Development of the 16 X-STR loci typing system and genetic analysis in a Shanghai Han population from China.
This study developed a new multiplex PCR system that simultaneously amplifies 16 X-STR loci in the same PCR reaction, and the polymorphism and mutation rates of these 16 X-STR loci were explored in a Shanghai Han population from China. These loci included DXS10134, DXS10159, DXS6789, DXS6795, DXS6800, DXS6803, DXS6807, DXS6810, DXS7132, DXS7424, DXS8378, DXS9902, GATA165B12, GATA172D05, GATA31E08, and HPRTB. Samples from 591 unrelated individuals (293 males and 298 females) and 400 two-generation families were successfully analyzed using this multiplex system. Allele frequencies and mutation rates of the 16 loci were investigated, with the comparison of allele frequency distributions among different populations performed. Polymorphism information contents of these loci were all >0.6440 except the locus DXS6800 (0.4706). Nine cases of mutations were detected in the 16 loci from the investigation of 9232 meioses. Pairwise comparisons of allele frequency distributions showed significant differences for most loci among populations from different countries and ethnic groups but not among the Han population living in other areas of China. These results suggest that the 16 X-STR loci system provides highly informative polymorphic data for paternity testing and forensic identification in the Han population in Shanghai, China, as a complementary tool.


Comparison of Speech Recognition in Cochlear Implant Users with Different Speech Processors.
Speech recognition in noisy environments is a challenge for both cochlear implant (CI) users and device manufacturers. CI manufacturers have been investing in technological innovations for processors and researching strategies to improve signal processing and signal design for better aesthetic acceptance and everyday use. This study aimed to compare speech recognition in CI users using off-the-ear (OTE) and behind-the-ear (BTE) processors. A cross-sectional study was conducted with 51 CI recipients, all users of the BTE Nucleus 5 (CP810) sound processor. Speech perception performances were compared in quiet and noisy conditions using the BTE sound processor Nucleus 5 (N5) and OTE sound processor Kanso. Each participant was tested with the Brazilian-Portuguese version of the hearing in noise test using each sound processor in a randomized order. Three test conditions were analyzed with both sound processors: (i) speech level fixed at 65 decibel sound pressure level in a quiet, (ii) speech and noise at fixed levels, and (iii) adaptive speech levels with a fixed noise level. To determine the relative performance of OTE with respect to BTE, paired comparison analyses were performed. The paired t-tests showed no significant difference between the N5 and Kanso in quiet conditions. In all noise conditions, the performance of the OTE (Kanso) sound processor was superior to that of the BTE (N5), regardless of the order in which they were used. With the speech and noise at fixed levels, a significant mean 8.1 percentage point difference was seen between Kanso (78.10%) and N5 (70.7%) in the sentence scores. CI users had a lower signal-to-noise ratio and a higher percentage of sentence recognition with the OTE processor than with the BTE processor.


Suppression of ovarian activity during the breeding season in suckling Japanese monkey (Macaca fuscata).
The menstrual cycle was examined in Japanese monkeys, short-day breeders, with or without nursing babies during the breeding season by determining the change in the plasma concentration of progesterone. Blood samples were obtained weekly from suckling and nonsuckling mothers for 6 months from September to February. Plasma concentrations of progesterone in suckling mothers did not show any apparent fluctuation and remained low throughout the study, while irregular menstruation was observed. In nonsuckling mothers, cyclic changes in plasma progesterone concentration accompanied by regular menstruation occurred from October. Annual birth rates were lower in monkeys housed in individual cages (17.6%) than in free-ranging monkeys in Miyajima colony, near Hiroshima in Japan (37.5%). These results indicate that the suckling stimulus for females with young born in spring is potent enough to suppress ovarian activity during the autumn breeding season.


[Multi-wavelength spectral aerosol scale height in inshore in contrast with that in inland].
In the present paper, based on the exponential attenuation of atmospheric aerosol concentration with height, so using continuous spectrum sun-photometer, forward scatter visibility sensor and hygrothermograph, the authors measured the atmosphere column optical characteristic and plane spectral extinction coefficient on earth on the base of two experiments at some edge of ocean at the same time, respectively, set up the calculative method of multi-wavelength spectral aerosol scale height. Firstly, the authors obtained atmospheric horizontal extinction coefficient with forward scattering visibility sensor, which subtracted molecular extinction coefficient, and could get aerosol extinction coefficient near ground; Then, selecting sea salt model, using OPAC software, the authors also could calculate the aerosol extinction coefficient under different humidity (0%, 50%, 70%, 80%, 90%, 95%, 98% and 99%) and different wavelength (400, 450, 500, 550, 600, 650, 700 and 750 nm), the aerosol extinction coefficient was detected by visibility sensor, using interpolation method, respectively; Finally, using the data of atmospheric columniation optical thickness detected by continuous spectral sun-photometer and subtracted molecular optical thickness corresponding wavelengths were accounted out by Modtran 4. 0. The authors obtained the characteristic of spectral aerosol scale height of visible light (wavelength is 400, 440, 532, 550 and 690 nm): with wavelength increments, and spectral aerosol scale height was found to decline neither in inland nor in inshore in China; Spectral aerosol scale height in winter is higher than in summer in southeast inshore; but spectral aerosol scale height in winter is smaller in summer than in inland.


Clinical profile, diagnostic challenges, and outcomes in subacute/chronic cerebral sinus venous thrombosis.
To report clinical profile, diagnostic challenges, and outcomes in cases of subacute/chronic cerebral sinus venous thrombosis (CSVT) presenting to neuro-ophthalmologists/neurologists. This was a multicentric, retrospective, observational study. Records of patients with neuroimaging proven subacute/chronic CSVT seen the from January 1, 2016 to March 31, 2020 were analyzed. Data collected included duration of symptoms, diagnosing physician, ophthalmological vs. focal/generalized neurological symptoms, optic disc examination, perimetry, and neuroimaging findings. Statistical analysis was performed using STATA software. Forty-three patients with subacute (30)/chronic (13) CSVT were identified (32 males, 11 females). Median age was 37 (IQR 27-47) years. The presenting complaints were blurred vision 34 (79%), headaches in 25 (58%), vomiting 12 (28%), and diplopia 11 (26%). Eleven patients had associated sixth cranial nerve palsy. All but two patients had either disc edema/optic atrophy; four had unilateral disc edema at presentation. Ophthalmologists and neurologists diagnosed/suspected CSVT correctly in 13/29 (45%) and 11/14 (78.5%) patients, respectively. Most common initial alternate diagnosis was idiopathic intracranial hypertension in 12 (28%). Female gender, age ≤36, unilateral papilledema, not obtaining venogram at initial workup increased chances of initial alternate diagnosis. Median follow-up duration was 21 days. Average visual function remained stable in majority of patients at last follow-up. In total, 47.6% of patients had best-corrected visual acuity ≥20/30 at the final follow-up. In our series, subacute or chronic CSVT presented presented primarily with symptoms of intracranial hypertension. Unilateral papilledema, middle-aged patients, female gender, lack of focal/generalized neurological symptoms created diagnostic dilemma. Visual function remained stable in majority of patients.


School-Age Children's Actual Motor Competence and Perceived Physical Competence: A 3-Yr Follow-up.
This study examined school-age children's actual motor competence (MC) and perceived physical competence (PC) over 3 yr along with the covariate effects of gender and body mass index (BMI). Participants were 1121 (girls 573, boys 548) children (mean age, 11.26 ± 0.32 yr) from 35 randomly selected public schools across Finland. MC was assessed using three movement tests targeting locomotor, stability, and object control skills, and PC was assessed using the sport competence subscale of the Physical Self-Perception Profile via four-phase monitoring. MC and PC remained stable over time. Of the three variables, locomotor skills showed the strongest association with PC. Lower BMI was associated with advanced MC skills and a less steep decrease in locomotor and stability skills over time. The acquisition of fundamental motor skills in childhood and early adolescence is a prerequisite for enhancing MC and PC. The contribution of locomotor skills to PC indicated that versatile lower limb strength, speed, dynamic balance, and movement skills are important for positive subjective beliefs about PC capability. Increasing the MC skills of the children in most need, particularly those with high BMI scores, merits special attention.


Stability of nitroglycerin tablets in a unit of use pendant-type container.
A stainless steel pendant (Life-Link) designed to carry emergency quantities of nitroglycerin tablets was examined for compliance with FDA packaging restrictions for nitroglycerin. The results of the study indicate that the pendant is equal or superior to screw-capped glass containers presently required for packaging of nitroglycerin tablets. Tablets stored for up to 3 months retain potency and physical integrity. The pendant provides a simple, tight, convenient, and unbreakable container for carrying nitroglycerin tablets on a 24-hour basis.


Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism.
Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes.


Hepatitis E virus infection increases the risk of diabetes and severity of liver disease in patients with chronic hepatitis C virus infection.
Co-infection with hepatitis A or B viruses may aggravate liver injury in patients infected with hepatitis C virus (HCV). However, few studies have assessed co-infection with hepatitis E virus (HEV) and HCV. Therefore, this study aimed to assess the prevalence and impact of HEV infection among Brazilian patients with chronic HCV infection. This observational study included adult patients with chronic HCV infection who were naive to antiviral therapy from January 2013 to March 2016. A total of 181 patients were enrolled, and HEV serology and PCR were performed for all patients. Seropositivity for anti-HEV IgG was detected in 22 (12.0%) patients and anti-HEV immunoglobulin M in 3 (1.6%). HEV RNA showed inconclusive results in nine (4.9%) patients and was undetectable in the remaining patients. HEV serology positive patients had more severe liver disease, characterized by liver fibrosis ≥3 versus ≤2 (p<0.001), Aspartate Aminotransferase-to-Platelet Ratio Index of ≥1.45 (p=0.003), and Fibrosis-4 score of ≥3.25 (p=0.001). Additionally, the odds of HEV-positive patients developing diabetes mellitus were 3.65 (95% CI 1.40-9.52) times the corresponding odds of HEV-negative patients. A case-control-based histological analysis (n=11 HEV-HCV-positive patients and n=22 HCV-positive patients) showed no significant differences between the groups. This prevalence is higher than that reported in previous studies of the general population in Brazil. Thus, HEV infection may influence the severity of liver disease and may represent an additional risk of developing diabetes mellitus in patients with HCV infection.


