Medical Students Show Lower Physical Activity Levels and Higher Anxiety Than Physical Education Students: A Cross-Sectional Study During the COVID-19 Pandemic.
Objective: This study aimed to compare the time in physical activity (PA) [light (LPA), moderate and vigorous (MVPA)] and sedentary behavior (SB) (weekdays, weekends, or both) between Medical (MED) and Physical Education (PE) students who underwent remote classes imposed by the COVID-19. In addition, we compared symptoms of depression and anxiety and sleep quality. Methods: A cross-sectional study (272 MED and 95 PE students). The International Physical Activity Questionnaire (IPAQ), Beck Inventory (Anxiety, Depression), and Pittsburgh Sleep Quality were used to assess PA and SB, anxiety and depression symptoms, and quality of sleep, respectively. The data are presented as median and interquartile intervals 25-75. Results: We observed statistically significant differences between MED and PE students for MVPA [MED: 165 min per week (0-360) vs. PE: 420 min per week (180-670), p < 0.001], SB Total [MED: 10 h per day (8-12) vs. PE: 7 h per day (5-10), p < 0.001)], and anxiety symptoms [MED: 13 points (5-23) vs. PE: six points (2-16), p < 0.001)]. Conclusion: Together, our findings indicate that MED students spent less time in MVPA and more time in SB than PE students. MED students also presented worse mental health in the pandemic situation imposed by the COVID-19.


The mitochondrial genomes of ladybird beetles and implications for evolution and phylogeny.
Ladybirds formed the most familiar beetle group, namely the family Coccinellidae, whose internal relationships remain unclear. In particular, the subfamily relationships could not be well resolved in previous studies based on the conventional nuclear and/or mitochondrial gene fragments. In this study, we used next-generation sequencing to obtain new mitochondrial genomes (mitogenomes) from 13 species representing four coccinellid subfamilies (i.e., Coccinellinae, Epilachninae, Coccidulinae and Chilocorinae). Together with 24 existing mitogenome sequences of Cucujoidea, we conducted phylogenetic analyses to investigate the deep phylogenetic relationships in Coccinellidae, under maximum likelihood and Bayesian inference criteria. The analyses from nucleotide datasets resulted in a largely identical tree topology, where Epilachninae and Coccinellinae were monophyletic groups. The Scymninae and Coccidulinae were recovered as non-monophyletic. Amino acids differed from nucleotides in that the Epilachninae was retrieved as paraphyletic, with respect to Epilachna admirabilis. Ancestral state reconstruction suggested that the plant eating ladybird beetles arose within an aphidophagous/coccidophagous clade. In addition, three independent shifts toward coccidophagy and one shift toward mycophagy occurred in Coccinellidae.


Recessive X-linked ichthyosis: lack of immunologically detectable steroid sulfatase enzyme protein.
Patients with recessive X-linked ichthyosis (RXLI), one hereditary form of scaly skin, lack activity of the enzyme steroid sulfatase in all tissues studied. To investigate the molecular defect underlying the lack of enzyme activity, we prepared antisera against normal enzyme by injecting normal placental microsomal suspensions or partially purified steroid sulfatase into rabbits. Antibody activity was assessed by immunoprecipitation of detergent solubilized steroid sulfatase. In addition, we prepared rabbit antisera against RXLI placental microsomal suspensions. To detect immunologically cross-reactive material in patients' placentas, extracts were studied by immunoblot techniques and by competition with normal enzyme for antibody binding. Patients' extracts did not contain immunoreactive material co-migrating on electrophoresis with purified enzyme nor did they inhibit immunoprecipitation of normal enzyme. Sera from rabbits immunized with RXLI placental microsomes contain no antibodies to normal steroid sulfatase, as judged by their failure to immunoprecipitate normal enzyme or to react with normal steroid sulfatase on immunoblot. Thus the mutation in RXLI appears to reduce steroid sulfatase enzyme protein as well as enzyme activity.


Hemispheric specialization in the detection of subjective objects.
Three experiments were conducted to examine hemispheric specialization for the detection of subjective objects. In the first two experiments, observers searched for the presence of a square defined by subjective contours. The first experiment demonstrated that the left hemisphere made more errors for detecting these objects. The second experiment showed that the increased errors were due to the left hemisphere responding to the individual features of the objects and not the objects as a whole. In the second experiment, the right hemisphere was also faster for detecting the absence of a subjective object. A third experiment was conducted to determine if performance for the right hemisphere was due to object level processing. It was shown that the right hemisphere only makes illusory conjunctions for features within perceptual groups while the left hemisphere makes illusory conjunctions both within and across perceptual groups, providing converging evidence for object level processing in the right hemisphere. The results suggest that the right hemisphere conjoins feature information for the perception of objects.


Hierarchical and parallel mechanisms in the organization of visual cortex.
We argue that it seems fruitful to regard the retino-geniculate-cortical pathway, and perhaps the visual pathways in general, as comprising distinct neuronal channels which begin with the major groupings of ganglion cells, and subserve distinct functions within the overall operation of the visual system. One problem for future work is to determine the extent and, equally importantly, the limitations of the idea of independently functioning neuronal channels operating within the visual system. Some evidence of those limitations is already available. Kulikowski and Tolhurst have provided evidence suggesting that pattern detection is mediated by the X-like system at high spatial frequencies and by the Y-like system at low frequencies, but that at intermediate frequencies, both systems are likely to contribute to this function. Again, there is already physiological and psychophysical evidence of inhibitory interaction between X- and Y-cell systems, which may contribute to their functioning. That is, although there is little evidence of excitatory interaction between W-, X- and Y-cell systems, at least up to the first cortical synapse, the functioning of, say, the X-cell system may depend on the inhibitory influences impinging on it from Y-cell activity. Further, it may prove to be the case that one cell 'system' may be involved in several distinct functions and considerable work may be required to establish whether or not these functions can be considered constituent parts of an overall function, such as 'ambient' or 'foveal' vision. In the following section we suggest a classification and terminology for visual neurones which may provide a framework for future work on these lines.


Effects of CGP 11305 A, a new reversible and selective inhibitor of MAO A, on biogenic amine levels and metabolism in the rat brain.
CGP 11305 A [4-(5-methoxy-7-bromo-benzofuranyl-2)piperidine HCl), a reversible, selective inhibitor of MAO A, increased the levels of rat brain noradrenaline, dopamine, and serotonin dose-dependently and to approximately the same extent. Concomitantly, it lowered the levels of their metabolites, MHPG-SO4, HVA, DOPAC, and 5-HIAA. When compared with the irreversible MAO A inhibitor clorgyline, the effects of CGP 11305 A were of much shorter duration. Moreover, the increases of noradrenaline and serotonin and the decreases of their metabolites MHPG-SO4 and 5-HIAA were smaller after CGP 11305 A than after clorgyline in equieffective doses for MAO A inhibition. CGP 11305 A decreased the synthesis of catecholamines and serotonin less markedly than clorgyline. This is probably due to the reversibility of the interaction of the compound with MAO A. In contrast to CGP 11305 A, clorgyline increased the level of dopamine less than those of noradrenaline and serotonin. This is explained by assuming that dopamine synthesis is particularly sensitive to end product inhibition. CGP 11305 A also exhibited some inhibitory properties on the uptake of serotonin and, to a lesser degree, of noradrenaline in vitro and in vivo. Compared with MAO inhibition, however, uptake inhibition required 30-100 times higher doses.


Primary bone grafting does not improve the results in severely displaced distal radius fractures.
We prospectively randomised 45 patients ages 20-70 years with distal radius fractures of Older type III and IV to one of two treatment groups. One group was treated with closed reduction, primary bone grafting, and external fixation for 3 weeks, followed by a plaster cast that allowed volar flexion, for an additional 3 weeks. The other group was treated with closed reduction and external fixation for 6 weeks. The functional and radiographic results were evaluated. There was no difference between the two groups in either clinical or radiographic outcome. We do not recommend external fixation and primary bone grafting as a routine method in these fractures.


Comparative efficacy of alternative primary therapies for Plasmodium falciparum infections in Malawi.
In Malawi, where high levels of chloroquine resistance were shown using a modified 7-day in vivo test, amodiaquine and pyrimethamine-sulfadoxine were evaluated as alternative initial therapies for Plasmodium falciparum infections in children under 5 years old. Therapy success rates, judged by parasite clearance by day 7 after initiation of therapy, were significantly greater among 39 children treated with amodiaquine at 10 mg/kg (90%), 37 receiving amodiaquine at 25 mg/kg (97%), and 34 receiving pyrimethamine-sulfadoxine (100%) at a dose of 25 mg sulfadoxine/kg, than among those treated with chloroquine at a dose of 25 mg/kg (59%) (P = 0.01). Extension of the follow-up period of those receiving amodiaquine (25 mg/kg) and pyrimethamine-sulfadoxine to 21 d revealed a progressively increasing rate of parasite recrudescence in the amodiaquine group (34%), but no recrudescence in the pyrimethamine-sulfadoxine group. These results suggest that, in Malawi, amodiaquine and pyrimethamine-sulfadoxine are superior to chloroquine in producing prompt clearance of P. falciparum parasites among young children, and that pyrimethamine-sulfadoxine alone is superior to the 4-aminoquinolines in sustaining P. falciparum clearance.


Disposing of the self: the role of attachment in the disposition process.
It is well established that individuals have strong attachment to many possessions, but they cannot keep all these possessions forever. Disposition has received relatively limited attention in the literature though it is clear that disposition is significantly influenced by attachment. We review the burgeoning number of studies examining how possession attachment influences disposition. Attachment is influential at each stage of the disposition process, from the decision to stop using an object, the decision to dispose of an object, and the choice of disposal type. We end with a call for further research on disposal, particularly that which considers the role of object attachment at earlier stages of the disposition process.


