Extraordinary reflection and refraction from natural hyperbolic materials.
The reflection and refraction were theoretically investigated for a linearly-polarized wave incident upon the surface of a naturally hyperbolic material. We proposed that this material is uniaxial and possesses two hyperbolic-frequency bands (HB-I and HB-II), whose optical axis is arbitrarily pointed. We paid our attention to reflective and refractive features in the HBs and predicted some extraordinary phenomena. The double reflection was found, where the reflective wave contains a transverse electric branch and a transverse magnetic branch with different amplitudes and phases. The asymmetry of reflection exists and the reflective coefficient abnormally decreases as the incident angle is enlarged. The double refraction inside the material means two refractive branches (the o-wave and e-wave). For the e-wave, there is a special frequency point (SP) in either HB, depending on the orientation of the optical axis. The e-wave and reflective wave exhibit completely different behaviors on the two sides of the SP. The e-wave is a normal refractive wave on the left side of the SP, but it is an evanescent wave on the right side. Its energy-flux seriously deviates from the incident plane and is highly condensed at the inner surface near the SP. It is more interesting that the energy-flux density of the e-wave in the HB-II can even be much larger than that of the incident wave and is opposite in direction on the two sides of the SP, which means an evident radiation-switching effect. The o-wave is a normal refractive wave in the HB-I, but it is an evanescent wave in the HB-II. The above results and conclusions were obtained from the hexagonal boron nitride (hBN). These unique properties may be very useful in optical or optoelectronic technology.


Regulation of cyclic electron flow in C₃ plants: differential effects of limiting photosynthesis at ribulose-1,5-bisphosphate carboxylase/oxygenase and glyceraldehyde-3-phosphate dehydrogenase.
Cyclic electron flow around photosystem I (CEF1) is thought to augment chloroplast ATP production to meet metabolic needs. Very little is known about the induction and regulation of CEF1. We investigated the effects on CEF1 of antisense suppression of the Calvin-Benson enzymes glyceraldehyde-3-phosphate dehydrogenase (gapR), and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) small subunit (SSU), in tobacco (Nicotiana tabacum cv. Wisconsin 38). The gapR, but not ssuR, mutants showed substantial increases in CEF1, demonstrating that specific intermediates, rather than slowing of assimilation, induce CEF1. Both types of mutant showed increases in steady-state transthylakoid proton motive force (pmf) and subsequent activation of the photoprotective q(E) response. With gapR, the increased pmf was caused both by up-regulation of CEF1 and down-regulation of the ATP synthase. In ssuR, the increased pmf was attributed entirely to a decrease in ATP synthase activity, as previously seen in wild-type plants when CO₂ levels were decreased. Comparison of major stromal metabolites in gapR, ssuR and hcef1, a mutant with decreased fructose 1,6-bisphosphatase activity, showed that neither the ATP/ADP ratio, nor major Calvin-Benson cycle intermediates can directly account for the activation of CEF1, suggesting that chloroplast redox status or reactive oxygen species regulate CEF1.


High affinity binding of albicidin phytotoxins by the AlbA protein from Klebsiella oxytoca.
Albicidins are a family of phytotoxins and antibiotics which play an important role in the pathogenesis of sugarcane leaf scald disease. The albA gene from Klebsiella oxytoca encodes a protein which inactivates albicidin by heat-reversible binding. Albicidin ligand binding to a recombinant AlbA protein, purified by means of a glutathione S-transferase gene fusion system, is an almost instant and saturable reaction. Kinetic and stoichiometric analysis of the binding reaction indicated the presence of a single high affinity binding site with a dissociation constant of 6.4 x 10(-8) M. The AlbA-albicidin complex is stable from 4 to 40 degrees C, from pH 5 to 9 and in high salt solutions. Treatment with protein denaturants released all bound albicidin. These properties indicate that AlbA may be a useful affinity matrix for selective purification of albicidin antibiotics. AlbA does not bind to p-nitrophenyl butyrate or alpha-naphthyl butyrate, the substrates of the albicidin detoxification enzyme AlbD from Pantoea dispersa. The potential exists to pyramid genes for different mechanisms in transgenic plants to protect plastid DNA replication from inhibition by albicidins.


Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2.
Arsenic trioxide (As(2)O(3)) is a potent inducer of apoptosis of malignant cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As(2)O(3) induces phosphorylation/activation of the MAPK signal-integrating kinases (Mnks) 1 and 2 in leukemia cell lines. Such activation is defective in cells with targeted disruption of the p38alpha MAPK gene, indicating that it requires upstream engagement of the p38 MAPK pathway. Studies using Mnk1(-/-) or Mnk2(-/-), or double Mnk1(-/-)Mnk2(-/-) knock-out cells, establish that activation of Mnk1 and Mnk2 by arsenic trioxide regulates downstream phosphorylation of the eukaryotic initiation factor 4E at Ser-209. Importantly, arsenic-induced apoptosis is enhanced in cells with targeted disruption of the Mnk1 and/or Mnk2 genes, suggesting that these kinases are activated in a negative-feedback regulatory manner, to control generation of arsenic trioxide responses. Consistent with this, pharmacological inhibition of Mnk activity enhances the suppressive effects of arsenic trioxide on primary leukemic progenitors from patients with acute leukemias. Taken together, these findings indicate an important role for Mnk kinases, acting as negative regulators for signals that control generation of arsenic trioxide-dependent apoptosis and antileukemic responses.


Single implant-supported two-unit cantilever fixed partial dentures in the posterior region: a retrospective case series with a mean follow-up of 6.5 years.
The aim of this retrospective study was to evaluate the implant survival, clinical and radiographic outcomes, and patient satisfaction of single implant-supported two-unit cantilever fixed partial dentures in the posterior region. Patients who received a single implant-supported fixed partial denture with a cantilever in the posterior region between January 2004 and February 2018 were included. Survival rate of the implants and the fixed partial dentures and data regarding the marginal bone level, presence of plaque, calculus, bleeding on probing, mucosa health, pocket probing depth, and patient satisfaction were collected during an evaluation visit. Complications were recorded from the medical records. Twenty-three patients (mean age 64 ± 13 years) with 28 implants could be included in the study. The mean follow-up period was 6.5 ± 4.8 years at the time of data collection. The survival rate of the implants and fixed partial dentures was 100%. Mean marginal bone loss for the mesial and distal side of the implants was 0.41 mm (SD 1.18 mm) and 0.63 mm (SD 0.98 mm) respectively. A high prevalence of peri-implant-mucositis (89.3%) and peri-implantitis (17.9%) was observed as well as a limited number of technical complications. Patients were quite satisfied, as reflected by a mean VAS score of 94.0 ± 7.2 points (range 0-100) and a OHIP-NL49 score of 10.8 (range 0-196). Single implant-supported fixed partial dentures with a mesial or distal cantilever can be a predictable treatment option in the posterior region, with stable peri-implant bone levels, minor technical complications, and very content patients. However, the prevalence of peri-implant mucositis and peri-implantitis was high. ISRCTN, ISRCTN79055740 , Registered on March 14, 2021 - -Retrospectively registered.


[Muscular isokinetic dynamometry].
In the past, muscular strength has primarily been measured using isometric, isotonic or tensiometric techniques. The advent of isokinetic dynamometers has supplied an objective method of measuring peak torque throughout a full range of motion at a predetermined speed of contraction. An isokinetic contraction is a refinement of the controlled motion concept. The isokinetic contraction is dynamic, but the speed of the motion is held constant by a special device. In this way, resistance is in direct ratio to the varying force applied through the full course of a natural movement. The purpose of this study was to determine the peak torque of quadriceps (Q), and hamstrings (H), and their biomechanical angle of production, H to Q ratio and bilateral comparisons of these variables for the first time in a Southamerican population. Twenty healthy and voluntary males (age: 21.9 +/- 3.1 years, height 193.2 +/- 6.5 cm, weight: 84.2 +/- 5.2 kgs.), were tested on the Cybex II Dynamometer and Cybex Data Reduction Computer (CDRC). Quadriceps and hamstrings peak torque (pkTQ), in Newton-meters, were obtained at angular velocities of 60, 180 and 240 degrees. sec-1. Also, the angle of the range of motion at which peak torque occurred in both directions, H and Q peak torque to body weight ratios, H to Q ratio were measured. Finally, CDRC provided the bilateral comparison of the different variables expressed in percentages. All measurements were automatically corrected for the effect of gravity. The absolute maximal pkTQ of dominant (D), and non-dominant (ND), quadriceps at 60 degrees/sec was DQ 297 +/- 25 Nwm and nDQ 303 +/- 13 Nwm.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of a new powerful bone-anchored hearing system: a comparison study.
The recent introduction of digital hearing aid technology for bone-conduction devices employing percutaneous stimulation may be beneficial for patients with conductive and mixed hearing loss and single sided deafness. Performance of a recently released sound processor for bone-anchored implants, the Ponto Pro Power from Oticon Medical (bone-conduction device 2 [BCD2]), was compared with that of the Baha Intenso from Cochlear (bone-conduction device 1 [BCD1]). Direct comparison of the subject's own device (BCD1) with the new device (BCD2) was examined in a nonrandomized design. Subjects were initially tested with BCD1. BCD2 was tested after a 4 wk acclimatization period. Eighteen subjects with mixed hearing loss and with at least 4 mo experience with BCD1 completed the study. Mean air-conduction and bone-conduction thresholds averaged across the frequencies of 500, 1000, 2000, and 4000 Hz were 73.9 and 34.2 dB HL, respectively. Performance of the two devices was evaluated objectively by measuring aided free-field thresholds, speech perception in quiet, and speech perception in noise. A subjective evaluation was carried out with the Abbreviated Profile of Hearing Aid Benefit (APHAB) (Cox and Alexander, 1995) and the Speech, Spatial and Qualities of Hearing Scale (SSQ) questionnaire (Gatehouse and Noble, 2004). In addition, user experiences, user satisfaction, and device preference were obtained via proprietary questionnaires. Statistical significance was established with analysis-of-variance (ANOVA) and paired t-statistics with Bonferroni correction. Aided free-field thresholds and speech reception thresholds (SRTs) in quiet were not statistically significantly different for either device (p > 0.05). In contrast, SRTs in noise were 2.0 dB lower (p < 0.001) for BCD2 than for BCD1. APHAB questionnaire scores on all subscales provided statistically significantly greater benefit (p < 0.05) for BCD2 than for BCD1. Also, with the SSQ most items in the speech and sound quality domain were significantly more favorable (p < 0.05) for BCD2 than for BCD1. Finally, all subjects preferred BCD2 over BCD1 with 14 subjects reporting a strong preference and four subjects an average preference for the digital signal processing provided by BCD2 over previous technology provided by BCD1.


