems, and criminality. Executive deficits were assessed using self-ratings and laboratory tests of working memory, inhibition, and shifting. The results showed that adults with ADHD were more impaired with regard to academic functioning, current occupational status, daily life functioning, criminality, and some aspects of social functioning. The ADHD subgroup with executive deficits had more impairments than the subgroup without executive deficits with regard to academic functioning, current occupational status, and criminality. Conclusively, ADHD in adulthood is related to significant impairment in many areas of daily functioning, also compared to patients with other psychiatric disorders. Executive functioning deficits appear to at least partly explain these impairments.


[The action of bacterial antagonists on the aerobic microflora of human skin].
The authors have investigated antagonistic action of museum strains-antagonists Bacillus subtilis 2896, B. licheniformis 254 and Escherichia coli M-17 against 698 strains of staphylococci, 518 micrococci, 315 corynebacteria, 74 aerobic bacilli and 26 enterobacteria isolated from the surface of stomach and skin of 102 healthy people of different sex. The investigations have shown that B. subtilis 2896 and E. coli M-17 were most active: they inhibited the growth of micrococci, corynebacteria, bacilli, enterobacteria and pseudomonads. Bacteria B. licheniformis have manifested the less antagonistic effect of representatives of skin microbiocenoses. These are B. subtilis and E. coli M-17 that are recommended for clinical testing with the purpose of correction of skin microbiocenoses and for preventing from the development of pyo-septic complications of skin.


Tolerance and cardiovascular effects of single dose felodipine/beta-blocker combinations in healthy subjects.
The effects of single oral doses of 10 mg felodipine and four beta-blockers (100 mg metoprolol, 5 mg pindolol, 80 mg propranolol, and 10 mg timolol) were evaluated alone and in combination in a 10-way crossover, double-blind, placebo-controlled trial in 10 healthy male volunteers randomized to the medication sequence according to a latin square design. Adverse effects were recorded from spontaneous complaints and investigator observations. Heart rate (HR), PR interval, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured supine, standing, and after treadmill exercise, before and 2 h after drug administration. The adverse effects experienced with felodipine were as expected for a vasodilator. Seven subjects mentioned complaints voluntarily on the combinations while three experienced side effects receiving felodipine or beta-blocker alone. Felodipine increased resting HR significantly. Timolol produced a greater depression of exercise heart rate than the other beta-blockers, indicating that the dose given was not equivalent to that of the other beta-blockers. Pindolol was ineffective in preventing the increase in supine HR produced by felodipine. Felodipine did not alter PR interval at any level of activity, but rate-corrected supine PR interval was prolonged slightly by felodipine. Metoprolol and timolol significantly prolonged standing PR interval. All beta-blockers prolonged exercise PR interval. Felodipine/beta-blocker combinations did not prolong PR interval more than beta-blockers alone. Prolonged PR interval was the result of reduced HR and direct inhibition of atrioventricular (AV) conduction. Only timolol and the timolol/felodipine combination lowered supine systolic blood pressure significantly. Timolol and all beta-blocker/felodipine combinations reduced exercise SBP significantly.


Marivirga aurantiaca sp. nov., a halophilic nitrite-reducing bacterium, isolated from intertidal surface sediments.
A novel Gram-stain-negative strain, designated S37H4T, was isolated from an intertidal surface sediment sample collected from Zhanjiang City, Guangdong province, south PR China. Cells of the strain were aerobic, non-flagellated, long rod-shaped and motile by gliding. S37H4T could grow at 4-40 °C, pH 7.0-8.5 and in 2.0-15.0 % NaCl, with optimal growth at 25-30 °C, pH 7.5 and 9.0 % NaCl, respectively. S37H4T was capable of nitrite removal under high-salt conditions, and there were three denitrification genes, nirK, norB and nosZ, in its genome. The results of phylogenetic analyses based on the 16S rRNA gene and genome sequences indicated that S37H4T represented a member of the genus Marivirga and formed a subclade with Marivirga lumbricoides JLT2000T. S37H4T showed the highest 16S rRNA sequence similarity to M. lumbricoides JLT2000T (98.3 %) and less than 97.0 % similarity with other type strains of species of the genus Marivirga. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between S37H4T and the reference type strains of species of the genus Marivirga were 70.7-74.3 % and 18.2-19.2 %, respectively. The major fatty acids of S37H4T were iso-C15 : 0, iso-C15 : 1G, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c). The major respiratory quinone of this novel strain was MK-7, and the predominant polar lipids were identified as phosphatidylethanolamine, an unidentified aminolipid, an unidentified phospholipid and three unidentified lipids. The results of analyses of phylogenetic, genomic, physiological and biochemical characteristics indicated that S37H4T represented a novel species of the genus Marivirga, for which the name Marivirga aurantiaca sp. nov. is proposed. The type strain is S37H4T (= GDMCC 1.1866T = KACC 21922T).