The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism.
The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions in some types of stem cell, but its role in hematopoietic stem cells (HSCs) is unknown. Here, we show that the Dlk1-Gtl2 locus plays a critical role in preserving long-term repopulating HSCs (LT-HSCs). Through transcriptome profiling in 17 hematopoietic cell types, we found that ncRNAs expressed from the Dlk1-Gtl2 locus are predominantly enriched in fetal liver HSCs and the adult LT-HSC population and sustain long-term HSC functionality. Mechanistically, the miRNA mega-cluster within the Dlk1-Gtl2 locus suppresses the entire PI3K-mTOR pathway. This regulation in turn inhibits mitochondrial biogenesis and metabolic activity and protects LT-HSCs from excessive reactive oxygen species (ROS) production. Our data therefore show that the imprinted Dlk1-Gtl2 locus preserves LT-HSC function by restricting mitochondrial metabolism.


History of opioid use as a risk factor for current use and mental health consequences among retired National Football League athletes: A 9-year follow-up investigation.
Many retired National Football League (NFL) athletes manage pain with opioids during their playing careers and in retirement, though the longitudinal association between opioid use and health outcomes pertinent to an NFL career are not yet known. This study aimed to assess the relationship between opioid use in 2010 and current use, depressive symptoms, and health related quality of life (HRQoL) among NFL retirees. Former NFL athletes from the Retired NFL Players Association initially recruited in 2010 for a study examining risk factors of opioid use and misuse were re-contacted (N = 89) from 2018 to 2019 and administered measures of pain, opioid use, depressive symptoms, and HRQoL. Binomial regression examined the association between 2010 opioid use with current use, moderate-severe depressive symptoms, and average and above HRQoL (physical and mental) while controlling for covariates. Nearly 50 % of retirees using opioids in 2010 currently used. Compared to non-users, retirees who used opioids in 2010 had greater odds of current use (AOR: 3.71, 95 % CI: 1.02-13.56, p = 0.046) and experiencing moderate-severe depressive symptoms (AOR: 5.93, 95 % CI: 1.15-30.54, p = 0.033). Retirees reporting use in 2010 also evidenced lower odds of reporting average or above mental HRQoL (AOR: 0.13, 95 % CI: 0.03-0.67, p = 0.015) compared to non-users. This study showed that among NFL retirees, early retirement opioid use predicted current use and deleterious effects on mental health, including moderate-severe depressive symptoms approximately nine years later. This investigation further supports the importance of early intervention of pain and opioid use among this population.


High throughput screen of small molecules as potential countermeasures to galactic cosmic radiation induced cellular dysfunction.
Space travel increases galactic cosmic ray exposure to flight crews and this is significantly elevated once travel moves beyond low Earth orbit. This includes combinations of high energy protons and heavy ions such as 56Fe or 16O. There are distinct differences in the biological response to low-energy transfer (x-rays) or high-energy transfer (High-LET). However, given the relatively low fluence rate of exposure during flight operations, it might be possible to manage these deleterious effects using small molecules currently available. Virtually all reports to date examining small molecule management of radiation exposure are based on low-LET challenges. To that end an FDA approved drug library (725 drugs) was used to perform a high throughput screen of cultured cells following exposure to galactic cosmic radiation. The H9c2 myoblasts, ES-D3 pluripotent cells, and Hy926 endothelial cell lines were exposed to a single exposure (75 cGy) using the 5-ion GCRsim protocol developed at the NASA Space Radiation Laboratory (NSRL). Following GCR exposure cells were maintained for up to two weeks. For each drug (@10µM), a hierarchical cumulative score was developed incorporating measures of mitochondrial and cellular function, oxidant stress and cell senescence. The top 160 scores were retested following a similar protocol using 1µM of each drug. Within the 160 drugs, 33 are considered to have an anti-inflammatory capacity, while others also indirectly suppressed pro-inflammatory pathways or had noted antioxidant capacity. Lead candidates came from different drug classes that included angiotensin converting enzyme inhibitors or AT1 antagonists, COX2 inhibitors, as well as drugs mediated by histamine receptors. Surprisingly, different classes of anti-diabetic medications were observed to be useful including sulfonylureas and metformin. Using a hierarchical decision structure, we have identified several lead candidates. That no one drug or even drug class was completely successful across all parameters tested suggests the complexity of managing the consequences of galactic cosmic radiation exposure.


Suppressive effect of TNF-alpha and IL-1 on alveolar fibroblast proliferation in sarcoidosis.
The nature of soluble factors that regulate fibroblast proliferation have not been finally characterized. Our aim was to study the role of tumour necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) in the suppressive activity of alveolar macrophages on autologous lung fibroblasts proliferation in sarcoidosis. We found that supernatants recovered from alveolar macrophages suppressed the proliferation of alveolar fibroblast in sarcoidosis by 35.5 +/- 1.13% compared to 3 +/- 16% in controls (p < 0.001 between the two groups). This suppression correlated with high content of TNF-alpha and IL-1 in sarcoidosis patients stage II-III (7.7 +/- 2.9 ng/ml TNF-alpha and 157 +/- 53 U/ml IL-1 compared to 3.4 +/- 2.4 ng/ml TNF-alpha and 43 U/ml IL-1 in controls; p < 0.01 and p < 0.001, respectively). Both cytokines in sarcoidosis stage I were within the normal ranges. Exogenous TNF-alpha (1000-0.5 ng/ml) and IL-1 (500-0.24 ng/ml) had an additive suppressive activity on fibroblast proliferation which was partially reversed by indomethacin.


Safety considerations during cardiac and pulmonary rehabilitation program.
As more and more patients with cardiac and pulmonary diseases are living longer lives, the need for cardio-pulmonary rehabilitation continues to grow. The goal of this article is to provide clinicians of rehabilitation medicine with an overview of the safety concerns and strategies to implement in the rehabilitation of patients with cardiac and/or pulmonary disorder.


Dual Targeting of v-ATPase and mTORC1 Signaling Disarms Multidrug-Resistant Cancers.
Chemotherapeutic treatments are frequently impeded by the development of multidrug resistance (MDR). In this issue of Cell Chemical Biology, Wang et al. (2020) identify the natural product verucopeptin as having therapeutic potential toward MDR cancer cell types by targeting v-ATPase and mTORC1 signaling.


Photo-CIDNP MAS NMR beyond the T1 limit by fast cycles of polarization extinction and polarization generation.
In nanosecond-laser flash photo-CIDNP MAS NMR, polarization generation (PG) proceeds much faster than longitudinal spin relaxation. With a nanosecond-laser setup linked to the NMR console the repetition time of the experiment is then limited by the minimum recycle delay of the NMR spectrometer and the maximum repetition rate of laser flashes. These limits can only be reached if polarization left after the NMR experiment is completely canceled before the next laser flash. We introduce a presaturation pulse sequence, based on three (pi/2) (13)C pulses and optimized timing and phase cycling that allows for such efficient polarization extinction (PE). The technique is demonstrated on selectively isotope labeled bacterial reaction centers (RCs) of Rhodobacter (Rb.) sphaeroides wildtype (WT). High-quality (13)C photo-CIDNP MAS NMR spectra are obtained using cycle rates up to 4 Hz. The PE-PG strategy proposed here provides a general experimental scheme for reduction of measurement time in magnetic resonance experiments based on fast PG.


Qualitative assessment of programmatic constraints in delivery of effective interventions for improving maternal nutrition in Bangladesh.
Maternal undernutrition is highly prevalent in most of the developing countries. Prevalence of both extremes of maternal malnutrition (undernutrition and overweight/obesity) are common in those countries. For Bangladesh, the scenario is not different. The Government of Bangladesh recognises maternal nutrition as a public health priority and addresses the issue in its policies and programmes. We identified and analysed the existing maternal nutrition programmes and determined the bottlenecks in implementing the programmes in Bangladesh using qualitative approach. We followed a qualitative research approach and conducted 25 key informant interviews with the programme managers and policymakers, 10 in-depth interviews with the service providers and six focus group discussions with the pregnant women to identify the constraints of programme implementation. We analysed data using thematic and inductive approaches of qualitative research methods. We have found that successful implementation of maternal nutrition intervention was being hampered by both the demand and supply side issues. On the demand side, major constraints were financial inability of the families to avail maternal nutrition-related services, ignorance of the family members and cultural barriers of using maternal nutrition-related services. Lack of priority and heavy workload of the service providers, lack of human resources, poor monitoring system, lack of medicine to supply and incoordination have been identified as major supply-side constraints in providing maternal nutrition-related interventions in Bangladesh. Both supply side and demand side issues are responsible for the existing bottlenecks in implementing maternal nutrition-related programmes in Bangladesh. Findings of this study will help the policymakers to learn about the programmatic constraints regarding maternal nutrition services in Bangladesh.


Nitric oxide applications prior and simultaneous to potentially excitotoxic NMDA-evoked calcium transients: cell death or survival.
Nitric oxide (NO) is a molecule that plays a prominent role in neurotoxic as well as neuroprotective pathways. Here, we investigated the effects of NO on potentially excitotoxic glutamate-induced intracellular calcium ([Ca2+]i) dynamics. Our hypothesis was that pre- and coexposure to NO in conjunction with glutamate receptor stimulation modulates [Ca2+]i responses differentially. [Ca2+]i transients, assessed by the fluorescent cytosolic Ca2+ indicator dye fluo-4, were elicited in mouse striatal neurons by consecutive NMDA applications (200 microM for 100 s each). Subgroups of neuronal cultures were additionally exposed to a NO donor (S-nitroso-N-acetyl-d,l-penicillamine, SNAP, 50-500 microM), either by pre- (for 6 h prior to NMDA) or cotreatment (for 30 min during NMDA). Pretreatment with NO led to dramatically decreased NMDA-evoked [Ca2+]i rises in comparison to controls (NMDA alone). Annexin V/propidium iodide staining showed consistently that NO pretreatment is protective against NMDA-induced cell death. In contrast, NO/NMDA cotreatment caused a potentiation of [Ca2+]i rises, whereby the duration of [Ca2+]i transients following NMDA application was prolonged and remained at an increased plateau level. Simultaneous application of the mitochondrial permeability transition pore (mtPTP) blocker cyclosporin A (2 microM) during the NO/NMDA cotreatment prevented the deregulation of [Ca2+]i. The observed [Ca2+]i deregulation was accompanied by a decrease in the mitochondrial membrane potential as indicated by tetramethylrhodamine methylester (TMRM) fluorescence. These findings suggest that NO can act in a protective way due to preconditioning or can have a possibly detrimental impact in case of acute release. They provide a possible explanation for the ambivalence of NO in neurodegenerative processes where glutamate receptor stimulation and mitochondrial [Ca2+]i sequestration are causally involved.


