Voluntary running attenuates behavioural signs of low back pain: dimorphic regulation of intervertebral disc inflammation in male and female SPARC-null mice.

OBJECTIVE: To examine the effect of running exercise on behavioral measures of pain and intervertebral disc (IVD) inflammation in the SPARC-null mouse model. METHODS: Male and female 8-month old SPARC-null and age-matched control mice received a home cage running wheel or a control, fixed wheel for 6 months. Behavioral assays were performed to assess axial discomfort (grip test) and radiating leg pain (von Frey, acetone tests) and voluntary running was confirmed. Expression of inflammatory mediators (TNF-α, IL-1ß, IL-2, IL-10, CCL5, CXCL1, CXCL5, RANKL, M-CSF, and VEGF) in IVDs was determined. Additional inflammatory (IL-1ß, IL-1Ra, CXCR1, CXCR2) and macrophage phenotypic markers (ITGAM, CD80, CD86, CD206, Arg1) in IVDs were investigated by qPCR. RESULTS: Voluntary running attenuated behavioral measures of pain in male and female SPARC-null mice. Increases in mediators including IL-1ß, CXCL1 and CXCL5 were observed in SPARC-null compared to control IVDs. After 6 months of running, increases in M-CSF and VEGF were observed in male SPARC-null IVDs. In females, pro-inflammatory mediators, including CXCL1 and CXCL5 were downregulated by running in SPARC-null mice. qPCR analysis further confirmed the anti-inflammatory effect of running in female IVDs with increased IL-1Ra mRNA. Running induced upregulation of the macrophage marker ITGAM mRNA in males. CONCLUSIONS: Voluntary running reversed behavioral signs of pain in male and female mice and reduced inflammatory mediators in females, but not males. Thus, the therapeutic mechanism of action may be sex-specific.

Considerations for Dose Selection and Clinical Pharmacokinetics/Pharmacodynamics for the Development of Antibacterial Agents.

In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled "Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens" to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. This and the accompanying minireview on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this minireview include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as on dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.

Differential expression of two C-type lectins in grass carp Ctenopharyngodon idella and their response to grass carp reovirus.

The cDNAs of two C-type lectins in grass carp Ctenopharyngodon idella, galactose-binding lectin (galbl) and mannose-binding lectin (mbl), were cloned and analysed in this study. Both of them exhibited the highest expression level in liver, whereas their expression pattern differed in early phase of embryonic development. Following exposure to grass carp reovirus (GCRV), the mRNA expression level of galbl and mbl was significantly up-regulated in liver and intestine.

Lichen planus pemphigoides associated with chronic hepatitis B virus infection.

Lichen planus pemphigoides (LPP) is a rare autoimmune dermatosis with the features of both lichen planus (LP) and bullous pemphigoid (BP). Although in rare cases, LPP has been associated with several medications and conditions, it is generally considered an idiopathic disorder, and its pathogenesis remains uncertain. We report a 56-year-old woman who presented with a 2-year history of flat-topped, polygonal, violaceous-colored papules and some bullae. She was diagnosed with chronic hepatitis B virus (HBV) infection, which had been treated intermittently with entecavir. Histopathological examination showed the typical features of LP with subepidermal blisters, and with linear deposits of IgG along the basement membrane zone on direct immunofluorescence. Immunoblotting revealed antibodies directed at the BP180 and BP230 antigens. We diagnosed the patient with LPP, and treated the condition with systemic steroids and dapsone. To our knowledge, this is the first report of LPP in a patient with chronic HBV infection.

The influence of the earthworm Lampito mauritii (Kinberg) on the activity of selected soil enzymes in cadmium-amended soil.