Patterns of mycoplasma shedding in the milk of dairy cows with intramammary mycoplasma infection.
To determine patterns of mycoplasma shedding in the milk of dairy cows with intramammary mycoplasma infection. Prospective clinical trial. 10 Holstein cows with intramammary mycoplasma infection. Milk samples were collected from each cow daily for 28 days and plated on mycoplasma agar to evaluate shedding patterns. To determine whether enrichment improved recovery of organisms, some samples were also inoculated in mycoplasma enrichment medium and incubated for 4 days prior to plating. Somatic cell count (SCC) was determined in samples collected weekly. Mycoplasma organisms were not isolated from 81 of 280 (29%) composite milk samples, but > 10(6) colonies/mL were obtained from 151 (54%). Similarly, mycoplasma organisms were not isolated from 433 of 1,008 (43%) quarter milk samples, but > 10(6) colonies/mL were obtained from 392 (39%). For 71 of 104 (68%) samples, mycoplasma organisms were isolated both following direct plating and following enrichment; for 24 of 104 (23%), mycoplasma organisms were isolated only following enrichment; and for 9 of 104 (9%), mycoplasma organisms were isolated only after direct plating. There was a linear correlation between logarithm of the SCC and logarithm of the number of colony-forming units of mycoplasma per milliliter of milk for composite and quarter milk samples. Shedding of organisms was inconsistent in dairy cows with intramammary mycoplasma infection, increasing the risk of misdiagnosis if multiple milk samples are not tested.


Protein and lipid metabolism adjustments in silver catfish (Rhamdia quelen) during different periods of fasting and refeeding.
The fish may experience periods of food deprivation or starvation which produce metabolic changes. In this study, adult Rhamdia quelen males were subjected to fasting periods of 1, 7, 14, and 21 days and of refeeding 2, 4, 6, and 12 days. The results demonstrated that liver protein was depleted after 1 day of fasting, but recovered after 6 days of refeeding. After 14 days of fasting, mobilization in the lipids of the muscular tissue took place, and these reserves began to re-establish themselves after 4 days of refeeding. Plasmatic triglycerides increased after 1 day of fasting, and decreased following 2 days of refeeding. The glycerol in the plasma oscillated constantly during the different periods of fasting and refeeding. Changes in the metabolism of both protein and lipids during these periods can be considered as survival strategies used by R. quelen. The difference in the metabolic profile of the tissues, the influence of the period of fasting, and the type of reserves mobilized were all in evidence.


D1 dopamine receptor activation required for postsynaptic expression of D2 agonist effects.
D1 and D2 dopamine receptors exert synergistic effects on the firing rates of basal ganglia neurons and on the expression of stereotyped behavior in rats. Moreover, the ability of D2 agonists to induce changes in basal ganglia single unit activity and spontaneous motor activity is dependent upon the presence of endogenous dopamine to stimulate D1 receptors; in rats treated with alpha-methyl-rho-tyrosine to reduce endogenous dopamine levels, the neurophysiological and behavioral effects of the D2 agonist quinpirole are significantly attenuated, while the effects of nonselective agonists like apomorphine, which stimulate both D1 and D2 receptors, or combinations of a D2 agonist and a D1 agonist are not attenuated. Thus, the previously held view that D2 receptors alone are responsible for evoking the changes in behavior and basal ganglia output induced by nonselective dopamine agonists and endogenous dopamine is not supported by these results, which indicate that these phenomena require concurrent stimulation of both dopamine receptor subtypes.


Role of lysine, tryptophan and calcium in the beta-elimination activity of a low-molecular-mass pectate lyase from Fusarium moniliformae.
An extracellular pectate lyase from Fusarium moniliformae was purified to homogeneity by affinity chromatography followed by gel filtration, with a yield of 76.5%. Laser desorption MS of the enzyme gave a molecular mass of 12,133.5 +/- 2.5 Da. The pectate lyase was a glycoprotein with a 5% carbohydrate content and had a pl value of 9.1. Atomic-emission spectrometry showed that Ca2+ was a part of the holoenzyme held by carboxy groups of the protein. These results support the hypothesis of a putative Ca2+ site suggested by Yodder, Keen and Jurnak [(1993) Science 260, 1503-1507] in the crystal structure of pectate lyase C of Erwinia chrysanthemi. Loss of Ca2+ was observed by treatment with EGTA or carboxy-modifying Woodward's reagent K, with subsequent loss of enzyme activity. Tryptophan fluorescence quenching showed that Ca2+ does not affect binding of substrate to enzyme. Chemical-modification and substrate-protection studies showed the presence of lysine and tryptophan at or near the active site of the pectate lyase. Chemically modified enzyme showed no major structural changes as determined by CD. Amino acid analyses of native, trinitrobenzenesulphonate (TBNS)-treated and substrate-protected TNBS-treated enzyme showed that a single essential residue of lysine is present at or near the active-site. Substrate-affinity studies showed that tryptophan could be essential for substrate binding, whereas lysine could be involved in the catalysis. Fluorescence quenching further confirmed the involvement of tryptophan in substrate binding. The reaction mechanism involving beta-elimination by this enzyme is discussed.