Light-induced atomic desorption in a compact system for ultracold atoms.
In recent years, light-induced atomic desorption (LIAD) of alkali atoms from the inner surface of a vacuum chamber has been employed in cold atom experiments for the purpose of modulating the alkali background vapour. This is beneficial because larger trapped atom samples can be loaded from vapour at higher pressure, after which the pressure is reduced to increase the lifetime of the sample. We present an analysis, based on the case of rubidium atoms adsorbed on pyrex, of various aspects of LIAD that are useful for this application. Firstly, we study the intensity dependence of LIAD by fitting the experimental data with a rate-equation model, from which we extract a correct prediction for the increase in trapped atom number. Following this, we quantify a figure of merit for the utility of LIAD in cold atom experiments and we show how it can be optimised for realistic experimental parameters.


On the Role of a Conserved Tryptophan in the Chromophore Pocket of Cyanobacteriochrome.
The cyanobacteriochrome Slr1393 can be photoconverted between a red (Pr) and green absorbing form (Pg). The recently determined crystal structures of both states suggest a major movement of Trp496 from a stacking interaction with ring D of the phycocyanobilin (PCB) chromophore in Pr to a position outside the chromophore pocket in Pg. Here, we investigated the role of this amino acid during photoconversion in solution using engineered protein variants in which Trp496 was substituted by natural and non-natural amino acids. These variants and the native protein were studied by various spectroscopic techniques (UV-vis absorption, fluorescence, IR, NIR and UV resonance Raman) complemented by theoretical approaches. Trp496 is shown to affect the electronic transition of PCB and to be essential for the thermal equilibrium between Pr and an intermediate state O600. However, Trp496 is not required to stabilize the tilted orientation of ring D in Pr, and does not play a role in the secondary structure changes of Slr1393 during the Pr/Pg transition. The present results confirm the re-orientation of Trp496 upon Pr → Pg conversion, but do not provide evidence of a major change in the microenvironment of this residue. Structural models indicate the penetration of water molecules into the chromophore pocket in both Pr and Pg states and thus water-Trp contacts, which can readily account for the subtle spectral changes between Pr and Pg. Thus, we conclude that reorientation of Trp496 during the Pr-to-Pg photoconversion in solution is not associated with a major change in the dielectric environment in the two states.


CYP1A1 modifies the effect of maternal exposure to environmental tobacco smoke on child behavior.
Maternal environmental tobacco smoke (ETS) has been identified as a key risk factor for problem behavior in children, but the role of genetic susceptibility is not clear. The purpose of this study was to examine the metabolic genetic modification effect of exposure to ETS in nonsmoking mothers on child behavior at 2 years of age. A prospective cohort study was conducted among 191 mothers who gave births between 2004 and 2005 and their infants in Taiwan. The mothers completed a questionnaire before delivery in which they provided information on exposure to ETS during pregnancy. Four metabolic genes, CYP1A1 MspI, CYP1A1 Ile462Val, GSTT1, and GSTM1 were isolated from both maternal and infant DNA samples. Children's behavior problems at 2 years of age were reported by their mothers using the Child Behavior Checklist/1.5-5. Multiple linear models were used to estimate the effects of ETS and genotype on child behavior. Maternal ETS exposure was associated with the anxious score. The ETS-exposed group with both the CYP1A1 MspI and the CYP1A1 Ile462Val variants had higher scores, as reflected in total CBCL score as well as scores on the internalizing scale and its emotional subdomain, the anxious scale, and the externalizing scale and its aggressive subdomain. Child behavioral problems may be associated with prenatal ETS exposure, and this effect may be modified by infant CYP1A1 MspI and CYP1A1 Ile462Val genes.


Hairy cell leukemia.
Hairy cell leukemia is a malignancy with a variable course that can be relatively indolent or rapidly fatal. Alterations in the immune system are responsible for much of the morbidity and mortality from hairy cell leukemia. More than 60% of patients die from infection, and infections are both pyogenic and nonpyogenic. Many patients have transfusion requirements, and bleeding complications can also occur. Treatment strategies for hairy cell leukemia have evolved and are being modified as more is learned about the disease. Splenectomy is the initial treatment when patients become symptomatic, and if the disease progresses after splenectomy, chlorambucil offers good control in many patients. Radiation can be used for local palliation, as when complications such as bulky adenopathy or bone lesions occur. Initial studies using interferon in the treatment of hairy cell leukemia look encouraging, but more investigation is necessary before the role of interferon in treatment of hairy cell leukemia is determined.


Experimental infection of domestic pigeons with pigeon circovirus.
Pigeon circovirus (PiCV) infection and young pigeon disease syndrome (YPDS), associated with high morbidity and mortality, have been recognized in young racing pigeons from large portions of Central Europe. There exist a number of data indicating that YPDS is a consequence of PiCV infection and subsequent immunosuppression. In order to prove PiCV to be one of the crucial factors of YPDS, an experimental infection with PiCV was performed under controlled conditions. Twenty-four domestic pigeons (Columba livia forma domestica) were divided into two groups with 12 pigeons each; an infection group and a control group. All birds were between their fourth to eighth week of life. Pigeons in the infection group were infected both intramuscularly and orally with PiCV purified from naturally infected birds, while pigeons in the control group received a placebo. To test a possible influence of the PiCV infection on the immune system, the animals in both groups were vaccinated simultaneously, on the same day, against PMV-1 (Lasovac plus, IDT, Dessau-Tornau, Germany). Weekly virologic testing showed a viraemic period, and excretion of the infection virus, in pigeons in the infection group. Replication of PiCV could be proved on the basis of histologic findings of multiglobular inclusion bodies, mainly observed in macrophages of the bursa of Fabricius. A PiCV, genetically distinct from the experimental virus, was detected in the control group by polymerase chain reaction (PCR) testing, but any histologic findings comparable to the infection group were absent. None of the pigeons revealed clinical signs of illness, or hints that immunosuppression had occurred, regardless of their group. The absence of stressful conditions, considered as a trigger for the development of YPDS, may be responsible for the failure of disease reproduction in our infection model.


Real-world treatment patterns and clinical outcomes in patients receiving palbociclib combinations for HR+/HER2- advanced/metastatic breast cancer in Japan: Results from the IRIS study.
The incidence of breast cancer is rising in Japan, particularly in postmenopausal women. The CDK 4/6 inhibitor palbociclib has demonstrated efficacy in clinical studies in patients with hormone receptor-positive (HR+), human epidermal growth factor 2 (HER2)-negative advanced/metastatic breast cancer (ABC/MBC). The Ibrance Real World Insights (IRIS) study (NCT03159195) collected real-world data for palbociclib-treated patients in several countries including Japan, where such data are currently scarce. IRIS was a retrospective chart review study of patients with confirmed HR+/HER2- ABC/MBC receiving palbociclib according to approved indications in real-world clinical practice. In Japan, physicians each abstracted data from patient medical records for up to eight sequential patients treated with palbociclib plus an aromatase inhibitor (P+AI) or fulvestrant (P+F). Outcomes included progression-free rates (PFRs) and survival rates (SRs). Fifty-eight physicians abstracted data for 170 patients receiving palbociclib in the first (64.1%) or second or later line (35.9%), in combination with AI (51.2%) or fulvestrant (48.8%). Median follow-up was 10.4 months. Most patients were initiated on palbociclib 125 mg/d (P+AI, 63.2%; P+F, 78.3%). PFRs at 12 and 24 months were 76.2% and 52.6%, respectively, for P+AI and 71.6% and 65.6%, respectively for P+F. PFRs at 12 and 24 months were 85.4% and 66.5%, respectively, for first-line palbociclib combinations and 56.4% and 50.7%, respectively, for second- or later-line palbociclib combinations. In this analysis of the Japanese IRIS cohort, outcomes in terms of PFRs and SRs appear to be better with first- versus second or later-line palbociclib, regardless of the endocrine partner.


Complete molar pregnancy with coexisting normal twin complicated by hyperthyroidism that resulted in normal alive delivery: A case report from Wolaita Sodo, Ethiopia.
It is a rare condition in twin pregnancies for a fetus to coexist with a complete hydatidiform mole, present with complications, and result in a healthy neonate. Only a few cases have been reported upon review of the literature. Early diagnosis is essential because this type of pregnancy is associated with serious complications and management challenges. The complications associated with these pregnancies include antepartum hemorrhage, hyperthyroidism, preeclampsia, prematurity, fetal death, and gestational trophoblastic neoplasia. Here, we describe a case of dizygotic twin pregnancy in which a complete mole coexists with a normal fetus, complicated by hyperthyroidism, that resulted in the birth of a 1700-g female alive neonate who is euthyroid to a 25-year-old primigravida at a gestational age of 33 weeks by emergency cesarean section for an indication of a twin pregnancy molar coexisting with an alive fetus in labor. The mother had been on conservative management and treated as an inpatient for hyperthyroidism. In our country, there have been three case reports of partial moles with coexisting alive fetuses, but this is the first case report of a complete mole with a coexisting alive fetus.


Surgical treatment approach of cervicothoracic junction spinal tuberculosis in pediatric: A case report.
The cervicothoracic junction is prone to infection by tuberculosis bacteria, which leads to spinal instability. Meanwhile, cervicothoracic junction spinal tuberculosis is a disease that affects the C7 to T3 vertebral, and it accounts for 5% of all spinal tuberculosis cases. Surgical procedures of treating this disease vary, and the most commonly used method is the combined anterior and posterior approach. This case report presents the disease with uncommon location in pediatric, which is rarely reported, and performed with the single-stage posterior approach to treat the patient, which showed a good clinical and radiological result. A 15-years old girl with one-month history of progressive inferior paraplegia (within a month, her muscle strength went from score 5 to 0) initially complained of neck pain, gradual weakness of the lower extremities, and hypoesthesia below T4. The spine's MRI also showed a tuberculous spondylitis in the T1 to T3 vertebral and a huge paravertebral abscess at the C5 to T3 level. Subsequently, an adequate decompression, debridement, maintenance and reinforcement of stability as well as deformity correction were carried out using the single-stage posterior approach. The cervicothoracic junction spinal tuberculosis with huge paravertebral abscess makes surgical procedures difficult, specifically in pediatric patients. However, the single stage posterior approach produced a better clinical and radiological result with a short operation time. The selection of appropriate surgical approach management with good perioperative planning as well as effective medical management improved the patient's condition.


