Activity of the Streptomyces coelicolor stress-response sigma factor sigmaH is regulated by an anti-sigma factor.
The alternative sigma factor sigmaH has been shown to play an important role in stress response and morphological differentiation in Streptomyces coelicolor. Its gene, sigH, is located in an operon with the gene encoding proposed anti-sigma factor UshX, and one of the promoters directing expression of the operon is dependent upon sigH. To clarify the function of S. coelicolor UshX, both the sigmaH and UshX proteins were overproduced in Escherichia coli and purified. In an in vitro transcription assay, sigmaH, after complementation with S. coelicolor core RNA polymerase, was able to recognize the sigH-dependent promoter, sigH-P2. This transcription was inhibited by UshX, if it was incubated with sigmaH prior to the addition of the core RNA polymerase. When sigmaH and UshX were incubated and electrophoresed through non-denaturing polyacrylamide gels, they formed a specific complex. These results showed that UshX is a specific anti-sigma factor for sigmaH, and the S. coelicolor sigH operon is directly autoregulated.


Quantification of Lipid Abundance and Evaluation of Lipid Distribution in Caenorhabditis elegans by Nile Red and Oil Red O Staining.
Caenorhabditis elegans is an exceptional model organism in which to study lipid metabolism and energy homeostasis. Many of its lipid genes are conserved in humans and are associated with metabolic syndrome or other diseases. Examination of lipid accumulation in this organism can be carried out by fixative dyes or label-free methods. Fixative stains like Nile red and oil red O are inexpensive, reliable ways to quantitatively measure lipid levels and to qualitatively observe lipid distribution across tissues, respectively. Moreover, these stains allow for high-throughput screening of various lipid metabolism genes and pathways. Additionally, their hydrophobic nature facilitates lipid solubility, reduces interaction with surrounding tissues, and prevents dissociation into the solvent. Though these methods are effective at examining general lipid content, they do not provide detailed information about the chemical composition and diversity of lipid deposits. For these purposes, label-free methods such as GC-MS and CARS microscopy are better suited, their costs notwithstanding.


Validation of the in vivo CD1 mouse splenocyte micronucleus test.
In order to validate the in vivo micronucleus test in mouse splenocytes using the cytokinesis block method, 14 compounds with various mechanisms of action were tested: three direct alkylating agents (mitomycin C, ethylnitrosourea, beta-propiolactone), seven indirect alkylating agents (cyclophosphamide, benzo[a]pyrene, diethylnitrosamine, dimethylnitrosamine, 4-aminophenol, 4-aminobiphenyl, 1,1-dimethylhydrazine), two intercalating agents (acridine orange, ethidium bromide) and two spindle poisons (vincristine, colchicine). Male mice were dosed once with the compound, and spleen samples were taken 2 or 14 days after treatment. A significant increase in the binucleated micronucleated splenocyte rate was observed with all the alkylating and intercalating agents at at least one sampling time. In contrast, no increase in the binucleated micronucleated splenocyte rate was observed with the spindle poisons. In conclusion, under these experimental conditions, this in vivo test seems appropriate for the detection of clastogenic compounds including compounds that cannot be detected in the bone marrow micronucleus test. The limit of this test, as expected, is the lack of detection of aneugenic compounds.


Deliberate Establishment of Asymptomatic Bacteriuria-A Novel Strategy to Prevent Recurrent UTI.
We have established a novel strategy to reduce the risk for recurrent urinary tract infection (UTI), where rapidly increasing antibiotic resistance poses a major threat. Epidemiologic studies have demonstrated that asymptomatic bacteriuria (ABU) protects the host against symptomatic infections with more virulent strains. To mimic this protective effect, we deliberately establish ABU in UTI-prone patients, who are refractory to conventional therapy. The patients are inoculated with Escherichia coli (E. coli) 83972, now widely used as a prototype ABU strain. Therapeutic efficacy has been demonstrated in a placebo-controlled trial, supporting the feasibility of using E. coli 83972 as a tool to prevent recurrent UTI and, potentially, to outcompete antibiotic-resistant strains from the human urinary tract. In addition, the human inoculation protocol offers unique opportunities to study host-parasite interaction in vivo in the human urinary tract. Here, we review the clinical evidence for protection using this approach as well as some molecular insights into the pathogenesis of UTI that have been gained during these studies.


Comparison of claw health and milk yield in dairy cows on elastic or concrete flooring.
This article reports on the effects of elastic (rubber) flooring compared with concrete flooring on claw health and milk yield in dairy cows. Milk yield and activity data of 53 complete lactations from 49 cows were recorded by an automatic milking system in the University of Munich Livestock Center dairy herd. Cows were kept in a loose housing system on concrete-slatted or rubber-matted slatted flooring. Claws were trimmed and measured linearly in combination with claw lesion diagnosis 3 times during one lactation period (including the transition phase). An automatic milking system recorded milk yield and activity. The net horn growth of the claws increased on elastic flooring. Therefore, correct and frequent claw trimming is at least as important for claw health in dairy herds kept on rubber flooring as for those on concrete-slatted flooring. Cows housed on rubber had an increased incidence of sole ulcers. Sole hemorrhages (except for hemorrhages associated with sole ulcers) occurred less frequently on rubber than on concrete. Results concerning digital dermatitis were difficult to assess, because manual manure scraping on rubber required sprinkling the flooring twice daily, which additionally moistened the digital skin of the cows. This might explain the greater incidence of digital dermatitis on elastic flooring. The incidence of clinically lame cows did not differ between flooring types. Cows showed greater activity on rubber, most likely caused by the more comfortable walking surface compared with the concrete-slatted flooring. The greater activity may indicate better overall health of high-yielding dairy cows on rubber flooring. Milk yield, however, did not differ between flooring types.


The teleost fish PepT1-type peptide transporters and their relationships with neutral and charged substrates.
In teleosts, two PepT1-type (Slc15a1) transporters, i.e., PepT1a and PepT1b, are expressed at the intestinal level. They translocate charged di/tripeptides with different efficiency, which depends on the position of the charged amino acid in the peptide and the external pH. The relation between the position of the charged amino acid and the capability of transporting the dipeptide was investigated in the zebrafish and Atlantic salmon PepT1-type transporters. Using selected charged (at physiological pH) dipeptides: i.e., the negatively charged Asp-Gly and Gly-Asp, and the positively charged Lys-Gly and Gly-Lys and Lys-Met and Met-Lys, transport currents and kinetic parameters were collected. The neutral dipeptide Gly-Gln was used as a reference substrate. Atlantic salmon PepT1a and PepT1b transport currents were similar in the presence of Asp-Gly and Gly-Asp, while zebrafish PepT1a elicited currents strongly dependent on the position of Asp in the dipeptide and zebrafish PepT1b elicited small transport currents. For Lys- and Met-containing dipeptides smaller currents compared to Gly-Gln were observed in PepT1a-type transporters. In general, for zebrafish PepT1a the currents elicited by all tested substrates slightly increased with membrane potential and pH. For Atlantic salmon PepT1a, the transport current increased with negative potential but only in the presence of Met-containing dipeptides and in a pH-dependent way. Conversely, large currents were shown for PepT1b for all tested substrates but Gly-Lys in Atlantic salmon. This shows that in Atlantic salmon PepT1b for Lys-containing substrates the position of the charged dipeptides carrying the Lys residue defines the current amplitudes, with larger currents observed for Lys in the N-terminal position. Our results add information on the ability of PepT1 to transport charged amino acids and show species-specificity in the kinetic behavior of PepT1-type proteins. They also suggest the importance of the proximity of the substrate binding site of residues such as LysPepT1a/GlnPepT1b for recognition and specificity of the charged dipeptide and point out the role of the comparative approach that exploits the natural protein variants to understand the structure and functions of membrane transporters.


Nanodroplet-Mediated Low-Energy Mechanical Ultrasound Surgery.
Mechanical ultrasound surgery methods use short, high-intensity pulses to fractionate tissues. This study reports the development of a two-step technology for low-energy mechanical ultrasound surgery of tissues using nanodroplets to reduce the pressure threshold. Step 1 consists of vaporizing the nanodroplets into gaseous microbubbles via megahertz ultrasound excitation. Then, low-frequency ultrasound is applied to the microbubbles, which turns them into therapeutic warheads that trigger potent mechanical effects in the surrounding tissue. The use of nanoscale nanodroplets coupled with low-frequency ultrasound reduces the pressure threshold required for mechanical ultrasound surgery by an order of magnitude. In addition, their average diameter of 300 nm can overcome challenges associated with the size of microbubbles. Optimization experiments were performed to determine the ultrasound parameters for nanodroplet vaporization and the subsequent microbubble implosion processes. Optimal vaporization was obtained when transmitting a 2-cycle excitation pulse at a center frequency of 5 MHz and a peak negative pressure of 4.1 MPa (mechanical index = 1.8). Low-frequency insonation of the generated microbubbles at a center frequency of 850, 250 or 80 kHz caused enhanced contrast reduction at a center frequency of 80 kHz, compared with the other frequencies, while operating at the same mechanical index of 0.9. Nanodroplet-mediated insonation of ex vivo chicken liver samples generated mechanical damage. Low-frequency treatment at a mechanical index of 0.9 and a center frequency of 80 kHz induced the largest lesion area (average of 0.59 mm2) compared with 250- and 850-kHz treatments with the same mechanical index (average lesions areas of 0.29 and 0.19 mm2, respectively, p < 0.001). The two-step approach makes it possible to conduct both the vaporization and implosion stages at mechanical indices below 1.9, thus avoiding undesired mechanical damage. The findings indicate that coupled with low-frequency ultrasound, nanodroplets can be used for low-energy mechanical ultrasound surgery.