[Recent studies on Aujesky's dissease in pigs and cattle (author's transl)].
A standardized test model for Aujeszky disease (AD) vaccines in pigs is described. The first two vaccines tested, a modified live virus (MLV) vaccine and an inactivated vaccine, failed to produce satisfactory results. The inactivated vaccine induced a short-lived, but clear-cut increase in body temperature in some of the vaccinated pigs; the MLV-vaccine was shown to spread. Complete protection against intranasal (i.n.) challenge was not achieved with either vaccine in five-month-old pigs that had been vaccinated once or even twice two to three months previously. However, the vaccinated pigs were less severely affected, and for shorter periods, than were the control animals; losses from death did not occur. In the control groups, at least thirty per cent died, the average growth of the remainder was arrested for more than three weeks. The mean period of arrested growth after challenge of pigs vaccinated once with the MLV-vaccine was slightly shorter than that following a single vaccination with the inactivated vaccine: 5.8 and 9.5 days respectively. The average virus excretion of vaccinated pigs after challenge was less and was not as protracted as in unvaccinated controls. In pigs from sows hyperimmunized with the inactivated vaccine, maternal antibodies afforded partial protection against i.n. challenge at the age of two months. However, five-month-old pigs were fully susceptible, although most of them continued to show low levels of neutralizing antibody. The average virus excretion after challenge in the two age-groups was comparable with that in control pigs. Cattle were effectively protected by vaccination with the inactivated vaccine against i.n. challenge with AD-virus. It is recommended to vaccinate "threatened" cattle twice, for instance in the autumn when they are removed from the pastures for indoor housing. The possibility that temperature reactions may occur should be taken into account.


History of childhood abuse and neglect and suicidal behavior at hospital admission.
Suicide is a major public health problem. Preventive measures have been sought by identifying risk factors. This study evaluates the association of childhood abuse and neglect with suicidal behavior at the time of psychiatric hospital admission. A total of 120 subjects (72 females; mean age 42.5 +/- 15.6 years old) admitted from August 2006 to July 2007 completed the Childhood Trauma Questionnaire (CTQ) to assess severity of exposure to childhood maltreatment. Thereof 62 (51.6%) patients presented with suicidal behavior at admission. Patients who had attempted suicide had significantly higher CTQ scores. Regression analysis indicated that shorter illness duration and severity of childhood maltreatment were predictors of suicidal behavior at admission. The study showed that inpatients of a psychiatric unit of a general hospital who experienced severe childhood abuse or neglect were significantly more likely to present with suicidal behavior. History of childhood maltreatment should be evaluated as an associated risk factor of suicidal behavior at admission of psychiatric inpatients.


An adaptive Kalman filter technique for context-aware heart rate monitoring.
Traditional physiological monitoring systems convert a person's vital sign waveforms, such as heart rate, respiration rate and blood pressure, into meaningful information by comparing the instant reading with a preset threshold or a baseline without considering the contextual information of the person. It would be beneficial to incorporate the contextual data such as activity status of the person to the physiological data in order to obtain a more accurate representation of a person's physiological status. In this paper, we proposed an algorithm based on adaptive Kalman filter that describes the heart rate response with respect to different activity levels. It is towards our final goal of intelligent detection of any abnormality in the person's vital signs. Experimental results are provided to demonstrate the feasibility of the algorithm.


Rapid accumulation of intracellular 2-keto-3-deoxy-6-phosphogluconate in an Entner-Doudoroff aldolase mutant results in bacteriostasis.
The accumulation of 2-keto-3-deoxy-6-phosphogluconate, the key intermediate of the Entner-Doudoroff pathway, has long been thought to inhibit growth of bacteria, but careful measurements of 2-keto-3-deoxy-6-phosphogluconate accumulation by growing cells and the correlation of intracellular 2-keto-3-deoxy-6-phosphogluconate levels to growth inhibition had not been made. A system designed for this purpose was developed in Escherichia coli strains, allowing 2-keto-3-deoxy-6-phosphogluconate accumulation to be experimentally induced and measured by extraction of the cell pool. Addition of gluconate to a strain which lacked 2-keto-3-deoxy-6-phosphogluconate aldolase and overproduced 6-phosphogluconate dehydratase resulted in an increase in the intracellular concentration of 2-keto-3-deoxy-6-phosphogluconate from undetectable levels to 2.0 mM within 15 s, as measured by anion-exchange HPLC. The accumulation of 2-keto-3-deoxy-6-phosphogluconate was correlated with an immediate and significant decrease in growth; this inhibition was determined to be bacteriostatic and not bactericidal. It had been proposed that the mechanism of 2-keto-3-deoxy-6-phosphogluconate toxicity involves competitive inhibition of 6-phosphogluconate dehydrogenase and the consequent block of the pentose phosphate pathway. An experiment addressing this hypothesis failed to provide any supporting data.


Diallyl disulfide inhibits TNFα-induced CCL2 release by MDA-MB-231 cells.
Monocyte chemotactic protein-1 (MCP-1/CCL2) is released by tumor tissues, serving as a potent chemokine enabling directional homing of mononuclear cells to tumor tissue, which subsequently differentiate into tumor-associated macrophages (TAMs) via TGFβ1 signaling. TAMs readily invade tumor tissue and continue to synthesize pro-oncogenic proteins including tumor growth factors, matrix proteases (metastasis), angiogenic factors (neovascularization) and CCL2. Substances, which can attenuate or block the initial release of CCL2 have been shown to prevent cancer-associated inflammative pro-oncogenic processes. In the current study, we investigated the effects of the organosulfur compound diallyl disulfide (DADS), a natural constituent of Allium sativum (garlic) on suppression of TNFα-induced release of CCL2 from triple-negative human breast tumor (MDA-MB-231) cells. Using an initial adipokine/chemokine protein panel microarray, the data show a predominant expression profile in resting/untreated MDA-MB-231 cells for sustained release of IL6, IL8, plasminogen Activator Inhibitor 1 and TIMP1/2. Treatment with TNFα (40 ng/ml) had no effect on many of these molecules, with a single major elevation in release of CCL2 (~1,300-fold up-regulation). TNFα-induced CCL2 release was reversed by a sub-lethal concentration of DADS (100 μM), evident in antibody based assays. These findings provide evidence to support another avenue of anticancer/chemopreventative properties attributable to garlic constituents through immunomodulation.