A Novelty Detection Approach for Tendons of Prestressed Concrete Bridges Based on a Convolutional Autoencoder and Acceleration Data.
The most important structural element of prestressed concrete (PSC) bridges is the prestressed tendon, and in order to ensure safety of such bridges, it is very important to determine whether the tendon is damaged. However, it is not easy to detect tendon damage in real time. This study proposes a novelty detection approach for damage to the tendons of PSC bridges based on a convolutional autoencoder (CAE). The proposed method employs simulation data from nine accelerometers. The accuracies of CAEs for multi-vehicle are 79.5%⁻85.8% for 100% and 75% damage severities with all error levels and 50% damage severity without error. However, the accuracies for 50% damage severity with 5% and 10% error levels drop to 69.4%⁻73.3%. The accuracies of CAEs for single-vehicle ranges from 90.1%⁻95.1% for all damage severities and error levels that are satisfactory. The findings indicate that the CAE approach for multi-vehicle can be effective when the damages are severe, but not when moderate. Meanwhile, if acceleration data can be obtained for single-vehicle, then the CAE approach can provide a highly accurate and robust method of tendon damage detection in PSC bridges in use, even if the measurement errors are significant.


Optimism Bias in the Design of Phase III Randomized Control Trials Evaluating PD-1/PD-L1 Targeting Monoclonal Antibodies.
Many randomized control trials (RCTs) evaluating programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) targeting monoclonal antibodies (mAbs) have been completed or are in progress. We examined hypothesized hazard ratios (HHRs) and observed hazard ratios (OHRs) from published RCTs evaluating these mAbs. Publications of RCTs evaluating at least one PD-1/PD-L1 targeting mAbs approved by the US Food and Drug Administration were identified through PubMed searches. The primary reports of RCTs were retrieved. Two investigators extracted HHR, OHR for the primary endpoint among other data elements independently. The differences (∆HR) in HHR and OHR were analyzed statistically. A separate search was conducted for secondary reports after longer follow-ups, the updated OHR was extracted. Forty-nine RCTs enrolling 36 867 patients were included. The mean HHR and OHR were 0.672 and 0.738 respectively. The mean ∆HR was 0.067 (range: -0.300 to 0.895; 95% confidence interval (CI), 0.003-0.130). HHR was met or exceeded in 22 (45%) RCTs. OHR was ≥ 1.0 in 6 RCTs (12%). PD-L1 expression was not associated with the magnitude of effect. Of 18 RCTs with follow-up reports, the magnitude of benefit decreased in 8 RCTs with extended follow-ups. The majority of published RCTs evaluating PD-1/PD-L1 targeting mAbs did not achieve their hypothesized magnitude of benefit. The optimism bias requires attention from the cancer clinical research community given the number of these agents in development and the intense interest in evaluating these agents in a variety of disease settings.


Hydrogels Classification According to the Physical or Chemical Interactions and as Stimuli-Sensitive Materials.
Hydrogels are attractive biomaterials with favorable characteristics due to their water uptake capacity. However, hydrogel properties are determined by the cross-linking degree and nature, the tacticity, and the crystallinity of the polymer. These biomaterials can be sorted out according to the internal structure and by their response to external factors. In this case, the internal interaction can be reversible when the internal chains are led by physicochemical interactions. These physical hydrogels can be synthesized through several techniques such as crystallization, amphiphilic copolymers, charge interactions, hydrogen bonds, stereo-complexing, and protein interactions. In contrast, the internal interaction can be irreversible through covalent cross-linking. Synthesized hydrogels by chemical interactions present a high cross-linking density and are employed using graft copolymerization, reactive functional groups, and enzymatic methods. Moreover, specific smart hydrogels have also been denoted by their external response, pH, temperature, electric, light, and enzyme. This review deeply details the type of hydrogel, either the internal structure or the external response. Furthermore, we detail some of the main applications of these hydrogels in the biomedicine field, such as drug delivery systems, scaffolds for tissue engineering, actuators, biosensors, and many other applications.


Haemodynamic aspects of lower limb arterial reconstruction using Dacron and Goretex prostheses.
We have studied some haemodynamic consequences of vascular grafts of less than 8 mm diameter by animal studies on dogs before and after aortofemoral bypass with either knitted Dacron 5 mm internal diameter (6 dogs) or Goretex 6 mm internal diameter (7 dogs) prostheses between 17 and 24 cm in length. Both materials gave an increased velocity of pulse wave transmission for pressure and flow and an increase in resistance to pulsatile flow. The effects were more severe with Dacron than with Goretex. Pressure index and pressure pulsatility were not significantly altered, but flow pulsatility index, peak flow rate, and peak flow acceleration were all significantly reduced after both implants. These results are due to mismatching of mechanical properties leading to an increased impedance to pulsatile flow.


Comparison of features by MRI and radiographs of the interphalangeal finger joints in patients with hand osteoarthritis.
To examine the construct validity of MRI in the detection of structural hand osteoarthritis features with conventional radiography (CR) as reference and explore the association between radiographic severity and MRI-defined pathology. 106 hand osteoarthritis patients (97 women, mean age 68.9 years (SD 5.6)) had 1.0T contrast-enhanced MRI and CR of the dominant hand. The 2nd-5th interphalangeal joints were scored according to the preliminary Oslo hand osteoarthritis MRI score and Kellgren-Lawrence (KL) scale and Osteoarthritis Research Society International atlas for radiographs. The authors compared the number of joints with structural features by MRI and CR (Wilcoxon signed-rank test) and examined concordance at the individual joint level. The OR of MRI features in joints with doubtful (KL grade 1), mild (2) and moderate/severe (≥3) radiographic osteoarthritis was estimated by generalised estimating equations (KL grade 0 as reference). MRI detected approximately twice as many joints with erosions and osteophytes compared with CR (p<0.001), but identification of joint space narrowing, cysts and malalignment was similar. The sensitivity of MRI was very high for osteophytes (1.00) and erosions (0.95), while specificity was lower (0.22 and 0.63). The prevalence of most MRI features increased with radiographic severity, but synovitis was more frequent in joints with mild osteoarthritis (OR2.1, 95% CI 1.4 to 3.2) than in moderate/severe osteoarthritis (OR1.4, 95% CI 1.0 to 2.2). MRI detected more osteophytes and erosions than CR, suggesting that erosive osteoarthritis may be more common than indicated by CR. Synovitis was most common in mild osteoarthritis. Whether this is due to burn-out of inflammation in late disease must be investigated further.


Nasal Polyps in Children: The Early Origins of a Challenging Adulthood Condition.
Nasal polyps (NPs) are benign inflammatory masses causing chronic nasal obstruction, usually associated with underlying chronic rhinosinusitis (CRS), which are rarely reported in childhood. The interest in NPs has recently increased due to new therapeutic options, namely biological agents, such as dupilumab, and an update of the European position paper on this topic was released in 2020, providing a detailed classification for these lesions and also discussing diagnostic and therapeutic approaches also in children. In childhood, NPs usually represent red flags for systemic diseases, such as cystic fibrosis and immunodeficiencies. This review outlines the recent data on NPs in childhood, focusing on predisposing factors for CRS as well as on the potential endotypes in this particular age group, for which further studies are required in order to better clarify their pathogenesis and to identify molecular biomarkers that could help achieve more personalized treatments.


"Proton-pump inhibitor-first" strategy versus "step-up" strategy for the acute treatment of reflux esophagitis: a cost-effectiveness analysis in Japan.
Gastroesophageal reflux disease (GERD) is a common condition, and acid-suppressing agents are the mainstays of treatment. For the acute medical management of GERD, two different strategies can be proposed: either the most effective therapy, i.e., proton-pump inhibitors (PPIs), can be given first, or histamine H2-receptor antagonists (H2RAs) can be attempted first (the "step-up" approach). A clinical decision analysis comparing the PPI-first strategy and the H2RA-first "step-up" strategy for the acute treatment of reflux esophagitis in Japan was performed, using a Markov chain approach. The PPI-first strategy was consistently superior to the step-up strategy with regard to clinical outcomes for the patient and with regard to cost-effectiveness (direct cost per patient to achieve clinical success). This superiority was robust within the plausible range of probabilities according to the sensitivity analyses. The PPI-first strategy is superior to the H2RA-first "step-up" strategy with regard to both efficacy and cost-effectiveness and therefore, the PPI-first strategy is the preferred therapeutic approach for the acute medical treatment of reflux esophagitis.


Premenopausal ovariectomy-related bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate.
The purpose of this study was to contrast the effects of conventional estrogen treatment with medroxyprogesterone on cancellous and cortical bone change in the first year following premenopausal ovariectomy. This 1-year double-blind randomized therapy trial was stratified by osteoporosis family history and performed in an academic medical center and community hospitals. Premenopausal women 45 +/- 5 years old, postovariectomy for benign diseases were provided 600 mg/day of calcium and randomized to daily therapy with conjugated equine estrogen (CEE, 0.6 mg) or medroxyprogesterone (MPA, 10 mg). The primary outcome variable was spinal quantitative computed tomography (QCT) bone density change over 1 year with additional outcomes of dual-energy X-ray absorptiometry (DXA) of proximal femur (FN), whole body (WB), and spine segment (WBS) and N-telopeptide, bone-specific alkaline phosphatase, and other bone marker, hormonal, and weight changes. Results in the 33 women completing the study, whose initial bone densities were normal (QCT 133 mg/cm3, femoral neck 0.94 g/cm2, whole body DXA 1.13 g/cm2), showed annual QCT loss during CEE therapy of -11.5 mg/cm3 (p < 0.0007) and MPA bone loss of -19.7 mg/cm3 (p < 0.0001). Losses were marginally greater on MPA than CEE (p = 0.04). Extremely high postovariectomy (5 days) and pretreatment resorption markers (> 3 SD above premenopausal normal levels) were significantly related to bone loss. Across the year, resorption decreased during CEE but increased on MPA treatment. Significant DXA bone losses were prevented by CEE treatment (-1.4% FN, -.4% WB, and -1.5% WBS, all NS). However, DXA bone loss was not prevented by MPA treatment (-5% FN, -2.8% WB, and -6.1% WBS, all p < 0.03). Average weight gain was significant (+ 3.2 +/- 4.0 kg) and greater on CEE than MPA (+ 4.7 vs. + 2.0 kg, p = 0.049). In conclusion, CEE therapy did not prevent significant 8% cancellous spinal bone loss in the first year following premenopausal ovariectomy, despite supplementation with 600 mg/day of calcium, good control of vasomotor symptoms, and nearly 5 kg of gain in weight. Significant DXA bone loss, however, was prevented by CEE, but not by MPA therapy. These unexpected results were statistically related to high bone resorption following ovariectomy, which CEE suppressed but MPA did not. Bone formation markers increased during MPA therapy but were unchanged during CEE therapy.