In vitro activity of tedizolid against clinical isolates of Staphylococcus lugdunensis and Staphylococcus haemolyticus from Europe and the United States.
Staphylococcus lugdunensis and Staphylococcus haemolyticus are unique among CoNS in that the former often causes aggressive disease, while the latter consistently exhibits high rates of multidrug resistance. We evaluated the in vitro susceptibility of contemporary (2012-2013) isolates from both pathogens to tedizolid and comparators, using standard methodology. Results were interpreted using CLSI and EUCAST breakpoints. Overall, 106 S. lugdunensis and 103 S. haemolyticus isolates were collected from 51 medical centers in the United States and 30 centers in 18 European countries. Tedizolid showed good activity against S. lugdunensis (MIC50/MIC90: 0.12/0.12 mg/L) and S. haemolyticus (MIC50/MIC90: 0.12/0.12 mg/L), inhibiting all isolates at MIC ≤0.25 mg/L. Based on the EUCAST breakpoint for staphylococci and when substituting the CLSI breakpoint for Staphylococcus aureus, all isolates were tedizolid susceptible. All isolates were also susceptible to linezolid, but the in vitro potency of tedizolid was 4-fold greater than that of linezolid against both S. lugdunensis and S. haemolyticus, based on MIC90 values. S. lugdunensis exhibited ≥99% susceptibility to vancomycin, teicoplanin, gentamicin, levofloxacin, and trimethoprim-sulfamethoxazole; 7% of isolates were resistant to tetracycline, 11% to clindamycin, and 2% were methicillin-resistant. S. haemolyticus exhibited high rates of resistance to commonly used anti-staphylococcal agents: 71% of isolates were resistant to methicillin, 36%-37% to clindamycin, and 30%-50% to gentamicin. These in vitro findings suggest that tedizolid could be an alternative treatment option for infections due to these medically important CoNS pathogens. Additional clinical evaluation and continued surveillance of tedizolid in vitro activity against S. lugdunensis and S. haemolyticus are warranted.


Platelet thrombus formation in patients with end-stage renal disease before and after hemodialysis as measured by the total thrombus-formation analysis system.
Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) often experience bleeding. However, mechanisms behind this bleeding tendency are incompletely understood but may involve platelet dysfunction. We, therefore, studied platelet-dependent thrombus formation in flowing whole blood inside a microchip coated with collagen, and its association with circulating von Willebrand factor (VWF). Blood samples were obtained in 22 patients before and after HD. The area under the 10 min flow pressure curve in a microchip (AUC10) reflecting total platelet thrombogenicity was measured, using the Total Thrombus-formation Analysis System (T-TAS01). AUC10 < 260 indicates platelet dysfunction. VWF activity and antigen in plasma were also assayed. VWF levels were moderately elevated and increased further after HD (P < 0.01 or lower). In contrast, AUC10 before and after HD was < 260 in 17/22 patients and < 130 in 15/22 patients, with no statistically significant difference in pre- vs post-HD measurements, indicating reduced platelet thrombogenicity, but with some variability as 5/22 patients showed normal platelet responsiveness. AUC10 and VWF activity or antigen levels in plasma were not correlated, either before or after HD. Most ESRD patients display moderate-to-severe platelet dysfunction as assessed by shear-induced platelet-dependent thrombus formation with T-TAS01. HD does not influence platelet function despite HD-induced elevations in VWF. T-TAS01 should be further evaluated as a tool in the assessment of bleeding risk in patients on HD.


The dynamics of conformational isomerization in flexible biomolecules. I. Hole-filling spectroscopy of N-acetyl tryptophan methyl amide and N-acetyl tryptophan amide.
The conformational isomerization dynamics of N-acetyl tryptophan methyl amide (NATMA) and N-acetyl tryptophan amide (NATA) have been studied using the methods of IR-UV hole-filling spectroscopy (HFS) and IR-induced population transfer spectroscopy (IR-PTS), which were developed for this purpose. Single conformations of these molecules were selectively excited in well-defined NH stretch fundamentals. This excess energy was used to drive conformational isomerization. By carrying out the infrared excitation early in a supersonic expansion, the excited molecules were recooled into their zero-point levels, partially refilling the hole created in the ground state population of one of the conformers, and creating gains in population in other conformers. These changes in population were detected using laser-induced fluorescence downstream in the expansion. In HFS, the IR wavelength is fixed and the UV laser tuned in order to determine where the population went following selective infrared excitation. In IR-PTS, the UV is fixed to monitor the population of a given conformation, and the IR is tuned to record the IR-induced changes in the population of the monitored conformer. Besides demonstrating the capability of the experiment to change the downstream conformational population distribution, the IR-PTS scans were used to extract two quantitative results: (i) The fractional populations of the conformers in the absence of the infrared, and (ii) the isomerization quantum yields for each of the six unique amide NH stretch fundamentals (three conformers each with two amide groups). The method for obtaining quantum yields is described in detail. In both NATMA and NATA, the quantum yields show modest conformational specificity, but only a hint of vibrational mode specificity. The prospects for the hole-filling technique for providing insight into energy flow in large molecules are discussed, leaving a more detailed theoretical modeling to the adjoining paper [Evans et al. J. Chem. Phys. 120, 148 (2004)].


Development of Recombinase Polymerase Amplification Combined with Lateral Flow Detection Assay for Rapid and Visual Detection of Ralstonia solanacearum in Tobacco.
Bacterial wilt caused by Ralstonia solanacearum is a serious soilborne disease that results in severe losses to tobacco (Nicotiana tabacum) production in China. In this study, a novel RPA-LFD assay for the rapid visual detection of R. solanacearum was established using recombinase polymerase amplification (RPA) and lateral-flow dipstick (LFD). The RPA-LFD assay was performed at 37°C in 30 min without complex equipment. Targeting the sequence of the RipTALI-9 gene, we designed RPA primers (Rs-rpa-F/R) and an LF probe (Rs-LF-probe) that showed high specificity to R. solanacearum. The sensitivity of RPA-LFD assay to R. solanacearum was the same as that in conventional PCR at 1 pg genomic DNA, 103 CFU/g artificially inoculated tobacco stems, and 104 CFU/g artificially inoculated soil. The RPA-LFD assay could also detect R. solanacearum from plant and soil samples collected from naturally infested tobacco fields. These results suggest that the RPA-LFD assay developed in this study is a rapid, accurate molecular diagnostic tool with high sensitivity for the detection of R. solanacearum.


Attempted synthesis of ortho-phenylene phosphino-tritylium cations.
With the synthesis of ortho-phenylene phosphino-tritylium cations as an objective, we generated (2-lithiophenyl)diphenylphosphine and (2-lithiophenyl)di-isopropylphosphine and allowed these organolithium reagents to react with benzophenone. The resulting phosphino-triarylcarbinols were allowed to react with HBF4 in the presence of trifluoroacetic anhydride in order to generate the corresponding cations. Instead of the targeted ortho-phenylene phosphino-tritylium, the cations formed in these reactions were identified as the four-membered phosphonium species 7,7-bis(phenyl)-8,8-bis(phenyl)-7-phosphoniabicyclo[4.2.0]octa-1,3,5-triene (3+) and 7,7-bis(phenyl)-8,8-bis(isopropyl)-7-phosphoniabicyclo[4.2.0]octa-1,3,5-triene (4+), which were both isolated as tetrafluoroborate salts. The structure of these compounds has been confirmed by X-ray analysis. These new cations are thermally unstable and isomerize into the corresponding 5,10-dihydro-5,5-diphenyl-10-phenyl-acridophosphinium (5+) and 5,10-dihydro-5,5-di(isopropyl)-10-phenyl-acridophosphinium (6+) as tetrafluoroborate salts. These reactions suggest the involvement of ortho-phenylene phosphino-tritylium cations, which would be obtained by dissociation of the R3P+-CAr3 bonds in 4+ and 5+This article is part of the themed issue 'Frustrated Lewis pair chemistry'.


Horner's syndrome in Wegener's granulomatosis: report of four cases.
Four patients with active Wegener's granulomatosis had Horner's syndrome, which was the only neurological involvement in one. Two others had multiple mononeuropathy and one a multiple cranial neuropathy. Horner's syndrome occurred in the active stage and improved with treatment of Wegener's granulomatosis.


Further opportunities for cost reduction of medical care.
The already high and still rising cost of health care has become a matter of serious concern and a subject of political dispute. The problem has no magic cures but, as is shown here, there are a number of promising modifications in current practice that promise to reduce the required outlays without impairing appropriate health care. Continual reports of new medicines, new tests, and new procedures have created an urgent need for careful comparison and evaluation of the advantages and beneficial results that these innovations offer. The same is true for the growing knowledge of genetic variations, which affects the course of therapy for some patients. Costs also can be saved, in some instances, by utilization of medical therapy, rather than interventional procedures. Preventive medicine provides still more opportunities for cost savings. This paper provides an overview of promising potential approaches to reduce the cost of health care.


IR-REMPI double resonance spectroscopy: the near-IR spectrum of NO-Ar revisited.
We describe a new approach to IR-UV double resonance spectroscopy of NO-containing van der Waals complexes. The basic idea combines REMPI detection through a hot band transition with a simultaneous frequency scan of the IR and UV lasers in such a way that the combined photon energy is kept constant throughout the scan, matching a UV resonance transition in the system. As a result, the two-dimensional frequency problem is reduced to a fixed number of one-dimensional frequency scans, each defined by a particular photon energy sum. The method is applied to the near-IR spectrum of NO-Ar using hot band detection via the electronic A state of the complex. In the frequency range from 3718 to 3765 cm(-1), we recorded the previously known vibrational bands with improved frequency resolution. The increased sensitivity of the present experiment allowed us to measure for the first time their overtone, combination, and hot bands. Through the comparison with results of a close-coupling (CC) calculation, we were able to assign most of the rovibrational structures of the spectrum. Except for the first intermolecular stretch level, the band positions and rotational structures of the observed bands are in good agreement with the predictions of the CC calculations.


[Chaotic atrial tachycardia-induced cardiomyopathy: report of an isolated case].
Chaotic atrial tachycardia is a rare arrhythmia that has no known etiology and that usually inflicts upon newborn infants. The diagnosis is established using the surface electrocardiogram (ECG) which shows a spectacular polymorphism and irregularity of the atrial electrical activity. Clinical tolerability is variable depending on the ventricular rhythm. Cases that are not well tolerated and cases who do not recover spontaneously require medical treatment which relies mainly on amiodarone and other class IC anti-arrhythmic drugs. There is usually complete recovery during the first few months of life. The authors present the case of a female patient who was diagnosed with chaotic atrial tachycardia with induced cardiomyopathy following birth. She was successfully treated with amiodarone but had several relapses of the arrhythmia upon discontinuation of the drug. Although this observation is classic in its presentation, we consider that it is useful to remember this rare and frequently forgotten syndrome and to report the unique and particular aspects of our case and its evolution.