Year-Round Shotgun Metagenomes Reveal Stable Microbial Communities in Agricultural Soils and Novel Ammonia Oxidizers Responding to Fertilization.
The dynamics of individual microbial populations and their gene functions in agricultural soils, especially after major activities such as nitrogen (N) fertilization, remain elusive but are important for a better understanding of nutrient cycling. Here, we analyzed 20 short-read metagenomes collected at four time points during 1 year from two depths (0 to 5 and 20 to 30 cm) in two Midwestern agricultural sites representing contrasting soil textures (sandy versus silty loam) with similar cropping histories. Although the microbial community taxonomic and functional compositions differed between the two locations and depths, they were more stable within a depth/site throughout the year than communities in natural aquatic ecosystems. For example, among the 69 population genomes assembled from the metagenomes, 75% showed a less than 2-fold change in abundance between any two sampling points. Interestingly, six deep-branching Thaumarchaeota and three complete ammonia oxidizer (comammox) Nitrospira populations increased up to 5-fold in abundance upon the addition of N fertilizer. These results indicated that indigenous archaeal ammonia oxidizers may respond faster (are more copiotrophic) to N fertilization than previously thought. None of 29 recovered putative denitrifier genomes encoded the complete denitrification pathway, suggesting that denitrification is carried out by a collection of different populations. Altogether, our study identified novel microbial populations and genes responding to seasonal and human-induced perturbations in agricultural soils that should facilitate future monitoring efforts and N-related studies.IMPORTANCE Even though the impact of agricultural management on the microbial community structure has been recognized, an understanding of the dynamics of individual microbial populations and what functions each population carries are limited. Yet, this information is important for a better understanding of nutrient cycling, with potentially important implications for preserving nitrogen in soils and sustainability. Here, we show that reconstructed metagenome-assembled genomes (MAGs) are relatively stable in their abundance and functional gene content year round, and seasonal nitrogen fertilization has selected for novel Thaumarchaeota and comammox Nitrospira nitrifiers that are potentially less oligotrophic than their marine counterparts previously studied.


Habitual cold-water swimming and upper respiratory tract infection.
It has long been claimed that non-wetsuit cold water swimming (CWS) benefits health (1), and anecdotally cold-water swimmers claimed to suffer fewer and milder infections, though this was not directly measured. A boost to immunity is biologically plausible: stress hormones are released during cold-water immersion (2), and short-term stress may ready the immune system for injury or infection (3). However, very few studies have investigated immune system markers and/or actual illness in habitual cold-water swimmers.


From roads to biobanks: Roadkill animals as a valuable source of genetic data.
To protect biodiversity we must understand its structure and composition including the bacteria and microparasites associated with wildlife, which may pose risks to human health. However, acquiring this knowledge often presents challenges, particularly in areas of high biodiversity where there are many undescribed and poorly studied species and funding resources can be limited. A solution to fill this knowledge gap is sampling roadkill (animals that die on roads as a result of collisions with circulating vehicles). These specimens can help characterize local wildlife and their associated parasites with fewer ethical and logistical challenges compared to traditional specimen collection. Here we test this approach by analyzing 817 tissue samples obtained from 590 roadkill vertebrate specimens (Amphibia, Reptilia, Aves and Mammalia) collected in roads within the Tropical Andes of Ecuador. First, we tested if the quantity and quality of recovered DNA varied across roadkill specimens collected at different times since death, exploring if decomposition affected the potential to identify vertebrate species and associated microorganisms. Second, we compared DNA stability across taxa and tissues to identify potential limitations and offer recommendations for future work. Finally, we illustrate how these samples can aid in taxonomic identification and parasite detection. Our study shows that sampling roadkill can help study biodiversity. DNA was recovered and amplified (allowing species identification and parasite detection) from roadkill even 120 hours after death, although risk of degradation increased overtime. DNA was extracted from all vertebrate classes but in smaller quantities and with lower quality from amphibians. We recommend sampling liver if possible as it produced the highest amounts of DNA (muscle produced the lowest). Additional testing of this approach in areas with different environmental and traffic conditions is needed, but our results show that sampling roadkill specimens can help detect and potentially monitor biodiversity and could be a valuable approach to create biobanks and preserve genetic data.