Frozen/thawed platelets: importance of osmotic tolerance and platelet subpopulations.
Me2SO cryopreserved platelets circulate in vivo, reduce bleeding time, and have hemostatic properties but their functional recovery is only half that of the fresh material. Poor osmotic response is often reported as the cause of the freezing injury. Osmotic excursions on 1- and 5-day-old platelets have been studied. Platelets stored for 5 days have a lesser capability to regulate their volume particularly after an initial swelling. This is attributed to the reduction of discoid cell number, 80% vs 62% for 1-day-old and 5-day-old platelets, respectively. After freezing, hypotonic stress response is reduced from 86 to 39% for 1-day-old and 73 to 31% for 5-day-old platelets. This reduction in function is supported by a similar reduction of discoid cells from 80 to 40% for 1-day-old and 62 to 32% for 5-day-old platelets. The integrity of the cytoskeleton is critical for the osmotic response. Freezing recovery is significantly lowered in the presence of propylene glycol, which alters actin. This contrasts with the recovery of platelets treated with anti-aggregating agents. Platelets show a greater viability after freezing and thawing when PGI2 is added. It is postulated that freshly collected platelets, which are heterogeneous, contain populations of cells that are more sensitive to freezing than others. More tolerant cells remain discoid after freezing and are also less susceptible to storage lesions. Therefore, the maintenance of the integrity of the membrane and the cytoskeleton should be considered for the development of preservation methodologies.


Measurement of femoral geometry in type I and type II osteoporosis: differences in hip axis length consistent with heterogeneity in the pathogenesis of osteoporotic fractures.
The epidemiologic patterns of vertebral and femoral fractures are sufficiently different to suggest that they represent distinct disorders (type I versus type II osteoporosis) although osteopenia is common in both. To determine whether differences in femoral geometry, one of the main determinants of bone quality, might contribute to the heterogeneity in osteoporotic fractures, we obtained dual energy X-ray absorptiometry scans on 210 women age 60 or older, including 105 type I fracture cases, 30 type II patients, and 75 controls. Hip axis length, measured on the scan printout, was significantly increased (p < 0.01) in hip fracture patients compared with women with postmenopausal osteoporosis, whereas femoral neck density (BMD) was equal in both groups. The best discrimination between both fracture types was obtained by a logistic regression model based on age and axis length. Adding BMD to the model did not improve the discriminative power (p = 0.67). These data provide further evidence that geometric characteristics may be implicated in hip fracture risk. Furthermore, these findings suggest that an increase in hip axis length may predispose osteopenic subjects to a femoral localization of fragility fractures, consistent with the postulated heterogeneity in the pathogenesis of osteoporotic fractures.


N-terminal domain of myelin basic protein inhibits amyloid beta-protein fibril assembly.
Accumulation of amyloid β-protein (Aβ) into brain parenchymal plaques and the cerebral vasculature is a pathological feature of Alzheimer disease and related disorders. Aβ peptides readily form β-sheet-containing oligomers and fibrils. Previously, we reported a strong interaction between myelin basic protein (MBP) and Aβ peptides that resulted in potent inhibition of fibril assembly (Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2007) J. Biol. Chem. 282, 9952-9961; Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2009) Biochemistry 48, 4720-4727). MBP is recognized as a highly post-translationally modified protein. In the present study, we demonstrate that human MBP purified from either brain or a bacterial recombinant expression system comparably bound to Aβ and inhibited Aβ fibril assembly indicating that post-translational modifications are not required for this activity. We also show that purified mouse brain MBP and recombinantly expressed mouse MBP similarly inhibited Aβ fibril formation. Through a combination of biochemical and ultrastructural techniques, we demonstrate that the binding site for Aβ is located in the N-terminal 64 amino acids of MBP and that a stable peptide (MBP1) comprising these residues was sufficient to inhibit Aβ fibrillogenesis. Under conditions comparable with those used for Aβ, the fibrillar assembly of amylin, another amyloidogenic peptide, was not inhibited by MBP1, although MBP1 still bound to it. This observation suggests that the potent inhibitory effect of MBP on fibril formation is not general to amyloidogenic peptides. Finally, MBP1 could prevent the cytotoxic effects of Aβ in primary cortical neurons. Our findings suggest that inhibition of Aβ fibril assembly by MBP, mediated through its N-terminal domain, could play a role in influencing amyloid formation in Alzheimer disease brain and corresponding mouse models.


Relationship between Interferon Beta-1A Administration and Intracranial Vascular Tone Regulation in Patients with Relapsing-Remitting Multiple Sclerosis: A Pilot Study.
Interferon beta (IFN-β) therapy is one of the most commonly prescribed immunomodulatory therapies in relapsing-remitting multiple sclerosis (RRMS). A reversible cerebral vasoconstriction syndrome (RCVS), associated with IFN-β use, has been recently described. For this reason, we tested the effect of once a week intramuscular administration of IFN-β-1A on the function of cerebral vessels in a cohort of RRMS patients. Using transcranial Doppler (TCD) ultrasound, we measured the mean blood flow velocity (MFV) in intracranial vessels 10 h after IFN-β administration. Measurements showed a significant increase in MFV compared to the baseline values in some vessels.


Quantitative relation between intermolecular and intramolecular binding of pro-rich peptides to SH3 domains.
Flexible linkers are often found to tether binding sequence motifs or connect protein domains. Here we analyze three usages of flexible linkers: 1), intramolecular binding of proline-rich peptides (PRPs) to SH3 domains for kinase regulation; 2), intramolecular binding of PRP for increasing the folding stability of SH3 domains; and 3), covalent linking of PRPs and other ligands for high-affinity bivalent binding. The basis of these analyses is a quantitative relation between intermolecular and intramolecular binding constants. This relation has the form K(i) = K(e0)p for intramolecular binding and K(e) = K(e01)K(e02)p for bivalent binding. The effective concentration p depends on the length of the linker and the distance between the linker attachment points in the bound state. Several applications illustrate the usefulness of the quantitative relation. These include intramolecular binding to the Itk SH3 domain by an internal PRP and to a circular permutant of the alpha-spectrin SH3 domain by a designed PRP, and bivalent binding to the two SH3 domains of Grb2 by two linked PRPs. These and other examples suggest that flexible linkers and sequence motifs tethered to them, like folded protein domains, are also subject to tight control during evolution.


[Pulmonary hemorrhage as the initial manifestation of Behçet's disease].
Pulmonary hemorrhage in Behçet's disease is exceptional. It usually presents as a hemoptysis and appears in advanced stages. A patient is described who sought medical care for oral and genital lesions, arthritis and progressive dyspnea. Analytical data showed anemia and chest X-ray revealed a bilateral interstitial pattern. A fiber bronchoscopy was performed which confirmed the existence of a diffuse pulmonary hemorrhage. Corticosteroid and azatioprine administration resolved the hemorrhage. Pulmonary hemorrhages in Behçet's disease are reviewed and in view of a available literature therapeutic possibilities are discussed.


A voltammetric study of interdomain electron transfer within sulfite oxidase.
Protein film voltammetry of chicken liver sulfite oxidase (SO) bound at the pyrolytic graphite "edge" or modified gold electrodes shows that catalytic electron transport is controlled by the inherent electrochemical characteristics of the heme b domain and conformational changes that allow intramolecular electron transfer with the molybdenum active site. In the absence of sulfite, a single nonturnover electrochemical signal is observed at +90 mV (vs SHE) that is assigned to heme b. In the presence of sulfite, this signal transforms into a catalytic wave at similar potential. The shape and negligible pH dependence of this wave indicate that catalytic turnover is controlled by the one-electron transfers through heme b. The smaller turnover numbers obtained in this experiment (k(cat) approximately 2-4 s(-1), as compared to 100 s(-1) in solution) suggest that only a small fraction of SO is bound at the electrode in a manner that permits the conformational change necessary for fast interdomain electron transfer.


Estrogen replacement increases beta-adrenoceptor-mediated relaxation of rat mesenteric arteries.
The purpose of the present study was to determine whether estrogen replacement in ovariectomized rats could modulate arterial diameter responses to beta-adrenoceptor activation. Under relaxed conditions (0.1 mM papaverine) there were no differences in the lumen diameter of isolated, pressurized (50 mm Hg) mesenteric arteries from nontreated (191.7 +/- 13.8 microns; n = 19) versus those from estrogen-treated (190.1 +/- 11 microns; n = 14) ovariectomized Sprague-Dawley rats. In arteries precontracted with noradrenaline (0.3-1 microM), isoprenaline (0.01-10 microM)-induced relaxation was significantly increased in arteries from ovariectomized estrogen-treated rats (52.4 +/- 2% of the maximal relaxation induced by 0.1 mM papaverine, vs. 33.3 +/- 6.5%; p < 0.01). The half-maximal concentration value was 0.04 +/- 0.05 microM in estrogen-treated rats and 0.4 +/- 0.1 microM in nontreated rats (p < 0.01). This response was inhibited by propranolol (1 microM) in both groups to a comparable extent (61.5%), and was unaffected by endothelial removal. Forskolin (0.01-10 microM) induced similar concentration-dependent vasodilation in arteries of both groups of rats with no differences in sensitivity or maximal response. These results suggest that isoprenaline acts through beta-adrenoceptors present on vascular smooth muscle and that estrogen replacement enhances the relaxant responses induced by beta-adrenoceptor activation by an endothelium-independent mechanism.