The effects of cadmium (CdCl2·7H2O) on cellulase, urease, amylase, invertase and phosphatase were assessed for a period of 45 days in the presence and absence of earthworms [Lampito mauritii (Kinberg)] in alfisol soil. The activities of all enzymes significantly increased with longer incubation times (45 days) under laboratory conditions in both control and Cd-amended soils (both with and without earthworm incubation). However, the activities of all enzymes decreased with increasing Cd concentrations under laboratory conditions, both in the presence and absence of earthworms. In the presence of earthworms, cellulase, urease, invertase and amylase activities increased. However, phosphatase activity was lower in most of the Cd-amended soils in the presence of earthworms compared to its activity levels in soils lacking earthworms. These results show that earthworms modulated the stress imposed by Cd by providing suitable substrates, which in turn acted as stimulants for extracellular enzyme secretion by microbes, and by removing Cd through its accumulation in the tissues of the earthworms.

Cultivation of a bacterial consortium with the potential to degrade total petroleum hydrocarbon using waste activated sludge.

Waste activated sludge was aerobically treated to demonstrate multiple uses such as cultivating an oil degrading bacterial consortium; studying the influence of a bulking agent (peat moss) and total petroleum hydrocarbon concentration on bacterial growth and producing a soil conditioner using waste activated sludge. After 30 days of incubation, the concentration of oil-degrading bacteria was 4.3 x 10(8) CFU g(-1) and 4.5 x 10(8) CFU g(-1) for 5 and 10 g of total petroleum hydrocarbon, respectively, in a mixture of waste activated sludge (1 kg) and peat moss (0.1 kg). This accounts for approximately 88.4 and 91.1%, respectively, of the total heterotrophic bacteria (total-HB). The addition of bulking agent enhanced total-HB population and total petroleum hydrocarbon-degrading bacterial population. Over 90% of total petroleum hydrocarbon degradation was achieved by the mixture of waste activated sludge, bulking agent and total petroleum hydrocarbon. The results of physico-chemical parameters of the compost (waste activated sludge with and without added peat moss compost) and a substantial reduction in E. coli showed that the use of this final product did not exhibit risk when used as soil conditioner. Finally, the present study demonstrated that cultivation of total petroleum hydrocarbon-degrading bacterial consortium and production of compost from waste activated sludge by aerobic treatment was feasible.

Proteins involved in DNA damage response pathways and survival of stage I non-small-cell lung cancer patients.

BACKGROUND: Biological complexity leads to significant variation in the survival of patients with stage I non-small-cell lung cancer (NSCLC). DNA damage response (DDR) pathways play a critical role in maintaining genomic stability and in the progression of NSCLC. Therefore, the development of a prognostic biomarker focusing on DDR pathways is an intriguing issue. PATIENTS AND METHODS: Expression of several proteins (ATM, ATMpS1981, γH2AX, 53BP1, 53BP1pS25, Chk2, Chk2pT68, MDC1, MDC1pS964, BRCA1pS1423, and ERCC1) and overall survival were investigated in 889 pathological stage I NSCLC patients. RESULTS: Low expression of BRCA1pS1423 or ERCC1 was significantly associated with worse survival in the whole cohort of patients. Analysis performed based on histology revealed that low expression of γH2AX, Chk2pT68, or ERCC1 was a poor prognostic factor in squamous cell carcinoma patients [adjusted hazard ratio (aHR), Cox P: 1.544, 0.012 for γH2AX; 1.624, 0.010 for Chk2pT68; 1.569, 0.011 for ERCC1]. The analysis of the interaction between two proteins showed that this effect was more pronounced in squamous cell carcinoma patients. However, these effects were not detected in adenocarcinoma patients. CONCLUSIONS: The proteins involved in DDR pathways exhibited differential expression between squamous cell carcinoma and adenocarcinoma and were important determinants of survival in stage I squamous cell carcinoma patients.

Electrical properties of 10-nm-radius n-type gate all around twin Si nanowire field effect transistors.

The electrical properties of 10-nm-radius n-type gate all around (GAA) twin Si nanowire field effect transistors (TSNWFETs) and field effect transistors (FETs) without nanowires were investigated to understand their device characteristics. The electrical characteristics of the GAA TSNWFETs and FETs with bulk boron concentrations of 1 x 10(18) and 1 x 10(16) cm(-3) were simulated by using three-dimensional technology computer-aided design simulation tools of sentaurus taking into account quantum effects. The simulation results showed that the on-current level of the TSNWFETs was larger than that of FETs, and the subthreshold swing and the drain induced barrier lowing of the TSNWFETs were smaller than those of FETs. The current density and conduction band edge profiles in the TSNWFETs clarified the dominant current paths. The simulation results showed that the on-current/off-current ratio increased with increasing bulk boron concentration, and the stand-by current level decreased.