An open-label trial of citalopram for major depression in patients with hepatitis C.
Hepatitis C affects nearly 4 million Americans. Depression is a common comorbid condition in this population and may be induced by interferon alfa, an approved treatment for hepatitis C. Depression is a major indicator for discontinuation of interferon therapy. This open-label study examines the effect of citalopram on measures of depression and quality of life and tests of liver function in subjects with hepatitis C and major depressive disorder. Subjects were recruited by advertisement; those with DSM-IV major depressive disorder were included in the study. Subjects received citalopram for 8 weeks starting at 20 mg/day. Dosage adjustments were made as the physicians deemed clinically necessary. No dosages were increased prior to week 4 of the study. Hamilton Rating Scale for Depression (HAM-D) scores, Clinical Global Impressions-Severity of Illness scale (CGI-S) scores, Medical Outcomes Study Short Form Health Survey (SF-36) ratings, Symptom Checklist-90-Revised (SCL-90-R) scores, and liver function tests were obtained at baseline, 4 weeks, and 8 weeks. A total of 15 patients (10 men, 5 women) participated in this study. The mean daily dose of citalopram at endpoint was 26.67 mg. Mean HAM-D scores decreased significantly with treatment (F = 36.3, df = 2,42; p = .0001). Thirteen of the 15 subjects demonstrated a clinical response, defined as a 50% or greater reduction in HAM-D scores. CGI-Severity of Illness scores also improved significantly (p = .0001). Subjects demonstrated statistically significant improvement (p < .05) on all of the SF-36 subscales. Statistically significant improvements (p < .05) were also demonstrated on all subscales of the SCL-90-R. Tests of liver function showed no significant worsening of aspartate aminotransferase, alanine aminotransferase, or gamma-glutamyltransferase levels. These results suggest that depression in patients with hepatitis C may be effectively and safely treated with citalopram.


High Prevalence of Metallo-β-Lactamase-Producing Enterobacter cloacae From Three Tertiary Hospitals in China.
Enterobacter cloacae has recently emerged as one of the most common carbapenem-resistant Enterobacteriaceae. The emergence and spread of metallo-β-lactamase-producing E. cloacae have posed an immediate threat globally. Here, we investigated the molecular characteristics of 84 carbapenem-resistant Enterobacter cloacae (CREL) collected from three tertiary hospitals in China between 2012 and 2016. Species identification and antimicrobial susceptibility testing were performed using a VITEK-2 system. Carbapenems, polymyxins B, and tigecycline were tested by broth microdilution method. The carbapenem in activation method (CIM) and cefoxitin three-dimensional test were used to detect carbapenemase and AmpC β-lactamase, respectively. Isolates were screened for β-lactam resistance genes by PCR, and expression of ompC and ompF was determined by qRT-PCR. Genetic relatedness was performed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), while selected isolates were subjected to whole-genome sequencing. Among the 84 CREL isolates, 50 (59.5%) were detected as carbapenemase producers. NDM-1 was the dominant carbapenemase (80.0%), followed by IMP-26 (8.0%) and IMP-4 (6.0%). Notably, we identified the first NDM-1 and IMP-1 co-producing E. cloacae, carrying plasmids of several incompatibility (Inc) groups, including IncHI2, IncHI2A, and IncN. Most isolates showed decreased expression of ompC and/or ompF, and contained a broad distribution of ESBLs and AmpC β-lactamases. These findings suggested that different molecular mechanisms, including carbapenemase, ESBL and/or AmpC plus loss of porins, have contributed to carbapenem resistance. The bla NDM-1-harboring plasmids contained highly conserved gene environment around bla NDM-1 (bla NDM-1-ble MBL-trpF-dsbD-cutA1-groES-groEL), which could be associated with the potential dissemination of bla NDM-1. IMP-type MBL was located within a variety of integrons and usually contained various gene cassettes encoding multidrug resistance. These isolates produced 54 different pulsotypes, and were classified into 42 STs by MLST. Nineteen bla NDM-1-positive E. cloacae isolates obtained from Ningxia had the same pulsotype (PFGE type 1), belonging to ST78 within clonal complex 74 (CC74). The plasmid-based replicon typing indicated that IncX3 plasmids mediated the dissemination of bla NDM-1 among these homologous strains. This is the first report on the outbreak of NDM-1-producing E. cloacae ST78 with contribution of IncX3 plasmids in Northwestern China. There's an immediate need to intensify surveillance attentively to prevent and control the further spread of NDM-1 in China.


Equipoise across the patient population: optimising recruitment to a randomised controlled trial.
This paper proposes a novel perspective on the value of qualitative research for improving trial design and optimising recruitment. We report findings from a qualitative study set within the OPEN trial, a surgical randomised controlled trial (RCT) comparing two interventions for recurrent bulbar urethral stricture, a common cause of urinary problems in men. Interviews were conducted with men meeting trial eligibility criteria (n = 19) to explore reasons for accepting or declining participation and with operating urologists (n = 15) to explore trial acceptability. Patients expressed various preferences and understood these in the context of relative severity and tolerability of their symptoms. Accounts suggest a common trajectory of worsening symptoms with a particular window within which either treatment arm would be considered acceptable. Interviews with clinician recruiters found that uncertainty varied between general and specialist sites, which reflect clinicians' relative exposure to different proportions of the patient population. Recruitment post referral, at specialist sites, was challenging due to patient (and clinician) expectations. Trial design, particularly where there are fixed points for recruitment along the care pathway, can enable or constrain the possibilities for effective accrual depending on how it aligns with the optimum point of patient equipoise. Qualitative recruitment investigations, often focussed on information provision and patient engagement, may also look to better understand the target patient population in order to optimise the point at which patients are approached. ISRCTN Registry, ISRCTN98009168 . Registered on 29 November 2012.