Stability of Furosemide 5 mg/mL in Polypropylene Syringes.
Furosemide parenteral solutions are routinely used in our hospital. However, the stability in transparent syringes is unknown. In this study, transparent polypropylene syringes were filled with 8 mL and 50 mL of furosemide 5-mg/mL solution. The furosemide was analyzed by high-performance liquid chromatography and assays were performed up to 35 days of storage of the syringes at 4°C protected from light, plus 24 hours at 20°C exposed to daylight. In addition, the appearance and pH of the solutions were determined. A microbiological assay using tryptic soy broth was also performed. Both types of syringes remained colorless, clear, and free from visible particles throughout the study period. The pH did not change, and concentrations remained between 95% and 105% of the stated concentration. None of the syringes filled with culture media exhibited bacterial or fungal growth. In conclusion, ready-to-administer furosemide 5-mg/mL, 8-mL, and 50-mL polypropylene syringes are stable for up to 35 days when stored in a refrigerator at 4°C protected from light, plus 24 hours at 20°C unprotected from light. These results allow maximum storage time in stock and the ability of 24-hour continuous infusion at ambient room temperature without protecting the syringe against light.


Transcription factors mediate the enzymatic disassembly of promoter-bound 7SK snRNP to locally recruit P-TEFb for transcription elongation.
The transition from transcription initiation into elongation is controlled by transcription factors, which recruit positive transcription elongation factor b (P-TEFb) to promoters to phosphorylate RNA polymerase II. A fraction of P-TEFb is recruited as part of the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP), which inactivates the kinase and prevents elongation. However, it is unclear how P-TEFb is captured from the promoter-bound 7SK snRNP to activate elongation. Here, we describe a mechanism by which transcription factors mediate the enzymatic release of P-TEFb from the 7SK snRNP at promoters to trigger activation in a gene-specific manner. We demonstrate that Tat recruits PPM1G/PP2Cγ to locally disassemble P-TEFb from the 7SK snRNP at the HIV promoter via dephosphorylation of the kinase T loop. Similar to Tat, nuclear factor (NF)-κB recruits PPM1G in a stimulus-dependent manner to activate elongation at inflammatory-responsive genes. Recruitment of PPM1G to promoter-assembled 7SK snRNP provides a paradigm for rapid gene activation through transcriptional pause release.


Nuclear actin polymerization is required for transcriptional reprogramming of Oct4 by oocytes.
Amphibian oocytes can rapidly and efficiently reprogram the transcription of transplanted somatic nuclei. To explore the factors and mechanisms involved, we focused on nuclear actin, an especially abundant component of the oocyte's nucleus (the germinal vesicle). The existence and significance of nuclear actin has long been debated. Here, we found that nuclear actin polymerization plays an essential part in the transcriptional reactivation of the pluripotency gene Oct4 (also known as Pou5f1). We also found that an actin signaling protein, Toca-1, enhances Oct4 reactivation by regulating nuclear actin polymerization. Toca-1 overexpression has an effect on the chromatin state of transplanted nuclei, including the enhanced binding of nuclear actin to gene regulatory regions. This is the first report showing that naturally stored actin in an oocyte nucleus helps transcriptional reprogramming in a polymerization-dependent manner.


[Chronic subdural hematoma simulating a TIA. Implications for the management transient neurological deficit].
Chronic subdural hematoma that generally happens after cranial trauma doesn't have clinical manifestations until days or weeks after the traumatism. Due to the lesions nature, symptoms are almost always progressive and presentation as transient ischemic attacks (TIA) is very uncommon. We describe 2 cases of chronic subdural hematoma that started simulating TIA and we discuss its implications in the management of those patients who had presented transient neurological deficit.


Comparative studies of the specificities of -chymotrypsin and subtilisin BPN'. Studies with flexible substrates.
A series of arylalkanoate esters and alpha-acetamidoarylalkanoate esters were tested as substrates for alpha-chymotrypsin and subtilisin BPN'. Chymotrypsin hydrolysed N-acetyl-l-phenylalanine methyl ester and methyl 4-phenylbutyrate faster than their respective higher and lower homologues, whereas methyl 2-acetamido-6-phenylhexanoate and methyl 6-phenylhexanoate were better substrates for subtilisin than their lower homologues. N-Acetyl-l-tryptophan methyl ester and its analogue, N-acetyl-3-(1-naphthyl)-alanine methyl ester, were hydrolysed 23 times faster by chymotrypsin than by subtilisin. These results indicate that the binding site of alpha-chymotrypsin is roughly 1.1nm (11A) long and curved, whereas that of subtilisin is a longer system and less curved. The stereo-specificity during the hydrolysis of typical substrates by both enzymes was found to vary over a wide range. The enhancing effect of the alpha-acetamido group in the l-series of substrates and the detrimental effect in the d-series of substrates also varies considerably.


Molecular characterization of a 1p36 chromosomal duplication and in utero interference define ENO1 as a candidate gene for polymicrogyria.
While chromosome 1p36 deletion syndrome is one of the most common terminal subtelomeric microdeletion syndrome, 1p36 microduplications are rare events. Polymicrogyria (PMG) is a brain malformation phenotype frequently present in patients with 1p36 monosomy. The gene whose haploinsufficiency could cause this phenotype remains to be identified. We used high-resolution arrayCGH in patients with various forms of PMG in order to identify chromosomal variants associated to the malformation and characterized the genes included in these regions in vitro and in vivo. We identified the smallest case of 1p36 duplication reported to date in a patient presenting intellectual disability, microcephaly, epilepsy, and perisylvian polymicrogyria. The duplicated segment is intrachromosomal, duplicated in mirror and contains two genes: enolase 1 (ENO1) and RERE, both disrupted by the rearrangement. Gene expression analysis performed using the patient cells revealed a reduced expression, mimicking haploinsufficiency. We performed in situ hybridization to describe the developmental expression profile of the two genes in mouse development. In addition, we used in utero electroporation of shRNAs to show that Eno1 inactivation in the rat causes a brain development defect. These experiments allowed us to define the ENO1 gene as the most likely candidate to contribute to the brain malformation phenotype of the studied patient and consequently a candidate to contribute to the malformations of the cerebral cortex observed in patients with 1p36 monosomy.


Reduced severity of Rh-haemolytic disease after anti-D immunoglobulin.
A total of 2459 Rh-negative women who received anti-D immunoglobulin after a Rh-positive pregnancy were followed up in at least one subsequent pregnancy. There was a failure of protection rate of 1-6%. Follow-up of 53 subsequent infants of mother in whom protection had failed showed that the infants were less severely affected than would have been expected. This was confirmed by a comparative statistical analysis of the present series and a series of first affected cases before anti-D immunoglobulin was available, using the antibody titre during pregnancy and the haemoglobin levels at delivery.


Telomere and ribosomal DNA repeats are chromosomal targets of the bloom syndrome DNA helicase.
Bloom syndrome is one of the most cancer-predisposing disorders and is characterized by genomic instability and a high frequency of sister chromatid exchange. The disorder is caused by loss of function of a 3' to 5' RecQ DNA helicase, BLM. The exact role of BLM in maintaining genomic integrity is not known but the helicase has been found to associate with several DNA repair complexes and some DNA replication foci. Chromatin immunoprecipitation of BLM complexes recovered telomere and ribosomal DNA repeats. The N-terminus of BLM, required for NB localization, is the same as the telomere association domain of BLM. The C-terminus is required for ribosomal DNA localization. BLM localizes primarily to the non-transcribed spacer region of the ribosomal DNA repeat where replication forks initiate. Bloom syndrome cells expressing the deletion alleles lacking the ribosomal DNA and telomere association domains have altered cell cycle populations with increased S or G2/M cells relative to normal. These results identify telomere and ribosomal DNA repeated sequence elements as chromosomal targets for the BLM DNA helicase during the S/G2 phase of the cell cycle. BLM is localized in nuclear bodies when it associates with telomeric repeats in both telomerase positive and negative cells. The BLM DNA helicase participates in genomic stability at ribosomal DNA repeats and telomeres.


The Reductive Dehydroxylation Catalyzed by IspH, a Source of Inspiration for the Development of Novel Anti-Infectives.
The non-mevalonate or also called MEP pathway is an essential route for the biosynthesis of isoprenoid precursors in most bacteria and in microorganisms belonging to the Apicomplexa phylum, such as the parasite responsible for malaria. The absence of this pathway in mammalians makes it an interesting target for the discovery of novel anti-infectives. As last enzyme of this pathway, IspH is an oxygen sensitive [4Fe-4S] metalloenzyme that catalyzes 2H+/2e- reductions and a water elimination by involving non-conventional bioinorganic and bioorganometallic intermediates. After a detailed description of the discovery of the [4Fe-4S] cluster of IspH, this review focuses on the IspH mechanism discussing the results that have been obtained in the last decades using an approach combining chemistry, enzymology, crystallography, spectroscopies, and docking calculations. Considering the interesting druggability of this enzyme, a section about the inhibitors of IspH discovered up to now is reported as well. The presented results constitute a useful and rational help to inaugurate the design and development of new potential chemotherapeutics against pathogenic organisms.


Disturbances in acid-base balance during hypophosphatemia and phosphate depletion.
Phosphate depletion leads to bone resorption, resulting in the accession of alkali to the blood and urine. There may also be a release of lactic acid from liver, resulting from ATP depletion and intracellular alkalosis. In general, the net result of these tissue effects is an alkali load discharged into the extracellular fluid. In the kidneys, phosphate depletion causes impaired proximal tubular reabsorption of bicarbonate, and perhaps other substrates, owing in all likelihood to both intracellular alkalosis and depletion of ATP. This impaired proximal capacity to reclaim bicarbonate results in hyperchloremic acidosis. The distal nephron may contribute to acidosis by virtue of inability to produce titratable acid (phosphate-free urine) and perhaps impaired ammonia production. Severe phosphate depletion, therefore, tends to produce hyperchloremic acidosis as a result of a diminished capacity for bicarbonate reclamation in the proximal tubule and probably some impairment of bicarbonate regeneration in the distal nephron. These effects, when marked, ultimately outweigh the contribution of alkali coming from bone breakdown. In the liver, phosphate depletion may stimulate lactic acid production by reducing hepatic ATP stores (Pasteur effect) and producing intracellular alkalosis. ATP depletion may also limit hepatic uptake of lactate. Finally, in muscle cells ATP depletion, resulting from either profound hypophosphatemia or the metabolism of massive fructose loads, may eventuate in frank rhabdomyolysis.