Subphrenic abscess formation following superselective transcatheter chemoembolization for hepatocellular carcinoma.
In order to achieve better results with hepatocellular carcinoma (HCC), repeated treatment using transcatheter hepatic arterial chemoembolization (TAE) with or without percutaneous ethanol injection (PEI) has been widely performed. A 73-year-old woman underwent a repeated (second) TAE two months following the primary TAE in combination with PEI. Prior to TAE, computed tomography (CT) with angiography revealed that the peripheral liver segment adjacent to the HCC was supplied exclusively via arterial flow without portal circulation. Following TAE, she developed an extrahepatic abscess with clinical and radiological evidence of ruptured HCC. A high-grade fever and right hypochondrial pain were sustained by day 10 after TAE, and CT showed a low-density mass extending into the subphrenic fluid collection. One hundred milliliters of infected fluid was drained by ultrasound-guided percutaneous aspiration from the collection. Following drainage, her clinical course was uneventful. Extrahepatic abscess formation is a rare complication of TAE, and, to our knowledge, only three cases of subphrenic abscess have been reported in the English literature. Severe ischemic necrosis of the arterial-feeding liver tissues devascularized by repeated TAE was considered to be a major contributor to this clinical condition. Early clinical suspicion combined with surgical management is mandatory in preventing serious morbidity of peritonitis accompanying repeated TAE.


Proximal flow to middle cerebral artery is associated with higher thrombus density in terminal internal carotid artery occlusion.
Proximal collaterals may determine the composition of occluding thrombi in acute ischemic stroke (AIS) in addition to source, hematocrit, time, and medication. Here, we performed a retrospective study of 39 consecutive patients with radiological evidence of I-, L-, and T-type terminal internal carotid artery occlusion. Middle cerebral artery (MCA) thrombus density was assessed on noncontrast enhanced CT and proximal collaterals on CT angiography. In patients with presence of proximal collaterals to the MCA we detected more hyperdense clots (P = 0.003) and a higher frequency of leptomeningeal collaterals (P = 0.008). We expand the spectrum of factors that potentially determine clot perviousness and evolution of ischemic stroke.


Plasma amino acid concentrations in patients with coronary heart disease: a comparison between U.K. Indian Asian and Caucasian men.
The pattern of plasma free amino acids (PFAAs) of subjects with coronary heart disease (CHD) and controls was investigated. PFAA concentrations of CHD patients (29 Caucasian, 20 U.K. Indian Asian) and controls (36 Caucasian, 27 U.K. Indian Asian) were analyzed by high-performance liquid chromatography (HPLC). Plasma free alanine, tyrosine, and isoleucine concentrations were higher in U.K. Indian Asians compared with Caucasians. Plasma free alanine concentration was higher in CHD patients compared with controls, and the difference was mainly related to the presence of diabetes or elevated blood glucose in the former. Plasma free cysteine concentration was higher in CHD patients compared with controls; this does not seem to be affected by the eating habits of the two races, and seems to be a good marker for CHD and better than that of homocysteine. The data obtained in the present study showed no major alteration in PFAAs pattern in CHD patients except for that of cysteine.


[Tocolysis in the first half of pregnancy].
This study includes a total of 60 gravidae with a pregnancy between 8 and 17 weeks of gestation and the signs of threatened abortion (contractions and bleeding). The sonographic examination had shown in 14 patients no gestational sac in the uterus; in 6 patients a deformed gestational sac; in 5 patients a fetus without signs of vitality. In all these patients curettage was performed. In 32 gravidae a therapy seems to be successful: in terms of bedrest and the administration of 0.33 mcg/min Hexoprenaline as a continuous infusion. In only 3 patients an abortion occurred before the end of the 20th week of gestation. In 29 gravidae pregnancy continued undisturbed.


[Echo-guided transperineal and transrectal prostatic biopsy: complications of the 2 methods].
We evaluated the complications of transrectal and transperineal ultrasound-guided prostatic biopsy in 280 patients. All patients underwent antibiotic prophylaxis with a different scheme according to the approach for the biopsy. Urine culture and, in some patients, blood culture have been collected after biopsy. We have reported the same rate of complications for the two modalities except for a lower rate of positive urine culture and blood culture in the group of patients submitted to transperineal biopsy; this type of approach, then, should be considered of first choice in some patients with a higher risk of infections.


RNaseH2 mutants that cause Aicardi-Goutieres syndrome are active nucleases.
Mutations in the genes encoding the RNaseH2 and TREX1 nucleases have been identified in patients with Aicardi-Goutieres syndrome (AGS). To determine if the AGS RNaseH2 mutations result in the loss of nuclease activity, the human wild-type RNaseH2 and four mutant complexes that constitute the majority of mutations identified in AGS patients have been prepared and tested for ribonuclease H activity. The heterotrimeric structures of the mutant RNaseH2 complexes are intact. Furthermore, the ribonuclease H activities of the mutant complexes are indistinguishable from the wild-type enzyme with the exception of the RNaseH2 subunit A (Gly37Ser) mutant, which exhibits some evidence of altered nuclease specificity. These data indicate that the mechanism of RNaseH2 dysfunction in AGS cannot be simply explained by loss of ribonuclease H activity and points to a more complex mechanism perhaps mediated through altered interactions with as yet identified nucleic acids or protein partners.


Non-HDL cholesterol is a good predictor of the risk of increased arterial stiffness in postmenopausal women in an urban Brazilian population.
Increased arterial stiffness is an important determinant of the risk of cardiovascular disease. Lipid profile impairment, especially hypercholesterolemia, is associated with stiffer blood vessels. Thus, the aim of this study was to determine which of the five circulating lipid components (high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL), total cholesterol (TC) and triglycerides) is the best predictor of increased arterial stiffness in an urban Brazilian population. A random sample of 1,662 individuals from the general population of Vitoria, Brazil (25-64 years), was selected, and lipid components were measured using standard methods. Pulse wave velocity was measured using a non-invasive automatic device, and increased arterial stiffness was defined as a pulse wave velocity ≥10 m/s. In men, only total cholesterol (OR=1.59; CI=1.02 to 2.48, p=0.04) was associated with the risk of increased arterial stiffness. In women, HDL-C (OR=1.99; CI=1.18 to 3.35, p=0.01) and non-HDL-C (OR=1.61; CI=1.01 to 2.56, p=0.04) were good predictors of the risk of increased arterial stiffness. However, these associations were only found in postmenopausal women (OR=2.06; CI=1.00 to 4.26, p=0.05 for HDL-C and OR=1.83; CI=1.01 to 3.33, p=0.04 for non-HDL-C). Our findings indicate that both HDL-C and non-HDL-C are good predictors of the risk of increased arterial stiffness in postmenopausal women in an urban Brazilian population and may be useful tools for assessing the risk of arterial stiffness.


Prevalence of Precursory Signs of Atypical Femoral Fractures in Patients Receiving Bone-Modifying Agents for Bone Metastases: A Cross-Sectional Study.
Patients on bone-modifying agents (BMAs) for bone metastases are at risk of atypical femoral fractures (AFFs), which can lead to a sudden deterioration in performance status. In this study, we sought to determine the prevalence of radiographic precursory signs of AFF in patients on oncologic BMAs. Forty-two patients (23 men, 19 women; mean age 68.8 ± 10.0 years) on oncologic BMAs (zoledronate for >3 years and/or denosumab for >1 year) and without clinical symptoms were enrolled between 2019 and 2021. All patients were receiving denosumab at enrollment and 5 had previously used zoledronate. The mean duration of BMA use was 31.2 ± 18.5 months. Radiographs of both femurs were screened for precursory signs of AFF (e.g., thickening of the lateral cortex). The patients were divided into two groups according to thickening status and compared by duration of BMA use. They were also divided into three groups by duration of BMA use (12-23 months, n = 18; 24-59 months, n = 19; ≥60 months, n = 5), and the prevalence of apparent thickenings was examined. As a result, 18 patients (42.9%) showed minute local or diffuse thickening and 10 (23.8%) showed apparent local thickening. The duration of BMA use was significantly longer in patients with apparent thickening than in those without (47.3 ± 23.6 months [n = 10] versus 26.2 ± 13.5 months [n = 32]; p < 0.05). The prevalence of apparent thickening increased with increasing duration of BMA use (12-23 months, 5.6%; 24-59 months, 31.6%; ≥60 months, 60.0%). In conclusion, radiographic precursory signs of AFF are common in patients on oncologic BMAs. Radiographic screening for AFF could be relevant in patients who have been on long-term oncologic BMAs, even if asymptomatic. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.


Precompetitive anxiety and self-confidence in athletes with disability.
This study examined the precompetition temporal patterning of competitive anxiety components in 42 athletes with disability who participated at the national level and at the national trials for the Paralympic Games in a variety of sports. All subjects completed a modified version of the Competitive State Anxiety Inventory-2 which measures intensity and direction of the competitive anxiety response on three occasions before competition (1 wk., 2 hr., and 20 min.). Analysis suggested that for cognitive and somatic dimensions athletes with disabilities show a similar precompetition anxiety response to athletes without disability. However, there appear to be some differences, particularly in the intensity of self-confidence, as athletes with disability reported a reduction of self-confidence just prior to competition.


Bioavailability of lead to juvenile swine dosed with soil from the Smuggler Mountain NPL Site of Aspen, Colorado.
Bioavailability of lead (Pb) has become an issue in quantifying exposure of sensitive populations and, where necessary, establishing cleanup levels for contaminated soil. Immature swine were used as a model for young children to estimate the degree to which Pb from two fully characterized composite samples from the Smuggler Mountain Superfund Site in Aspen, Colorado may be bioavailable to resident children. The composite soils contained 14,200 and 3870 micrograms Pb/g of soil. Relative and absolute enteric bioavailabilities of Pb in soil (oral dose groups of 75,225, and 675 micrograms Pb/kg body wt/day) were estimated by comparison with an orally administered soluble Pb salt (lead acetate = PbAc2.3H2O) (dose groups of 0, 75, and 225 micrograms Pb/kg body wt/day) and an intravenously administered aqueous solution of Pb (100 micrograms Pb/kg/ day) from the same trihydrate salt administered daily for 15 days to 50 juvenile swine. The biological responses (area under the blood Pb concentration-time curve, and the terminal liver-, kidney-, and bone-lead concentrations) produced by Pb from PbAc2.3H2O and lead-contaminated soils were determined. This study revealed Pb from soil containing 14,200 micrograms Pb/g of soil had a bioavailability relative to Pb from PbAc (RBA), ranging from 56% based on the area under the blood lead concentration-time curve (AUC) versus dose, to 86% based on calculations from liver-Pb loading versus dose. Similarly, Pb from soil containing 3870 micrograms Pb/g of soil had an RBA ranging from 58% based on the AUC versus dose, to 74% based on calculations from liver- and kidney-Pb loading versus dose. Bioavailability of Pb in soils may be more or less than EPA's default RBA of 60%, therefore, measuring site-specific RBAs provides a basis for improved exposure and risk assessment.