Computational modeling of orientation tuning dynamics in monkey primary visual cortex.
In the primate visual pathway, orientation tuning of neurons is first observed in the primary visual cortex. The LGN cells that comprise the thalamic input to V1 are not orientation tuned, but some V1 neurons are quite selective. Two main classes of theoretical models have been offered to explain orientation selectivity: feedforward models, in which inputs from spatially aligned LGN cells are summed together by one cortical neuron; and feedback models, in which an initial weak orientation bias due to convergent LGN input is sharpened and amplified by intracortical feedback. Recent data on the dynamics of orientation tuning, obtained by a cross-correlation technique, may help to distinguish between these classes of models. To test this possibility, we simulated the measurement of orientation tuning dynamics on various receptive field models, including a simple Hubel-Wiesel type feedforward model: a linear spatiotemporal filter followed by an integrate-and-fire spike generator. The computational study reveals that simple feedforward models may account for some aspects of the experimental data but fail to explain many salient features of orientation tuning dynamics in V1 cells. A simple feedback model of interacting cells is also considered. This model is successful in explaining the appearance of Mexican-hat orientation profiles, but other features of the data continue to be unexplained.


10-Methoxydihydrofuscin, fuscinarin, and fuscin, novel antagonists of the human CCR5 receptor from Oidiodendron griseum.
Two new compounds, 10-methoxydihydrofuscin (1) and fuscinarin (2), and one known compound, fuscin (3), have been isolated from the soil fungus Oidiodendron griseum. These compounds were found to compete effectively with macrophage inflammatory protein (MIP)-1 alpha for binding to human CCR5, an important anti HIV-1 target that interferes with HIV entry into cells. The structures of these compounds were elucidated by spectroscopic methods.


Cytogenetics of the Hybridogenetic Frog Pelophylax grafi and Its Parental Species Pelophylax perezi.
Hybrid taxa from the genus Pelophylax can propagate themselves in a modified way of sexual reproduction called hybridogenesis ensuring the formation of clonal gametes containing the genome of only one parental (host) species. Pelophylax grafi from South-Western Europe is a hybrid composed of P. ridibundus and P. perezi genomes and it lives with a host species P. perezi (P-G system). Yet it is unknown, whether non-Mendelian inheritance is fully maintained in such populations. In this study, we characterize P. perezi and P. grafi somatic karyotypes by using comparative genomic hybridization, genomic in situ hybridization, fluorescent in situ hybridization, and actinomycin D-DAPI. Here, we show the homeology of P. perezi and P. grafi somatic karyotypes to other Pelophylax taxa with 2n = 26 and equal contribution of ridibundus and perezi chromosomes in P. grafi which supports F1 hybrid genome constitution as well as a hemiclonal genome inheritance. We show that ridibundus chromosomes have larger regions of interstitial (TTAGGG)n repeats flanking the nucleolus organizing region on chromosome no. 10 and a high quantity of AT pairs in the centromeric regions. In P. perezi, we found species-specific sequences in metaphase chromosomes and marker structures in lampbrush chromosomes. Pericentromeric RrS1 repeat sequence was present in perezi and ridibundus chromosomes, but the blocks were stronger in ridibundus. Various cytogenetic techniques applied to the P-G system provide genome discrimination between ridibundus and perezi chromosomal sets. They could be used in studies of germ-line cells to explain patterns of clonal gametogenesis in P. grafi and broaden the knowledge about reproductive strategies in hybrid animals.


SO2 Capture at Low Pressure in a Prototypical MIL-53 Aluminum MOF Family: The Influence of Pore Expansion.
Not only is excellent performance in SO2 capture by porous materials (uptake above 17 mmol g-1) relevant, but also finding a correlation between the architecture changes into a family and their SO2 adsorption is very useful. In this contribution, we studied the SO2 adsorption behavior (at very low pressure) of an Al(III)-MOF family that shares the pore architecture of MIL-53. The results indicate an inversely proportional trend for the SO2 capture and pore expansion, since by increasing the length of the channel pore, the SO2 uptake gradually decreases. In addition, this trend is clearly observed in the heat of adsorption, which describes the interaction between the SO2 molecule and the μ-OH functional group. These finding are supported by experimental analysis and computational studies.


Acquired nasopharyngeal stenosis: a warning and review.
To present and discuss the clinical presentation and treatment planning in children with acquired nasopharyngeal stenosis (NPS) following tonsillectomy and adenoidectomy. Case series. Tertiary care center. Nine children identified over 2 years (1995-1996) with newly diagnosed NPS were evaluated. Seven of these children underwent adenoidectomy using a potassium titanyl phosphate laser technique at a neighboring facility. These children were aged 15.6 to 62.1 months at the time of original surgery, and all presented with nasal obstruction and mouth breathing beginning within 10 weeks after surgery. In addition, 5 had newly documented obstructive sleep apnea. Of the 9 children, 1 required a tracheotomy. After undergoing an adenoidectomy, chronic rhinosinusitis developed and aggressive medical treatment failed in 4 children. Time from symptom onset to diagnosis of NPS ranged from 2 to 34 months. The diagnosis of NPS depends on obtaining a thorough medical history and conducting a physical examination that includes nasopharyngoscopy. Most children underwent a computed tomographic scan prior to repair. The scarring encountered in these patients involved the soft palate and the posterior pharyngeal wall and/or choanae bilaterally. Five children had no identifiable eustachian tube opening into the nasopharynx, and all 5 children had chronic otitis media with effusion or persistent otorrhea. Nasopharyngeal stenosis following adenoidectomy and/or tonsillectomy is difficult to correct. Multiple surgeries may be required to relieve the obstruction. Standard operative techniques using the lateral pharyngeal flap and transpalatal or endoscopic intranasal approaches were adapted to the clinical situation. Prolonged use of nasal stents is mandatory to produce a nasopharyngeal opening. Adjunctive treatment may include pressure equalization tubes. However, the best treatment remains prevention.