[Enzyme systems of insecticide detoxication in the Colorado beetle].
The activity of three enzymatic systems of xenobiotic metabolism (cytochrome P-450-dependent monooxygenases, non-specific esterases and glutathione S-transferases) was studied at different stages of development of the Colorado potato beetle (Leptinotarsa decemlineata). Significant sex and ontogenetic differences in the content of cytochrome P-450, position of maxima of CO-difference spectra of the cytochrome P-450 reduced form and substrate specificity of cytochrome P-450 were revealed. The activity of non-specific esterases was shown to increase depending on the age of larvae. The insecticide 1-naphtholenol methylcarbamate which is metabolized by the system of cytochrome P-450-dependent monooxygenases is more toxic in the larvae than at the imago stage, which is correlated with the activity of this system at different stages of ontogenesis. The microsomal monooxygenase inhibitor, piperonylbutoxide, increases the insecticide toxicity in the Colorado beetle imago more than 2-fold. The experimental results testify to different contribution of the detoxication systems to the sensitivity of the Colorado beetle to insecticides at various metamorphosis stages.


A systematic review of the budget impact analyses for antitumor drugs of lung cancer.
Budget impact analyses (BIAs) are used for reimbursement decisions and drug access medical insurance, as a supplement to cost-effectiveness analyses (CEAs). We systematically reviewed BIAs for antitumor drugs of lung cancer to provide reference for high-value drug budget impact analyses and decision making. We conducted a literature search on PubMed, EMbase, The Cochrane Library, China National Knowledge Infrastructure and Wanfang Data Knowledge Service Platform from 2010 to 2019. The methodological indicators and result information of the budget impact analyses were extracted and evaluated for quality. A total of 14 studies on the budget impact for antitumor drugs of lung cancer were included, and the overall quality was good. Half of studies were from developed countries. Nine of the studies were designed using the BIA cost calculation model, and two were simulated using the Markov model Monte Carlo model. From all studies, only 14.3% reported model validation. The budget impact results of the same drug in different countries were inconsistent. Included studies evaluating budget impact analyses for anti-tumor drugs of lung cancer showed variability in the methodological framework for BIAs. The budget impact analyses of high-value drugs need to be more stringent to ensure the accuracy of the parameters, and should provide reliable results based on real data to decision-making departments, which should carefully consider access to lung cancer drugs.


Effects of polychlorinated biphenyls on the development of neuronal cells in growth period; structure-activity relationship.
Polychlorinated biphenyls (PCBs) are accumulated in our body through food chain and cause a variety of adverse health effects including neurotoxicities such as cognitive deficits and motor dysfunction. In particular, neonates are considered as a high risk group for the neurotoxicity of PCBs exposure. The present study attempted to analyze the structure-activity relationship among PCB congeners and the mechanism of PCBs-induced neurotoxicity. We measured total protein kinase C (PKC) activities, PKC isoforms, reactive oxygen species (ROS), and induction of neurogranin (RC-3) and growth associated protein-43 (GAP-43) mRNA in cerebellar granule cells of neonatal rats with phorbol 12, 13-dibutyrate ([(3)H]PDBu) binding assay, western blot, ROS assay, and reverse transcription PCR (RT-PCR) analysis respectively following the different structural PCBs exposure. Only non-coplanar PCBs showed a significant increase of total PKC-α and βII activity as measured with [(3)H]PDBu binding assay. ROS were more increased with non-coplanar PCBs than coplanar PCBs. The mRNA levels of RC-3 and GAP-43 were more induced with non-coplanar PCBs than coplanar PCBs, indicating that these factors may be useful biomarkers for differentiating non-coplanar PCBs from coplanar PCBs. Non-coplanar PCBs may be more potent neurotoxic congeners than coplanar PCBs. This study provides evidences that non-coplanar PCBs, which have been neglected in the risk assessment processes, should be added in the future to improve the quality and accuracy of risk assessment on the neuroendocrinal adverse effects of PCBs exposures.


Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma.
We compared functional imaging modalities including PET with 6-(18)F-fluorodopamine ((18)F-DA) with (123)I-metaiodobenzylguanidine ((123)I-MIBG) and somatostatin receptor scintigraphy (SRS) with (111)In-pentetreotide in nonmetastatic and metastatic pheochromocytoma (PHEO). We studied 25 men and 28 women (mean age +/- SD, 44.2 +/- 14.2 y) with biochemically proven nonmetastatic (n = 17) or metastatic (n = 36) PHEO. Evaluation included anatomic imaging with CT or MRI and functional imaging that included at least 2 nuclear medicine modalities: (18)F-DA PET, (123)I-MIBG scintigraphy, or SRS. Sensitivity of functional imaging versus anatomic imaging was assessed on a per-patient and a per-region basis. For this available cohort, on a per-patient basis overall sensitivity (combined for nonmetastatic and metastatic PHEO) was 90.2% for (18)F-DA PET, 76.0% for (123)I-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for (18)F-DA PET, 63.4% for (123)I-MIBG scintigraphy, and 64.0% for SRS. If available, (18)F-DA PET should be used in the evaluation of PHEO, because it is more sensitive than (123)I-MIBG scintigraphy or SRS. If (18)F-DA PET is not available, (123)I-MIBG scintigraphy (for nonmetastatic or adrenal PHEO) and SRS (for metastatic PHEO) should be the first alternative imaging methods to be used.


Family Satisfaction With Nursing Home Care: Findings and Implications From Two State Comparison.
Family satisfaction, while recognized as important, is frequently missing from validated measures of long-term care quality. This is the first study to compare family satisfaction across two states using validated measures and to compare the organizational and structural factors associated with higher family satisfaction with nursing home care. Data sources are family satisfaction surveys from Minnesota (MN) and Ohio (OH), linked to facility characteristics from Certification and Survey Provider Enhanced Reports (CASPER) for both states (N = 378 facilities for MN; N = 926 facilities for OH). Activities and food were among lowest rated items in both states. Relationships with staff were the highest rated domain. Higher occupancy rates, smaller facility size, and non-profit ownership consistently predicted better satisfaction in both states. Our findings show consistent organizational factors associated with family satisfaction and provide further evidence to the validity of family satisfaction as a person-centered measure of quality. This lays the foundation for tool development on the national level.


Postmenopausal status according to years since menopause as an independent risk factor for the metabolic syndrome.
Features of the metabolic syndrome such as abdominal adiposity, insulin resistance, and dyslipidemia develop with the transition from pre- to postmenopausal status in women. We investigated the effects of postmenopausal status on the prevalence of the metabolic syndrome according to years since menopause. We studied 1,002 women, 618 premenopausal and 384 postmenopausal, who participated in annual health examinations at Anam Hospital in Seoul, Korea. Using multivariate logistic regression analysis, we determined that postmenopausal status was an independent risk factor for the metabolic syndrome. Moreover, after controlling for age and body mass index, postmenopausal women had an increased risk of the metabolic syndrome (odds ratio, 2.93; 95% CI, 1.62-5.33) and the abnormalities of its individual components. The risk for the metabolic syndrome increased up to 14 years since menopause, then decreased. For its individual components, postmenopausal women with 5 to 9 years since menopause had the highest risk of high blood pressure; postmenopausal women with less than 5 years since menopause had an increased risk of abdominal obesity and high glucose. With 10 to 14 years since menopause, postmenopausal women had an increased risk of high triglycerides. Postmenopausal status is an independent risk factor for the metabolic syndrome and all of its individual components. The risk for the metabolic syndrome increased up to 14 years since menopause. In addition, postmenopausal status has effects during different periods since menopause for each of these components.


Saving the injured: Rescue behavior in the termite-hunting ant Megaponera analis.
Predators of highly defensive prey likely develop cost-reducing adaptations. The ant Megaponera analis is a specialized termite predator, solely raiding termites of the subfamily Macrotermitinae (in this study, mostly colonies of Pseudocanthotermes sp.) at their foraging sites. The evolutionary arms race between termites and ants led to various defensive mechanisms in termites (for example, a caste specialized in fighting predators). Because M. analis incurs high injury/mortality risks when preying on termites, some risk-mitigating adaptations seem likely to have evolved. We show that a unique rescue behavior in M. analis, consisting of injured nestmates being carried back to the nest, reduces combat mortality. After a fight, injured ants are carried back by their nestmates; these ants have usually lost an extremity or have termites clinging to them and are able to recover within the nest. Injured ants that are forced experimentally to return without help, die in 32% of the cases. Behavioral experiments show that two compounds, dimethyl disulfide and dimethyl trisulfide, present in the mandibular gland reservoirs, trigger the rescue behavior. A model accounting for this rescue behavior identifies the drivers favoring its evolution and estimates that rescuing enables maintenance of a 28.7% larger colony size. Our results are the first to explore experimentally the adaptive value of this form of rescue behavior focused on injured nestmates in social insects and help us to identify evolutionary drivers responsible for this type of behavior to evolve in animals.


RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes.
Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability.