Gene-expression-based quality scores indicate optimal harvest point in Bordetella pertussis cultivation for vaccine production.
The evolution of vaccine product quality during batch cultivation of Bordetella pertussis, the causative agent of whooping cough, was investigated with the goal to determine the optimal harvest point. The process was explored by measuring mRNA expression at frequent intervals during cultivation. The genes that are involved in virulence are already known for this product and changes in their expression levels are proposed to be indicative for product quality. A quantitative product quality score is calculated based on the expression levels of these virulence genes, which allows comparison of expected product quality between culture samples. Product quality scores were maximal throughout the logarithmic growth phase, but dropped significantly at the start of the stationary phase. This showed that the decreasing lactate and glutamate concentrations towards the end of the batch are critical for product quality. On-line measurement of these nutrients allows the cultivation process to be harvested at the optimal harvest point, increasing process robustness and consistency.


Blocking of Pseudomonas aeruginosa and Ralstonia solanacearum Lectins by plant and microbial branched polysaccharides used as food additives.
Pseudomonas aeruginosa antibiotic resistance prompted the search for glycodecoys that would block its lectin-dependent adhesion to human cells. We have used the lectins of this pathogen, PA-IL (galactophilic LecA) and PA-IIL (fucophilic LecB), and two additional pathogenic bacterial lectins, CV-IIL (fucophilic, of Chromobacterium violaceum) and RS-IIL (mannophilic, of Ralstonia solanacearum), for assaying the pathogenic lectin-blocking abilities of some plant and microbial polysaccharidic food additives, adding the mannophilic plant lectin Con A as a reference. Locust-bean and guar galactomannans and acacia gum very strongly inhibited PA-IL. The other lectins, excluding CV-IIL, were very strongly inhibited by yeast mannan. Xanthan and inulin were weak inhibitors. The differential blocking of these lectins by galactosylated branches of plant polysaccharides and by mannan matched their inhibition by avian egg whites, human milk, and royal jelly (protecting animal embryos and neonates from infections). The nondigestability and nontoxicity of the food additives are advantageous for curing gastrointestinal and external infections.


Plastic Surgery Subinternships: Current Perspectives and Future Considerations.
Subinternships are an important feature of the integrated plastic and reconstructive surgery residency application process. In our experience, there exists institutional heterogeneity in how subinterns are evaluated, how they are given feedback, and how their performance is compared across institutions. In this report, we conducted standardized interviews with 9 past and present integrated plastic and reconstructive surgery residency program directors, eliciting their expert opinions on current limitations of subinternships as a method of medical student education and evaluation. There near-unanimous agreement that subinternships were an important tool for evaluating the intangible traits of subinterns, with emphasis on teamwork, work ethic, and preparation for cases. However, our respondents suggested that subinterns lack direct feedback about real-time subinternship performance, and that there is a lack of transparency to subinterns regarding the quality of letters of recommendation. In the current system of subinternship evaluation, the letter-writer's reputation possibly overshadows the subintern's actual performance, which can be unfair to the student. We encourage the academic plastic and reconstructive surgery community to work toward more consistent and equitable evaluation of subinterns to the benefit of both residency applicants and programs.


Second Tunisian case of Anti -Tja mediated recurrent abortions.
The diagnosis and the treatment of rare phenotypes remain a problematic situation in many countries especially in Tunisia. Individuals with rare phenotype may develop clinically significant red cell antibodies directed against the high incidence Antigens they lack. A 35 years old patient was referred to our laboratory to explain a high incidence (twelve) of recurrent miscarriage during the first and second terms of pregnancy. This patient was grouped as O Rhesus: 1, -2, -3, 4, 5 K:-1. In her plasma we identified a pan-reactive anti-PP1PK antibody (anti-Tja) recognized to be responsible of spontaneous recurrent abortions. The red cell phenotype was P1 and Tja negative. More investigations concluded to the absence of auto and other allo-antibodies association. Therapeutic plasmapheresis from early stages was suggested for the future pregnancy to remove anti-public antibodies in order to maintain normal placenta functions. The Anti-Tja antibody, naturally occurring in patients with rare p phenotype, has the ability to induce recurrent spontaneous miscarriages and to cause immediate hemolytic transfusion reactions. Despite the absence of compatible donors in her family, this patient is not in an impasse situation because two donors with the same phenotype were identified when investigating a first case in 2013.


Maternal control, cognitive style, and childhood anxiety: a test of a theoretical model in a multi-ethnic sample.
This study tested a theoretical model of the interrelations among controlling parenting, negative cognitive styles, children's anxiety, and race/ethnicity. The model suggests that, in general, cognitive style mediates the relation between maternal control and child anxiety but that the set of associations may differ as a function of ethnicity. African American (n = 235), Latin American (n = 56), and European American (n = 136) children completed measures of their anxiety, cognitive schemas reflecting impaired autonomy/performance and disconnection/rejection domains, and maternal control. Results indicated that a disconnection/rejection negative cognitive style mediated the effect of perceived maternal control on childhood anxiety only for the European American group. Maternal control was associated with the impaired autonomy/performance cognitive style for each of the three ethnic groups and with a disconnection/rejection cognitive style only for the European American and Latin American groups. Maternal control had an indirect effect on anxiety through the disconnection/rejection cognitive style for the Latin American group. The results are discussed in terms of how the model presented extends current theories of anxiety problems to African American and Latin American children by noting that significant cultural variations may exist in how parenting practices and cognitive styles relate to children's anxiety levels.


Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy.
REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy.


Maintaining Balance.
Writing this biography forced me to look back over my career as a scientist, teacher, wife, and mother. To my surprise, a lifelong theme emerged that I was unaware of, that is, the role of maintaining balance between work and family, science and teaching, mentorship and administration, and personal values and challenges. My primary mentor, Dr. Doris Calloway, demonstrated the importance of maintaining balance. My interest in nutrition started as a preschooler living on a farm where I learned firsthand the importance of balancing the expense of providing good nutrition to the livestock with potential income. In our small high school, I became acquainted with the fascinating field of chemistry, but found it critical to balance that interest with a politically correct field of study for a woman in the early 1960s. I chose dietetics for its strong roots in chemistry. As a US Army dietitian, I learned firsthand how to conduct metabolic studies and knew, immediately, that I had to balance that interest with future opportunities feasible for a dietitian. I chose the University of California, Berkeley, for my PhD because it needed to train dietitians in research to balance an emerging need to offer undergraduates a practicum in dietetics. My subsequent faculty appointment there enabled me to develop novel isotopic approaches for studying zinc and prenatal nutrition, and balance my research with teaching and administrative responsibilities. During the next 40 years, my work as a Berkeley professor led to appointments at the Western Human Nutrition Research Center and Children's Hospital Oakland Research Institute, while balancing my responsibilities as a wife and a mother to my two sons. Balance is defined as a condition in which different elements are equal or in the correct proportions. It is extremely satisfying to look back and see evidence of successfully balancing the disparate elements of my career.


Thermostability in rubredoxin and its relationship to mechanical rigidity.
The source of increased stability in proteins from organisms that thrive in extreme thermal environments is not well understood. Previous experimental and theoretical studies have suggested many different features possibly responsible for such thermostability. Many of these thermostabilizing mechanisms can be accounted for in terms of structural rigidity. Thus a plausible hypothesis accounting for this remarkable stability in thermophilic enzymes states that these enzymes have enhanced conformational rigidity at temperatures below their native, functioning temperature. Experimental evidence exists to both support and contradict this supposition. We computationally investigate the relationship between thermostability and rigidity using rubredoxin as a case study. The mechanical rigidity is calculated using atomic models of homologous rubredoxin structures from the hyperthermophile Pyrococcus furiosus and mesophile Clostridium pasteurianum using the FIRST software. A global increase in structural rigidity (equivalently a decrease in flexibility) corresponds to an increase in thermostability. Locally, rigidity differences (between mesophilic and thermophilic structures) agree with differences in protection factors.


Heterogeneity of hyperdiploid (51-67) childhood acute lymphoblastic leukemia.
We studied the fully banded chromosomes of 182 children with hyperdiploid (51-67) acute lymphoblastic leukemia (ALL) to better delineate the heterogeneity of this disease subtype. Forty-six percent of the cases had numerical changes exclusively, while the remainder had structural as well as numerical changes. Chromosome 21 was added most often (97% of cases), followed by chromosomes 6 (86%), X (81%), 14 (80%), 4 (76%), 18 (68%), 17 (68%), 10 (56%), 8 (34%) and 5 (26%). Chromosomal translocations, including the t(1;19)(q23;p13) and t(9;22)(q34;q11), were detected in only 20% of the cases, as compared with 50% in ALL in general. The most common structural alterations were duplication of the 1q arm and isochromosome of 17q, present in 25 (14%) and nine (5%) cases, respectively. The presence of absence of structural abnormalities in these cases did not influence event-free survival, as assessed in 168 patients enrolled in three successive protocols for children with newly diagnosed ALL. By contrast, patients with 51-55 chromosomes per leukemic cell (n=105) appeared to fare worse than the 56-67 subgroup (n=63) (5-year probability of event-free survival = 72 +/- 5% (s.e.) vs 86 +/- 5%; P=0.04 by the stratified log-rank test). The poorer prognosis of the 51-55 subgroup was partly due to the higher frequency of isochromosome of 17q; 6/7 patients with the isochromosome in this group have had an adverse event. Other unfavorable features within the hyperdiploid (51-55) ALL subgroup include a low prevalence of trisomies of chromosomes 4 and 10 and a higher proportion of patients with leukocyte counts greater than 50 X 10(9)/l when compared to hyperdiploid (56-67). Thus, ALL defined by 51-55 chromosomes appears to be a clinicobiologic entity quite distinct from cases with higher modal numbers.


Endogenous Rho-kinase signaling maintains synaptic strength by stabilizing the size of the readily releasable pool of synaptic vesicles.
Rho-associated kinase (ROCK) regulates neural cell migration, proliferation and survival, dendritic spine morphology, and axon guidance and regeneration. There is, however, little information about whether ROCK modulates the electrical activity and information processing of neuronal circuits. At neonatal stage, ROCKα is expressed in hypoglossal motoneurons (HMNs) and in their afferent inputs, whereas ROCKβ is found in synaptic terminals on HMNs, but not in their somata. Inhibition of endogenous ROCK activity in neonatal rat brainstem slices failed to modulate intrinsic excitability of HMNs, but strongly attenuated the strength of their glutamatergic and GABAergic synaptic inputs. The mechanism acts presynaptically to reduce evoked neurotransmitter release. ROCK inhibition increased myosin light chain (MLC) phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. Functional and ultrastructural changes induced by ROCK inhibition were fully prevented/reverted by MLC kinase (MLCK) inhibition. Furthermore, ROCK inhibition drastically reduced the phosphorylated form of p21-associated kinase (PAK), which directly inhibits MLCK. We conclude that endogenous ROCK activity is necessary for the normal performance of motor output commands, because it maintains afferent synaptic strength, by stabilizing the size of the readily releasable pool of synaptic vesicles. The mechanism of action involves a tonic inhibition of MLCK, presumably through PAK phosphorylation. This mechanism might be present in adults since unilateral microinjection of ROCK or MLCK inhibitors into the hypoglossal nucleus reduced or increased, respectively, whole XIIth nerve activity.