Impact of COVID-19 on TB epidemiology in South Korea.

SETTING: Five referral hospitals, South Korea.OBJECTIVE: To assess epidemiological changes in TB before and during the COVID-19 pandemic.DESIGN: This was a multicentre cohort study of 3,969 patients diagnosed with TB.RESULTS: We analysed 3,453 patients diagnosed with TB prior to the COVID-19 pandemic (January 2016-February 2020) and 516 during the pandemic (March-November 2020). During the pandemic, the number of patients visits declined by 15% from the previous 4-year average, and the number of patients diagnosed with TB decreased by 17%. Patients diagnosed during the pandemic were older than those diagnosed before the pandemic (mean age, 60.2 vs. 56.6 years, P < 0.001). The proportion of patients to have primary TB at a younger age (births after 1980) among those diagnosed with TB was significantly lower during the pandemic than before (17.8% in 2020 vs. 23.5% in 2016, 24.0% in 2017, 22.5% in 2018, 23.5% in 2019; P = 0.005).CONCLUSIONS: The COVID-19 pandemic resulted in a reduction in the number of visits to respiratory departments, leading to fewer patients being diagnosed with TB. However, our results suggest that universal personal preventive measures help to suppress TB transmission in regions with intermediate TB burden.

The Safety of Intra-arterial Tirofiban during Endovascular Therapy after Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: The safety and efficacy of tirofiban during endovascular therapy in patients undergoing intravenous thrombolysis with recombinant IV tPA remain unclear. This study aimed to investigate the safety and efficacy of intra-arterial tirofiban use during endovascular therapy in patients treated with IV tPA. MATERIALS AND METHODS: Using a multicenter registry, we enrolled patients with acute ischemic stroke who underwent endovascular therapy. Safety outcomes included postprocedural parenchymal hematoma type 2 and/or thick subarachnoid hemorrhage, intraventricular hemorrhage, and 3-month mortality. Efficacy outcomes included the successful reperfusion rate, postprocedural reocclusion, and good outcomes at 3 months (mRS scores of 0-2). The tirofiban effect on the outcomes was evaluated using a multivariable analysis while adjusting for potential confounders. RESULTS: Among enrolled patients, we identified 314 patients with stroke (279 and 35 patients in the no tirofiban and tirofiban groups, respectively) due to an intracranial artery occlusion who underwent endovascular therapy with intravenous thrombolysis. A multivariable analysis revealed no association of intra-arterial tirofiban with postprocedural parenchymal hematoma type and/or thick subarachnoid hemorrhage (adjusted OR, 1.07; 95% CI, 0.20-4.10; P = .918), intraventricular hemorrhage (adjusted OR, 0.43; 95% CI, 0.02-2.85; P = .467), and 3-month mortality (adjusted OR, 0.38; 95% CI, 0.04-1.87; P = .299). Intra-arterial tirofiban was not associated with good outcome (adjusted OR, 2.22; 95% CI, 0.89 -6.12; P = .099). CONCLUSIONS: Using intra-arterial tirofiban during endovascular therapy after IV tPA could be safe.

Charlson comorbidity index using administrative database in incident PD patients.