Neoadjuvant therapy for high-risk bulky regional melanoma.
Clinically detectable regional lymph node melanoma metastasis (AJCC stage IIIB-C) carries a risk of relapse and death that approaches 70% at 5 years. Surgical management is the cornerstone of therapy, with postoperative adjuvant therapy utilizing high-dose interferon alfa-2b (HDI). Neoadjuvant chemotherapy or immunotherapy in addition to surgery has been demonstrated to improve outcome in the management of patients with a variety of solid tumors. In patients with melanoma, the characteristics of the host immune response differ between patients with earlier stage and those with more advanced stages of disease (and particularly between those with measurable active disease and those without measurable gross disease) providing rationale for neoadjuvant approaches with immunotherapy. Host immune tolerance is now understood to impede the results of therapy for advanced disease, but appears to be less an issue for patients with microscopic high-risk operable disease, where the host may be more susceptible to immunologic interventions. Phase II studies have shown that neoadjuvant biochemotherapy has limited activity in melanoma patients with local-regional metastases, where chemotherapy may potentially alter the effects of immunotherapeutic agents. Studies of neoadjuvant HDI therapy for high-risk melanoma patients with bulky regional stage IIIB-C lymphadenopathy have shown unexpectedly high clinical and pathologic response rates, without increased morbidity. Through the design of neoadjuvant trials utilizing promising emerging melanoma therapeutics in which it is possible to obtain biopsy samples before and after therapy, a greater understanding of the dynamic interaction between tumors and the immune system is possible. This should lead to the identification of new targets for the treatment of melanoma and aid the development of new immunotherapy that may have greater specificity and less toxicity. This will simplify the evaluation of promising new combinations of agents with HDI to build on the clinical, immunologic, and molecular effect of this therapy for patients with melanoma.


First Demonstration of Antigen Induced Cytokine Expression by CD4-1+ Lymphocytes in a Poikilotherm: Studies in Zebrafish (Danio rerio).
Adaptive immunity in homeotherms depends greatly on CD4+ Th cells which release cytokines in response to specific antigen stimulation. Whilst bony fish and poikilothermic tetrapods possess cells that express TcR and CD4-related genes (that exist in two forms in teleost fish; termed CD4-1 and CD4-2), to date there is no unequivocal demonstration that cells equivalent to Th exist. Thus, in this study we determined whether CD4-1+ lymphocytes can express cytokines typical of Th cells following antigen specific stimulation, using the zebrafish (Danio rerio). Initially, we analyzed the CD4 locus in zebrafish and found three CD4 homologues, a CD4-1 molecule and two CD4-2 molecules. The zfCD4-1 and zfCD4-2 transcripts were detected in immune organs and were most highly expressed in lymphocytes. A polyclonal antibody to zfCD4-1 was developed and used with an antibody to ZAP70 and revealed double positive cells by immunohistochemistry, and in the Mycobacterium marinum disease model CD4-1+ cells were apparent surrounding the granulomas typical of the infection. Next a prime-boost experiment, using human gamma globulin as antigen, was performed and revealed for the first time in fish that zfCD4-1+ lymphocytes increase the expression of cytokines and master transcription factors relevant to Th1/Th2-type responses as a consequence of boosting with specific antigen.


Determination of trace heavy metal elements in aqueous solution using surface-enhanced laser-induced breakdown spectroscopy.
Heavy metal pollution is one of the main problems in water pollution, which is harmful to humans. Surface-enhanced laser-induced breakdown spectroscopy (SENLIBS) has been applied to detect trace amounts of heavy metal elements in aqueous solution; however, it is still a big challenge to explore the relationship between the LIBS detection sensitivity and the substrate's physical properties. In this work, four typical substrates, zinc (Zn), magnesium alloy (Mg), nickel (Ni), and silicon (Si), were compared; and the mechanism of spectral enhancement by different substrates in SENLIBS was investigated. The results indicated that the limit of detection (LoD) of heavy metal elements on different substrates is positively proportional to the boiling of the substrate. That is mainly because a higher plasma excitation temperature and electron density are obtained, leading to more intense collision between particles. The signal enhancement is associated with the lower boiling point of the substrate (corresponding to a lower ablation threshold and higher ablation quantity from the substrate). As a result, the best LoD was 0.0011 mg/L for chromium (Cr) and 0.004 mg/L for lead (Pb) on an optimal Zn substrate, respectively. The LoDs were sufficiently low to meet the drinking water sanitation standard. These results showed that the detection sensitivity of heavy metal elements in aqueous solution can be improved by choosing a substrate with a lower boiling point in SENLIBS.


Virological Outcome of Patients With HIV Drug Resistance Attending an Urban Outpatient Clinic in Uganda: A Need for Structured Adherence Counseling and Third-Line Treatment Options.
HIV drug resistance and suboptimal adherence are the main reasons for treatment failure among HIV-infected individuals. As genotypic resistance testing is not routinely available in resource-limited settings such as Uganda, data on transmitted and acquired resistance are sparse. This observational follow-up study assessed the virological outcomes of patients diagnosed with virological failure or transmitted HIV drug resistance in 2015 at the adults' outpatient clinic of the Infectious Diseases Institute in Kampala, Uganda. Initially, 2430 patients on antiretroviral therapy (ART) underwent virological monitoring, of which 190 had virological failure and were subsequently eligible for this follow-up study. Nine patients diagnosed with transmitted drug resistance were eligible. In patients with a viral load > 1000 copies/mL, genotypic resistance testing was performed. Of 190 eligible patients, 30 (15.8%) had either died or were lost to follow-up. A total of 148 (77.9%) were included, of which 98 had had a change of ART regimen, and 50 had received adherence counseling only. The majority was now on second-line ART (N = 130, 87.8%). The median age was 39 years (interquartile range: 32-46), and 109 (73.6%) were women. Virological failure was diagnosed in 29 (19.6%) patients, of which 24 (82.8%) were on second-line ART. Relevant drug resistance was found in 25 (86.2%) cases, of which 12 (41.3%) carried dual and 7 (24.1%) triple drug resistance. Two years after initial virological failure, most patients followed up by this study had a successful virological outcome. However, a significant proportion either continued to fail or died or was lost to follow-up.


A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia.
In our drug discovery program, we identified a novel orally available and brain-penetrant phosphodiesterase (PDE) 1 inhibitor, 3-methyl-7-(tetrahydro-2H-pyran-4-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]-methoxy}imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-141562). In the present study, we characterized the preclinical profile of DSR-141562. This compound has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over other PDE families and 65 other tested biologic targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the cGMP concentration, and it potently enhanced the increase of cGMP induced by a dopamine D1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. Since PDE1B is believed to regulate dopaminergic and glutamatergic signal transduction, we evaluated the effects of this compound using schizophrenia-related behavioral assays. DSR-141562 at 3-30 mg/kg potently inhibited methamphetamine-induced locomotor hyperactivity in rats, while it had only minimal effects on the spontaneous locomotor activity. Furthermore, DSR-141562 at 1-100 mg/kg did not induce any signs of catalepsy in rats. DSR-141562 at 0.3-3 mg/kg reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist, phencyclidine, in mice and rats, respectively. In common marmosets, DSR-141562 at 3 and 30 mg/kg improved the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia. SIGNIFICANCE STATEMENT: This is the first paper showing that a phosphodiesterase 1 inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Furthermore, we demonstrated that this compound improved cognitive function in the common marmoset, a nonhuman primate.


Circulating clonotypic B cells in classic Hodgkin lymphoma.
Although Hodgkin and Reed-Sternberg (HRS) cells are B lymphoid cells, they are unlike any normal cells of that lineage. Moreover, the limited proliferative potential of HRS cells belies the clinical aggressiveness of Hodgkin lymphoma (HL). More than 20 years ago, the L428 HL cell line was reported to contain a small population of phenotypic B cells that appeared responsible for the continued generation of HRS cells. This observation, however, has never been corroborated, and such clonotypic B cells have never been documented in HL patients. We found that both the L428 and KM-H2 HL cell lines contained rare B-cell subpopulations responsible for the generation and maintenance of the predominant HRS cell population. The B cells within the HL cell lines expressed immunoglobulin light chain, the memory B-cell antigen CD27, and the stem cell marker aldehyde dehydrogenase (ALDH). Clonal CD27(+)ALDH(high) B cells, sharing immunoglobulin gene rearrangements with lymph node HRS cells, were also detected in the blood of most newly diagnosed HL patients regardless of stage. Although the clinical significance of circulating clonotypic B cells in HL remains unclear, these data suggest they may be the initiating cells for HL.


Rapid visual tests: fast and reliable detection of ochratoxin A.
This paper reviews the early detection strategies that have been employed for the rapid monitoring of ochratoxin A (OTA) contamination of food. OTA, a mycotoxin mainly produced by some Aspergillus and Penicillium species, is found in cereals, coffee, wine, pork and grapes. To minimize the entry of this mycotoxin into the food chain, rapid diagnostic tools are required. To this end, the potential use of lateral flow devices has also been developed. In this study, we analyze the robustness of test strips using published methods for colorimetric detection. Different test formats are discussed, and challenges in the development of lateral flow devices for on-site determination of OTA, with requirements such as robustness, speed, and cost-effectiveness, are discussed.


Computed tomography assessment of bone lesions in patients with POEMS syndrome.
To describe the imaging findings on computed tomography (CT) and skeletal survey (SS) in patients with POEMS syndrome. We retrospectively reviewed, with institutional review board approval, the dysproteinemia database at our institution for patients with new diagnosis of POEMS syndrome between January 1998 and December 2008. Twenty-four patients were identified with PET/CT or CT and had skeletal survey (SS) available for review. Twenty-four patients were included in the study group with median age of 47 years. All CTs demonstrated at least one sclerotic lesion. The most common pattern was multiple small lesions, with 18 patients (75%) having at least 5 lesions less than 1 cm. The larger lesions had a central lytic component and were FDG avid. SS had a false negative rate of 36% (8 patients). Serial CT after treatment showed a decrease in size and number of sclerotic lesions in 53% of cases (13 patients), the majority showing increased sclerosis. Two patients had complete resolution of sclerotic lesions. CT identified sclerotic lesions in all study patients with POEMS syndrome, the majority being less than 1 cm in size, which were not identified radiographically. CT may demonstrate increased sclerosis or even resolution of sclerotic lesions corresponding to treatment response. • CT has high sensitivity in identifying sclerotic lesions in POEMS syndrome • Most common CT patterns are multiple, less than 1 cm, sclerotic lesions • Larger lesions have lytic centres and sclerotic margins • Skeletal surveys may have a false negative rate of 36% • Treatment response includes increased sclerosis, decrease in size or resolution of lesions.