Gender differences in the sleep habits of 11-13 year olds.
Sleep plays an important role in the physical and emotional development of adolescents. The aim of this study was to examine gender differences in sleep habits in a sample of 11-13 year olds. The study was carried out in the city of Patos de Minas, Brazil. The study cohort was composed of 200 students (96 boys and 104 girls) attending (in the morning or in the afternoon) the 5th, 6th or 7th grades, with ages ranging from 11 to 13 years. A Sleep Questionnaire developed at the Federal University of São Paulo was used in order to evaluate student sleep habits and schedules, as well as the overall quality of sleep. For the period between Friday night and Sunday morning, girls displayed longer sleep duration than did boys. During the week, students attending only afternoon classes woke up later than did students attending only morning classes. In addition, morning-class students showed more adverse effects on sleep, including irregular sleep/wakefulness circadian rhythms, when compared with afternoon-class students. Sleep habits are affected by gender and school schedule.


Molecular cloning and functional characterization of NtWRKY41a in the biosynthesis of phenylpropanoids in Nicotiana tabacum.
Phenylpropanoids are important secondary metabolites that have multifaceted effects on plant growth, development, and environmental adaptation. WRKY41 has been shown to repress anthocyanins synthesis in Arabidopsis, but its full roles in regulating plant phenylpropanoids metabolism still remains to be further studied. Here, we cloned two NtWRKY41 genes from N. tabacum genome, and NtWRKY41a showed higher expression levels than NtWRKY41b genes in all the tobacco tissues examined. Overexpression and knock-out of NtWRKY41a gene revealed that NtWRKY41a promoted the biosynthesis of Chlorogenic acid (CGA) and lignin, but repressed the accumulation of scopoletin and flavonoids in tobacco. Transcriptome analysis found 7 phenylpropanoids related differentially expressed genes (DEGs) between WT and NtWRKY41a-OE plants, among which the transcription of NtCCoAOMT and NtHST was significantly induced by posttranslational activation of NtWRKY41a, while those of NtF6'H1 and NtGT3 was significantly repressed by NtWRKY41a. Chromatin immunoprecipitation and Dual-Luc assays further indicated that NtWRKY41a could bind to the promoter regions of these four genes to regulate their transcription. Moreover, ectopic expression of NtWRKY41a also promoted the transcription of several NtLOX and NtHPL genes, which encode key enzymes involved in the oxylipin pathway. Our findings revealed new functions of NtWRKY41a in modulating the distribution of metabolism flux in phenylpropanoids pathway, and provided a promising target for manipulating phenylpropanoids contents in tobacco.


Can States Continue to Set the Agenda for Tobacco 21? Insights From US News Coverage Between 2012 and 2020.
Existing research on media examining the news content related to Tobacco 21 (T21) predate the adoption of most T21 laws. This study examined the discussion of T21 laws in top-circulating print media sources in the United States between 2012 and 2020. Systematic database searches using Access World News and Factiva identified T21-related news articles appearing in the top daily circulating newspapers in each state between January 2012 and December 2020 (n = 586 articles). Content analyses documented prevalence, types of articles and context related to framing of arguments for or against T21 laws. Newspaper coverage of T21 was highest in 2019 (42.8% of articles). The majority were news or features (75.4%) followed by editorials or opinions (24.6%) which largely supported T21. Most articles focused on state or local T21 action. Coverage of federal T21 increased in 2019. The most common argument supporting T21 included reducing youth tobacco prevalence (64.8%) while the most frequent objection was freedom infringement (25.1%). Tobacco and vape industries began voicing support for T21 in 2019. News coverage of state-level T21 in the United States began to increase in 2015 and peaked in 2019 with enactment of federal T21, a newsworthy event. As states adopt and amend T21 laws to align with federal law, advocates can use media to help shape the narrative and encourage strong T21 policies. This study described the volume and content of T21 print media coverage from 2012 to 2020, including common arguments used to support and oppose T21. Arguments in support of T21 included reducing youth tobacco use, particularly use of e-cigarettes, and related health effects while arguments against T21 focused on individual rights. Support for T21 reached a tipping point in 2019, including the tobacco industry's reversal in opposing such laws. States can and should continue to improve existing T21 laws and policies and increase public awareness about critical policy components such as inspection procedures and penalties.


Therapeutic lymphadenectomy in melanomas of the head and neck.
This retrospective study describes patients with loco-regionally metastasized melanoma of the head and neck. All patients underwent a therapeutic lymph node dissection. The 3-year survival rate was 35%. Duration of disease-free interval, number of lymph nodes involved, and extent of neck dissection proved of no influence on survival rates. Locoregional recurrence occurred in 10 patients and always proved to be a sign of systemic dissemination. Ultimately, 19 patients developed systemic disease. More than 40% developed cerebral metastases and the cerebrum was the second most involved site. As cerebral involvement occurs often in head and neck melanoma, a computed tomography or magnetic resonance imaging scan of the brain is recommended in the routine work-up before lymph node dissection. Furthermore, because the extent of the surgical procedure had no influence on local recurrence rate and overall survival, a selective approach, preserving functional structures, is advocated.


The interaction of the F plasmid killer protein, CcdB, with DNA gyrase: induction of DNA cleavage and blocking of transcription.
We have studied the interaction of the F plasmid killer protein CcdB with its intracellular target DNA gyrase. We confirm that CcdB can induce DNA cleavage by gyrase and show that this cleavage reaction requires ATP hydrolysis when the substrate is linear DNA, but is independent of hydrolysis when negatively supercoiled DNA is used. The 64 kDa domain of the gyrase A protein, which can catalyse DNA cleavage in the presence of the B protein and quinolone drugs, is unable to cleave DNA in the presence of CcdB unless the C-terminal 33 kDa domain of the gyrase A protein is also present. CcdB-induced DNA cleavage by gyrase requires a minimum length of DNA (> approximately 160 bp), whereas in the presence of quinolone drugs gyrase can cleave much shorter DNA molecules. We show that CcdB, like quinolones, can form a complex with gyrase which can block transcription by RNA polymerase. A model for the interaction of CcdB with gyrase involving the trapping of a post-strand-passage intermediate is suggested. We conclude that CcdB can stabilise a cleavage complex between DNA gyrase and DNA in a manner distinct from quinolones but, like the quinolone-induced cleavage complex, the CcdB-stabilised complex can also form a barrier to the passage of polymerases.


Growth prediction of Microcystis aeruginosa based on a secondary decomposition integration model.
Microcystis aeruginosa is the dominant species in the blooms of eutrophic lakes such as Taihu Lake in China. Chlorophyll-a is one of the most common indicators to characterize its biomass. The nonlinearity and unsteadiness of the chlorophyll-a sequence decrease the prediction accuracy. In this paper, a secondary decomposition prediction method based on the integration of wavelet decomposition, variational modal decomposition, and gated recurrent unit (WD-VMD-GRU) is proposed. First, the original sequence is decomposed once using wavelet decomposition (WD). Then, the components with higher sample entropy values are decomposed using variational modal decomposition (VMD). Finally, each component is predicted using a gated recurrent unit (GRU), and the final prediction results are obtained by reconstructing each component result. The decomposition effect is ranked as VMD > WD > CEEMDAN > EMD. The WD-VMD-GRU model has a significant advantage compared to the basic model, with an increase of over 6.5% in R2. The secondary decomposition reduces the difficulty of predicting GRU components and has better prediction performance. The RMSE, MAE, and R2 were 1.752, 1.450, 0.969 at 2-day prediction, and 3.169, 2.711, 0.908 at 6-day prediction. Therefore, the WD-VMD-GRU model is superior in accuracy to other methods and can provide a scientific basis for the growth prediction research of M. aeruginosa.


Rehabilitation of patients with anosognosia for hemiplegia due to intracerebral haemorrhage.
We have studied the differences in the lesions, concomitant symptoms and ADL levels in patients in acute-stage cerebral-haemorrhage and manifesting anosognosia. Twelve of 50 patients (24.0%) presented with anosognosia. The (+) group had longer intervals between onset and the first evaluation than did the (-) group, demonstrating severe sensory disturbance. The volume of haemorrhage was significantly larger in the (+) group. Anosognosia disappeared within 3 months in all cases. In the (+) group the time until discharge was long, with the ADL level at the time of discharge being low. Therefore, it was considered that anosognosia was important as an inhibitory factor hampering rehabilitation.


Growth of measles and subacute sclerosing panencephalitis viruses in human neural cell lines.
Growth of cell-free subacute sclerosing panencephalitis (SSPE) virus was compared with that of measles virus in three human neural cell lines; neuroblastoma, oligodendroglioma, and glioblastoma. The Edmonston strain of measles virus replicated in these neural cells as efficiently as in Vero cells. In contrast, the growth of the Mantooth strain of SSPE virus was suppressed moderately in neuroblastoma cells and markedly in oligodendroglioma and glioblastoma cells in spite of the induction of apparent cytopathic effects in these cells. Virus adsorption, defective interfering particles, interferon, and temperature sensitivity were not responsible for this low yield of SSPE virus in neural cell lines. Synthesis of viral proteins of SSPE virus was slower than that of measles virus in oligodendroglioma and glioblastoma cells. These results suggest that the slow rate of synthesis of viral proteins may be relevant to the low yield of SSPE virus in neural cells.