AIMS: Mortality risks in ESRD (end stage renal disease) patients are related to comorbid diseases. The Charlson Comorbidity Index (CCI) has been reported to be a strong predictor of survival in incipient ESRD patients. The authors studied the validity of CCI using administrative database according to International Classification of Disease, 10th revision (ICD-10) codes, to devise a more straightforward method of determining CCI than that based on medical records review. SUBJECTS AND METHODS: Incident peritoneal dialysis patients (N = 134) were enrolled from 1997 through 2007. We compared CCI scored by the administrative database (A-CCI) with CCI scored by medical records review (R-CCI). These CCI scores and patients' outcomes were analyzed. RESULTS: For all patients, mean A-CCI and R-CCI were 5.3 +/- 2.1 (range 2 - 11) and 5.4 +/- 2.1 (range 2 - 11), respectively. High correlation was found between A-CCI and R-CCI scores (r = 0.88, p < 0.01). The sensitivity of A-CCI was high (0.57 - 1.00) for nine comorbidities, but sensitivities for chronic pulmonary disease and peptic ulcer disease were poor (< 0.50). However, specificity was excellent for most comorbidities. Three comorbidity groups were established by tertile ranking: low comorbidity (score = 2 - 4), moderate comorbidity (score = 5 - 6), and high comorbidity (score = 7-11). The mortality rates were; 7.17, 15.96, and 23.07/100 patient-years by A-CCI, and 6.69, 13.58 and 28.16/100 patient-years by R-CCI, respectively. CONCLUSION: CCI scores from administrative database using ICD-10 were similar to CCI scores by medical records review. This method is simple and valid to predict the outcomes of incipient PD patients.

The land use plan and water quality prediction for the Saemangeum reclamation project.

As the final closure of the world's longest sea dike of 33 km, the use of the Saemangeum reclaimed land becomes an issue in Korea. The Korean government has proclaimed that the Saemangeum Reclamation Project will be handled in an environmentally friendly manner but its effect on the water quality of reservoirs has always been controversial. This study was conducted to estimate the water quality of the Saemangeum reservoir using WASP5 according to the new land use plan adopted in 2007. Predictions on water quality shows that Dongjin reservoir would meet the standards for COD, T-P, and Chl-a if the wastewater from the Dongjin region was properly managed. However, T-P and Chl-a in Mangyeong reservoir would exceed the standards even without releasing the treated wastewater into the reservoir. With further reductions of 20% for T-P and Chl-a from the mouth of Mangyeong river, the water quality standards in the reservoir were achieved. This means that additional schemes, as well as water quality management programs established in the Government Master Plan in 2001, should be considered. Although the Saemangeum reservoir would manage to achieve the standards, it will enter a eutrophic state due to the high concentration of nutrients.

The effect of cationic polymer treatment on adhesion of iron oxide to eyelashes.

The aim of this study was to investigate the effect of iron oxide application on improving the volume of eyelashes. Iron oxide, having a negative surface charge in its natural form, was coated with commercial cationic polymers to increase its adhesion. The iron oxides coated with different types and concentrations of these polymers were incorporated into a basic mascara formula to test their volume effects by means of the weight difference of eyelashes.The results indicated that the type and concentration of coating materials affect the surface zeta potential and particle cluster size of iron oxides. The type of cationic polymer, especially, was shown to modify both factors of iron oxide. The obtained results also suggested that the volume effect of mascara increases with a higher positive surface zeta potential and a smaller particle cluster size of the coated iron oxides.

Metformin and tuberculosis risk in elderly patients with diabetes mellitus.

SETTING: Tuberculosis (TB) and diabetes mellitus (DM) remain global health concerns. Metformin has recently received attention for its anti-tuberculosis effects.OBJECTIVE: To evaluate the risk of TB development in elderly DM patients treated with metformin compared with sulfonylureas.DESIGN: We performed a retrospective cohort study using the National Health Insurance Service-Senior database. The participants were type-2 DM (T2DM) patients aged ≥60 years between 1 January 2003 and 31 December 2013. We matched each metformin user to a sulfonylurea user using a propensity score. A Cox proportional hazards model was used to compare the risk of TB in metformin and sulfonylurea users.RESULTS: After propensity score matching, 12,582 patients were in each group. The TB incidence was 280.2/100 000 person-years (py) for metformin users and 394.5/100 000 py for sulfonylurea users. Metformin users had a lower risk of TB development than sulfonylurea users (adjusted hazard ratio 0.74, 95%CI 0.58-0.95), and the results were stronger for male participants. A dose-response relationship between metformin use and TB development was found in both sexes.CONCLUSION: Metformin use was associated with a decreased risk of TB development among elderly T2DM patients compared with sulfonylurea use.