Adaptations to a Secondary School-Based Citizen Science Project to Engage Students in Monitoring Well Water for Arsenic during the COVID-19 Pandemic.
Secondary schools in Maine and New Hampshire have been involved in a citizen science program called "All About Arsenic" aimed at addressing arsenic contamination of well water, one of the most pressing public health issues in both states. Nearly half of the population of Maine and New Hampshire derive their drinking water from private wells which often have arsenic levels above the EPA limit of 10 ppb. Arsenic exposure can cause cancer, adverse cardiovascular effects, and other health problems. Addressing this issue in schools provides context and motivation for students to engage in scientific inquiry and acquire data literacy skills. This project involves students collecting well water samples for arsenic analysis, entering their data into an online citizen science data portal, Anecdata, and using Tuva online software tools to visualize and interpret their data. Students present their data at public meetings to inform community members of their findings with the goal of moving "data to action". The COVID-19 pandemic presented multiple challenges for teachers engaging their students in this citizen science project. We adapted our program and implemented a series of interventions aimed at supporting teachers in their continued efforts to engage their students the "All About Arsenic" project.


Women Empowerment and Its Relation with Health Seeking Behavior in Bangladesh.
Over the last few decades, Bangladesh has made significant progress towards achieving targets for the Millennium Development Goals (MDGs) and women empowerment. This study is aimed at identifying the levels and patterns of women empowerment in relation to health seeking behavior in Bangladesh. We conducted a cross-sectional study among 200 rural married women in Cox's Bazar district in Bangladesh using multi stage sampling technique and face-to-face interview. Data was collected on socio-economic characteristics, proxy indicators for women empowerment in mobility and health seeking behavior related decision making. Bivariate and multivariate regression analyses were performed to identify associations between women empowerment in relation to health seeking behavior on mobility and decision making, controlling the effect of other independent variables. The results showed that only 12% women were empowered to decide on their own about seeking healthcare and 8.5% in healthcare seeking for their children. In multivariate analysis women empowerment in health seeking behavior was higher among age group 25-34 years (OR 1.76, [CI = 0.82-3.21]), women's education, husband's education, age at marriage > 18 years (OR 6.38, [CI = 0.98-4.21]) and women's working status (OR 16.44, [CI = 0.79-2.71]). Women empowerment enhances their decision-making authority regarding health seeking behavior. Acknowledging and adopting the implications of these findings are essential for an integrated health and development strategy for Bangladesh and achieving the MDGs.


From anxiety to action-Experience of threat, emotional states, reactance, and action preferences in the early days of COVID-19 self-isolation in Germany and Austria.
The COVID-19 pandemic has interrupted everyday life virtually everywhere in the world, enabling real-life research on threat-and-defense processes. In a survey conducted within the first days of implementing social distancing measures in Austria and Germany, we aimed to explore the pathways from threat perception to preferences of defense strategies. We found that anxiety, approach-related affect, and reactance were specifically elicited by motivational (vs. epistemic) discrepancies. In a second step, we tested the mediating effect of anxiety, approach-related affect, and reactance on preferences regarding personal-social and concrete-abstract defenses. Experiencing anxiety was related to interest in security-related actions, and approach-affect was related to both personal projects and social media use. Participants experiencing reactance were more inclined to pursue personal projects (personal-abstract) and less interested in security-related (personal-concrete) actions. They also showed marginally lower system justification (social-abstract). Additionally, we examined the relationship of loneliness with defense strategies, showing that loneliness was associated with lower system justification and security behaviors. The results suggest that individuals deal with threat in their own ways, mostly depending on affective state and motivational orientation: Anxiety was related to security, approach-state to action (both social and personal), reactance to derogation of the system and disregard for security, while loneliness was associated with inaction.


Osteoblastic cell lines are not susceptible to HIV-1 infection.
Osteoblastic cells are in direct or indirect contact with lymphocytes and bone marrow cells that are the main targets of HIV-1. Therefore we analysed whether HIV-1 could infect these cells using three bone cell lines (HOS, MG-63, U2 OS) as a model. These cells were infected with HIV-1 (strain NL4-3) and the supernatants were harvested every day for 20 days for p24 antigen measured using an ELISA immunoassay. The DNA of infected cells was extracted at days 3, 9, and 12 and the PCR for gag gene was performed using Jurkat cell line as a negative control and ACH-2 cell line as a positive control. Our results demonstrated that HOS, MG-63 and U2 OS are not infected by HIV-1. These data were confirmed using PCR that is currently the most sensitive procedure available.


Using monkeys to explore perceptual "loss" versus "learning" models in English and Spanish voice-onset-time perception.
Cross-language research using synthetic voice-onset-time series over the past 40 years suggests that the Spanish lead contrast is acoustically less salient than the English lag contrast. This study examined monkey identification of a labial consonant-vowel voice-onset-time (CV VOT) series (-60 to +70 ms) in order to obtain a linguistically unbiased estimate of lead versus lag salience. Comparisons were made with both English and Spanish adult human listeners. In a classic two-choice identification test, monkey and Spanish functions were quite variable and showed evidence of sensitivity to three types of voicing cues (lead versus simultaneous versus lag). In contrast, English functions were highly categorical and showed sensitivity to only two types of cues (combined lead/simultaneous versus lag). Next, listeners were explicitly trained via feedback to differentiate stimuli crossing lead and lag boundaries. Here, monkey and Spanish performance was initially more symmetrical than English performance, with the latter showing reduced sensitivity to the lead boundary, but group differences disappeared after extended training. These results provide evidence for perceptual loss in English listeners for aspects of Spanish voicing lead perception.


Methotrexate induced false photosensitivity reaction.
Methotrexate is now being used in the treatment of a variety of intractable rheumatologic conditions. We report a patient with polymyositis who developed mild erythroderma after sun exposure. Forty-eight h later he received his weekly dose of methotrexate. Within 24 h the resolving rash erupted into an intense dusky red dermatitis with eventual formation of confluent bullae. The patient had a methotrexate induced ultraviolet reactivation reaction also known as a "false photosensitivity" reaction. This reaction has been reported in dermatologic publications but not in the rheumatologic literature.


Establishing baseline absolute risk of subsequent fracture among adults presenting to hospital with a minimal-trauma-fracture.
One in three women and one in five men are expected to experience a minimal-trauma-fracture after the age of 50-years, which increases the risk of subsequent fracture. Importantly, timely diagnosis and optimal treatment in the form of a fracture liaison service (FLS), has been shown to reduce this risk of a subsequent fracture. However, baseline risk of subsequent fracture among this group of FLS patients has not been well described. Therefore, this study aims to estimate absolute risk of subsequent fracture, among women and men aged 50-years or more, presenting to hospital with a minimal-trauma-fracture. Women and men aged 50-years or more with a minimal-trauma-fracture, presenting to hospitals across the South Western Sydney Local Health District between January 2003 and December 2017 were followed to identify subsequent fracture presentations to hospital. Absolute risk of subsequent fracture was estimated, by taking into account the competing risk of death. Between January 2003 and December 2017-15,088 patients presented to the emergency departments of the five hospitals in the SWSLHD (11,149, women [74%]), with minimal-trauma-fractures. Subsequent fractures identified during the follow-up period (median = 4.5 years [IQR, 1.6-8.2]), occurred in 2024 (13%) patients. Death during the initial hospital stay, or during a subsequent hospital visit was recorded among 1646 patients (11%). Women were observed to have 7.1% risk of subsequent fracture after 1-year, following an initial fracture; and, the risk of subsequent fracture after 1-year was 6.2% for men. After 5-years the rate among women was 13.7, and 11.3% for men, respectively. Cumulative risk of subsequent fracture when initial fractures were classified as being at proximal or distal sites are also presented. This study has estimated the baseline risk of subsequent fracture among women and men presenting to hospital with minimal trauma fractures. Importantly, this information can be used to communicate risk to patients deciding to attend an osteoporosis refracture prevention clinic, and highlight the need for screening, and initial of treatment when indicated, once a minimal-trauma-fracture has occurred.


CDK5RAP2 regulates centriole engagement and cohesion in mice.
Centriole duplication occurs once per cell cycle, ensuring that each cell contains two centrosomes, each containing a mother-daughter pair of tightly engaged centrioles at mitotic entry. Loss of the tight engagement between mother and daughter centrioles appears to license the next round of centriole duplication. However, the molecular mechanisms regulating this process remain largely unknown. Mutations in CDK5RAP2, which encodes a centrosomal protein, cause autosomal recessive primary microcephaly in humans. Here we show that CDK5RAP2 loss of function in mice causes centriole amplification with a preponderance of single, unpaired centrioles and increased numbers of daughter-daughter centriole pairs. These results indicate that CDK5RAP2 is required to maintain centriole engagement and cohesion, thereby restricting centriole replication. Early in mitosis, amplified centrosomes assemble multipolar spindles in CDK5RAP2 mutant cells. Moreover, both mother and daughter centrioles are amplified and the excess mother centrioles template multiple primary cilia in CDK5RAP2 mutant cells.


Locally asymmetric introgressions between subspecies suggest circular range expansion at the Antirrhinum majus global scale.
Assessing processes of geographic expansion in contact zones is a crucial step towards an accurate prediction of the evolution of species genetic diversity. The geographic distribution of cytonuclear discordance often reflects genetic introgression patterns across a species geographic range. Antirrhinum majus pseudomajus and A. m. striatum are two interfertile subspecies that occupy nonoverlapping areas but enter in contact in many locations at the margin of their geographic distribution. We found that genetic introgression between both subspecies was asymmetric at the local scale and geographically oriented in opposite directions at both ends of their contact zone perimeter in the Pyrenees. Our results suggest that the geographic expansion of A. majus subspecies was circular around the perimeter of their contact zone and pinpoint the need to integrate different spatial scales to unravel complex patterns of species geographic expansion.


Psychological factors and visual fatigue in working with video display terminals.
To examine the part played by psychological factors in complaints about visual health reported by banking officers who work at video display terminals (VDTs). Out of a population of 385 bank workers, a group of 212 subjects without organic visual disturbances (as determined by ophthalmological examination) who share a work environment and job duties was selected. Three questionnaires were administered to these subjects: (a) the NIOSH job stress questionnaire; (b) a questionnaire investigating subjective discomfort related to environmental and lighting conditions of the workplace; (c) a questionnaire on the existence of oculovisual disturbances. Correlation and multiple regression analyses were performed to examine for the presence of predictors of asthenopia. Social support, group conflict, self esteem, work satisfaction, and underuse of skills were found to be predictors of visual complaints; social support played a part also as a moderating factor in the stress and strain model; this model accounted for 30% of the variance. Subjective environmental factors, although in some cases significantly correlated with asthenopia, were not found to be strong predictors of the symptoms. Some part of the complaints about visual health reported by VDT workers are likely indirect expressions of psychological discomfort related to working conditions.