Impact of Zika Virus on adult human brain structure and functional organization.
To determine the impact of Zika virus (ZIKV) infection on brain structure and functional organization of severely affected adult patients with neurological complications that extend beyond Guillain-Barré Syndrome (GBS)-like manifestations and include symptoms of the central nervous system (CNS). In this first case-control neuroimaging study, we obtained structural and functional magnetic resonance images in nine rare adult patients in the subacute phase, and healthy age- and sex-matched controls. ZIKV patients showed atypical descending and rapidly progressing peripheral nervous system (PNS) manifestations, and importantly, additional CNS presentations such as perceptual deficits. Voxel-based morphometry was utilized to evaluate gray matter volume, and resting state functional connectivity and Network Based Statistics were applied to assess the functional organization of the brain. Gray matter volume was decreased bilaterally in motor areas (supplementary motor cortex, specifically Frontal Eye Fields) and beyond (left inferior frontal sulcus). Additionally, gray matter volume increased in right middle frontal gyrus. Functional connectivity increased in a widespread network within and across temporal lobes. We provide preliminary evidence for a link between ZIKV neurological complications and changes in adult human brain structure and functional organization, comprising both motor-related regions potentially secondary to prolonged PNS weakness, and nonsomatomotor regions indicative of PNS-independent alternations. The latter included the temporal lobes, particularly vulnerable in a range of neurological conditions. While future studies into the ZIKV-related neuroinflammatory mechanisms in adults are urgently needed, this study indicates that ZIKV infection can lead to an impact on the brain.


Measurements of birth defect prevalence: which is most useful as a comparator group for pharmaceutical pregnancy registries?
Pharmaceutical pregnancy registries document birth defects and other complications reported in pregnancies exposed to specific medications or diseases. A baseline estimate of birth defect prevalence is necessary for comparison. To identify potential teratogenic signals, the pregnancy registry must have a comparator that most closely matches the exposed population and data collection methodology, which are characteristics that vary among the multiplicity of birth defect surveillance systems. The system that yields the most accurate prevalence data may be different from that most closely matching the pregnancy registry methods. State public health programs have highly accurate and precise statistics, but their populations are broader than those of a pharmaceutical pregnancy registry. Large collaborative databases may have a more useful covered population, but there are secondary problems related to data precision. Health care databases enroll large numbers of patients and have good information about exposures and health problems, but the data can be difficult to access and lack useful detail. Exposure-related databases are closer in population definition and collection methods, though the presence of different diseases and exposures can be problematic. Internal comparators are likely to be most useful in formal statistical analysis, but added cost and management burden and may require significantly increased registry enrollment. There is no ideal comparator, and this must be taken into account when planning a single-exposure or single-disease pregnancy registry.


Discontinuities in the internal elastic lamina: a comparison of coronary and internal mammary arteries.
The internal elastic lamina (iel.) of the anterior descending branch of the left coronary artery, and the internal mammary artery, were studied in 166 unselected subjects of different ages and races. The coronary artery showed substantial defects in the iel. even in the first few years of life, while the iel. of the mammary artery showed only minimal defects in all age groups. The defects in the iel. were associated with the presence of medial cells in the intima, and the thickness of the intima was correlated with the magnitude of the defects in the iel. (Correlation coefficient 0.95 for the coronary artery and 0.80 for the mammary artery). Small arteries involved in chronic inflammatory or neoplastic disease showed a similar relationship if the vessel were present in an edematous area. These vessels which do not usually show intimal thickening, displayed a thickened intima in the vicinity of defects of the iel. It is suggested that the pronounced difference in the incidence of arteriosclerosis between the coronary and internal mammary arteries is related to these defects in the internal elastic lamina.


High-Intensity Exercise Training Protects the Brain Against Autoimmune Neuroinflammation: Regulation of Microglial Redox and Pro-inflammatory Functions.
Background: Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and it's model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia. Methods: We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)-reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary (SED) and HICT healthy mice, as well as 5-days post EAE induction (before the onset of disease), were analyzed ex vivo for reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines. Results: Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell, and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein (MCP) in response to PLP-stimulation. Conclusions: These findings point to the critical role of training intensity in neuroprotection. HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity, and pro-inflammatory responses involved in the propagation of autoimmune neuroinflammation.