A review of the clinical evidence for exercise in osteoarthritis of the hip and knee.
Osteoarthritis (OA) is a chronic joint disease with the hip and knee being commonly affected lower limb sites. Osteoarthritis causes pain, stiffness, swelling, joint instability and muscle weakness, all of which can lead to impaired physical function and reduced quality of life. This review of evidence provides recommendations for exercise prescription in those with hip or knee OA. A narrative review was performed. Conservative non-pharmacological strategies, particularly exercise, are recommended by all clinical guidelines for the management of OA and meta-analyses support these exercise recommendations. Aerobic, strengthening, aquatic and Tai chi exercise are beneficial for improving pain and function in people with OA with benefits seen across the range of disease severities. The optimal exercise dosage is yet to be determined and an individualized approach to exercise prescription is required based on an assessment of impairments, patient preference, co-morbidities and accessibility. Maximising adherence is a key element dictating success of exercise therapy. This can be enhanced by the use of supervised exercise sessions (possibly in class format) in the initial exercise period followed by home exercises. Bringing patients back for intermittent consultations with the exercise practitioner, or attendance at "refresher" group exercise classes may also assist long-term adherence and improved patient outcomes. Few studies have evaluated the effects of exercise on structural disease progression and there is currently no evidence to show that exercise can be disease modifying. Exercise plays an important role in managing symptoms in those with hip and knee OA.


Assessing short-term impacts of PM2.5 constituents on cardiorespiratory hospitalizations: Multi-city evidence from China.
Apart from concentrations of particulate mass, PM2.5-associated effects on health may largely depend on its chemical components. However, little is known regarding the underlying effects of specific PM2.5 constituents. The study included nearly 1 million hospital admissions from five Chinese cities during 2015-2017. Based on the modified Community Multiscale Air Quality model, our study simulated daily concentrations of PM2.5 and five main components. We used a time-stratified case-crossover design with conditional logistic regression models to estimate short-term effects of PM2.5 constituents on cause-specific hospital admissions. Per interquartile range increase in exposure to PM2.5, elemental carbon, organic carbon, nitrate, sulfate and ammonium at lag 04-day was related to an excess risk (ER%) for non-accidental admissions of 1.6% [95% confidence interval: 1.1-2.0], 1.9% [1.3-2.4], 1.0% [0.5-1.6], 1.2% [0.4-2.0], 1.2% [0.9-1.5] and 1.4% [0.9-1.9], respectively. Great heterogeneities of constituents-admission associations existed in diverse causes and constituents. This study provided multi-center high-quality evidence that hospital admissions, particularly those for ischemic heart disease (ER% ranging from 2.3 to 5.4% at lag 04-day) and pneumonia (1.9-5.1% at lag 4-day), could be triggered by short-term exposures to ambient PM2.5 constituents. Relatively stronger constituents-admission associations were found among females for respiratory causes and the elderly for cardiovascular causes.


Accelerated Aggregation Studies of Monoclonal Antibodies: Considerations for Storage Stability.
Aggregation of mAbs is a crucial concern with respect to their safety and efficacy. Among the various properties of protein aggregates, it is emerging that their size can potentially impact their immunogenicity. Therefore, stability studies of antibody formulations should not only evaluate the rate of monomer loss but also determine the size distribution of the protein aggregates, which in turn depends on the aggregation mechanism. Here, we study the aggregation behavior of different formulations of 2 monoclonal immunoglobulins (IgGs) in the temperature range from 5°C to 50°C over 52 weeks of storage. We show that the aggregation kinetics of both antibodies follow non-Arrhenius behavior and that the aggregation mechanisms change between 40°C and 5°C, leading to different types of aggregates. Specifically, for a given monomer conversion, dimer formation dominates at low temperatures, while larger aggregates are formed at higher temperatures. We further show that the stability ranking of different molecules as well as of different formulations is drastically different at 40°C and 5°C while it correlates better between 30°C and 5°C. Our findings have implications for the level of information provided by accelerated aggregation studies with respect to protein stability under storage conditions.


Apoptotic modifications affect the autoreactivity of the U1 snRNP autoantigen.
A hallmark of systemic autoimmune diseases is the presence of high titers of serum autoantibodies targeting a diversity of autoantigens. Most components of the U1 snRNP complex are autoantigenic in systemic lupus erythematosus (SLE) and SLE overlap syndrome, which is also called mixed connective tissue disease (MCTD). It is hypothesized that posttranslational modifications, in particular cell death-associated modifications, play an important role in breaking tolerance to self-antigens. Recently, it became clear that the U1 snRNP particle, more specifically its U1-70K protein component, displays a new epitope during apoptosis. This review intends to give an overview of the modifications that occur on the U1 snRNP autoantigens, especially those arising during cell death, to summarize recent data describing autoantibody reactivities with apoptosis-specific epitopes on the U1 snRNP complex, and to provide some insight into the mechanisms that might underlie the immune response to self-antigens.


The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways.
Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.


Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization.
Although lymph node (LN) metastasis is an important prognostic parameter in cervical cancer, the tissue remodeling at a pre-metastatic state is poorly documented in LNs. We here identified periostin (POSTN) as a component of non-metastatic LNs by applying proteomic analyses and computerized image quantifications on LNs of patients with cervical cancer. We provide evidence for remarkable modifications of POSTN and lymphatic vessel distributions and densities in non-metastatic sentinel and metastatic human LNs, when compared to distant non-metastatic LNs. POSTN deposition at a pre-metastatic stage was demonstrated in a pre-clinical murine model (the ear sponge assay). Its expression by fibroblastic LN cells was assessed by in situ hybridization and in vitro cultures. In vitro, POSTN promoted lymphatic endothelial cell functions and tumor cell proliferation. Accordingly, the in vivo injection of recombinant POSTN together with VEGF-C boosted the lymphangiogenic response, while the metastatic potential of tumor cells was drastically reduced using a POSTN blocking antibody. This translational study also supports the existence of an unprecedented dialog "in cascade", between the primary tumor and the first pelvic nodal relay in early cervical cancer, and subsequently from pelvic LN to para-aortic LNs in locally advanced cervical cancers. Collectively, this work highlights the association of POSTN deposition with lymphangiogenesis in LNs, and provides evidence for a key contribution of POSTN in promoting VEGF-C driven lymphangiogenesis and the seeding of metastatic cells.


Hypofractionated radiation treatment in early breast cancer: Results in a New Zealand setting.
High-quality evidence supports that hypofractionated radiation treatment (HFRT) is as effective and safe in early breast cancer as conventionally fractionated radiation treatment. HFRT with fewer treatments has potential benefits for both patients and radiation departments. Despite this, concerns about local control and toxicity with HFRT persist, such that many eligible patients do not receive HFRT. The local recurrence rates and acute toxicity after HFRT was analyzed in our center in Christchurch, New Zealand. An audit was undertaken of all early breast cancer (T1-2 and N0-1) patients treated with HFRT from Jan 21, 2004, to December 31, 2006, dating from the adoption of HFRT in our department. Sixty-eight percent of the patients during this time received HFRT (274/402). Acute toxicity was prospectively recorded and local, regional and distant recurrences were documented. A total of 274 patients were analyzed with a median follow-up of 7 years (range 0.55-9.5 years). Eleven of 274 patients had local recurrence only. The local recurrence-free survival was 97.2% and 95.8% at 7 years. The skin, lethargy and breast pain acute toxicity was less than grade 3, except for one patient experiencing grade 3 breast pain. Low local recurrence rates and acceptably low acute toxicity were achieved in a local setting with HFRT, comparable to results achieved in large randomized controlled trials. HFRT is a valid option for eligible patients and its use should be encouraged.


Psychosis or temporal lobotomy: SPECT findings in a paraplegic patient with chronic mental illness.
To ascertain if single proton emission computerized tomography (SPECT) imaging involving a patient with a history of head trauma, paraplegia, and chronic mental illness, would provide useful information regarding diagnosis and treatment. A case report. SPECT data indicated a convexity of the temporal lobe; it was significantly crumpled inward in the location of the traumatic blow suffered 18 years earlier. The center of hypoperfusion suggested a complete disruption of connections between the temporal lobe and Broca's area, and a practically ablated left temporal area. The patient was reclassified with an organic psychosis and as an individual who might benefit more from medications to treat temporal lobe irritability rather than antipsychotic medications. Despite these findings and recommendations, psychiatric personnel discharged the patient without implementation. He is currently in critical condition following a suicide attempt.


[Prevalence of psychiatric disorders in men and women hospitalized in a internal medicine service of a hospital of Santiago, Chile].
Mental disorders may interfere, aggravate or mimic medical conditions. To study the prevalence of psychiatric disorders among patients hospitalized in a medical ward of a general hospital. A structured interview for DSM-III, devised for "non patients", was applied to 203 men and 203 women, aged 11 to 90 years old, hospitalized in an internal medicine service of a public hospital. Thirty four psychiatric conditions that can be discriminated with the instrument and others that complied with DSM-III criteria, were investigated. There was a 60% prevalence of mental disorders among men (alcohol dependency in 26%, delirium or dementia in 10.8%, anxiety disorders in 10.4%, major depression in 7.8% and adaptation disorders in 3%). Among women, the prevalence of mental disorders was 65% (major depression in 23.2%, anxiety disorders in 14.3%, adaptation disorders in 8.4%, dementia in 5.6%, delirium in 3% and alcohol dependency in 2.5%). Most conditions were of moderate or mild intensity. Two or more conditions coexisted in 40% of cases. Only in 8% of these subjects, a psychiatric consultation was requested. There is a high frequency of psychiatric disorders among medical patients. These must be adequately diagnosed and treated.