Prenatal diagnosis of Desbuquois dysplasia Type 1: Utilization of high-density SNP array to map homozygosity and identify the gene.
Desbuquois dysplasia (DBQD1 [MIM 251450]) is an autosomal recessive chondrodysplasia with micromelia, severe joint laxity and dislocations, and a characteristic radiographic "monkey wrench" appearance at the proximal femur. Type 1 Desbuquois dysplasia is caused by mutations in CANT1 and is distinct from Type 2, caused by mutations in XYLT1, in that the former has unique hand anomalies including accessory phalangeal ossification centers, advanced carpal bone maturation, and/or axial phalangeal deviation. Severe prenatal presentations have been rarely reported. We report a Pakistani female in a consanguineous relationship with a diagnosis of Type 1 Desbuquois dysplasia in three consecutive pregnancies. Multiple similar severe fetal limb anomalies were detected by ultrasound in Pregnancy 1 and 2. Regions of homozygosity within the single nucleotide polymorphism (SNP)-microarray from both terminated fetuses were compared, revealing CANT1 as a likely disease-causing candidate gene. Insufficient fetal DNA precluded confirmatory testing, therefore parents were tested; both had a previously reported heterozygous CANT1 mutation (c.643G>T; Glu215Term). The patient presented with a third pregnancy revealing similarly abnormal limb position and probable polysyndactyly by ultrasound. Targeted testing of CANT1 revealed homozygous c.643G>T CANT1 mutations and this pregnancy was terminated. In clinical situations in which ample DNA is not available or more expensive testing (e.g., whole exome sequencing) with a longer turnaround time is not feasible, utilization of SNP-microarray in consanguineous families at risk for rare autosomal recessive disorders may dramatically narrow the list of candidate genes.


Instruments measuring the disease-specific quality of life of family carers of people with neurodegenerative diseases: a systematic review.
Neurodegenerative diseases, such as dementia, have a profound impact on those with the conditions and their family carers. Consequently, the accurate measurement of family carers' quality of life (QOL) is important. Generic measures may miss key elements of the impact of these conditions, so using disease-specific instruments has been advocated. This systematic review aimed to identify and examine the psychometric properties of disease-specific outcome measures of QOL of family carers of people with neurodegenerative diseases (Alzheimer's disease and other dementias; Huntington's disease; Parkinson's disease; multiple sclerosis; and motor neuron disease). Systematic review. Instruments were identified using 5 electronic databases (PubMed, PsycINFO, Web of Science, Scopus and the International Bibliography of the Social Sciences (IBSS)) and lateral search techniques. Only studies which reported the development and/or validation of a disease-specific measure for adult family carers, and which were written in English, were eligible for inclusion. The methodological quality of the included studies was evaluated using the COnsensus based Standards for the selection of health Measurement Instruments (COSMIN) checklist. The psychometric properties of each instrument were examined. 676 articles were identified. Following screening and lateral searches, a total of 8 articles were included; these reported 7 disease-specific carer QOL measures. Limited evidence was available for the psychometric properties of the 7 instruments. Psychometric analyses were mainly focused on internal consistency, reliability and construct validity. None of the measures assessed either criterion validity or responsiveness to change. There are very few measures of carer QOL that are specific to particular neurodegenerative diseases. The findings of this review emphasise the importance of developing and validating psychometrically robust disease-specific measures of carer QOL.


Influence of anesthesia on autoregulation of the cerebral blood flow.
Autoregulation of the cerebral blood flow is a wellknown fact. In normal man the arterial pressure can vary from 80 mm Hg to 150 mm Hg without a change in the normal cerebral blood flow of 50 ml/100 g/min. The mechanism which is responsible for this autoregulation is not clearly understood. Several theories were proposed to explain this phenomenon. 1. The tissue pressure increases with an increase of the arterial pressure. A mechanical process should neutralize an increase of the cerebral blood flow. 2. The metabolic theory says that a decrease of the blood pressure, without a change of metabolism, involves an increase of the PaCO2, and a decrease of the PaO2. Those two factors provoke a decrease of the vascular tone. 3. The myogenic theory explains autoregulation by the fact that a change of the transmural pressure in the small vessels, involves a change in the activity of the smooth muscles of the vessels. 4. The exact mechanism of the autonomic nervous system in the autoregulation of the cerebral blood flow is still obscure. In some pathological conditions autoregulation is completely lost or is functioning not optimal: hypoxia, hypercapnia and brain contusion. We have measured the cerebral blood flow before and after an intravenous injection of 5 mg thiopental (Pentothal) on occasion of a carotid angiography in man. We noticed a decrease of the cerebral blood flow and at the same moment a decrease of the arterial pressure. We thought that maybe barbiturates could influence autoregulation. Our results could not prove this hypothesis. For ethical reasons we could not make the necessary measurements to prove or to reject this hypothesis (i.e. intracranial pressure, deep controlled hypotension). In the literature there are arguments which support this hypothesis although most workers found an intact autoregulation after a barbiturate anesthesia. Some workers saw that the increase of the cerebral blood flow by increasing the PaCO2 was depressed by barbiturates and exhausted by halothane and cyclopropane. As autoregulation is a more vulnerable mechanism than CO2 reactivity as seen in clinical situations, it could be true that anesthetics do influence autoregulation.


Thymus Extracellular Matrix-Derived Scaffolds Support Graft-Resident Thymopoiesis and Long-Term In Vitro Culture of Adult Thymic Epithelial Cells.
The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen-specific response. A diverse population of stroma cells provides surface-bound and soluble molecules that orchestrate the intrathymic maturation and selection of developing T cells. Forming an intricate 3D architecture, thymic epithelial cells (TEC) represent the most abundant and important constituent of the thymic stroma. Effective models for in and ex vivo use of adult TEC are still wanting, limiting the engineering of functional thymic organoids and the understanding of the development of a competent immune system. Here a 3D scaffold is developed based on decellularized thymic tissue capable of supporting in vitro and in vivo thymopoiesis by both fetal and adult TEC. For the first time, direct evidences of feasibility for sustained graft-resident T-cell development using adult TEC as input are provided. Moreover, the scaffold supports prolonged in vitro culture of adult TEC, with a retained expression of the master regulator Foxn1. The success of engineering a thymic scaffold that sustains adult TEC function provides unprecedented opportunities to investigate thymus development and physiology and to design and implement novel strategies for thymus replacement therapies.


[Current morphofunctional studies of the optic nerve and retina in difficult diagnostic cases].
Thirty-four patients (53 eyes) with suspected optic nerve and retinal diseases were examined. For differential diagnosis, the authors used current studies of the ocular neurosensory apparatus, such as retinal tomography, computer static perimetry, and electrophysiologial techniques, including multifocal electroretinography. The complex use of structural and functional studies of the retina and optic nerve established the valid diagnosis in all difficult clinical cases.


Inspired gas-induced vascular change in tumors with magnetic-resonance-guided near-infrared imaging: human breast pilot study.
This study investigates differences in the response of breast tumor tissue versus healthy fibroglandular tissue to inspired gases. Cycles of carbogen and oxygen gas are administered while measuring the changes with magnetic-resonance-guided near-infrared imaging in a pilot study of breast cancers. For two patients, analyses are performed with cross-correlation techniques, which measure the strength of hemodynamic modulation. The results show that the overall vasoresponse, indicated by total hemoglobin, of healthy tissue has approximately a 72% and 41% greater correlation to the gas stimulus than the tumor region, in two patients respectively, when background physiological changes are controlled. These data support the hypothesis that tumor vasculature has a poorly functioning vasodilatory mechanism, most likely caused by dysfunctional smooth muscle cells lining the vasculature. This study presents a methodology to quantitatively analyze inspired gas changes in human breast tumors, and demonstrates this technique in a pilot patient population.


Retinyl ester synthesis by the isolated perfused-ventilated neonatal rabbit lung.
Retinyl ester is present in lung but it is unknown if retinyl ester synthesis occurs in that organ. In this study, [3H]-Retinol was perfused into the pulmonary artery of isolated-perfused-ventilated neonatal rabbit lungs. Alumina chromatography was used to separate retinol from retinyl ester in hexane extracts of lung tissue. [3H]-Retinyl ester synthesis did occur and was perfusion time and perfusate [3H]-retinol concentration dependent. Documentation of [3H] retinyl ester synthesis was also made by HPLC analysis of the retinyl ester fraction before and after methanolic KOH hydrolysis. Isolated lung clearly can synthesize retinyl ester.


[Pleomorphic adenoma: a case treated by laryngotracheal resection and reconstruction].
Benign Pleomorphic Adenoma (PA) is a tumor rarely found in tracheal and laryngotracheal sites. A review of the literature published since 1922 has revealed only 30 certain cases of which 3 presented simultaneous involvement of both larynx and trachea. The present work describes the thirty-first case (the fourth with a laryngotracheal localization), diagnosed in a white, 40-year-old male who had been complaining of acute dyspnea for the last three years. Initially these symptoms had been interpreted as asthmatic crises. During one of these episodes, the patient underwent emergency tracheotomy and a laryngotracheoscopy revealed a rounded cricotracheal lesion with smooth surface and approximately 4 cm in cranio-caudal diameter. The mass occupied 90% of the air space and originated from the posterolateral right portion of the cricoid, and from the first 3 tracheal rings. CT and esophagoscopy ruled out its transmural invasion into the esophagus. Under rigid bronchoscopy, assisted NdYAG laser debulking was performed for biopsy purposes. The histological diagnosis was benign AP. For this reason a Grillo cricotracheal resection was performed with exeresis of the cricoid arch, mucosa of the cricoid plate and the first 4 tracheal rings. Reconstruction of the respiratory tract was achieved through termino-terminal cricothyrotracheal anastomosis. The initial diagnosis was confirmed and the resection edges were without evidence of neoplasm. Post-operative recovery proceeded without complications and the patient was discharged 7 days after surgery. Endoscopic and radiological follow-up after 30 months is still negative for any neoplastic recurrences. The laryngo-tracheal lumen is within the norm and cord motility has been preserved. The authors then describe the clinical, anatomopathological and radiological elements which prove useful in evaluating tracheal neoplasms and they underline the problems of differential diagnosis between benign AP and adenoid-cystic carcinoma. In addition, the various therapeutic options are discussed with special attention being focused on surgery through external approaches. Given the location of the AP described, the Grillo procedure-most commonly used in cases of inflammatory cricotracheal stenoses-proved well suited to the loco-regional control of the neoplasm. Stringent respect for some parts of this surgical technique make it possible to reduce post-operative complications to a minimum.