Unclassified Mixed Germ Cell-Sex Cord-Stromal Tumor of the Ovary: An Unusual Case Report.
Unclassified mixed germ cell-sex cord-stromal tumor (UMGC-SCST) is a rare ovarian neoplasm composed of germ cells and sex cord elements, which occurs in genetically and phenotypically normal women without the usual histological features seen in gonadoblastoma. Few cases have been reported in the literature so far. The age of presentation is more frequent in girls younger than 10 years of age, although it can also occur in adult women. It can be associated with isosexual pseudoprecocity. The preferred management is the resection of the gonad that contains the tumor and the conservation of the opposite ovary and tube. This is a case of a 14-year-old patient, with precocious puberty and normal phenotype, diagnosed with this kind of ovarian tumor. A fertility preserving surgery with the resection of the right ovarian tumor and tube was performed. The patient was classified as stage IA according to the 2014 International Federation of Gynecology and Obstetrics (FIGO). She received adjuvant chemotherapy with bleomycin-etoposide-cisplatin for three cycles. After a follow-up of 24 months, she was found to be asymptomatic and free of relapse.


Homozygous female Becker muscular dystrophy.
We report, for the first time, on a female Becker muscular dystrophy (BMD) patient with homozygous dystrophin deletion. The 14-year-old patient, product of consanguineous parents, presented with a 7-year history of exercise intolerance and recurrent myoglobinuria. Although CK was elevated to 1,800 U/L, no muscle weakness, atrophy, or hypertrophy was seen on examination. Muscle pathology demonstrated a minimal dystrophic change and faint dystrophin staining pattern. Semi-quantitative PCR of dystrophin revealed a homozygous dystrophin deletion of exons 45-55, which is predicted to remove 593 amino acids without frame shifting. Western blot analysis of skeletal muscle for dystrophin showed a 306 kDa band; thus, we made a diagnosis of female BMD. We confirmed identical deletion in both father and mother, in hemizygous and heterozygous modes, respectively. Neither female Duchenne muscular dystrophy (DMD) nor BMD due to homozygous dystrophin mutation has ever been identified although female DMD has been found in patients with Turner syndrome or unilateral parental disomy for X chromosome. Our results indicate that dystrophinopathy can also be caused in females by homozygosity, albeit rare.


Pharmaceutical technology management--profitable business avenue.
Growing research expenditure, regulatory framework and generic erosion have forced pharmaceutical companies globally to resort to pharmaceutical technology management (PTM). Indeed, the pharmaceutical industry has witnessed the impact of innovative drug delivery and device technologies and their influence on business. PTM has given a new business insight with greater profits and enhancement of product franchise. Promising breakthrough technologies have not been able to reach a commercial platform largely owing to lack of capital at the preliminary stages of the product development program. Intellectual property plays a considerable role in protecting innovative technologies. Joint ventures and strategic alliances also become important for commercializing a new technology. The synergy of PTM with options of in-licensing is expected to infuse newer opportunities to the pharmaceutical business.


Immune restoration Klebsiella lymphadenitis.
A subset of HIV-infected patients who receive antiretroviral therapy (ART) develop immune restoration syndrome. A case of immune restoration Klebsiella lymphadenitis is described. Fine needle aspiration cytology remains a useful investigative tool in the post-ART era, particularly in the diagnosis of persistent generalized lymphadenopathy, infection and malignancy of the lymph nodes.


Plastic Surgeons Nationwide Share Experience Regarding Telemedicine in Initial Patient Screening and Routine Postoperative Visits.
Physicians attempted to continue providing patient care through the SARS-CoV2 (COVID-19) pandemic. Surgeons embraced telemedicine as patient evaluation transitioned from physical encounters to virtual appointments. However, there is a paucity in the literature on the utility of telemedicine within plastic surgery or how it can meet patients' needs. A survey study was created to assess surgeons' involvement and experience with telemedicine. Subjective experience was assessed on a five-point Likert scale (1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree, 5 = strongly agree). This survey was distributed to the members of the American Society of Plastic Surgeons. Data were collected and analyzed via RedCap. Of the total 177 plastic surgeons who responded, 139 (78.5%) surgeons reported the implementation of telemedicine during the pandemic. Plastic surgeons felt that they were able to establish rapport (3.9 ± 0.9), meet the goals of the encounter (3.6 ± 1.0), and efficiently evaluate patients (3.5 ± 1.2). Plastic surgeons reported their overall experience was between helpful and neutral (3.2 ± 1.3). Most plastic surgeons have implemented telemedicine in their practice. The majority of telemedicine use was for breast, cosmetic, and reconstructive patient care. Telemedicine was most frequently used for initial patient screening and routine postoperative visits. Surgeons plan to continue using telemedicine when appropriate for patient screening and routine or unexpected postoperative visits in the future. Many have found utility of telemedicine in providing patient care and it is likely that telemedicine will be a part of routine practice moving forward.


Neuronavigation. Principles. Surgical technique.
Neuronavigation and stereotaxy are techniques designed to help neurosurgeons precisely localize different intracerebral pathological processes by using a set of preoperative images (CT, MRI, fMRI, PET, SPECT etc.). The development of computer assisted surgery was possible only after a significant technological progress, especially in the area of informatics and imagistics. The main indications of neuronavigation are represented by the targeting of small and deep intracerebral lesions and choosing the best way to treat them, in order to preserve the neurological function. Stereotaxis also allows lesioning or stimulation of basal ganglia for the treatment of movement disorders. These techniques can bring an important amount of confort both to the patient and to the neurosurgeon. Neuronavigation was introduced in Romania around 2003, in four neurosurgical centers. We present our five-years experience in neuronavigation and describe the main principles and surgical techniques.


Mapping the high throughput SEREX technology screening for novel tumor antigens.
Advances in novel tumor-associated antigen (TAA) screening strategy have accelerated the identification and characterization of biomarkers and potential target molecules for tumor subtyping, diagnosis and therapeutics, which may facilitate early detection and diagnosis of the diseases individually and enhance treatment approaches for cancer. Over the past decades, a plethora of non-invasive methodologies dedicated to identify novel target molecules have been primarily focusing on the discovery of human tumor antigens recognized by the autologous antibody repertoire or cytotoxic T lymphocytes, among which serological analysis of recombinant cDNA expression libraries (SEREX) technology is chronologically first established and is of outstanding sensitivity and antigen coverage. This approach involves immunoscreening cDNA libraries extracted from fresh tumor tissues with sera from cancer patients to identify gene products recognized by IgG antibody. SEREX-defined clones can be directly sequenced and their expression profiles can be readily determined, allowing for immediate structural definition of the antigenic target and subsequent identification of TAAs and their cognate autoantibodies. This review is not only devoted to outline the SEREX technology and its advantages, drawbacks and recent modifications currently available for discovering provocative tumor antigens, but also to translate these SEREX-defined peptides into valuable cancer-specific signatures that would aid in the development of diagnostics, prognostics and therapeutics for cancer patients.


Effect of cooking on radiation-induced chemical markers in beef and pork during storage.
Raw and cooked beef and pork loins were irradiated at 0 or 5 kGy. The radiation-induced marker compounds, such as hydrocarbons, 2-alkylcyclobutanones (2-ACBs), and sulfur volatiles, were determined after 0 and 6 mo of frozen storage. Two hydrocarbons (8-heptadecene [C(17:1)] and 6,9-heptadecadiene [C(17:2)]) and two 2-ACBs (2-dodecylcyclobutanone [2-DCB] and 2-tetradecylcyclobutanone [2-TCB]) were detected only in irradiated raw and cooked meats. Although precooked irradiated meats produced more hydrocarbons and 2-ACBs than the irradiated cooked ones, the amounts of individual hydrocarbons and 2-ACBs, such as 8-heptadecene, 6,9-heptadecadiene, 2-DCB, and 2-TCB, were sufficient enough to detect whether the meat was irradiated or not. Dimethyl disulfide and dimethyl trisulfide were also determined only in irradiated meats but dimethyl trisulfide disappeared after 6 mo of frozen storage under oxygen-permeable packaging conditions. The results indicated that 8-heptadecene, 6,9-heptadecadiene, 2-DCB, 2-TCB, and dimethyl disulfide, even though they were decreased with storage, could be used as marker compounds for the detection of irradiated beef and pork regardless of cooking under the frozen conditions for 6 mo. Radiation-induced chemical changes such as specific hydrocarbons, 2-ACBs, and sulfur volatiles may be used as potential identification markers by regulatory authorities to confirm irradiation history of frozen stored raw or cooked beef and pork.


Deconstruction of the Surgical Approach to the Jugular Foramen Region: Anatomical Study.
Introduction The jugular foramen occupies a complex and deep location between the skull base and the distal-lateral-cervical region. We propose a morphometric anatomical model to deconstruct its surgical anatomy and offer various quantifiable target-guided exposures and angles-of-attack. Methods Six cadaveric heads (12 sides) were dissected using a combined postauricular infralabyrinthine and distal transcervical approach with additional anterior transstyloid and posterior far lateral exposures. We identified anatomical landmarks and combined new and previously described contiguous triangles to expose the region; we defined the jugular and deep condylar triangles. Angles-of-attack to the jugular foramen were measured after removing the digastric muscle, styloid process, rectus capitis lateralis, and occipital condyle. Results Removing the digastric muscle and styloid process allowed 86.4° laterally and 85.5° anteriorly, respectively. Resecting the rectus capitis lateralis and jugular process provided the largest angle-of-attack (108.4° posteriorly). The occipital condyle can be drilled in the deep condylar triangle only adding 30.4° medially. A purely lateral approach provided a total of 280.3°. Cutting the jugular ring and mobilizing the vein can further expand the medial exposure. Conclusion The microsurgical anatomy of the jugular foramen can be deconstructed using a morphometric model, permitting a surgical approach customized to the pathology of interest.


Enhancement of l-Pipecolic Acid Production by Dynamic Control of Substrates and Multiple Copies of the pipA Gene in the Escherichia coli Genome.
l-Pipecolic acid is an important rigid cyclic nonprotein amino acid, which is obtained through the conversion of l-lysine catalyzed by l-lysine cyclodeaminase (LCD). To directly produce l-pipecolic acid from glucose by microbial fermentation, in this study, a recombinant Escherichia coli strain with high efficiency of l-pipecolic acid production was constructed. This study involves the dynamic regulation of the substrate concentration and the expression level of the l-lysine cyclodeaminase-coding gene pipA. In terms of substrate concentration, we adopted the l-lysine riboswitch to dynamically regulate the expression of lysP and lysO genes. As a result, the l-pipecolic acid yield was increased about 1.8-fold as compared with the control. In addition, we used chemically inducible chromosomal evolution (CIChE) to realize the presence of multiple copies of the pipA gene on the genome. The resultant E. coli strain XQ-11-4 produced 61 ± 3.4 g/L l-pipecolic acid with a productivity of 1.02 ± 0.06 g/(L·h) and a glucose conversion efficiency (α) of 29.6% in fermentation. This is the first report that discovered multiple copies of pipA gene expression on the genome that improves the efficiency of l-pipecolic acid production in an l-lysine high-producing strain, and these results give us new insight for constructing the other valuable biochemicals derived from l-lysine.