Homarine, a common metabolite in edible Mediterranean molluscs: occurrence, spectral data and revision of a related structure.
Homarine was isolated from nine edible species of marine molluscs belonging to classes Gastropoda, Bivalvia, and Cephalopoda. A thorough chromatographic, NMR and MS study provided evidence that homarine is a common and abundant metabolite of all these species. This study casts doubt on a previous assertion that 1,1'-dimethyl-[2,2']-bipyridinium is a metabolite of the Bivalve Callista chione.


Pathological Impact of Tau Proteolytical Process on Neuronal and Mitochondrial Function: a Crucial Role in Alzheimer's Disease.
Tau protein plays a pivotal role in the central nervous system (CNS), participating in microtubule stability, axonal transport, and synaptic communication. Research interest has focused on studying the role of post-translational tau modifications in mitochondrial failure, oxidative damage, and synaptic impairment in Alzheimer's disease (AD). Soluble tau forms produced by its pathological cleaved induced by caspases could lead to neuronal injury contributing to oxidative damage and cognitive decline in AD. For example, the presence of tau cleaved by caspase-3 has been suggested as a relevant factor in AD and is considered a previous event before neurofibrillary tangles (NFTs) formation.Interestingly, we and others have shown that caspase-cleaved tau in N- or C- terminal sites induce mitochondrial bioenergetics defects, axonal transport impairment, neuronal injury, and cognitive decline in neuronal cells and murine models. All these abnormalities are considered relevant in the early neurodegenerative manifestations such as memory and cognitive failure reported in AD. Therefore, in this review, we will discuss for the first time the importance of truncated tau by caspases activation in the pathogenesis of AD and how its negative actions could impact neuronal function.


The effect of DDT on vitamin D metabolism and calcium binding activity in the chick.
The mechanism of DDT impaired calcium absorption was studied in control, DDT fed and starved chicks. The metabolism of [3H]cholecalciferol was the same in the 3 groups, but the DDT fed and starved chicks had less intestinal calcium binding activity than the control chicks. These results suggest that DDT impaired calcium absorption and intestinal calcium binding activity may be a result of DDT induced anorexia.


Estimating the Association Between Exposome and Psychosis as Well as General Psychopathology: Results From the ABCD Study.
The exposome comprises all nongenetic factors an individual is exposed to across their lifespan. Research suggests that exposomic vulnerability for schizophrenia is associated not only with psychosis but also, to a degree, with general psychopathology. Here, we investigated to what degree exposome factors are associated with psychosis and general psychopathology. Data were retrieved from the 1-year follow-up assessment of a large U.S. adolescent sample (n = 11,235), the Adolescent Brain Cognitive Development (ABCD) Study. Iterative factor analyses of environmental exposures (n = 798) allowed calculation of 6 exposome factors: household adversity, neighborhood environment, day-to-day experiences, state-level environment, family values, pregnancy/birth complications. Bifactor modeling of clinical symptoms (n = 93) allowed calculation of a general psychopathology factor (p-factor) and 6 subdomains, including a psychosis subdomain. We applied linear regression analyses to estimate the association of exposome factors with the p-factor and psychosis subdomain, respectively. Individual analyses showed that 5 exposome factors were significantly associated with the p-factor after multiple-comparison correction. In the mutually adjusted model, all exposome factors were significantly associated with the p-factor. Psychosis was particularly associated with 3 exposome factors, with the mutually adjusted model yielding the following results: household adversity (β = 0.04, 95% CI, 0.01 to 0.07), day-to-day experiences (β = 0.10, 95% CI, 0.08 to 0.12), and pregnancy/birth complications (β = 0.03, 95% CI, 0.01 to 0.05). Our findings demonstrate that multifaceted environmental background is associated with mental disorders. Psychosis was particularly associated with prenatal, perinatal, and childhood (household and school) adversities, although these exposome domains were also associated with psychopathology. The exposome approach can help understand neurodevelopmental psychopathology.


Evaluating the Merit of a Syringol Derived Fluorophore as a Charge Transfer Probe for Detection of Serum Albumins.
In this article a syringol-π-benz[e]indolium based donor-acceptor fluorophore has been reported. The fluorophore shows a solvent polarity dependent change in the absorption and emission spectra in solution. A combined spectroscopic and time dependent density functional theory (TDDFT) studies reveal higher dipole moment of the fluorophore in the excited state, resulting positive solvatochromism. In physiological pH, the phenol group in the fluorophore is easily deprotonated owing to the electron pulling effect of the substituents. Consequently, the phenolate (PhO-) becomes a strong active donor in the new donor-acceptor pair. In aqueous solution, the new phenolate fluorochrome shows negligible fluorescence due to energy loss via non-radiative pathways from the low-lying polar excited states. The fluorochrome can detect human and bovine serum albumins in physiological buffer solution with high selectivity. The underlying mechanism of human serum albumin (HSA) detection was estimated to be strong (1.46 × 105 M-1, ΔG = -7.05 kcal/mol) supramolecular complexation between the fluorophore and albumin in hydrophobic binding site III-B. The linear relationship between fluorescence intensity and HSA concentration extends from 40 mg/L to an impressive upper limit (540 mg/L), thereby opening an opportunity for albumin detection in a broad range of health conditions. The practical applicability of the fluorophore was tested in spiked urine samples and a good correlation was observed between fluorescence intensity and the concentration of human serum albumin in neutral aqueous samples.


Environments and Hosts Structure the Bacterial Microbiomes of Fungus-Gardening Ants and their Symbiotic Fungus Gardens.
The fungus gardening-ant system is considered a complex, multi-tiered symbiosis, as it is composed of ants, their fungus, and microorganisms associated with either ants or fungus. We examine the bacterial microbiome of Trachymyrmex septentrionalis and Mycetomoellerius turrifex ants and their symbiotic fungus gardens, using 16S rRNA Illumina sequencing, over a region spanning approximately 350 km (east and central Texas). Typically, microorganisms can be acquired from a parent colony (vertical transmission) or from the environment (horizontal transmission). Because the symbiosis is characterized by co-dispersal of the ants and fungus, elements of both ant and fungus garden microbiome could be characterized by vertical transmission. The goals of this study were to explore how both the ant and fungus garden bacterial microbiome are acquired. The main findings were that different mechanisms appear to explain the structure the microbiomes of ants and their symbiotic fungus gardens. Ant associated microbiomes had a strong host ant signature, which could be indicative of vertical inheritance of the ant associated bacterial microbiome or an unknown mechanism of active uptake or screening. On the other hand, the bacterial microbiome of the fungus garden was more complex in that some bacterial taxa appear to be structured by the ant host species, whereas others by fungal lineage or the environment (geographic region). Thus bacteria in fungus gardens appear to be acquired both horizontally and vertically.


Stretch-Induced Intimal Failure in Isolated Cerebral Arteries as a Function of Development.
Recent clinical studies have shown that traumatic brain injury is a significant risk factor for stroke. Motivated to better understand possible mechanisms of this association, we studied subfailure disruption of the intima in overstretched sheep cerebral arteries, as this has been implicated in the increased risk of stroke following blunt cerebrovascular injury. Middle cerebral arteries from four age groups (ranging from fetal to adult) were stretched axially to failure, and intimal disruption was captured with a video camera. All vessels demonstrated intimal disruption prior to catastrophic failure, with nearly all incurring disruption at stretch values well below those at ultimate stress (means of 1.56 and 1.73, respectively); the lowest stretch associated with intimal disruption was 1.29. The threshold of intimal failure was independent of age. Additional analysis showed that disruption included failure of both the endothelium and internal elastic lamina. Although our experiments were conducted at quasi-static rates, the results likely have important implications for vessel function following trauma. Future work should seek to identify subfailure disruption of the cerebrovasculature in head trauma.


Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats.
The orexin (hypocretin) system is important for reward-driven motivation but has not been implicated in the expression of a multiphenotype addicted state. Rats were assessed for economic demand for cocaine before and after 14 days of short access, long access, or intermittent access (IntA) to cocaine. Rats were also assessed for a number of other DSM-5-relevant addiction criteria following differential access conditions. Orexin system function was assessed by quantification of numbers and activity of orexin cells, pharmacological blockade of the orexin-1 receptor, and subregion-specific knockdown of orexin cell populations. IntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than long access or short access. IntA was accompanied by an increase in number and activity of orexin-expressing neurons within the lateral hypothalamic subregion. This increase in orexin cell number and activity persisted during protracted withdrawal from cocaine for at least 150 days and was accompanied by enhanced incubation of craving in the same rats. Selective knockdown of lateral hypothalamic orexin neurons reduced motivation for cocaine, and orexin-1 receptor signaling played a larger role in drug seeking after IntA. We provide the first evidence that lateral hypothalamic orexin system function extends beyond general reward seeking to play a critical role in expression of a multiphenotype addiction-like state. Thus, the orexin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addiction-like behavior in rats.


Reliability and smallest real difference of the ankle lunge test post ankle fracture.
This study aimed to determine the reliability and the smallest real difference of the Ankle Lunge test in an ankle fracture patient population. In the post immobilisation stage of ankle fracture, ankle dorsiflexion is an important measure of progress and outcome. The Ankle Lunge test measures weight bearing dorsiflexion, resulting in negative scores (knee to wall distance) and positive scores (toe to wall distance), for which the latter has proven reliability in normal subjects only. A consecutive sample of ankle fracture patients with permission to commence weight bearing, were recruited to the study. Three measurements of the Ankle Lunge Test were performed each by two raters, one senior and one junior physiotherapist. These occurred prior to therapy sessions in the second week after plaster removal. A standardised testing station was utilised and allowed for both knee to wall distance and toe to wall distance measurement. Data was collected from 10 individuals with ankle fracture, with an average age of 36 years (SD 14.8). Seventy seven percent of observations were negative. Intra and inter-rater reliability yielded intra class correlations at or above 0.97, p < .001. There was a significant systematic bias towards improved scores during repeated measurement for one rater (p = .01). The smallest real difference was calculated as 13.8mm. The Ankle Lunge test is a practical and reliable tool for measuring weightbearing dorsiflexion post ankle fracture.