[A case of hepatectomy for liver metastasis after pancreatoduodenectomy for carcinoma of ampulla of Vater].
After curative resection of carcinoma of ampulla of Vater, 5-year survival rate has been reported ranging from 40% to 60%. Two major causes of the treatment failure are local recurrence and liver metastasis. Liver metastases are often multiple and are associated with poor prognosis. There have been few reports on long-term survivors after hepatectomy for metastatic liver tumors from carcinoma of ampulla of Vater. We report a 42 year-old female patient with solitary hepatic metastasis from carcinoma of ampulla of Vater, which was successfully treated by hepatectomy 69 months after curative Whipple's operation. Histologic examination of the resected specimen had revealed stage IB moderately-differentiated, intestinal type adenocarcinoma (T2N0M0). Since neither local recurrence or distant metastasis were detected, the patient underwent liver segmentectomy. Histologic study confirmed the presence of metastatic liver tumor from carcinoma of ampulla of Vater. She is doing well without evidence of recurrence at 20 months after hepatectomy.


Identification of biomarkers for colorectal cancer through proteomics-based approaches.
The early detection of colorectal cancer is one of the great challenges in the battle against this disease. However, owing to its heterogeneous character, single markers are not likely to provide sufficient diagnostic power to be used in colorectal cancer population screens. This review provides an overview of recent studies aimed at the discovery of new diagnostic protein markers through proteomics-based approaches. It indicates that studies that start with the proteomic analysis of tumor tissue or tumor cell lines (near the source) have a high potential to yield novel and colorectal cancer-specific biomarkers. In the next step, the diagnostic accuracy of these candidate markers can be assessed by a targeted ELISA assay using serum from colorectal cancer patients and healthy controls. Instead, direct proteomic analysis of serum yields predominantly secondary markers composed of fragments of abundant serum proteins that may be associated with tumor-associated protease activity, and alternatively, immunoproteomic analysis of the serum antibody repertoire provides a valuable tool to identify the molecular imprint of colorectal cancer-associated antigens directly from patient serum samples. The latter approach also allows a relatively easy translation into targeted assays. Eventually, multimarker assays should be developed to reach a diagnostic accuracy that meets the stringent criteria for colorectal cancer screening at the population level.


Validation of In Vitro Trained Transcriptomic Radiosensitivity Signatures in Clinical Cohorts.
Transcriptomic personalisation of radiation therapy has gained considerable interest in recent years. However, independent model testing on in vitro data has shown poor performance. In this work, we assess the reproducibility in clinical applications of radiosensitivity signatures. Agreement between radiosensitivity predictions from published signatures using different microarray normalization methods was assessed. Control signatures developed from resampled in vitro data were benchmarked in clinical cohorts. Survival analysis was performed using each gene in the clinical transcriptomic data, and gene set enrichment analysis was used to determine pathways related to model performance in predicting survival and recurrence. The normalisation approach impacted calculated radiosensitivity index (RSI) values. Indeed, the limits of agreement exceeded 20% with different normalisation approaches. No published signature significantly improved on the resampled controls for prediction of clinical outcomes. Functional annotation of gene models suggested that many overlapping biological processes are associated with cancer outcomes in RT treated and non-RT treated patients, including proliferation and immune responses. In summary, different normalisation methods should not be used interchangeably. The utility of published signatures remains unclear given the large proportion of genes relating to cancer outcome. Biological processes influencing outcome overlapped for patients treated with or without radiation suggest that existing signatures may lack specificity.


Zebra finches have a light-dependent magnetic compass similar to migratory birds.
Birds have a light-dependent magnetic compass that provides information about the spatial alignment of the geomagnetic field. It is proposed to be located in the avian retina and mediated by a light-induced, radical-pair mechanism involving cryptochromes as sensory receptor molecules. To investigate how the behavioural responses of birds under different light spectra match with cryptochromes as the primary magnetoreceptor, we examined the spectral properties of the magnetic compass in zebra finches. We trained birds to relocate a food reward in a spatial orientation task using magnetic compass cues. The birds were well oriented along the trained magnetic compass axis when trained and tested under low-irradiance 521 nm green light. In the presence of a 1.4 MHz radio-frequency electromagnetic (RF)-field, the birds were disoriented, which supports the involvement of radical-pair reactions in the primary magnetoreception process. Birds trained and tested under 638 nm red light showed a weak tendency to orient ∼45 deg clockwise of the trained magnetic direction. Under low-irradiance 460 nm blue light, they tended to orient along the trained magnetic compass axis, but were disoriented under higher irradiance light. Zebra finches trained and tested under high-irradiance 430 nm indigo light were well oriented along the trained magnetic compass axis, but disoriented in the presence of a RF-field. We conclude that magnetic compass responses of zebra finches are similar to those observed in nocturnally migrating birds and agree with cryptochromes as the primary magnetoreceptor, suggesting that light-dependent, radical-pair-mediated magnetoreception is a common property for all birds, including non-migratory species.


Furosemide blocks basolateral membrane Cl- permeability in gallbladder epithelium.
In Necturus gallbladders bathed in a NaCl Ringer solution buffered with 10 mM HCO3(-)-1% CO2, furosemide (added to the serosal solution) caused a concentration-dependent hyperpolarization of both cell membranes that was slow and reversible. At 10(-3) M furosemide, the basolateral membrane voltage (Vcs) increased significantly from -71 +/- 3 to -85 +/- 3 mV, the depolarization of Vcs elicited by a 10-fold rise in serosal [K+] increased from 34 +/- 4 to 50 +/- 1 mV, the depolarization elicited by lowering serosal [Cl-] from 98 to 8.1 mM was reduced from 15 +/- 1 to 1 +/- 1 mV, and the depolarization in response to lowering serosal [HCO3-] from 10 to 1 mM was reduced from 13 +/- 1 to 5 +/- 0.4 mV. Furosemide could in principle decrease the basolateral membrane Cl- conductance (Gcl), increase the basolateral membrane K+ conductance, or have a combined effect. To distinguish among these possibilities, we estimated the resistance of the basolateral membrane (Rb) by means of two-point intraepithelial cable analysis experiments. Furosemide increased Rb by 22%, which indicates that furosemide reduces basolateral membrane Gcl. The effect cannot be attributed to inhibition of apical membrane anion exchange by serosal addition of furosemide, because base secretion from cells to lumen is unchanged. We conclude that furosemide blocks reversibly basolateral membrane electrodiffusive Cl- permeability. A concomitant stimulation of basolateral membrane electrodiffusive K+ permeability is also possible.


Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16.
Detection of pathogenic nucleic acids is essential for mammalian innate immunity. IFN-inducible protein IFI16 has emerged as a critical sensor for detecting pathogenic DNA, stimulating both type I IFN and proinflammatory responses. Despite being predominantly nuclear, IFI16 can unexpectedly sense pathogenic DNA in both the cytoplasm and the nucleus. However, the mechanisms regulating its localization and sensing ability remain uncharacterized. Here, we propose a two-signal model for IFI16 sensing. We first identify an evolutionarily conserved multipartite nuclear localization signal (NLS). Next, using FISH and immunopurification, we demonstrate that IFI16 detects HSV-1 DNA primarily in the nucleus, requiring a functional NLS. Furthermore, we establish a localization-dependent IFN-β induction mediated by IFI16 in response to HSV-1 infection or viral DNA transfection. To identify mechanisms regulating the secondary cytoplasmic localization, we explored IFI16 posttranslation modifications. Combinatorial MS analyses identified numerous acetylations and phosphorylations on endogenous IFI16 in lymphocytes, in which we demonstrate an IFI16-mediated IFN-β response. Importantly, the IFI16 NLS was acetylated in lymphocytes, as well as in macrophages. Mutagenesis and nuclear import assays showed that NLS acetylations promote cytoplasmic localization by inhibiting nuclear import. Additionally, broad-spectrum deacetylase inhibition triggered accumulation of cytoplasmic IFI16, and we identify the acetyltransferase p300 as a regulator of IFI16 localization. Collectively, these studies establish acetylation as a molecular toggle of IFI16 distribution, providing a simple and elegant mechanism by which this versatile sensor detects pathogenic DNA in a localization-dependent manner.


Three-dimensional limb lengthening after total knee arthroplasty in a simulation study.
Limb lengthening after total knee arthroplasty (TKA) has been reported in some cases, all of which were evaluated using two-dimensional images. To our knowledge, no case has been evaluated using three-dimensional (3D) images. We investigated 3D limb lengthening after TKA. We simulated 100 varus knees using 3D templating software. Virtual TKA was performed to maintain the original joint line by conducting a measured-resection technique. We examined the relationships of 3D distance between the femoral head center and ankle center before and after TKA, degree of hip-knee-ankle angle (HKA) improvement, and degree of flexion contracture angle improvement. All cases showed limb lengthening (average, 9.4 ± 6.0 mm). The coefficients of correlation with limb lengthening and the degree of HKA improvement and the degree of flexion contracture angle improvement were good (0.730 and 0.751, respectively). The correlation between the degree of total improvement (the degree of HKA improvement + the degree of flexion contracture angle improvement) and limb lengthening was strong (r = 0.896). The expected limb lengthening when performing measured-resection TKA is expressed as 0.58 × (the degree of HKA improvement + the degree of flexion contracture angle improvement) mm and is a useful index.


Prognostic impact of atrial fibrillation in patients with severe acute respiratory syndrome coronavirus 2 infection.
The prognostic impact of atrial fibrillation (AF) in patients with severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection has not been well evaluated. We estimated the prognostic implications of AF in SARS-CoV-2 confirmed patients.The OpenData4Covid19 (https://hira-covid19.net) project is a global research collaboration on coronavirus disease (COVID-19), hosted by the Ministry of Health and Welfare of Korea and the Health Insurance Review and Assessment Service of Korea. This dataset comprises all COVID-19-tested patients and their individual histories of medical service use from January 1, 2017 to May 15, 2020. All patients >19 years with confirmed SARS-CoV-2 infection were included. The primary endpoint was a composite of death and intensive care unit admission.In total, 7162 adults with SARS-CoV-2 infection were included in this study. The prevalence of AF was 1.8% (n = 130). Patients with AF had unfavorable characteristics, such as older age and higher prevalence of comorbidities. The primary endpoint was more common in patients with AF than in those without (33.9% vs 12.9%, P < .001). In the multivariable model, age (odds ratio [OR]: 1.035, 95% confidence interval [CI]: 1.030-1.040), female sex (OR: 0.618, 95% CI: 0.535-0.713), diabetes (OR: 1.341, 95% CI: 1.093-1.580), and chronic kidney disease (OR: 2.714, 95% CI: 1.541-4.777) were associated with the primary endpoint. However, AF was not an independent predictor of the primary endpoint (OR: 1.402, 95% CI: 0.932-2.108).Patients with AF and concomitant SARS-CoV-2 infection had more comorbidities and a worse prognosis. However, an independent association between AF and adverse clinical outcomes was not evident.