Functional properties of human embryonic stem cell-derived cardiomyocytes: intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction.
Since cardiac transplantation is limited by the small availability of donor organs, regeneration of the diseased myocardium by cell transplantation is an attractive therapeutic modality. To determine the compatibility of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) (7 to 55 days old) with the myocardium, we investigated their functional properties regarding intracellular Ca2+ handling and the role of the sarcoplasmic reticulum in the contraction. The functional properties of hESC-CMs were investigated by recording simultaneously [Ca2+]i transients and contractions. Additionally, we performed Western blot analysis of the Ca2+-handling proteins SERCA2, calsequestrin, phospholamban, and Na+/Ca2+ exchanger (NCX). Our major findings are, first, that hESC-CMs displayed temporally related [Ca2+]i transients and contractions, negative force-frequency relations, and lack of post-rest potentiation. Second, ryanodine, thapsigargin, and caffeine did not affect the [Ca2+]i transient and contraction, indicating that at this developmental stage, contraction depends on transsarcolemmal Ca2+ influx rather than on sarcoplasmic reticulum Ca2+ release. Third, in agreement with the notion that a voltage-dependent Ca2+ current is present in hESC-CMs and contributes to the mechanical function, verapamil completely blocked contraction. Fourth, whereas hESC-CMs expressed SERCA2 and NCX at levels comparable to those of the adult porcine myocardium, calsequestrin and phospholamban were not expressed. Our study shows for the first time that functional properties related to intracellular Ca2+ handling of hESC-CMs differ markedly from the adult myocardium, probably due to immature sarcoplasmic reticulum capacity.


Tonography assessment using quantitative and qualitative analysis of the aqueous humor outflow mechanism.
To perform qualitative evaluation of the aqueous humor (AH) outflow mechanism in glaucoma and nonglaucoma patients by means of tonography assessment and mathematical analysis. Sixty-two primary open angle and 58 pseudoexfoliation glaucoma patients were recruited in a non-interventional, observational study between 2004 and 2007. Qualitative and quantitative outflow assessment was acquired by means of a digital tonographer and mathematical analysis. Qualitative results were represented using slope analysis of the change of the AH outflow rate over the tonography study. The results were compared to the control group (CG; n=100) as well as to a pseudoexfoliation group (PEX; n=46). Regarding quantitative analysis, glaucoma groups exhibited significantly lower outflow facility compared to nonglaucoma ones (p<0.001). Outflow facility value was significantly correlated to cup to disc ratio (Pearson correlation r=-0.3, p<0.001). Regarding qualitative analysis, the primary open-angle glaucoma (POAG) group presented a significant profile variation at the beginning of the tonography, expressed as an increased resistance of the AH outflow. Both glaucoma groups exhibited profile stabilization at the end of the measurement, suggesting that the outflow rate remained constant, while nonglaucoma groups followed a continuous reduction of the AH outflow rate throughout the study. The POAG, PXG, PEX, and CG groups demonstrated both qualitative and quantitative tonographic profile differences. The observed differences in the glaucoma groups suggest a distinct pathomechanism between POAG and PXG. It is suggested that POAG patients have a temporary disruption of the AH flow pathway, while PXG patients have a generalized increased flow resistance.


E2DR: A Deep Learning Ensemble-Based Driver Distraction Detection with Recommendations Model.
The increasing number of car accidents is a significant issue in current transportation systems. According to the World Health Organization (WHO), road accidents are the eighth highest top cause of death around the world. More than 80% of road accidents are caused by distracted driving, such as using a mobile phone, talking to passengers, and smoking. A lot of efforts have been made to tackle the problem of driver distraction; however, no optimal solution is provided. A practical approach to solving this problem is implementing quantitative measures for driver activities and designing a classification system that detects distracting actions. In this paper, we have implemented a portfolio of various ensemble deep learning models that have been proven to efficiently classify driver distracted actions and provide an in-car recommendation to minimize the level of distractions and increase in-car awareness for improved safety. This paper proposes E2DR, a new scalable model that uses stacking ensemble methods to combine two or more deep learning models to improve accuracy, enhance generalization, and reduce overfitting, with real-time recommendations. The highest performing E2DR variant, which included the ResNet50 and VGG16 models, achieved a test accuracy of 92% as applied to state-of-the-art datasets, including the State Farm Distracted Drivers dataset, using novel data splitting strategies.


Neuromuscular respiratory failure in Guillain-Barre Syndrome: evaluation of clinical and electrodiagnostic predictors.
Guillain-Barre Syndrome (GBS) has an unpredictable clinical course with up to 30% of patients requiring assisted ventilation during the course of their illness. Successful management mandates anticipation, prompt recognition and optimal treatment of neuromuscular respiratory failure in GBS. To identify clinical and electrodiagnostic predictors of neuromuscular respiratory paralysis in GBS. Forty six patients of GBS were studied over a 6 year period, the study being 2 year retrospective and 4 year prospective. Clinical and electrodiagnostic data were compared between ventilated (28) and non-ventilated (18) patients. The clinical parameters assessed were median age, gender, antecedent infection, prior lung disease, time to peak disability, bifacial weakness, upper limb weakness, bulbar paralysis, neck weakness and autonomic dysfunction. Electrodiagnostic studies included motor nerve conduction studies in 11 ventilated and 13 non-ventilated patients, done prior to maximum disability in each group. Multiple logistic regression analysis was used to compare the two groups. Comparing the clinical data in the ventilated and non-ventilated groups, 'early peak disability', autonomic dysfunction and bulbar weakness predicted the onset of respiratory paralysis. Age, gender, neck or bifacial weakness, upper limb paralysis, or preceding infection did not influence the development of neuromuscular respiratory weakness. Electrodiagnostic testing revealed abnormal H reflex and F waves to be the commonest abnormality in either group. Although data was not sufficient for statistical analysis, the presence of markedly attenuated Compound Muscle Action Potentials inexcitable motor nerves and denervation changes on the electromyography, was commoner in the ventilated group. Thirty six patients received treatment with either plasmapheresis (12) or intravenous immunoglobulin (24). Overall mortality was 5, all 5 patients being on assisted ventilation. Early progression to peak disability, bulbar dysfunction and autonomic instability predicted the development of neuromuscular respiratory paralysis in GBS. Early electrodiagnostic studies in this series suggest axonopathic GBS as a predictor of respiratory paralysis, a finding that needs to be evaluated with sufficient data to permit statistical analysis.


Functional electrical stimulation of dorsiflexor muscle: effects on dorsiflexor strength, plantarflexor spasticity, and motor recovery in stroke patients.
To evaluate the therapeutic effects of Functional Electrical Stimulation (FES) of the tibialis anterior muscle on plantarflexor spasticity, dorsiflexor strength, voluntary ankle dorsiflexion, and lower extremity motor recovery with stroke survivors. We conducted a prospective interventional study. Rehabilitation ward, physiotherapy unit and gait analysis laboratory. Fifty-one patients with foot drop resulting from stroke. The functional electrical stimulation (FES) group (n=27) received 20-30 minutes of electrical stimulation to the peroneal nerve and anterior tibial muscle of the paretic limb along with conventional rehabilitation program (CRP). The control group (n=24) treated with CRP only. The subjects were treated 1 hr per day, 5 days a week, for 12 weeks. Plantarflexor spasticity measured by modified ashworth scale (MAS), dorsiflexion strength measured by manual muscle test (MMT), active/passive ankle joint dorsiflexion range of motion, and lower-extremity motor recovery by Fugl-Meyer assessment (FMA) scale. After 12 weeks of treatment, there was a significant reduction in a plantarflexor spasticity by 38.3% in the FES group and 21.2% in control group (P< 0.05), between the beginning and end of the trial. Dorsiflexor muscle strength was increased significantly by 56.6% and 27.7% in the FES group and control group, respectively. Similarly, voluntary ankle dorsiflexion and lower-extremity motor function improved significantly in both the groups. No significant differences were found in the baseline measurements among groups. When compared with control group, a significant improvement (p< 0.05) was measured in all assessed parameters in the FES group at post-treatment assessment, thus FES therapy has better effect on recovery process in post-stroke rehabilitation. Therapy combining FES and conventional rehabilitation program was superior to a conventional rehabilitation program alone, in terms of reducing spasticity, improving dorsiflexor strength and lower extremity motor recovery in stroke patients.


A new name for Dendronephthya kukenthali Gravier, 1908 (Octocorallia, Nephtheidae): Dendronephthya perezi nom. n.
The World Register of Marine Species (WoRMS) is an online resource, which provides the most comprehensive database of scientific names of marine organisms (WoRMS, 2018). WoRMS is regularly retrieved by multidisciplinary researchers around the globe, regarded as a source of reliable taxonomic information. The database is continuously improved by taxonomic experts, which frequently have to address issues raised by users and other editors (Costello et al., 2013). This study is a result of one of these exchanges of knowledge stimulated by WoRMS.