Determination of pharmaceutically related compounds by suppressed ion chromatography: III. Role of electrolytic suppressor design.
For the hyphenation of ion chromatography to nebulising detectors or mass spectrometry, suppression of the non-volatile ionic eluent to water is a required step to avoid elevated detector baselines. Presented here is a study of three new designs of electrolytic suppressors, incorporating high ion-exchange capacity screens and high ion-exchange capacity membranes in different thickness and compositions. These designs aim to minimise hydrophobic interactions of the suppressor with organic analytes and to provide higher compatibility with eluents containing acetonitrile. In comparison with a commercially available electrolytic suppressor and also a commercially available chemical suppressor, the new high-capacity suppressor showed superior performance, exhibiting minimal interactions with a test set of analytes under the examined conditions. This led to the attainment of high recoveries of the analytes after suppression (93-99% recovery) and significantly reduced band broadening during suppression. The new suppressor has been shown to perform well under both isocratic and gradient elution conditions.


HIV-1 reverse transcriptase and antiviral drug resistance. Part 1.
HIV-1 reverse transcriptase (RT) contributes to the development of resistance to all anti-AIDS drugs by introducing mutations into the viral genome. At the molecular level, mutations in RT result in resistance to RT inhibitors. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleoside inhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have been determined in complexes with substrates and/or inhibitors, and the structures have illuminated different conformational and functional states of the enzyme. Understanding the molecular mechanisms of resistance to NRTIs and NNRTIs, and their complex relationships, may help in designing new drugs that are periodically required to overcome existing as well as emerging trends of drug resistance.


Murine T-cell differentiation antigen CD8 is a direct substrate of protein kinase C.
Murine T cell differentiation antigen CD8 alpha (Lyt-2) is phosphorylated in vivo after phorbol 12-myristate 13-acetate (PMA) treatment of cells. Concanavalin A,dibutyryl cAMP and calcium ionophore are unable to stimulate phosphate incorporation into CD8 alpha. Depletion of cellular protein kinase C (PKC) by prolonged PMA treatment abolished this phosphorylation, suggesting that PKC is required for this effect. Using the amino acid sequence derived from cloning CD8 alpha, peptides encompassing both possible intracellular phosphorylation sites were made and used to test the ability of various kinases to phosphorylate CD8 alpha sequences. Only the proximal serine peptide was a kinase substrate, and of PKC, cAMP-dependent kinase and the multifunctional calcium/calmodulin-dependent kinase, only PKC was able to phosphorylate this peptide. These studies provide the first definitive evidence that CD8 alpha is a direct substrate of PKC.


Human patellar cartilage: echo planar diffusion-weighted MR imaging findings at 3.0 T.
To explore the findings of diffusion-weighted imaging (DWI) and the diffusion characteristics on patellar cartilage in healthy adults. Thirty healthy subjects were studied on SIEMENS 3.0-T Trio Tim magnetic resonance (MR) scanner. The apparent diffusion coefficient (ADC) values of the patellar cartilage were measured in different areas. The patellar cartilage demonstrated homogeneously high signal intensity on the images of DWI and maps of ADC. The ADC values displayed a spatial dependency, approximately (1.17 ± 0.31)×10(-3) mm(2)/s of the entire cartilage. Diffusion-weighted MR imaging may display articular cartilage structure. There is a consistent pattern of spatial variation of the ADC values.


Reduction of mucoid Staphylococcus epidermidis adherence to intraocular lenses by selected antimicrobial agents.
The effect of low concentrations of various antimicrobial agents on the adherence of mucoid Staphylococcus epidermidis to intraocular lenses was investigated. Adherent growth of S. epidermidis on to polymethylmethacrylate lenses was greatly diminished by ciprofloxacin and clindamycin (>75%), followed by ceftazidime ( approximately 50%) and less affected by gentamicin and vancomycin (<25%) compared to the adherent growth of control untreated cells. The reduction in adherence growth was concentration-dependent and found to be due to the inhibition of slime production since no growth inhibition was observed at the concentrations used. Cell surface hydrophobicity was markedly reduced in parallel to the inhibition of adherence as compared to the control cells. The differential effect of antibiotics on adherence, regardless of their antimicrobial activity, may have a clinical significance in reducing the incidence of postoperative endophthalmitis and intraocular inflammation due to the reduction of cell adherence.


Developing a Platform for Global Health Dermatology Mentorship and Collaboration: Introducing the International Alliance for Global Health Dermatology.
The International Alliance for Global Health Dermatology (GLODERM) was formed in 2019 with the aim to unite efforts toward skin health, open to members from any health profession, any country, and at any stage of training. This article highlights the case for such an alliance; discusses existing opportunities and gaps in global health dermatology; describes the development of a new international alliance; proposes future directions; and reflects on lessons learned.


TWEAK-Fn14 pathway inhibition protects the integrity of the neurovascular unit during cerebral ischemia.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts via binding to a cell surface receptor named Fn14. To study the role of this cytokine in the regulation of the permeability of the neurovascular unit (NVU) during cerebral ischemia, TWEAK activity was inhibited in wild-type mice with a soluble Fn14-Fc decoy receptor administered either immediately or 1 h after middle cerebral artery occlusion (MCAO). Administration of Fn14-Fc decoy resulted in faster recovery of motor function and a 66.4%+/-10% decrease in Evans blue dye extravasation when treatment was administered immediately after MCAO and a 46.1%+/-13.1% decrease when animals were treated 1 h later (n=4, P<0.05). Genetic deficiency of Fn14 resulted in a 60%+/-12.8% decrease in the volume of the ischemic lesion (n=6, P<0.05), and a 87%+/-22% inhibition in Evans blue dye extravasation 48 h after the onset of the ischemic insult (n=6, P<0.005). Compared with control animals, treatment with Fn14-Fc decoy or genetic deficiency of Fn14 also resulted in a significant inhibition of nuclear factor-kappaB pathway activation, matrix metalloproteinase-9 activation and basement membrane laminin degradation after MCAO. These findings show that the cytokine TWEAK plays a role in the disruption of the structure of the NVU during cerebral ischemia and that TWEAK antagonism is a potential therapeutic strategy for acute cerebral ischemia.


Influence of hip prostheses on high energy photon dose distributions.
Radiotherapy treatment of patients having a hip prosthesis is a common problem facing dosimetrists and physicists when the treatment plan requires irradiation of the pelvic area. To quantify the perturbation of these devices, attenuation studies were done with 6 and 18 MV photon beams using various hip prostheses models with varying size and composition. These studies have shown that an attenuation of as much as 50% can be found in a single beam profile under the prosthesis. We have studied the capability of a dose planning system to predict the transmission of these devices as compared with measurements.


Reduced survival in patients who return to dialysis after kidney allograft failure.
The outcome of patients who return to dialysis after Kidney allograft failure (KAF) remains unclear. Our aim was to compare the outcome of KAF patients vs two different types of transplant naive incident dialysis (TNID) patients, those on the waiting list (WL) and those with a kidney transplant contraindication (KTC). We performed an observational study using data from the Argentinian Dialysis Registry between 2005 and 2016. We compare mortality between KAF, WL, and KTC. We included 75 722 patients of which 2734 were KAF. Survival between the three cohorts (KAF vs WL (n = 14 630) vs KTC (n = 58 358) revealed a significant difference (log-rank test: P < .0001) indicating worse survival for KTC patients and best survival for WL. We found that KAF patients had as poor outcome as KTC patients after multivariate adjustment. Cox regression showed that age >65 years: HR: 1.845 (1.79-1.89) P < .0001, transient catheter: HR: 1.303 (1.26-1.34) P < .0001, diabetic: HR: 1.273 (1.22-1.31) P < .0001, hepatitis C: HR: 1.156 (1.09-1.22) P < .0001, and albumin: HR: 1.247 (1.21-1.28) P < .0001 were associated with mortality. Patients who return to dialysis after KAF have higher mortality than WL patients and similar to KTC patients.


[On fingertips of "washerwoman's hands" (author's transl)].
An investigation method is proposed to find out quantitatively the beginning and the degree of "washerwoman's hands" at the fingertips. To answer the question, for how long there was contact with a fluid medium, systematic investigations are necessary to measure the width of the "cristae papillares" of several test persons with an onlight-photomicroscope under similar fluid conditions.


Effect of Over- and Underfeeding on Body Composition and Related Metabolic Functions in Humans.
Methodological limitations of body composition methods limit the validity of changes in body composition that are used to interpret metabolic outcome parameters of weight loss and weight gain. Direct assessment of energy balance is necessary for the assessment of early weight changes (i.e., within the 1st week of weight change), whereas body composition analysis with a high accuracy and a low minimal detectable change is recommended to assess ongoing changes. The sequence of underfeeding and overfeeding impacts the method inherent assumptions, and the considerable day-to-day and inter-individual variance in body composition changes is a challenge to the precision of methods. Weight loss-associated changes in body composition do not resemble their changes with subsequent hypercaloric re-feeding. Individual body components are related to specific metabolic functions where the structure-function relationships change with changes in energy balance. Analysis of structure-function relationships in response to weight changes needs to address (a) the validity, precision, and different outcome parameters of body composition methods and (b) the variance of results taking into account study protocols and the dynamics of weight changes. As for future studies, repeated measurements of body weight, body composition, and metabolic functions are needed before, during, and after weight changes focusing on the intra- and interindividual variances of weight change rather than on mean data only.


Modeling cooking of chicken meat in industrial tunnel ovens with the Flory-Rehner theory.
In this paper we present a numerical model describing the heat and mass transport during the cooking of chicken meat in industrial tunnels. The mass transport is driven by gradients in the swelling pressure, which is described by the Flory-Rehner theory, which relates to the water holding capacity (WHC). For cooking temperatures up to boiling point and practical relevant cooking times, the model renders good prediction of heat and mass transport and the total loss of moisture. We have shown that for cooking temperatures above boiling point, the model has to be extended with the dynamic growth of capillary water (drip) channels. Furthermore, we discuss that the Flory-Rehner theory provides the proper physical basis for describing the change of the WHC by a wide variety of factors like salt and pH.