P-Bodies: Composition, Properties, and Functions.
Processing bodies (P-bodies) are cytoplasmic ribonucleoprotein (RNP) granules primarily composed of translationally repressed mRNAs and proteins related to mRNA decay, suggesting roles in post-transcriptional regulation. P-bodies are conserved in eukaryotic cells and exhibit properties of liquid droplets. However, the function of P-bodies in translational repression and/or mRNA decay remains contentious. Here we review recent advances in our understanding of the molecular composition of P-bodies, the interactions and processes that regulate P-body liquid-liquid phase separation (LLPS), and the cellular localization of mRNA decay machinery, in the context of how these discoveries refine models of P-body function.


Retinogeniculate synaptic properties controlling spike number and timing in relay neurons.
Retinal ganglion cells (RGC) transmit visual signals to thalamocortical relay neurons in the lateral geniculate nucleus via retinogeniculate synapses. Relay neuron spike patterns do not simply reflect those of RGCs, but the mechanisms controlling this transformation are not well understood. We therefore examined synaptic properties controlling the strength and precision of relay neuron firing in mouse (p28-33) brain slices using physiological stimulation patterns and a combination of current clamp and dynamic clamp. In tonic mode (-55 mV), activation of single RGC inputs elicited stereotyped responses in a given neuron. In contrast, responses in different neurons varied from unreliable, to faithfully following, to a gain in the number of spikes. Dynamic clamp experiments indicated these different responses primarily reflected variability in the amplitudes of the N-methyl-d-aspartate (NMDA) and AMPA components. Each of these components played a distinct role in transmission. The AMPA component evoked a single precisely timed, short-latency spike per stimulus, but efficacy decreased during repetitive stimulation due to desensitization and depression. The NMDA component elicited longer-latency spikes and multiple spikes per stimulus and became more effective during repetitive stimuli that led to NMDA current summation. We found that in burst mode (-75 mV), where low-threshold calcium spikes are activated, AMPA and NMDA components and synaptic plasticity influenced spike number, but no combination enabled relay cells to faithfully follow the stimulus. Thus the characteristics of AMPA and NMDA currents, the ratio of these currents and use-dependent plasticity interact to shape how RGC activity is conveyed to relay neurons.


Assessment of serum biomarkers in rats after exposure to pesticides of different chemical classes.
There is increasing emphasis on the use of biomarkers of adverse outcomes in safety assessment and translational research. We evaluated serum biomarkers and targeted metabolite profiles after exposure to pesticides (permethrin, deltamethrin, imidacloprid, carbaryl, triadimefon, fipronil) with different neurotoxic actions. Adult male Long-Evans rats were evaluated after single exposure to vehicle or one of two doses of each pesticide at the time of peak effect. The doses were selected to produce similar magnitude of behavioral effects across chemicals. Serum or plasma was analyzed using commercial cytokine/protein panels and targeted metabolomics. Additional studies of fipronil used lower doses (lacking behavioral effects), singly or for 14 days, and included additional markers of exposure and biological activity. Biomarker profiles varied in the number of altered analytes and patterns of change across pesticide classes, and discriminant analysis could separate treatment groups from control. Low doses of fipronil produced greater effects when given for 14 days compared to a single dose. Changes in thyroid hormones and relative amounts of fipronil and its sulfone metabolite also differed between the dosing regimens. Most cytokine changes reflected alterations in inflammatory responses, hormone levels, and products of phospholipid, fatty acid, and amino acid metabolism. These findings demonstrate distinct blood-based analyte profiles across pesticide classes, dose levels, and exposure duration. These results show promise for detailed analyses of these biomarkers and their linkages to biological pathways.


New phenylethanoid glycosides from Veronica pectinata var. glandulosa and their free radical scavenging activities.
A known phenylethanoid glycoside, ehrenoside (1), was isolated together with three new phenylethanoid glycosides, verpectoside A (2), B (3) and C (4) from the aerial parts of Veronica pectinata var. glandulosa. On the basis of spectral analysis (UV, FAB-MS, 1H-, 13C- and 2D-NMR), compounds 2-4 were determined to be 2-(3,4-dihydroxyphenyl)ethyl-O-alpha-L-arabinopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->3)]-(4-O-trans-feruloyl)-beta-D-glucopyranoside, 2-(3,4-dihydroxyphenyl)ethyl-O-beta-D-glucopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->3)]-(4-O-trans-caffeoyl)-beta-D-glucopyranoside and 2-(3,4-dihydroxyphenyl)ethyl-O-beta-D-glucopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->3)]-(4-O-trans-feruloyl)-beta-D-glucopyranoside, respectively. Isolated phenylethanoid glycosides exhibited potent radical scavenging activity against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical.


Cyanogenic glucosides: the biosynthetic pathway and the enzyme system involved.
In vitro studies with a microsomal system obtained from etiolated sorghum seedlings have indicated a biosynthetic pathway for cyanogenic glucosides involving amino acids, N-hydroxyamino acids, aldoximes, nitriles and cyanohydrins. NADPH is an essential cofactor. Simultaneous measurements of tyrosine metabolism and oxygen consumption show that three molecules of oxygen are consumed for each molecule of p-hydroxymandelonitrile produced. This indicates the operation of three monooxygenases in the pathway and implies the involvement of one hitherto undetected intermediate in the pathway. The nature of this intermediate is unknown. Gel filtration and sucrose gradient centrifugation of the microsomal system resulted in a more than tenfold increase in specific activity. Attempts to further purify the system did not produce preparations of higher specific activity because of a simultaneous partial loss of essential components as demonstrated by reconstitution experiments.


Pulse propagation in decorated granular chains: An analytical approach.
We study pulse propagation in one-dimensional chains of spherical granules decorated with small grains placed between large granules. The effect of the small granules can be captured by replacing the decorated chains by undecorated chains of large granules of appropriately renormalized mass and effective interaction between the large granules. This allows us to obtain simple analytic expressions for the pulse propagation properties using a generalization of the binary collision approximation introduced in our earlier work [Phys. Rev. E 80, 031303 (2009); Phys. Rev. E 69, 037601 (2004)].


Apolipoprotein E-Mimetic Peptide COG1410 Promotes Autophagy by Phosphorylating GSK-3β in Early Brain Injury Following Experimental Subarachnoid Hemorrhage.
COG1410, a mimetic peptide derived from the apolipoprotein E (apoE) receptor binding region, exerts positive effect on neurological deficits in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). Currently the neuroprotective effect of COG1410 includes inhibiting BBB disruption, reducing neuronal apoptosis, and neuroinflammation. However, the effect and mechanism of COG1410 to subcellular organelles disorder have not been fully investigated. As the main pathway for recycling long-lived proteins and damaged organelles, neuronal autophagy is activated in SAH and exhibits neuroprotective effects by reducing the insults of EBI. Pharmacologically elevated autophagy usually contributes to alleviated brain injury, while few of the agents achieved clinical transformation. In this study, we explored the activation of autophagy during EBI by measuring the Beclin-1 and LC3B-II protein levels. Administration of COG1410 notably elevated the autophagic markers expression in neurons, simultaneously reversed the neurological deficits. Furthermore, the up-regulated autophagy by COG1410 was further promoted by p-GSK-3β agonist, whereas decreased by p-GSK-3β inhibitor. Taken together, these data suggest that the COG1410 might be a promising therapeutic strategy for EBI via promoting autophagy in SAH.


Simultaneous Therapy with Intravitreal Dexamethasone Implant and Bevacizumab for the Treatment of Macular Edema.
To investigate the safety profile and benefits of a short-term simultaneous treatment regimen combining two drugs-an intravitreal implant of dexamethasone with an intravitreal injection of bevacizumab-in patients with macular edema. This was a retrospective, non-randomized, open-label case series study. Patients were treated between April 2014 and July 2015 and were diagnosed with recurrent macular edema secondary to diabetic retinopathy and retinal vein occlusion. They underwent simultaneous treatment with an intravitreal injection of bevacizumab (1.25 mg) and an intravitreal implant of dexamethasone (0.7 mg). Patients were evaluated at baseline and at each subsequent visit with a complete ophthalmological examination and spectral-domain optical coherence tomography (OCT) scans. They were examined 24 hours after the treatment, and then followed up after 30 days and 60 days. Twenty patients (representing 20 eyes) were included in the study. At the time of injection (i.e., baseline), the best-corrected visual acuity (BCVA) was 0.758 ± 0.42 logarithm of the minimum angle of resolution (logMAR). It improved significantly to 0.51 ± 0.33 logMAR at 1 month and to 0.5 ± 0.34 logMAR at 2 months (P ≤ 0.03). The median baseline central macular thickness (CMT) was 542 µm (interquartile range, 466 - 751 µm). The median CMT decreased significantly to 321 µm (interquartile range, 288-381 µm) at 1 month and 310 µm (interquartile range, 286 - 354 µm) at 2 months (P ≤ 0.0002). The mean intraocular pressure (IOP) increased from 14.9 ± 2.29 mmHg (at baseline) to 16.5 ± 2.99 mmHg (P = 0.04) after 2 months. Two (10%) eyes showed cataract progression. There were no other ocular or systemic complications for the duration of this study. Simultaneous therapy combining a dexamethasone implant plus bevacizumab for macular edema may be an attractive treatment regimen with an acceptable safety profile.


Two-dimensional Janus-like particles on a triangular lattice.
We have studied the phase behavior of a two-dimensional system of Janus-like particles on a triangular lattice using the Monte Carlo method in a grand canonical ensemble. Assuming that each particle can take on only one of the six orientations, two versions of the model have been considered. In the first version, the strength of attractive interactions has been assumed to depend on the degree to which the attractive patches of neighboring particles overlap. In the second version, it has been assumed that it is the same for any mutual orientations, in which the attractive patches overlap. It has been demonstrated that both models lead to qualitatively different phase behaviors. In the case of the first model, the self-assembly leads to different stripped structures depending on the density and temperature. In particular, we have found that, at sufficiently low temperatures, condensation leads from a very dilute lamellar gas phase to a high density zigzag phase. At intermediate temperatures, the system undergoes two first-order phase transitions, while, at sufficiently high temperatures, only one continuous transition takes place. The phase diagram has been estimated. In the case of the second model, we have found only one first-order transition at low temperatures. This transition occurs between a dilute gas-like phase and the ordered phase, which forms a kagome lattice of density equal to 6/7. A further increase of the density has been demonstrated to lead to the reorientation of particles and the formation of a dense glass-like structure.