Does robotic TME bring difference in lymph node yield and quality of TME?
Oncological outcomes of the robotic low anterior rectal resection with total mesorectal excision (TME) are still under discussion. Few studies have proven that robotic TME (rTME) is a safe and equivalent method for treatment of rectal carcinoma. But there is almost no comparison between the rTME and conventional TME in terms of the number of lymph nodes obtained and the quality of the TME. A single institution retrospective study was designed in a cohort of 261 patients. Cohort was divided into two groups depending on the type of surgery (rTME versus TME) and within these two groups, patients were divided according to whether they underwent neoadjuvant chemoradiation (nCHRT) or did not. The primary objective of the study was to compare obtained number of the lymph nodes in specimen. Secondary objectives were comparison of the quality of the TME and the number of positive circumferential resection margins. Results of the study have shown no significant difference in number of the lymph nodes obtained by the rTME and TME. There was no difference in the quality of the TME, neither in the group with the previous nCHRT nor in the group without a nCHRT. With results from the study we consider the rTME to be non-inferior to the conventional TME. Therefore, at least identical oncological results can be expected in patients treated by the rTME.


Platelets exposed to elevated levels of endogenous thrombopoietin in vivo have a reduced response to megakaryocyte growth and development factor in vitro.
Thrombopoietin (TPO), or megakaryocyte growth and development factor (MGDF), has been shown to potentiate the sensitivity of normal human platelets to various agonists in vitro. The present study investigated the functional and biochemical properties of platelets from mice rendered thrombocytopenic by sublethal irradiation with regard to the reactivity to recombinant murine MGDF (rmMGDF) in vitro. During the course of reversible thrombocytopenia following irradiation, platelets from irradiated mice which had lower platelet counts and reciprocally higher plasma TPO levels showed lower reactivity to rmMGDF in agonist-induced platelet aggregation. Intravenous injections of recombinant soluble murine c-Mpl (sMpl), which has the ability to capture TPO, after irradiation restored the reactivity of platelets at the platelet nadir to rmMGDF. On the other hand, platelets prepared from normal mice 3 h after a single intravenous injection of pegylated rmMGDF did not respond to rmMGDF. There was a marked decrease in c-Mpl and Janus kinase 2 (JAK2) in platelets from irradiated mice at the platelet nadir. Similar results were observed with platelets from mice administered pegylated rmMGDF. JAK2 was only moderately decreased, however, in platelets from mice given sMpl after irradiation. These results indicate that exposure of platelets to increased endogenous TPO levels in vivo in thrombocytopenic mice leads to a reduction in the platelet reactivity to rmMGDF in vitro. Further, these results suggest that the c-Mpl-mediated signaling pathway, which is essential for the priming effect of rmMGDF, is defective in thrombocytopenic murine platelets.


Automated and Continuous Fatigue Monitoring in Construction Workers Using Forearm EMG and IMU Wearable Sensors and Recurrent Neural Network.
About 40% of the US construction workforce experiences high-level fatigue, which leads to poor judgment, increased risk of injuries, a decrease in productivity, and a lower quality of work. Therefore, it is essential to monitor fatigue to reduce its adverse effects and prevent long-term health problems. However, since fatigue demonstrates itself in several complex processes, there is no single standard measurement method for fatigue detection. This study aims to develop a system for continuous workers' fatigue monitoring by predicting the aerobic fatigue threshold (AFT) using forearm muscle activity and motion data. The proposed system consists of five modules: Data acquisition, activity recognition, oxygen uptake prediction, maximum aerobic capacity (MAC) estimation, and continuous AFT monitoring. The proposed system was evaluated on the participants performing fourteen scaffold-building activities. The results show that the AFT features have achieved a higher accuracy of 92.31% in assessing the workers' fatigue level compared to heart rate (51.28%) and percentage heart rate reserve (50.43%) features. Moreover, the overall performance of the proposed system on unseen data using average two-min AFT features was 76.74%. The study validates the feasibility of using forearm muscle activity and motion data to workers' fatigue levels continuously.


Life-style activities in older people without intellectual impairment: a population-based study.
Activities of daily living are important indicators of the functional status and wellbeing of older persons. Data derived from life-style activities of the community at large are important for such diverse purposes as characterising the individual's ability for independent living, studying normal ageing, or investigating social factors in rehabilitation. Our objective was to determine patterns in the life-style activities of people aged 65 years and older who had no intellectual impairment. The article is a cross-sectional study of a population-based sample. Eligible people were non-institutionalised and aged 65 years or older, resident in the province of Guadalajara, Spain, and without intellectual impairment as assessed by the 10-item Short Portable Mental Status Questionnaire. Questionnaires were administered by trained interviewers and included questions about the daily activities of the Adelaide Activities Profile (AAP), distributed among the four categories of domestic chores, household maintenance, service to others, and social activities. Each item was rated 0 = absent or 1 = present, and total scores ranged from 0 to 19. The sample included 192 men and 196 women from rural areas and 172 men and 220 women from urban areas. In the category of domestic chores, mean ratings for women (4.56, 95% CI 4.30 to 4.84) were significantly higher (p <0.05) than for men (1.36, 95% CI 1.11 to 1.62) both in urban and rural areas, except in the oldest age group (> or =85 years). In the subscale of household maintenance, also except for group of > or =85 years, men rated significantly higher (3.31, 95% CI 3.11 to 3.53) than women (2.34, 95% CI 2.21 to 2.47), independent of the place of residence. Women scored significantly higher than men in activities associated with service to others. Men younger than 80 years from rural areas were significantly more involved in social activities than women. In urban areas both sexes scored similarly in social activities The differences found among the AAP scales in relation to gender was a clear indication of the well established roles for men and women in our sociocultural context. The 19-item version of the AAP scale is a valuable survey instrument as an objective guide for studying activities related to life-style in community settings.