The relationship of axial length to cycloplegic refraction and keratometry in amblyopic eyes of hyperopic children.
In nonamblyopic eyes of hyperopic children, axial length has a consistent mathematical relationship to cycloplegic refraction and keratometry such that estimated axial length = ([-0.04 × refraction] + 2.98) × (corneal radius)]. The purpose of this study is to determine whether the pathophysiology of amblyopia affects this relationship. This a prospective case series of children 5 to 16 years of age diagnosed with esotropia related to uncorrected hyperopia who underwent keratometry and optical biometry by the IOLMaster in addition to cycloplegic refraction. The equation was assessed in affected eyes of consecutive children with unilateral amblyopia (at least 2 lines interocular difference with refractive correction). Of the 23 identified children (16 males, 7 females, 5-14 years of age), all had a cycloplegic spherical equivalent of ≥+2.75 D in at least one eye, 14 were anisometropic (by >1.00 D), and none had myopia. Estimated and measured axial lengths of amblyopic eyes were strongly correlated (Pearson coefficient 0.9; 95% confidence interval, 0.79-0.96) and did not differ significantly by the 2-sided paired t test (P = 0.3; difference between means, 0.1). The two values differed by ≤ 0.5 mm for most eyes (20/23) and were within 0.9 mm for all eyes, similar to what has been described for nonamblyopic eyes. The intraocular relationship of axial length to cycloplegic refraction and keratometry in hyperopic nonamblyopic eyes is maintained in hyperopic amblyopic eyes. Thus, the pathophysiology of amblyopia in this setting does not involve a mismatch among these biometric variables.


Early sex differences in central arterial wave reflection are mediated by different timing of forward and reflected pressure waves.
Non-invasive assessment of central arterial pulse wave augmentation has been proved to be useful in predicting cardiovascular adverse events. Previous studies have shown that pre-pubescent girls had greater central augmentation pressure compared with height-matched boys. This study sought to investigate which factors contribute to the body height-independent sexual differences in central arterial wave reflection observed in childhood. This cross-sectional study involved 819 children and adolescents (6-18 years of age) of both sexes. Phenotypes of central haemodynamic were obtained by radial applanation tonometry. Heart rate corrected augmentation index (Aix@75) was greater in girls compared with boys (2.9 ± 10.7 vs -1.7 ± 12.9%, P < .001) as well as the central augmented pressure (cAP; 1.3 ± 3.3 vs 0.1 ± 3.8 mm Hg, P < .001), even adjusting for age, heart rate and body height. Left ventricular ejection duration (ED) was longer (320 ± 26 vs 314 ± 24 ms, P = .004) and time to inflection point (Tr) was shorter in girls (139 ± 14 vs 141 ± 21 ms, P = .014). The reduction of Aix@75 with increasing body height was steeper in boys (-0.499 ± 0.030 vs -0.428 ± 0.036%/cm, P < .001) as well as the reduction of cAP with increasing body height (-0.108 ± 0.010 vs -0.066 ± 0.013 mm Hg/cm, P < .001). Body height-independent sexual differences observed in the pulse wave reflection indices from early adolescence were mediated by different timing of forward and reflected pressure waves.


The falciform ligament as a graft for portal-superior mesenteric vein reconstruction in pancreatectomy.
Tumor invasion or adherence to the portal vein-superior mesenteric vein (PV/SMV) may be encountered during pancreatic surgery. In such cases, venous resection and reconstruction might be required for complete resection of the tumor. We report an innovative technique in which the graft for PV/SMV reconstruction was made with the falciform ligament. Between May 2011 and July 2016, PV/SMV reconstruction with a falciform ligament graft was performed in 10 cases during pancreatectomy. Among these cases, including six cases with a patch graft and four cases with a conduit graft. Retrospective reviews of medical records and radiologic studies were performed. Ten patients with pancreatobiliary cancer underwent en bloc tumor resection with concurrent PV/SMV resection and reconstruction with a falciform ligament graft. There were six males and four females, and the mean age was 65.3 ± 9.4 (48-80) y. Using Doppler ultrasound examination, all 10 grafts were shown to be patent at postoperative 2 wk. However, occlusion was found in one case with conduit graft and stenosis in the other three cases with conduit graft using enhanced computed tomography at postoperative 2 mo. Complete patency was shown in three of six cases with patch graft and stenosis in the other three cases at 2 mo after the operation. Although occlusion or stenosis of the grafts was observed, no severe adverse events occurred, and normal liver function was discovered in all 10 cases at postoperative 2 mo. Falciform ligament grafts might be considered for reconstruction of PV/SMV in the absence of appropriate vascular grafts.


Selective localization of C atrial natriuretic peptide receptors in the rat brain.
We studied the distribution of C atrial natriuretic peptide (C-ANP) receptors in the rat brain after incubation with 125I-rANP, and competition with the selective C-ANP receptor competitor C-ANP(4-23) (10(-6) M). C-ANP receptors were selectively localized to a few structures, the external plexiform layer of the olfactory bulb, the arachnoid mater and the choroid plexus, and their amount corresponds to 25%, 75% and 35%, respectively, of the ANP specific binding. These data suggest specialized functions for C-ANP receptors in brain.


Development of a microscale red blood cell-shaped pectin-oligochitosan hydrogel system using an electrospray-vibration method: preparation and characterization.
To develop and characterize a microscale pectin-oligochitosan hydrogel microcapsule system that could be applied in such biological fields as drug delivery, cell immobilization/encapsulation, and tissue engineering. Microscale pectin-oligochitosan hydrogel microcapsules were prepared by using the vibration/electrostatic spray method. The morphology and chemistry of the hydrogel microcapsules were characterized by using scanning electron microscope (SEM) and Fourier Transform Infrared Spectroscopy (FTIR), respectively. The designed hydrogel microcapsule system was then used to study the responsiveness of the microcapsules to different simulated human body fluids as well as cell encapsulation. The designed hydrogel microcapsule system exhibited a large surface area-to-volume ratio (red blood cell-shaped) and great pH/enzymatic responsiveness. In addition, this system showed the potential for controlled drug delivery and three-dimensional cell culture. This system showed a significant potential not only for bioactive-agent delivery, especially to the lower gastrointestinal (GI) tract, but also as a three-dimensional niche for cell culture. In particular, the hydrogel microcapsule system could be used to create artificial red-blood-cells as well as blood substitutes.


Rebamipide attenuates Helicobacter pylori CagA-induced self-renewal capacity via modulation of β-catenin signaling axis in gastric cancer-initiating cells.
Rebamipide, a mucosal-protective agent, is used clinically for treatment of gastritis and peptic ulcers induced by Helicobacter pylori (H. pylori) which is associated with increased risk of gastric cancer. Although rebamipide is known to inhibit the growth of gastric cancer cells, the action mechanisms of rebamipide in gastric carcinogenesis remains elusive. Here, we show that rebamipide suppresses H. pylori CagA-induced β-catenin and its target cancer-initiating cells (C-IC) marker gene expression via upregulation of miRNA-320a and -4496. Rebamipide attenuated in vitro self-renewal capacity of H. pylori CagA-infected gastric C-IC via modulation of miRNA-320a/-4496-β-catenin signaling axis. Moreover, rebamipide enhanced sensitivity to chemotherapeutic drugs in CagA-expressed gastric C-IC. Furthermore, rebamipide suppressed tumor-initiating capacity of gastric C-IC, probably via suppression of CagA-induced C-IC properties. These data provide novel insights for the efficacy of rebamipide as a chemoprotective drug against H. pylori CagA-induced carcinogenic potential.


Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling.
TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.


Interplay of Coronary Artery Calcium and Risk Factors for Predicting CVD/CHD Mortality: The CAC Consortium.
This study sought to evaluate the association and burden of coronary artery calcium (CAC) with long-term, cause-specific mortality across the spectrum of baseline risk. Although CAC is a known predictor of short-term, all-cause mortality, data on long-term and cause-specific mortality are inadequate. The CAC Consortium cohort is a multicenter cohort of 66,636 participants without coronary heart disease (CHD) who underwent CAC testing. The following risk factors (RFs) were considered: 1) current cigarette smoking; 2) dyslipidemia; 3) diabetes mellitus; 4) hypertension; and 5) family history of CHD. During the 12.5-years median follow-up, 3,158 (4.7%) deaths occurred; 32% were cardiovascular disease (CVD) deaths. Participants with CAC scores ≥400 had a significantly increased risk for CHD and CVD mortality (hazard ratio [HR]: 5.44; 95% confidence interval [CI]: 3.88 to 7.62; and HR: 4.15; 95% CI: 3.29 to 5.22, respectively) compared with CAC of 0. Participants with ≥3 RFs had a smaller increased risk for CHD and CVD mortality (HR: 2.09; 95% CI: 1.52 to 2.85; and HR: 1.84; 95% CI: 1.46 to 2.31, respectively) compared with those without RFs. Across RF strata, CAC added prognostic information. For example, participants without RFs but with CAC ≥400 had significantly higher all-cause, non-CVD, CVD, and CHD mortality rates compared with participants with ≥3 RFs and CAC of 0. Across the spectrum of RF burden, a higher CAC score was strongly associated with long-term, all-cause mortality and a greater proportion of deaths due to CVD and CHD. Absence of CAC identified people with a low risk over 12 years of follow-up, with most deaths being non-CVD in nature, regardless of RF burden.


Tyrosine phosphorylation of mitogen-activated protein kinase in cells with tyrosine kinase-negative epidermal growth factor receptors.
Epidermal growth factor (EGF) treatment of cells expressing the human EGF receptor (EGFr) results in rapid tyrosine phosphorylation of several cellular proteins including mitogen-activated protein (MAP) kinase. EGF treatment of cells expressing a tyrosine kinase-inactive EGFr failed to induce the tyrosine phosphorylation of endogenous substrates in response to EGF; however, the tyrosine phosphorylation and activation of MAP kinase did occur. This observation indicates that MAP kinase is activated in response to a signal other than the tyrosine kinase activity of the EGFr. Because EGF does not stimulate cells expressing the inactive EGFr to proliferate, phosphorylation of MAP kinase may not be sufficient for the EGF-dependent mitogenesis.