Synthesis of doxorubicin-cyclodextrin conjugates.
Doxorubicin-gamma-cyclodextrin conjugates have been synthesized by the coupling of 14-bromodaunomycin with mono half-ester compounds linked to a 6-hydroxyl group of gamma-cyclodextrin. Release of drug from the conjugates in saline phosphate buffer solution and in vitro antitumor activity against L1210 leukemia cells were also investigated.


Human leukocyte elastase induces keratinocyte proliferation by epidermal growth factor receptor activation.
Epidermal hyperproliferation and neutrophil infiltration are major histopathological changes observed in psoriasis. Neutrophils contain human leukocyte elastase (HLE), which is released at sites of inflammation. HLE is present in psoriatic lesions and induces keratinocyte hyperproliferation in vitro and in vivo. To determine the molecular mechanisms linking a proteolytic effect of HLE and epidermal hyperproliferation, we examined the effects of HLE-induced signaling in human keratinocytes. Application of 100 nM HLE resulted in a transient calcium influx in FURA2-loaded human HaCaT keratinocytes observed by single-cell fluorescence imaging. The calcium signal was concentration dependent and was inhibited by addition of the HLE inhibitors elafin and secretory leukocyte protease inhibitor. The calcium signal was neither inhibited by pertussis toxin, cholera, or by pre-stimulation with trypsin. Incubation with the tyrosine kinase inhibitor genistein, a protein kinase C inhibitor, as well as incubation with neutralizing EGFR antibodies abolished the HLE-induced calcium influx. The supernatants of HLE-treated keratinocytes induced a calcium signal in separately cultured keratinocytes. This could be inhibited by the addition of anti-TGF-alpha antibodies. Application of HLE-induced keratinocyte proliferation, which could be inhibited by neutralizing of anti-EGFR and anti-TGF-alpha antibodies. Herein we demonstrate that HLE induces keratinocyte proliferation by proteolytic activation of an EGFR signaling cascade involving TGF-alpha.


Prurigo successfully treated with duloxetine hydrochloride.
Prurigo is a common skin disease characterised by erythematous macules and papules/nodules with severe pruritus. We report here two cases with treatment-resistant prurigo that were successfully treated with duloxetine hydrochloride, a serotonin-norepinephrine reuptake inhibitor. In vivo experiments with a mouse model of prurigo-like inflammation showed that duloxetine hydrochloride ameliorated not only scratching behaviours, but also skin inflammation. Duloxetine hydrochloride appears to be useful for treating prurigo via modulating itch signals and immune responses.


Effect of Diabetes-Trained Nurse Practitioners on Glycemic Outcomes: Their Suggested Use in Busy Primary Care Practices.
A Federally Qualified Health Center received ongoing external support for half-time salaries for two nurse practitioners to treat people with poorly controlled diabetes (A1C >9.0%) in the clinic's diabetes program using approved detailed treatment protocols. Patients were treated for 1 year and graduated from this program if their A1C fell to <7.5%. Ninety-one percent graduated, and treatment was deemed to have failed in 9% who did not achieve an A1C <7.5% by the end of the year of treatment. The suggestion is made to assign a specially trained diabetes nurse or physician assistant to serve many primary care providers at important clinical junctures to improve diabetes outcomes throughout busy primary care practices.


[Use of a calibrated melamine-formaldehyde latex for the luminescence microscopic study of phagocytosis in a macrophage culture].
The possibility has been demonstrated of the use of calibrated melamine-formaldehyde latex for studying phagocytosis as an object not undergoing intracellular digestion. Latex was discovered to be actively phagocytized by macrophages and to exert no toxic action on them. A study was made of the time course of changes in the color and brightness of the fluorescence of the latex phagocytized particles in macrophages intravitally fluorochrominated by acridine orange. These changes were demonstrated to be analogous to those observed previously during phagocytosis of bacteria and other objects. The data obtained demonstrate once more the transition of the fluorescent complex from lysosomes to phagosomes and the lack of the relationship of these changes with intracellular death and digestion of the phagocytized objects. The possibility has been also shown to differentiate between phagocytized particles of latex and those located outside the cells.


[Combination of selective intra-arterial infusion of an anticancer agent via the vascular access port with RF local hyperthermia].
It is desirable for multidisciplinary cancer treatments to be concentrated as selectively as possible onto the cancer-bearing organs in order to augment the anticancer effects and minimize the untoward effects. Combined treatments of selective intraarterial infusion of anticancer agents via an implanted Vascular Access Port with local hyperthermia using 13.56 MHz RF have been performed in 12 patients with extensive cancers. In 9 out of these 12 cases (75%), more than 50% reduction in tumor size has been obtained. Tumor-diminishing effect was more remarkable in patients who underwent bolus infusion of anticancer agents such as 1 mg/kg of mitomycin C under charcoal hemoperfusion for rapid removal of anticancer agents from the blood stream.


miR-29a-3p attenuates hypoxic pulmonary hypertension by inhibiting pulmonary adventitial fibroblast activation.
Activation of pulmonary adventitial fibroblasts plays a key role in the pulmonary vascular remodeling in hypoxic pulmonary hypertension. Previous studies showed that miRNAs participated in the regulation of fibroblast activation. This study explored the role of miR-29 in the activation of pulmonary adventitial fibroblasts and the therapeutic potential in hypoxic pulmonary hypertension. We found that hypoxia-induced pulmonary adventitial fibroblasts activation was accompanied with a drastic decrease of miR-29a-3p expression. Knockdown of hypoxia-inducible factor-1 α or Smad3 reversed the hypoxia-induced decrease of miR-29-3p in cultured pulmonary adventitial fibroblasts. In vitro, miR-29a-3p mimic inhibited the hypoxia-induced proliferation, migration, and secretion of pulmonary adventitial fibroblasts, suppressed the hypoxia-induced expression of α-smooth muscle actin and extracellular matrix collagen in pulmonary adventitial fibroblasts; however, miR-29a-3p inhibitor mimicked the effect of hypoxia on the activation of pulmonary adventitial fibroblasts. Further studies revealed that preventative or therapeutic administration of miR-29a-3p significantly decreased pulmonary artery pressure and right ventricle hypertrophy index and ameliorated pulmonary vascular remodeling in hypoxic pulmonary hypertension rats. These findings suggest that miR-29a-3p regulates the activation and phenotype of pulmonary adventitial fibroblasts in hypoxia and has preventative and therapeutic potential in hypoxic pulmonary hypertension.


Open thoracic anterolateral cordotomy for pain relief in children: report of 2 cases.
Open anterolateral cordotomy is an effective treatment option for adults with intractable pain, but it has seldom been attempted in children. In the 2 previously reported cases in children, the procedure was used within 10 days of death from neoplastic disease. In this paper the authors describe 2 cases in which open cordotomy was used successfully in children outside the immediate terminal phase of disease. Both patients experienced effective analgesia with minimal adverse effects. The authors propose that consideration of cordotomy as an option for the management of intractable pain in children does not need to be delayed until death is imminent.


Interactions between oxidative stress, lipid profile and antioxidants in breast cancer: a case control study.
Oxidant/antioxidant balance has been suggested as an important factor for initiation and progression of cancer. The objective of this study was to determine changes in the levels of malondialdehyde (MDA), nitric oxide (NO), total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, total antioxidant capacity (TAC), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities in serum samples of breast cancer patients (n=30) and healthy subjects (n=100). MDA and NO levels were found to be increased in breast cancer patients compared to the healthy subject group (p<0.05). Total cholesterol and triglycerides were elevated; and HDL- cholesterol level was found to be decreased in the cancer patients as compared to the healthy subjects (p<0.05). Compared to the healthy group, both serum TAC levels (p<0.001) and activity of SOD and GSH-Px (p=0.05) were found to be decreased in the breast cancer patients as compared to the healthy controls. Considering the data presented in this study, we suggest that free radicals induce lipid eroxidation and peroxidation of unsaturated fatty acid with decreased activity of enzymatic antioxidants in breast cancer.


An Empirical Study for Impacts of Measurement Errors on EHR based Association Studies.
Over the last decade, Electronic Health Records (EHR) systems have been increasingly implemented at US hospitals. Despite their great potential, the complex and uneven nature of clinical documentation and data quality brings additional challenges for analyzing EHR data. A critical challenge is the information bias due to the measurement errors in outcome and covariates. We conducted empirical studies to quantify the impacts of the information bias on association study. Specifically, we designed our simulation studies based on the characteristics of the Electronic Medical Records and Genomics (eMERGE) Network. Through simulation studies, we quantified the loss of power due to misclassifications in case ascertainment and measurement errors in covariate status extraction, with respect to different levels of misclassification rates, disease prevalence, and covariate frequencies. These empirical findings can inform investigators for better understanding of the potential power loss due to misclassification and measurement errors under a variety of conditions in EHR based association studies.


The taming of the cell penetrating domain of the HIV Tat: myths and realities.
Protein transduction with cell penetrating peptides over the past several years has been shown to be an effective way of delivering proteins in vitro and now several reports have also shown valuable in vivo applications in correcting disease states. An impressive bioinspired phenomenon of crossing biological barriers came from HIV transactivator Tat protein. Specifically, the protein transduction domain of HIV Tat has been shown to be a potent pleiotropic peptide in protein delivery. Various approaches such as molecular modeling, arginine guanidinium head group structural strategy, multimerization of PTD sequence and phage display system have been applied for taming of the PTD. This has resulted in identification of PTD variants which are efficient in cell membrane penetration and cytoplasmic delivery. In spite of these state of the art technologies, the dilemma of low protein transduction efficiency and target specific delivery of PTD fusion proteins remains unsolved. Moreover, some misconceptions about PTD of Tat in the literature require considerations. We have assembled critical information on secretory, plasma membrane penetration and transcellular properties of Tat and PTD using molecular analysis and available experimental evidences.


Phase I study of a five-day intermittent schedule for 1,2:5,6-dianhydrogalactitol (NSC-132313).
Because 1,2:5,6-dianhydrogalactitol (NSC-132313 (DAG; the main conversion reaction product of the treatment of dibromodulcitol by mild akali or human serum) showed considerable antitumor activity in various mouse and rat tumor systems, a phase I study in 50 patients was conducted with five daily iv treatments repeated every 6 weeks. Thrombocytopenia was the dose-limiting toxicity. At a dose of 40 mg/m2/day for 5 days, the median platelet nadir was 31,000/mm3 and occurred on day 20; the plate count returned to normal within 8 days. At the same dose, the median white blood cell (WBC) nadir was 2,300/mm3 also on day 20-, the WBC count returned to normal within 7 days. Anemia, nausea, and vomiting were usually mild to moderate. No renal, hepatic, central nervous system, cardiac, or pulmonary toxicity was identified. Antitumor effects of DAG were observed in patients with renal, bladder, and small-cell lung cancers. An iv dose of 20-30 mg/m2/day for 5 consecutive days, repeated every 5-6 weeks, was recommended for phase II studies.