Pharmacogenomics and COVID-19: clinical implications of human genome interactions with repurposed drugs.
The outbreak of Coronavirus disease 2019 (COVID-19) has evolved into an emergent global pandemic. Many drugs without established efficacy are being used to treat COVID-19 patients either as an offlabel/compassionate use or as a clinical trial. Although drug repurposing is an attractive approach with reduced time and cost, there is a need to make predictions on success before the start of therapy. For the optimum use of these repurposed drugs, many factors should be considered such as drug-gene or dug-drug interactions, drug toxicity, and patient co-morbidity. There is limited data on the pharmacogenomics of these agents and this may constitute an obstacle for successful COVID-19 therapy. This article reviewed the available human genome interactions with some promising repurposed drugs for COVID-19 management. These drugs include chloroquine (CQ), hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir (LPV/r), atazanavir (ATV), favipiravir (FVP), nevirapine (NVP), efavirenz (EFV), oseltamivir, remdesivir, anakinra, tocilizumab (TCZ), eculizumab, heme oxygenase 1 (HO-1) regulators, renin-angiotensin-aldosterone system (RAAS) inhibitors, ivermectin, and nitazoxanide. Drug-gene variant pairs that may alter the therapeutic outcomes in COVID-19 patients are presented. The major drug variant pairs that associated with variations in clinical efficacy include CQ/HCQ (CYP2C8, CYP2D6, ACE2, and HO-1); azithromycin (ABCB1); LPV/r (SLCO1B1, ABCB1, ABCC2 and CYP3A); NVP (ABCC10); oseltamivir (CES1 and ABCB1); remdesivir (CYP2C8, CYP2D6, CYP3A4, and OATP1B1); anakinra (IL-1a); and TCZ (IL6R and FCGR3A). The major drug variant pairs that associated with variations in adverse effects include CQ/HCQ (G6PD; hemolysis and ABCA4; retinopathy), ATV (MDR1 and UGT1A1*28; hyperbilirubinemia; and APOA5; dyslipidemia), NVP (HLA-DRB1*01, HLA-B*3505 and CYP2B6; skin rash and MDR1; hepatotoxicity), and EFV (CYP2B6; depression and suicidal tendencies).


Temporal Transition of Mechanical Characteristics of HUVEC/MSC Spheroids Using a Microfluidic Chip with Force Sensor Probes.
In this paper, we focus on the mechanical characterization of co-cultured spheroids of human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSC) (HUVEC/MSC spheroids). HUVEC/MSC spheroids aggregate during culture, thereby decreasing in size. Since this size decrease can be caused by the contractility generated by the actomyosin of MSCs, which are intracellular frames, we can expect that there is a temporal transition for the mechanical characteristics, such as stiffness, during culture. To measure the mechanical characteristics, we use a microfluidic chip that is integrated with force sensor probes. We show the details of the measurement configuration and the results of mechanical characterization of the HUVEC/MSC spheroids. To evaluate the stiffness of the spheroids, we introduce the stiffness index, which essentially shows a spring constant per unit size of the spheroid at a certain time during measurement. From the measurement results, we confirmed that the stiffness index firstly increased during the days of culture, although after four days of culture, the stiffness index decreased. We confirmed that the proposed system can measure the stiffness of HUVEC/MSC spheroids.


Framework for analyzing transformative technologies in life cycle assessment.
Emerging products and technologies pose unique challenges for the life cycle assessment (LCA) community, given the lack of data and inherent uncertainties regarding their development. An emerging technology that has the potential to be transformative and effect broad-scale change within society, as well as the underpinning assumptions associated with its life cycle, is particularly difficult to analyze. Despite the associated challenges, LCA methods must be developed for transformative technologies. The greatest improvement potential occurs at the early phases of technology development; therefore, prospective LCA results can be used to anticipate potential unintended consequences and develop design pathways that lead to preferential outcomes. This paper identifies and categorizes ten factors that influence the LCA results of transformative technologies in order to provide a formal structure for determining appropriate factors for inclusion within an LCA. Appropriate factors for an analysis should be selected according to the overall research questions of the study and are applicable to both attributional and consequential approaches to LCA.


Genomes of ubiquitous marine and hypersaline Hydrogenovibrio, Thiomicrorhabdus and Thiomicrospira spp. encode a diversity of mechanisms to sustain chemolithoautotrophy in heterogeneous environments.
Chemolithoautotrophic bacteria from the genera Hydrogenovibrio, Thiomicrorhabdus and Thiomicrospira are common, sometimes dominant, isolates from sulfidic habitats including hydrothermal vents, soda and salt lakes and marine sediments. Their genome sequences confirm their membership in a deeply branching clade of the Gammaproteobacteria. Several adaptations to heterogeneous habitats are apparent. Their genomes include large numbers of genes for sensing and responding to their environment (EAL- and GGDEF-domain proteins and methyl-accepting chemotaxis proteins) despite their small sizes (2.1-3.1 Mbp). An array of sulfur-oxidizing complexes are encoded, likely to facilitate these organisms' use of multiple forms of reduced sulfur as electron donors. Hydrogenase genes are present in some taxa, including group 1d and 2b hydrogenases in Hydrogenovibrio marinus and H. thermophilus MA2-6, acquired via horizontal gene transfer. In addition to high-affinity cbb3 cytochrome c oxidase, some also encode cytochrome bd-type quinol oxidase or ba3 -type cytochrome c oxidase, which could facilitate growth under different oxygen tensions, or maintain redox balance. Carboxysome operons are present in most, with genes downstream encoding transporters from four evolutionarily distinct families, which may act with the carboxysomes to form CO2 concentrating mechanisms. These adaptations to habitat variability likely contribute to the cosmopolitan distribution of these organisms.


[Extent of the use of systemic anti-infective agents in a rural health area in Asturias. Comparison of the years 1994 and 1995].
To establish how widely used systemic drugs against infection were in 1994 and 1995. To compare the interannual variation and evaluate whether this is consistent with CFyT interventions to improve prescription habits. Comparative before-and-after study without a control group. A rural Health Area with 57,536 inhabitants, 24.01% of whom were over 65. All the general practitioners in the Primary Care public network in this Health Area who prescribed medicines charged to the SNS (National Health Service) in 1994 and 1995. All the prescriptions billed to the SNS were processed. Prevalence of use was measured by the variable N(o)DDD/1,000 inhabitants per day. Annual values and variations were obtained for each medicine, therapeutic groupings and indicators proposed to measure aspects pursued in the interventions. Through the application of the DDD unit of measurement, broad data bases on medicine consumption can be exploited, and simplified intuitive information about the use of medicines can be obtained. The results of the variations in the indicators linked to the interventions show the efficacy of the interventions.


Homology modeling and site-directed mutagenesis reveal catalytic key amino acids of 3beta-hydroxysteroid-dehydrogenase/C4-decarboxylase from Arabidopsis.
Sterols become functional only after removal of the two methyl groups at C4 by a membrane-bound multienzyme complex including a 3beta-hydroxysteroid-dehydrogenase/C4-decarboxylase (3betaHSD/D). We recently identified Arabidopsis (Arabidopsis thaliana) 3betaHSD/D as a bifunctional short-chain dehydrogenase/reductase protein. We made use of three-dimensional homology modeling to identify key amino acids involved in 4alpha-carboxy-sterol and NAD binding and catalysis. Key amino acids were subjected to site-directed mutagenesis, and the mutated enzymes were expressed and assayed both in vivo and in vitro in an erg26 yeast strain defective in 3betaHSD/D. We show that tyrosine-159 and lysine-163, which are oriented near the 3beta-hydroxyl group of the substrate in the model, are essential for the 3betaHSD/D activity, consistent with their involvement in the initial dehydrogenation step of the reaction. The essential arginine-326 residue is predicted to form a salt bridge with the 4alpha-carboxyl group of the substrate, suggesting its involvement both in substrate binding and in the decarboxylation step. The essential aspartic acid-39 residue is in close contact with the hydroxyl groups of the adenosine-ribose ring of NAD+, in good agreement with the strong preference of 3betaHSD/D for NAD+. Data obtained with serine-133 mutants suggest close proximity between the serine-133 residue and the C4beta domain of the bound sterol. Based on these data, we propose a tentative mechanism for 3betaHSD/D activity. This study provides, to our knowledge, the first data on the three-dimensional molecular interactions of an enzyme of the postoxidosqualene cyclase sterol biosynthesis pathway with its substrate. The implications of our findings for studying the roles of C4-alkylated sterol precursors in plant development are discussed.


Mal/SRF is dispensable for cell proliferation in Drosophila.
The Mal/SRF transcription factor is regulated by the level of G-actin in cells and has important roles in cell migration and other actin-dependent processes in Drosophila. A recent report suggests that Mal/SRF and an upstream regulator, Pico, are required for cell proliferation and tissue growth in Drosophila. I find otherwise. Mutation of Mal or SRF does not affect cell proliferation in the fly wing. Furthermore, I cannot reproduce the reported effects of Pico RNAi or Pico overexpression on body size. Nevertheless, I can confirm that overexpression of Pico or Mal causes tissue overgrowth specifically in the fly wing--where SRF is most highly expressed. My results indicate that Mal/SRF can promote tissue growth when abnormally active, but is not normally required for tissue growth during development.