M13 bacteriophage production for large-scale applications.
Bacteriophage materials have the potential to revolutionize medicine, energy production and storage, agriculture, solar cells, optics and many other fields. To fulfill these needs, this study examined critical process parameters during phage propagation to increase phage production capability. A representative scale-down system was created in tube spin reactors to allow parallel experimentation with single- and multi-variable analysis. Temperature, harvest time, media composition, feed regime, bacteriophage, and bacteria concentration were analyzed in the scale-down system. Temperature, media composition, and feeding regimens were found to affect phage production more than other factors. Temperature affected bacterial growth and phage production inversely. Multi-variate analysis identified an optimal parameter space which provided a significant improvement over the base line method. This method should be useful in scaled production of bacteriophage for biotechnology.


An improved SUMO fusion protein system for effective production of native proteins.
Expression of recombinant proteins as fusions with SUMO (small ubiquitin-related modifier) protein has significantly increased the yield of difficult-to-express proteins in Escherichia coli. The benefit of this technique is further enhanced by the availability of naturally occurring SUMO proteases, which remove SUMO from the fusion protein. Here we have improved the exiting SUMO fusion protein approach for effective production of native proteins. First, a sticky-end PCR strategy was applied to design a new SUMO fusion protein vector that allows directional cloning of any target gene using two universal cloning sites (Sfo1 at the 5'-end and XhoI at the 3'-end). No restriction digestion is required for the target gene PCR product, even the insert target gene contains a SfoI or XhoI restriction site. This vector produces a fusion protein (denoted as His(6)-Smt3-X) in which the protein of interest (X) is fused to a hexahistidine (His(6))-tagged Smt3. Smt3 is the yeast SUMO protein. His(6)-Smt3-X was purified by Ni(2+) resin. Removal of His(6)-Smt3 was performed on the Ni(2+) resin by an engineered SUMO protease, His(6)-Ulp1(403-621)-His(6). Because of its dual His(6) tags, His(6)-Ulp1(403-621)-His(6) exhibits a high affinity for Ni(2) resin and associates with Ni(2+) resin after cleavage reaction. One can carry out both fusion protein purification and SUMO protease cleavage using one Ni(2+)-resin column. The eluant contains only the native target protein. Such a one-column protocol is useful in developing a better high-throughput platform. Finally, this new system was shown to be effective for cloning, expression, and rapid purification of several difficult-to-produce authentic proteins.


Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Report of a case with respiratory tract involvement.
The term "sinus histiocytosis with massive lymphadenopathy," introduced in 1969 by Rosai and Dorfman, refers to a newly recognized disease entity characterized by painless cervical lymphadenopathy, fever, leukocytosis, increased erythrocyte sedimentation rate, and hypergammaglobulinemia. The typical course is one of insidious onset, protracted duration of the active disease state, and eventual spontaneous remission, occasionally with subsequent recurrences. Lymph nodes other than those in the cervical area may be involved, and extranodal involvement can occur (such as in the orbit, skin, or respiratory tract). Clinically, this entity may closely simulate malignant lymphoma or nonneoplastic conditions with lymphadenopathy. We present a case in which this disease process extensively involved the respiratory tract and produced obstructive symptoms. The otorhinolaryngologist should be aware of this disease entity and should include it in the differential diagnosis for patients with cervical lymph node enlargement or bronchial obstruction.


Outcome of Santulli enterostomy in patients with immaturity of ganglia: single institutional experience from a case series.
Immaturity of ganglia (IG) is an extremely rare disease and always requires surgical intervention in the neonatal period, but without guidelines to choose the ideal enterostomy procedure, the timing of stoma closure remains controversial. The aim of this study was to report our experience using Santulli enterostomy for the treatment of nine infants diagnosed with IG. Patients who underwent Santulli enterostomy and were diagnosed with IG in our center between 2016 and 2021 were retrospectively studied. Temporary stoma occlusion and a 24-h delayed film of barium enema (BE) were performed to evaluate intestinal peristalsis function to determine the timing of stoma closure. The demographic data, clinical and radiological findings, stoma occlusion and stoma closure results were explored. A total of 9 infants underwent Santulli enterostomy and were diagnosed with IG postoperatively. Their median gestational age at birth was 36 weeks (range 31-42), and their median birth weight was 2765 g (range 1300-3400). All patients had symptom onset in the neonatal period, including abdominal distension and biliary vomiting. Eight patients showed obvious small bowel dilatation in the plain films, except for one patient's films that suggested gastrointestinal perforation with free gas downstream of the diaphragm. BE was performed in 6 patients, all of which had microcolons. The median age at operation was 3 days (range 1-23). Seven patients had an obvious transitional zone (TZ) during laparotomy, and the position of the TZ was 25-100 cm proximal above the ileocecal (IC) valve. Immature ganglion cells were present in the colon in 7 patients and the terminal ileum in 6 patients. The median age of successful stoma occlusion was 5 M (range 2-17) and 8 M (range 4-22) at ostomy closure. There was little or no barium residue in the 24-h delayed film of BE before stoma closure, and all patients were free of constipation symptoms during the follow-up. Santulli enterostomy appears to be a suitable and efficient procedure for IG, combined with temporary stoma occlusion and 24-h delayed film of BE to evaluate the recovery of intestinal peristalsis function.


[Perforation of the cervical esophagus and hypopharynx complicating surgery by an anterior approach to the cervical spine].
Difficult diagnostic and therapeutic problems are raised by perforations of the cervical oesophagus or hypopharynx in patients undergoing surgery to the cervical spine via an anterior approach. Based on their experience of three recent cases, the authors review the diagnostic approach, based on clinical examination and diatrizoate sodium oesophageal series, and propose conservative treatment consisting of surgical drainage with or without suture of the perforation and without removal of the osteosynthesis material, appropriate antibiotic therapy and hypercaloric enteral nutrition via nasogastric tube. The prevention of this complication is based on correct use of surgical retractors.


Associations between common sleep disturbances and cardiovascular risk in patients with obstructive sleep apnea: A large-scale cross-sectional study.
Studies have shown that obstructive sleep apnea (OSA) is inextricably linked with cardiovascular diseases (CVD). However, the roles of certain common sleep disturbances, such as low slow-wave sleep, excessive daytime sleepiness and short sleep duration, in the pathogenesis and progression of CVD in patients with OSA have not been determined. Therefore, we conducted a large cross-sectional study to explore the effect of low slow-wave sleep, excessive daytime sleepiness and short sleep duration on the risk of CVD in patients with OSA. Subjects were consecutively enrolled to participate in the sleep center of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. All OSA patients were diagnosed by standard polysomnography, while controls were all simple snorers. A total of 4,475 participants were strictly recruited. The Framingham Risk Score were employed to assess the 10-year risk of CVD, and logistic regression was used to measure the association between sleep disturbances and the moderate-to-high CVD risk. In the whole cohort, OSA, excessive daytime sleepiness, and low slow-wave sleep were all risk factors for the moderate-to-high 10-year CVD risk (odds ratio [OR] = 3.012, 95% confidence interval [CI] 2.418-3.751; OR = 1.407, 95% CI: 1.228-1.613, and OR = 0.973,95% CI: 0.967-0.980), but sleep duration did not contribute significantly to that risk. Whether in patients with OSA and controls, low SWS (<12.8%) could increase the risk of CVD. Subjective excessive daytime sleepiness would significantly increase the risk of CVD only in patients with severe OSA. It is important to pay more attention to the impact of sleep on cardiovascular health. Patients with sleep disturbances should adopt a healthy lifestyle and undergo regular follow-up of cardiovascular indicators to prevent cardiovascular complications. [http://www.chictr.org.cn/showproj.aspx?proj=43057], identifier [ChiCTr1900025714].


Laparoscopic colorectal cancer surgery reduces the adverse impacts of sarcopenia on postoperative outcomes: a propensity score-matched analysis.
Sarcopenia is a negative predictor for postoperative recovery. This study was performed to evaluate the short-term outcomes of laparoscopic surgery in colorectal cancer patients with sarcopenia. We conducted a study of patients who underwent curative surgeries for colorectal cancer in two centers from July 2014 to July 2018. In order to reduce selection bias, we conducted a propensity score matching analysis. Preoperative characteristics including age, gender, anemia, body mass index, hypoalbuminemia, America society of anesthesiology scores, epidural anesthesia, operative procedure, stoma, tumor location, and combined resection were incorporated in the model, and produced 58 matched pairs. The third lumbar skeletal muscle mass, handgrip strength, and 6 m usual gait speed were measured to define sarcopenia. Short-term outcomes were compared between the two groups. In a total of 1136 patients, 272 had sarcopenia diagnosed, and 227 were further analyzed in this study. Among them, 108 patients underwent laparoscopic colorectal surgery and 119 underwent open colorectal surgery. In the matched cohort, the clinical characteristics of the two groups were well matched. The laparoscopic group had significantly reduced overall complications (15.5% vs. 36.2%, P = 0.016) and shorter postoperative hospital stays (10.5 vs. 14, P = 0.027). Subgroup analysis of postoperative complications showed that the incidence of surgical complications (P = 0.032) was lower in the laparoscopic group. Hospitalization costs (P = 0.071) and 30-day readmissions (P = 0.215) were similar between the two groups. Laparoscopic surgery for colorectal cancer is a safe and feasible option with better short-term outcomes in patients with sarcopenia.


[Update on chemotherapy for bladder cancer. Update 2010].
This review summarizes results of neoadjuvant and adjuvant trials for locally advanced bladder cancer as well as data on systemic chemotherapy for metastatic urothelial cancer. Increasing attention has been drawn to targeted cancer therapies in the treatment of urothelial cancer in recent years. In future, molecular profiling will play a major role as a means to tailor individual therapy.