[MRI exploration of partial epilepsy].
Investigative strategies for partial epilepsy have evolved greatly since the advent of morphological MRI. MRI currently provides the most extensive and sensitive information for detecting and localizing brain anomalies. Technical progress has included new sequences (3D acquisition, inversion-recovery, fast spin-echo), new imaging planes (through the greater diameter of the hippocampus for temporal epilepsy, orbitao-meatal for extra-temporal epilepsy), high-resolution imaging, and better signal-noise ratio in addition to new procedurs such as NMR spectroscopy, diffusion/perfusion imaging, or functional MRI. One of the principal aims of MRI is to detect potentially epileptogenic brain anomalies useful for the detection and localization of the epileptic focus. MRI sensitivity is much greater than brain computed tomography, which excepting specific cases, is no longer contributive. Hippocampal sclerosis is a typical example of an epilepsy-related brain anomaly (mesial temporal lobe epilepsy) whose diagnosis has been changed by MRI. This entity was described by Bouchet and Cazauvieilh in 1825 who related anatomic postmortem findings to the clinical expression. Reliable diagnosis of hippocampal sclerosis can now be achieved with MRI, contributing to the diagnosis of mesial temporal lobe epilepsy. MRI can also contribute precious prognostic information, useful for both drug and surgical treatment. It has been demonstrated that the degree of response to drug treatment is not univocal and that certain lesions such as hippocampal sclerosis are generally associated with drug resistance. Sensitivity to drug therapy also varies with the type of cerebral dysgenesia. It has also been demonstrated that the a brain lesion identified at MRI is generally a factor of good prognosis after surgery. Continuing improvements in MRI techniques, widespread availability of technical facilities and new derived techniques contribute greatly to the usefulness of MRI for investigating partial epilepsy.


Xenogeneic cell therapy provides a novel potential therapeutic option for cancers by restoring tissue function, repairing cancer wound and reviving anti-tumor immune responses.
Conventional cancer treatments such as surgery, radiotherapy, chemotherapy and targeted therapy, not only destruct tumors, but also injure the normal tissues, resulting in limited efficacy. Recent advances in cancer therapy have aimed at changing the host milieu of cancer against its development and progression by targeting tumor microenvironment and host immune system to eradicate tumors. To the host body, tumors arise in tissues. They impair the normal healthy tissue physiological function, become chronically inflamed and develop non-healing or overhealing wounds as well as drive immuno-suppressive activity to escape immunity attack. Therefore, the rational therapeutic strategies for cancers should treat both the tumors and the host body for the best efficacy to turn the deadly malignant disease to a manageable one. Xenogeneic cell therapy (i.e. cellular xenotransplantation) using cells from non-human source animals such as pigs has shown promising results in animal studies and clinical xenotransplantation in restoring lost tissue physiological function and repairing the wound. However, the major hurdle of xenogeneic cell therapy is the host immunological barriers that are induced by transplanted xenogeneic cells to reject xenografts. Possibly, the immunological barriers of xenogeneic cells could be used as immunological boosters to activate the host immune system. Here, we hypothesized that because of the biological properties of xenogeneic cells to the recipient humans, the transplantation of xenogeneic cells (i.e. cellular xenotransplantation) into cancer patients' organs of the same origin with developed tumors may restore the impaired function of organs, repair the wound, reduce chronic inflammation and revive the anti-tumor immunity to achieve beneficial outcome for patients.


Isolation and Characterization of Shiga Toxin-Producing Escherichia coli from Retail Beef Samples from Eight Provinces in China.
While Shiga toxin-producing Escherichia coli (STEC) is a major foodborne pathogen worldwide, data on the molecular and phylogenetic properties of STEC isolates from retail beef samples in China remain scant. Fresh retail beef samples (n = 1062) were collected from eight provinces, and STEC isolates were recovered and characterized. PCR data showed that more than 50% of the samples were stx positive, and 82 STEC isolates were recovered from 14.8% (79/535) stx-positive enriched broths. In contrast, all ciprofloxacin resistant isolates (n = 19) and 13 cefotaxime (CTX) resistant isolates were eae positive and belonged to three serotypes: O111:H8, O26:H11, or O157:H7. Point mutations in quinolone resistance-determining regions and plasmid-mediated quinolone resistance determinants were identified in 16 and 20 isolates, respectively. BlaCTX-M and a point mutation (C-42T) in ampC promoter were detected in 15 and 8 of the CTX resistant isolates, respectively. In addition, macrolide resistance gene mphA was identified in eight azithromycin resistant O111:H8 isolates and one O26:H11 isolate. Single nucleotide polymorphism analysis demonstrated that the O26 and O157 isolates had multiple origins, but the O111 isolates were closely related. Taken together, our data demonstrated that several sequence types associated with hemolytic uremic syndrome from the retail beef samples in China had developed into dangerous multidrug resistant pathogens. The resistant phenotype can facilitate their transmission among the farm animals and human beings when there is an antimicrobial selective pressure.


Depression and anxiety in women with epilepsy during pregnancy and after delivery: a prospective population-based cohort study on frequency, risk factors, medication, and prognosis.
To assess incidence, prevalence, risk factors, and prognosis of peripartum depression and anxiety in a prospective study of women with epilepsy. Pregnancies in women with epilepsy (n=706) were compared to pregnancies in all women without epilepsy (n=106,511) including women with specified nonepileptic chronic diseases (n=8,372) in the Norwegian Mother and Child Cohort Study. The database was linked to the Medical Birth Registry of Norway. Depression and anxiety were assessed with validated questionnaires five times from the second trimester to 36 months after delivery. Blood was drawn for analysis of antiepileptic drug (AED) concentrations. Women with epilepsy more often had peripartum depression (26.7%) or anxiety (22.4%) than women without epilepsy (18.9% and 14.8%, respectively, p<0.001 for both comparisons) and women with other chronic diseases (23.1% and 18.4%, respectively, p=0.03 and 0.01). Women using AEDs during pregnancy were especially at risk regardless of AED type. The risk further increased with the use of multiple AEDs and with high doses and/or plasma levels. Risk factors associated with peripartum depression and/or anxiety in the epilepsy cohort were high seizure frequency, a history of physical and/or sexual abuse, adverse socioeconomic factors, previous loss of a child, AED use, unplanned pregnancy, and prepregnancy depression and/or anxiety. The recovery rate 3 years after delivery was lower for women with epilepsy with a history of depression/anxiety or physical/sexual abuse than for women without epilepsy. Depressed women with epilepsy were less frequently treated with antidepressive drugs during pregnancy than women without epilepsy. Women with epilepsy frequently have depression and anxiety during and after pregnancy. Patients at risk should be identified before delivery as depressive symptoms could be undertreated in this group.


Prognostic value of C-reactive protein in HIV-infected patients with Pneumocystis jirovecii pneumonia.
C-reactive protein (CRP) is a sensitive marker of inflammation and tissue damage. We aimed to describe CRP responses in HIV-infected patients presenting with Pneumocystis pneumonia (PCP), bacterial pneumonia (BP) and pulmonary tuberculosis (TB) and, in patients with PCP, to identify if elevated CRP has prognostic significance. Data obtained by case-note review of consecutive HIV-infected adults with acute respiratory episodes included admission CRP (elevated >5 mg/L), haemoglobin, white blood count, CD4 count and partial pressure of oxygen in the blood (PaO(2)), presence of pulmonary co-pathology/intercurrent infection and outcome (survival). Median (range) CRP in patients with BP = 120 mg/L (<5-620 mg/L), TB = 44 mg/L (<5-256.3 mg/L) and PCP = 35 mg/L (<5-254 mg/L). CRP was elevated in 93/103 (90.3%) patients with PCP; six patients died; and all had an elevated CRP. PaO(2) and CRP values were associated as follows: average CRP levels declined by 10% (95% confidence interval [CI] 0.20%) per kPa increase in PaO(2) = 0.002. Factors associated with death were higher CRP, odds ratio (OR) (95% CI) = 5.30 (1.61 to 17.51) per 100 mg/L increase, P = 0.006 and haemoglobin, OR (95% CI) = 0.52 (0.29 to 0.93) per g/dL, P = 0.033. CRP is elevated in the majority of HIV-infected patients with PCP, BP and TB. Admission CRP measurement lacks specificity, but in PCP elevations of CRP are associated with disease severity (PaO(2)) and poor outcome and might be used prognostically, together with other mortality risk factors; further prospective evaluation is needed.


Impact of Mental State on the Severity of Psoriasis Symptoms: A Study on Patient's Emotional Well-Being.
BACKGROUND Psoriasis is a chronic systemic skin disease affecting approximately 2% of the global population. In addition to the characteristic inflammatory changes on the skin, patients with psoriasis often experience comorbidities, including depressive symptoms and anxiety. This study aimed to investigate the relationship between the course of psoriasis and the mental state of patients. MATERIAL AND METHODS The study was conducted among 70 patients with psoriasis. An interview was conducted to assess the course of psoriasis. The Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS) were used. CRP concentration as well as VAS, NRS, and PASI scales were measured. The results were subjected to statistical analysis. RESULTS Psoriasis was severe in 50% of the patients. Most (52.8%) of patients had moderate pruritis (VAS) and 58.5% had moderate pain (NRS). Moderate depressive symptoms (BDI) were present in 60% of patients, 18.6% had pathological anxiety (HADS-A), and 18.6% had pathological depression (HADS-D). CRP levels were significantly associated with PASI, VAS, and NRS. CONCLUSIONS The mental state of the patient plays an essential role in the course of psoriasis, and negative emotions affect the severity of skin symptoms. Emotional stress to patients with psoriasis should be limited, which will undoubtedly contribute to overall improvement of health.


Academic achievement and course taking among language minority youth in U.S. schools: Effects of ESL placement.
The 1974 Lau decision requires that U.S. public schools ensure a meaningful education for students learning English. English as a Second Language (ESL) placement is an institutional response to the linguistic needs of these students; however, its academic implications remain largely unexplored. Using nationally representative data from the Educational Longitudinal Study (ELS), the effects of ESL placement on college preparatory course enrollment and academic achievement of language minority students are estimated, first with fixed effects regression models and then with multi-level propensity score matching techniques. While numerous school and individual level factors beyond language proficiency predict ESL placement, a significant negative estimated effect of ESL placement on science enrollment and cumulative GPA is consistently found. Perhaps more important, however, no positive effects of ESL placement on the achievement of language minority youth are found when accounting for English proficiency and other potential covariates.