Effectiveness of Ustekinumab Dose Escalation in Patients With Crohn's Disease.
A subset of patients with Crohn's disease (CD) do not respond to ustekinumab at the standard dose of 90 mg every 8 weeks. Little is known about the efficacy of shortening the interval between doses. We performed a retrospective study to determine the effectiveness of ustekinumab dose interval shortening, collecting data from 506 patients with CD who received subcutaneous ustekinumab 90 mg every 8 weeks at a single center. We obtained data from 110 patients who initially received subcutaneous ustekinumab 90 mg every 8 weeks and then had their interval shortened to every 4 weeks. Harvey Bradshaw Index (HBI) scores before and after the dose interval shortening was available for 78 patients in the cohort (71%), levels of C-reactive protein (CRP) for 60 patients (55%), and levels of fecal calprotectin for 8 patients (7%). Following dose interval shortening, the patients' median HBI decreased from 4.5 to 3 (P = .002), the median level of CRP decreased from 8 mg/L to 3 mg/L (P = .031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g (P = .57). Among patients who had an HBI >4, a level of CRP ≥5mg/dL, a level of fecal calprotectin >250ug/g, or endoscopic evidence for disease activity before dose interval shortening, after the dose interval was shortened, 28% achieved clinical remission (an HBI score ≤4), 22% had a normal level of CRP (<5 mg/dL), 50% had reduced levels of fecal calprotectin, and 36% achieved endoscopic remission. Shortening the ustekinumab 90 mg dose interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks improved clinical and biological indices of disease activity. Patients who lose response to the standard dose of ustekinumab might benefit from dose interval shortening, which was effective and safe.


Characteristics of growth inhibition of Lactobacillus casei by 4-nitroquinoline-n-oxide.
The bacteriostatic action of 4-nitroquinoline-n-oxide (4-NQO) for Lactobacillus casei is substantially reversed by d-and l-cysteine, glutathione, and 2,2-dihydroxy-1,4-dithiolbutane (dithioerythritol). The action appears to involve a chemical reaction between carbon atom 4 of 4-NQO and nucleophilic centers, such as -SH groups, located on essential cell constituents. The evidence presented indicates that the protective effect of d- and l-cysteine, glutathione, and dithioerythritol against the action involves reactions between 4-NQO and -SH compounds.


In Vitro Studies on the Antioxidant Property and Inhibition of α-Amylase, α-Glucosidase, and Angiotensin I-Converting Enzyme by Polyphenol-Rich Extracts from Cocoa (Theobroma cacao) Bean.
Background. This study sought to investigate the antidiabetic and antihypertensive mechanisms of cocoa (Theobroma cacao) bean through inhibition of α-amylase, α-glucosidase, angiotensin-1 converting enzyme, and oxidative stress. Methodology. The total phenol and flavonoid contents of the water extractable phytochemicals from the powdered cocoa bean were determined and the effects of the extract on α-amylase, α-glucosidase, and angiotensin-1 converting enzyme activities were investigated in vitro. Furthermore, the radicals [1,1-diphenyl-2 picrylhydrazyl (DPPH), 2,2..-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), hydroxyl (OH), and nitric oxide (NO)] scavenging ability and ferric reducing antioxidant property of the extract were assessed. Results. The results revealed that the extract inhibited α-amylase (1.81 ± 0.22 mg/mL), α-glucosidase (1.84 ± 0.17 mg/mL), and angiotensin-1 converting enzyme (0.674 ± 0.06 mg/mL [lungs], 1.006 ± 0.08 mg/mL [heart]) activities in a dose-dependent manner and also showed dose-dependent radicals [DPPH (16.94 ± 1.34 mg/mL), NO (6.98 ± 0.886 mg/mL), OH (3.72 ± 0.26 mg/mL), and ABTS (15.7 ± 1.06 mmol/TEAC·g] scavenging ability. Conclusion. The inhibition of α-amylase, α-glucosidase, and angiotensin-1 converting enzyme activities by the cocoa bean extract could be part of the possible mechanism by which the extract could manage and/or prevent type-2 diabetes and hypertension.


Seasonal Ely Copper Mine Superfund site shotgun metagenomic and metatranscriptomic data analysis.
High throughput sequencing data collected from acid rock drainage (ARD) communities can reveal the active taxonomic and functional diversity of these extreme environments, which can be exploited for bioremediation, pharmaceutical, and industrial applications. Here, we report a seasonal comparison of a microbiome and transcriptome in Ely Brook (EB-90M), a confluence of clean water and upstream tributaries that drains the Ely Copper Mine Superfund site in Vershire, VT, USA. Nucleic acids were extracted from EB-90M water and sediment followed by shotgun sequencing using the Illumina NextSeq platform. Approximately 575,933 contigs with a total length of 1.54 Gbp were generated. Contigs of at least a size of 3264 (N50) or greater represented 50% of the sequences and the longest contig was 488,568 bp in length. Using Centrifuge against the NCBI "nt" database 141 phyla, including candidate phyla, were detected. Roughly 380,000 contigs were assembled and ∼1,000,000 DNA and ∼550,000 cDNA sequences were identified and functionally annotated using the Prokka pipeline. Most expressed KEGG-annotated microbial genes were involved in amino acid metabolism and several KEGG pathways were differentially expressed between seasons. Biosynthetic gene clusters involved in secondary metabolism as well as metal- and antibiotic-resistance genes were annotated, some of which were differentially expressed, colocalized, and coexpressed. These data can be used to show how ecological stimuli, such as seasonal variations and metal concentrations, affect the ARD microbiome and select taxa to produce novel natural products. The data reported herein is supporting information for the research article "Characterization of an acid rock drainage microbiome and transcriptome at the Ely Copper Mine Superfund site" by Giddings et al. [1].


Inherited biochemical defects affecting the kidney.
The identification of a disease entity as one that is the result of a heritable defect offers the physician an opportunity to intervene in a variety of ways. As emphasized, knowledge of the heritable pattern of a particular disease allows the physician an opportunity to counsel family members in personal disease risk and the offspring. Such genetic counseling results in a reduction of affected cases for many inherited diseases. There is every expectation that similar approaches would be effective for inherited renal diseases. The heritable diseases are a favored group for investigative purposes since these diseases result from a single gene defect no matter how plieotropic the effects of that defect. Thus the investigator is capable of constant probing with tools available for identifying that one event or component that lies at the basis of the disease. The emphasis of this chapter is on those inherited renal diseases for which we have reached a high level of understanding of this single defect. In many of these diseases a single enzyme is identified as deficient and is the presumed genetic defect. In others (cystinuria, RTA, and cystinosis) the precise biochemical answers appear close at hand. Thus a variety of therapeutic approaches to overcome either the gene defect or ill effects of the gene defect emerge for diseases involving the kidney and are listed in Table 7. For some of these diseases the new diagnostic technique of prenatal diagnosis can be used (Table 8). This genetic option provides couples at risk for bearing affected offspring with reduced risk. For a number of other diseases that are not identified by amniocentesis, this risk can be effectively lowered to acceptable levels by use of artificial insemination. Thus the inherited diseases of the kidney are amenable to medical intervention at a variety of levels. Such intervention can predictably lead to a lowering of both the incidence and consequences of these gene defects.


Left hepatectomy in a patient with a Fontan circulation.
Patients with a Fontan circulation face the long term risk of cardiac cirrhosis and the subsequent development of hepatocellular carcinoma (HCC). A hepatectomy operation imposes significant risk on such patients as the Fontan circulation can be severely compromised. Here we present a 24-year-old woman post-Fontan operation who successfully underwent a left hepatectomy, and discuss the anaesthetic and surgical management.


Allopatric genetic origins for sympatric host-plant shifts and race formation in Rhagoletis.
Tephritid fruit flies belonging to the Rhagoletis pomonella sibling species complex are controversial because they have been proposed to diverge in sympatry (in the absence of geographic isolation) by shifting and adapting to new host plants. Here, we report evidence suggesting a surprising source of genetic variation contributing to sympatric host shifts for these flies. From DNA sequence data for three nuclear loci and mtDNA, we infer that an ancestral, hawthorn-infesting R. pomonella population became geographically subdivided into Mexican and North American isolates approximately 1.57 million years ago. Episodes of gene flow from Mexico subsequently infused the North American population with inversion polymorphism affecting key diapause traits, forming adaptive clines. Sometime later (perhaps +/-1 million years), diapause variation in the latitudinal clines appears to have aided North American flies in adapting to a variety of plants with differing fruiting times, helping to spawn several new taxa. Thus, important raw genetic material facilitating the adaptive radiation of R. pomonella originated in a different time and place than the proximate ecological host shifts triggering sympatric divergence.


Effect of feeding piglets with different extruded and nonextruded cereals on the gut mucosa and microbiota during the first postweaning week.
Two trials were conducted to evaluate the effect of different cereals in piglet diets on the jejunal mucosa and the ileal and cecal microbiota during the first postweaning days. In Trial 1, 48 newly weaned pigs (7.95 kg BW; 26 d of age) were individually housed and distributed among 3 experimental diets containing white rice (Oryza sativa), naked oats (Avena sativa), or barley (Hordeum vulgare) as the cereal source. At the start of the trial (weaning; day 0), 12 piglets were slaughtered and sampled to obtain initial reference values for histology and microbiology determinations. Additionally, 4 pigs per treatment per day were slaughtered and sampled at days 1, 2, and 6 postweaning. Villus height (VH), crypt depth (CD), and intraepithelial lymphocytes (IEL) in jejunal mucosa were measured, and microbiota in ileal and cecal digesta were evaluated by RFLP. The Manhattan distances between RFLP profiles were calculated and, for each treatment and sampling day, intragroup similarities (IGS) were estimated. In Trial 2, an additional 48 piglets were used (7.56 kg BW; 26 d of age), and the same experimental procedures were performed except that the 3 experimental diets contained extruded white rice, extruded naked oats, or extruded barley as the cereal source. A reduction in VH was observed in both trials from day 0 to 6 (P < 0.05). In Trial 1 (raw cereals), more IEL and deeper crypts were observed for the barley than for the naked oats based diets (P < 0.05). In Trial 2, no differences among extruded cereals were observed for the histological parameters. In Trial 1, feeding naked oats resulted in lower IGS (increased heterogeneity) of the microbiota in the ileum and in the cecum compared to rice and barley (P < 0.05). In Trial 2, the pigs fed extruded barley had lower IGS in the ileum than those fed extruded naked oats and extruded rice whereas in the cecum, both extruded barley and extruded rice resulted in lower IGS than extruded naked oats (P < 0.05). It is concluded that cereal nature affects the composition of the microbiota and the morphology of the gut mucosa in newly weaned pigs.