Integrative Analysis of Deregulated miRNAs Reveals Candidate Molecular Mechanisms Linking H. pylori Infected Peptic Ulcer Disease with Periodontitis.
Periodontitis is a highly prevalent oral infectious disease and has been increasingly associated with H. pylori infection, gastric inflammation, and gastric cancer but little is known about epigenetic machinery underlying this potentially bidirectional association. The present study is aimed at identifying key deregulated miRNA, their associated genes, signaling pathways, and compounds linking periodontitis with H. pylori-associated peptic ulcer disease. miRNA expression datasets for periodontitis-affected and H. pylori-associated peptic ulcer disease-affected tissues were sought from the GEO database. Differentially expressed miRNA (DEmiRNAs) were identified and the overlapping, shared-DEmiRNA between both datasets were determined. Shared-DEmiRNA-target networks construction and functional analyses were constructed using miRNet 2.0, including shared-DEmiRNA-gene, shared-DEmiRNA-transcription factor (TF), and shared-DEmiRNA-compound networks. Functional enrichment analysis for shared DEmiRNA-gene and shared DEmiRNA-TF networks was performed using the KEGG, Reactome, and Geno Ontology (GO) pathways. 11 shared-DEmiRNAs were identified, among which 9 showed similar expression patterns in both diseases, and 7 were overexpressed. miRNA hsa-hsa-mir-155-5p and hsa-mir-29a-3p were top miRNA nodes in both gene and TF networks. The topmost candidate miRNA-deregulated genes were PTEN, CCND1, MDM2, TNRC6A, and SCD while topmost deregulated TFs included STAT3, HIF1A, EZH2, CEBPA, and RUNX1. Curcumin, 5-fluorouracil, and the gallotanin 1,2,6-Tri-O-galloyl-beta-D-glucopyranose emerged as the most relevant linkage compound targets. Functional analyses revealed multiple cancer-associated pathways, PI3K pathways, kinase binding, and transcription factor binding among as enriched by the network-associated genes and TFs. Integrative analysis of deregulated miRNAs revealed candidate molecular mechanisms comprising of top miRNA, their gene, and TF targets linking H. pylori-infected peptic ulcer disease with periodontitis and highlighted compounds targeting both diseases. These findings provide basis for directing future experimental research.


Influence of diuretics on the concentration of proteins and other components of pleural transudates in patients with heart failure.
Diuretic therapy increases the total protein and lactate dehydrogenase concentrations in pleural fluid in patients with transudates due to heart failure, but the effect of diuresis on other substances in pleural fluid constituents is not known. Twenty-one patients with transudative pleural effusions due to congestive heart failure were prospectively studied. Repeated diagnostic thoracentesis (mean +/- SD = 3 +/- 1; range, 2 to 6) was performed until the effusions were radiographically unapparent (5 +/- 2 days). Thirty-one patients with congestive heart failure who underwent only a single thoracentesis after diuretic therapy served as controls. We measured the concentrations of various components of pleural effusions in the serum and in the pleural fluid, and determined the serum-pleural fluid gradient (serum concentration minus pleural fluid concentration) and ratio (serum concentration divided by pleural fluid concentration). The pleural concentrations of most components increased significantly (P <0.001) from the initial specimen to the final specimen: total protein, from 23 +/- 7 g/L to 33 +/- 9 g/L; albumin, from 13 +/- 4 g/L to 18 +/- 6 g/L; lactate dehydrogenase, from 177 +/- 62 U/L to 288 +/- 90 U/L; cholesterol, from 31 +/- 16 mg/dL to 52 +/- 22 mg/dL; and cholinesterase, from 1,304 +/- 616 U/L to 1,884 +/- 674 U/L. Expressed as percentage change, the increases in the serum-pleural fluid gradients for albumin (12% +/- 22%) and total protein (11% +/- 12%) were significantly less than the increases in their concentrations in pleural fluid (albumin, 47% +/- 49%; total protein, 48% +/- 40%) or in their pleural fluid/serum ratios (albumin, 27% +/- 29%; total protein, 38% +/- 34%). The concentrations of the biochemical components commonly measured in pleural fluid increase progressively during diuretic therapy. Calculation of the serum-pleural fluid gradients for protein and albumin may be the most useful way to distinguish transudates from exudates in patients with congestive heart failure who have undergone diuresis.


Therapeutic Effect of Neuraminidase-1-Selective Inhibition in Mouse Models of Bleomycin-Induced Pulmonary Inflammation and Fibrosis.
Pulmonary fibrosis remains a serious biomedical problem with no cure and an urgent need for better therapies. Neuraminidases (NEUs), including NEU1, have been recently implicated in the mechanism of pulmonary fibrosis by us and others. We now have tested the ability of a broad-spectrum neuraminidase inhibitor, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA), to modulate the in vivo response to acute intratracheal bleomycin challenge as an experimental model of pulmonary fibrosis. A marked alleviation of bleomycin-induced body weight loss and notable declines in accumulation of pulmonary lymphocytes and collagen deposition were observed. Real-time polymerase chain reaction analyses of human and mouse lung tissues and primary human lung fibroblast cultures were also performed. A predominant expression and pronounced elevation in the levels of NEU1 mRNA were observed in patients with idiopathic pulmonary fibrosis and bleomycin-challenged mice compared with their corresponding controls, whereas NEU2, NEU3, and NEU4 were expressed at far lower levels. The levels of mRNA for the NEU1 chaperone, protective protein/cathepsin A (PPCA), were also elevated by bleomycin. Western blotting analyses demonstrated bleomycin-induced elevations in protein expression of both NEU1 and PPCA in mouse lungs. Two known selective NEU1 inhibitors, C9-pentyl-amide-DANA (C9-BA-DANA) and C5-hexanamido-C9-acetamido-DANA, dramatically reduced bleomycin-induced loss of body weight, accumulation of pulmonary lymphocytes, and deposition of collagen. Importantly, C9-BA-DANA was therapeutic in the chronic bleomycin exposure model with no toxic effects observed within the experimental timeframe. Moreover, in the acute bleomycin model, C9-BA-DANA attenuated NEU1-mediated desialylation and shedding of the mucin-1 ectodomain. These data indicate that NEU1-selective inhibition offers a potential therapeutic intervention for pulmonary fibrotic diseases. SIGNIFICANCE STATEMENT: Neuraminidase-1-selective therapeutic targeting in the acute and chronic bleomycin models of pulmonary fibrosis reverses pulmonary collagen deposition, accumulation of lymphocytes in the lungs, and the disease-associated loss of body weight-all without observable toxic effects. Such therapy is as efficacious as nonspecific inhibition of all neuraminidases in these models, thus indicating the central role of neuraminidase-1 as well as offering a potential innovative, specifically targeted, and safe approach to treating human patients with a severe malady: pulmonary fibrosis.


Effects upon Nitrogen Sorption Analysis in Aerogels.
Nitrogen sorption at 77 K is a standard technique for the characterization of mesoporosity. However, it seemed to be unable to detect the full, theoretically expected pore volume in high-porosity aerogels. Investigating this problem, we found that if only the sample is sufficiently equilibrated upon sorption, the full pore volume is detected regardless of its porosity. As insufficient equilibration also effects the pore size distribution deduced from the isotherm, highly erroneous results can be avoided if complete equilibration upon each sorption step is assured. For compliant aerogels the effect of sample deformation during analysis has to be taken into account. Copyright 2001 Academic Press.


A case report of successful treatment with plasma exchange for adult-onset Still's disease with autoimmune hepatitis.
Adult onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology and pathogenesis. The disease is characterized by typical spiking fever with evanescent rash, sore throat, polyarthralgias or polyarthritis, and involvement of various organs. Most of the reported cases with liver involvement occurred during the period of treatment with hepatotoxic drugs, whereas AOSD associated autoimmune hepatitis (AIH) is extremely rare. AIH may be an indicator of the poor prognosis of AOSD. Herein we describe a case of successful treatment with plasma exchange for AOSD-associated AIH.


Self-identified Black Race as a Risk Factor for Intraocular Pressure Elevation and Iritis Following Prophylactic Laser Peripheral Iridotomy.
In primary angle closure suspects (PACS), self-identified Black race was a risk factor for intraocular pressure (IOP) elevation and iritis following laser peripheral iridotomy (LPI). Laser type was not associated with either immediate post-LPI IOP elevation or iritis in multivariate analysis. The aim was to determine the impact of laser type and patient characteristics on the incidence of IOP elevation and iritis after LPI in PACS. The electronic medical records of 1485 PACS (2407 eyes) who underwent either neodymium-doped yttrium-aluminum-garnet or sequential argon and neodymium-doped yttrium-aluminum-garnet LPI at the University of Pennsylvania between 2010 and 2018 were retrospectively reviewed. Average IOP within 30 days before LPI (baseline IOP), post-LPI IOP within 1 hour, laser type, laser energy, and the incidence of new iritis within 30 days following the procedure were collected. Multivariate logistic regression accounting for intereye correlation was used to assess factors associated with incidence of post-LPI IOP elevation and iritis, adjusted by age, sex, surgeon, and histories of autoimmune disease, diabetes, and hypertension. The incidence of post-LPI IOP elevation and iritis were 9.3% (95% confidence interval: 8.1%-10.5%) and 2.6% (95% CI: 1.9%-3.2%), respectively. In multivariate analysis, self-identified Black race was a risk factor for both IOP elevation [odds ratio (OR): 2.08 compared with White; P=0.002] and iritis (OR: 5.07; P<0.001). Higher baseline IOP was associated with increased risk for post-LPI IOP elevation (OR: 1.19; P<0.001). Laser type and energy were not associated with either post-LPI IOP elevation or iritis (P>0.11 for all). The incidence of immediate IOP elevation and iritis following prophylactic LPI was higher in Black patients independent of laser type and energy. Heightened vigilance and increased medication management before and after the procedure are suggested to help mitigate these risks.


Appraisal the potential of central iran, in the context of health tourism.
The aim of the present study was to appraisal the prose and cone of Shiraz City in terms of its potential in the context of health tourism. The statistical sample included medical and health tourism sector in the city of Shiraz in the northwest of Fars Province, south of Iran. The efficient authorities on the topic were identified through the hospitals engaging in medical tourism. The research was based on theoretical sampling through which the experienced people of extensive knowledge on medical tourism were interviewed. Active hospitals on attraction foreign patients averagely admit 15 and 50 foreign patients monthly and annually, respectively. Arab countries in the Persian Gulf were detected as the main marketing for Shiraz medical tourism. Oman encompassed the highest rate with 20% of admitted patients. Eye treatments with 30% and orthopedic with 6% were demonstrated as the highest and lowest rates in terms of foreign patients' needs, respectively. Closeness of cultural and religious beliefs and familial relationships on one hand and trusting to Iranian physicians on the other hand were amongst the most reasons for selecting Iran as a destination for medical tourism by patients. Implementing 4 strategies on monitoring medical tourism would result into significant improvement of attracting more foreigner patients not only into Shiraz but all around Iran. These items have been discussed in the text.