Child sexual abuse and attachment theory:are we rushing headlong into another controversy?
The child sexual abuse knowledge base has developed within a highly charged political and social context. As such, early theories of sexual abuse were susceptible to biases that reflected the larger sociocultural context. The purpose of this paper is to consider whether attachment theory as it is applied to child sexual abuse might also be susceptible to such biases. Although this paper concludes that attachment theory can potentially add an important dimension to the conceptualization of child sexual abuse and its dynamics, it is also suggested that attachment theory may remain at risk for becoming a vehicle for transmitting political and ideological agendas.


Bismuth Nanoparticle and Polyhydroxybutyrate Coatings Enhance the Radiopacity of Absorbable Inferior Vena Cava Filters for Fluoroscopy-Guided Placement and Longitudinal Computed Tomography Monitoring in Pigs.
Inferior vena cava filters (IVCFs) constructed with poly-p-dioxanone (PPDO) are promising alternatives to metallic filters and their associated risks and complications. Incorporating high-Z nanoparticles (NPs) improves PPDO IVCFs' radiopacity without adversely affecting their safety or performance. However, increased radiopacity from these studies are insufficient for filter visualization during fluoroscopy-guided PPDO IVCF deployment. This study focuses on the use of bismuth nanoparticles (BiNPs) as radiopacifiers to render sufficient signal intensity for the fluoroscopy-guided deployment and long-term CT monitoring of PPDO IVCFs. The use of polyhydroxybutyate (PHB) as an additional layer to increase the surface adsorption of NPs resulted in a 2-fold increase in BiNP coating (BiNP-PPDO IVCFs, 3.8%; BiNP-PPDO + PHB IVCFs, 6.2%), enabling complete filter visualization during fluoroscopy-guided IVCF deployment and, 1 week later, clot deployment. The biocompatibility, clot-trapping efficacy, and mechanical strength of the control PPDO (load-at-break, 6.23 ± 0.13 kg), BiNP-PPDO (6.10 ± 0.09 kg), and BiNP-PPDO + PHB (6.15 ± 0.13 kg) IVCFs did not differ significantly over a 12-week monitoring period in pigs. These results indicate that BiNP-PPDO + PHB can increase the radiodensity of a novel absorbable IVCF without compromising device strength. Visualizing the device under conventional radiographic imaging is key to allow safe and effective clinical translation of the device.


Raman imaging demonstrates FGF2-induced craniosynostosis in mouse calvaria.
Craniosynostosis is a severe craniofacial disease where one or more sutures, the fibrous tissue that lies between the cranial bones, fuses prematurely. Some craniosynostosis syndromes are known to be caused by mutations in fibroblast growth factor (FGF) receptors. Mutated FGF receptors are thought to cause constitutive signaling. In this study, heparin acrylic beads released fibroblast growth factor 2 (FGF2) to mimic constitutive signaling by mutated receptors, delivering FGF2 in addition to already existing normal tissue amounts. Fetal day 18.5 mouse sutures were treated with FGF2-soaked beads and cultured in serum free media for 48 h. We have shown previously that this treatment leads to fusion and increased Msx2 expression, but here we use near-infrared Raman imaging to simultaneously examine the mineral components and matrix components of cranial tissue while providing light microscopic spatial information. FGF2-treated mouse sutures show increased v1 phosphate and v1 carbonate bandwidths, indicating a slightly chemically modified mineral being rapidly deposited. In addition, FGF2-treated mouse sutures show a marked increase in mineral-to-matrix ratios compared to control mouse sutures, typical of increased mineralization.


Identification of operational clues to dry weight prescription in hemodialysis using bioimpedance vector analysis. The Italian Hemodialysis-Bioelectrical Impedance Analysis (HD-BIA) Study Group.
In patients undergoing hemodialysis (HD) cyclic body fluid changes are estimated by body weight variations, which may be misleading. Conventional bioelectrical impedance analysis (BIA) produces biased estimates of fluids in HD due to the assumption of constant tissue hydration. We used an assumption-free assessment of hydration based on direct measurements of the impedance vector. The impedance vector (standard BIA at 50 kHz frequency) was measured in 1367 HD patients, ages 16 to 89 years with BMI 17 to 31 kg/m2, 1116 asymptomatic (680 M and 436 F), and 251 with recurrent HD hypotension (118 M and 133 F) before and after two HD sessions (thrice weekly bicarbonate dialysis, 210 to 240 min) removing 2.7 kg fluid. The vector distribution of HD patients was compared to 726 healthy subjects with the same age and BMI range. Individual vector measurements (resistance and reactance components) were plotted on the gender specific 50th, 75th and 95th percentiles of the vector distribution in the healthy population (reference tolerance ellipses) as a resistance-reactance graph (RXc graph). The wet-dry weight cycling of HD patients was represented on the resistance-reactance plane with a definite, cyclical, backward-forward displacement of the impedance vector. The vectors of patients with HD hypotension were less steep and more often shifted to the right, out of the reference 75% tolerance ellipse, than asymptomatic patients. A wet-dry weight prescription, based on BIA indications, would bring the vectors of patients back into the 75% reference ellipse, where tissue electrical conductivity is restored. Whether HD patients with vector cycling within the normal third quartile ellipse have better outcome awaits confirmation by longitudinal evaluation.


Central giant cell granuloma of the mandibular condyle: a case report and review of the literature.
Central giant cell granuloma (CGCG) is a benign intraosseous lesion. The true nature of this lesion is controversial and remains unknown; the three competing theories are that it could be a reactive lesion, a developmental anomaly or a benign neoplasm. Furthermore, the actual aetiology of CGCG is still unclear, although inflammation, haemorrhage and local trauma have all been suggested; it has also been hypothesized that CGCG may have a genetic aetiology. Lesions central to the mandibular condylar head are very rare, with only three documented cases in the English language literature, none of which elaborates on the CT features. In this case report, a 31-year-old male patient complaining of a left pre-auricular mass underwent radiographic investigation. CT images revealed a lesion central to the mandibular condyle and demonstrated features that were highly suggestive of CGCG. The patient underwent surgical curettage, and the subsequent histopathological examination confirmed the diagnosis of CGCG. 3 years after the procedure the patient presented with a recurrence and underwent complete resection of the mandibular condyle with immediate reconstruction. This report presents CT characteristics of a rare occurrence of CGCG of the mandibular condyle, compares it with other published cases and poses the question of the role of radiology in predicting the degree of aggressive behaviour of these lesions before surgery.


The association between platelet transfusion and idiopathic pneumonia syndrome is unaffected by platelet product type.
Methods used to produce platelet (PLT) components, pooling of PLT-rich plasma (PRP-PLT) and apheresis (AP-PLT), may variably contribute to the pathogenesis and severity of idiopathic pneumonia syndrome (IPS). We performed a retrospective cohort study of 906 allogeneic hematopoietic cell transplant recipients to examine associations between PLT product type and risks of developing IPS and dying after IPS onset. Proportional hazards models included separate terms for the sum of all PLT transfusions and the sum of PRP-PLT units received in the 3 or 7 days before IPS onset. Similarly constructed models analyzed the outcome of time to death after IPS onset. All analyses were adjusted for known IPS risk factors. Patients received a median of three PRP-PLT transfusions (interquartile range [IQR], 0-6) and five AP-PLT transfusions (IQR, 1-13) while at risk for IPS. Seventy-five patients (8%) developed IPS by Posttransplant Day 120. The proportion of PRP-PLT transfusions was not associated with risk of developing IPS (3-day hazard ratio [HR] 0.98, 95% CI 0.74-1.29, p = 0.86; 7-day HR 1.00, 95% CI 0.86-1.15, p = 0.95) or dying after IPS onset (3-day HR 0.99, 95% CI 0.75-1.31, p = 0.97; 7-day HR 0.98, 95% CI 0.78-1.12, p = 0.47). The association between PLT transfusions and risk of developing IPS or dying after IPS onset does not differ according to PLT product type. Further research is required to identify potentially modifiable steps in PLT component production that contribute to IPS.


[Studies on the medicinal plant in the "Sambutsu-cho" of Higo Province possessed by the Kumamoto Clas (I): on the medicinal trees].
The Sambutsu-cho, a list of the natural products of the Kumamoto clan in Higo Province was dedicated to the Tokugawa shogunate in 1735. This book had many names of the plants, animals and minerals. In the plant kingdom, there were many names, wild and cultivated, of cereals, vegetables, fruits, trees, bamboos, herbs, seaweeds and mushrooms. In this report, I studied the species of the trees which were listed up by the Chinese names, Japanese standard and local names. I identified them and found 109 species. Among them, 67 species were medicinal plants. For example, the names of the crude drugs such as Gardeniae fructus, forsythiae fructus and phellodendri radix were found. The ratio of the medicinal plants was 61%.


Superficial venous morphometry in the antecubital fossa: An autonomous robotic ultrasound-based analysis.
The antecubital fossa is an important site for venepuncture and intravenous procedures. The size and location of a vein can affect the success of venepuncture and intravenous access. Several studies have investigated the superficial vein morphometry, but they had small sample sizes or focused on specific populations or groups. Therefore, we conducted a prospective study with large participants in general population to analyse the morphology of the antecubital superficial vein and identify the association of sex, age and body mass index (BMI) with the size and location of the vein. This study collected images of superficial veins prospectively using autonomous robotic ultrasound on the antecubital area between October and November 2020. We measured the superficial vein depth, vertical diameter and horizontal diameter at the antecubital area, extracted population characteristics (sex, age and BMI), and analysed a relationship between the vein dimensions and the characteristics. In this study, data from 461 participants (201 males and 260 females) with mean age of 41.1 years were produced. The mean vein depth, mean vertical diameter and mean horizontal diameter (±standard deviation) were 4.81 (±2.17), 3.01 (±1.10) and 4.46 (±1.60) mm, respectively. We found significant differences in vein dimensions between males and females, with males having larger vertical and horizontal diameters than females (p < 0.001). The study also revealed significant differences in vein depth and dimensions among age groups and BMI subgroups (p < 0.001). These findings revealed that the superficial vein in the antecubital area was oval, with a larger horizontal diameter than vertical diameter. Morphometry revealed differences in sex, age and BMI. Understanding variations in vein dimensions among different subgroups can help medical professionals improve success rate of venous access and patient safety.