Kernohan's notch phenomenon demonstrated by diffusion tensor imaging and transcranial magnetic stimulation.

Kernohan's notch phenomenon is the ipsilateral hemiplegia caused by compression of the contralateral cerebral peduncle against the tentorial edge by a supratentorial mass. Diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS) could be useful for exploring the state of the corticospinal tract (CST). This report attempts to demonstrate Kernohan's notch phenomenon in a patient with subdural haematoma by using DTI and TMS. One patient and six normal control subjects were recruited. The patient showed severe right hemiplegia even though the subdural haematoma was located in the right hemisphere. Brain CT at the time of onset showed right transtentorial herniation, and T2 weighted images at 6 weeks after onset showed a leucomalacic lesion on the left cerebral peduncle. DTI and TMS were performed at 6 weeks after onset. The fractional anisotrophy value of the left midbrain and medulla of the patient was found to be decreased in comparison with that of the control subjects. On fibre tractography for the CST, an interruption was observed in the left midbrain and medulla. The motor evoked potential obtained from the right hand muscle showed delayed latency, low amplitude and a higher excitatory threshold, thus indicating that the CST of the left hemisphere had been damaged. It seems that the CST had been damaged at the left midbrain, although subdural haematoma and transtentorial herniation had occurred in the right hemisphere in this patient. This report demonstrates Kernohan's notch phenomenon in this patient using DTI and TMS.

Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.

Identifying a core RNA polymerase surface critical for interactions with a sigma-like specificity factor.

Cyclic interactions occurring between a core RNA polymerase (RNAP) and its initiation factors are critical for transcription initiation, but little is known about subunit interaction. In this work we have identified regions of the single-subunit yeast mitochondrial RNAP (Rpo41p) important for interaction with its sigma-like specificity factor (Mtf1p). Previously we found that the whole folded structure of both polypeptides as well as specific amino acids in at least three regions of Mtf1p are required for interaction. In this work we started with an interaction-defective point mutant in Mtf1p (V135A) and used a two-hybrid selection to isolate suppressing mutations in the core polymerase. We identified suppressors in three separate regions of the RNAP which, when modeled on the structure of the closely related phage T7 RNAP, appear to lie on one surface of the protein. Additional point mutations and biochemical assays were used to confirm the importance of each region for Rpo41p-Mtf1p interactions. Remarkably, two of the three suppressors are found in regions required by T7 RNAP for DNA sequence recognition and promoter melting. Although these essential regions of the phage RNAP are poorly conserved with the mitochondrial RNAPs, they are conserved among the mitochondrial enzymes. The organellar RNAPs appear to use this surface in an alternative way for interactions with their separate sigma-like specificity factor, which, like its bacterial counterpart, provides promoter recognition and DNA melting functions to the holoenzyme.

Glucose repression of yeast mitochondrial transcription: kinetics of derepression and role of nuclear genes.

Yeast mitochondrial transcript and gene product abundance has been observed to increase upon release from glucose repression, but the mechanism of regulation of this process has not been determined. We report a kinetic analysis of this phenomenon, which demonstrates that the abundance of all classes of mitochondrial RNA changes slowly relative to changes observed for glucose-repressed nuclear genes. Several cell doublings are required to achieve the 2- to 20-fold-higher steady-state levels observed after a shift to a nonrepressing carbon source. Although we observed that in some yeast strains the mitochondrial DNA copy number also increases upon derepression, this does not seem to play the major role in increased RNA abundance. Instead we found that three- to sevenfold increases in RNA synthesis rates, measured by in vivo pulse-labelling experiments, do correlate with increased transcript abundance. We found that mutations in the SNF1 and REG1 genes, which are known to affect the expression of many nuclear genes subject to glucose repression, affect derepression of mitochondrial transcript abundance. These genes do not appear to regulate mitochondrial transcript levels via regulation of the nuclear genes RPO41 and MTF1, which encode the subunits of the mitochondrial RNA polymerase. We conclude that a nuclear gene-controlled factor(s) in addition to the two RNA polymerase subunits must be involved in glucose repression of mitochondrial transcript abundance.