Fractionation and Biological Activities of Water-Soluble Polysaccharides from Sclerotium of Tiger Milk Medicinal Mushroom, Lignosus rhinocerotis (Agaricomycetes).
This study investigated antioxidant and anti-inflammatory properties, and the direct cytotoxic effect of Lignosus rhinocerotis fractions, especially the polysaccharide fraction, on nasopharyngeal carcinoma cells. L. rhinocerotis crude extract was obtained through hot water extraction. The precipitate saturated with 30% ammonium sulfate was purified with ion-exchanged chromatography. Gel permeation chromatography multiangle laser light scattering analysis equipped with light scattering and UV signals revealed two district groups of polymers. A total of four peaks were observed in the total carbohydrate test. Fraction C, which was the second region of the second peak eluted with 0.3 M NaOH, showed the highest integrated molecular weight, whereas fraction E had the lowest integrated molecular weight of 19,790 Da. Fraction A contained the highest β-D-glucan content. Enzymatic analysis showed that most of the polysaccharide fractions contained β-1-3 and β-1-6 skeletal backbones. The peak eluted with 0.6 M NaOH was separated in fraction D (flask 89-92) and fraction E (93-96). The results showed that fraction E expressed higher antioxidant activities than fraction D whereas fraction D expressed higher chelating activity than fraction E. The extract saturated with 30% ammonium sulfate exhibited higher reducing power than the extract saturated with 100% ammonium sulfate. Fractions D and E significantly inhibited the secretion of tumor necrosis factor-α in lipopolysaccharide-stimulated RAW 264.7 macrophages in a dose-dependent manner. There was no apparent difference in the viability of cells exposed or unexposed to L. rhinocerotis fractions.


A strong neuroprotective effect of the autonomous C-terminal peptide of IGF-1 Ec (MGF) in brain ischemia.
The ischemic stroke is the third leading cause of death in developed countries. The C-terminal peptide of mechano-growth factor (MGF), an alternatively spliced variant of insulin-like growth factor 1 (IGF-1), was found to function independently from the rest of the molecule and showed a neuroprotective effect in vivo and in vitro. In vivo, in a gerbil model of transient brain ischemia, treatment with the synthetic MGF C-terminal peptide provided very significant protection to the vulnerable neurons. In the same model, ischemia evoked increased expression of endogenous MGF in the ischemia-resistant hippocampal neurons, suggesting that the endogenous MGF might have an important neuroprotective function. In an in vitro organotypic hippocampal culture model of neurodegeneration, the synthetic peptide was as potent as the full-length IGF-1 while its effect lasted significantly longer than that of recombinant IGF-1. While two peptides showed an additive effect, the neuroprotective action of the C-terminal MGF was independent from the IGF-1 receptor, indicating a new mode of action for this molecule. Although MGF is known for its regenerative capability in skeletal muscle, our findings demonstrate for the first time a neuroprotective role against ischemia for this specific IGF-1 isoform. Therefore, the C-terminal MGF peptide has a potential to be developed into a therapeutic modality for the prevention of neuronal damage.


Budd-Chiari Syndrome following COVID-19 infection: a case report.
Budd-Chiari Syndrome (BCS) is a rare disorder that affects the liver and is caused by blockage of the hepatic veins. Coronavirus disease 2019 (COVID-19) has been linked to an increased risk of developing BCS due to its ability to cause inflammation in the body, which can lead to clotting disorders. A 43-year-old female presented to the emergency department complaining of severe epigastric and right upper quadrant pain and progressive abdominal distention. Upon examination, investigation, and triphasic liver computed tomography with contrast, the patient was diagnosed with BCS. The patient was started on anticoagulant therapy with low-molecular-weight heparin and supportive treatment. She was hospitalized for 3 weeks and discharged on oral warfarin 5 mg/day after showing clinical improvement. Hepatosplenomegaly and abdominal distention after COVID-19 infection raise suspicion for BCS. Therefore, early detection of these signs is essential for immediate management.


A leg ulcer with hard, yellow projections.
Gout is a multisystem disease that may present in different ways. We report an elderly man who presented with a large ulcer of the left leg with hard yellow projections evolving for one year. Analytical study revealed a normal uric acid level, but histopathology showed a focal basophilic acellular material compatible with a gouty tophus. This tophus represents the cardinal feature of advanced gout and may present several challenges to wound care professionals. In fact, the ulcer in our patient persisted after one-year follow-up. Our aim is to alert clinicians about a rare cutaneous presentation of gout that may be increasingly diagnosed.


A comparison of renal function following the infusion of Ringer solution into systemic and portal veins in the dog.
The increase of sodium and water excretion by the kidney following intravenous Ringer solution infused into a femoral vein (vena femoralis) or into an intestinal vein (vena portae ) has been studied in anaesthetized dogs. The functional parameters of renal function have been compared during volume expansion with 1.5-2.0% of body weight Ringer solution and "over-hydration" by 2.5% Ringer loading over 60 minutes. No significant difference in sodium excretion and urine output resulted from 0.25 ml/kg/min Ringer solution when infused by the two routes. When the animals were infused with 2.5% body weight Ringer solution (0.66 ml/kg/min i.v.), a marked increase in water excretion was observed with a smaller increment in sodium excretion, and the urine became hyposmotic as compared with the plasma osmolarity. No difference has been found in the glomerular filtration rate and in the PAH clearance. Glomerular filtration rate, sodium excretion and urine flow rate were not significantly different for the two routes when the same Ringer solution load was infused. These experiments did not provide evidence for the participation of the liver in the control of sodium excretion during extracellular fluid volume expansion induced by Ringer solution infusion.


Memory Impairment in Relapsing-Remitting Multiple Sclerosis Using a Challenging Semantic Interference Task.
Objective: Episodic memory is frequently impaired in Multiple Sclerosis (MS), but the cognitive characteristics and neuropsychological processes involved remain controversial. Our aim was to study episodic memory dysfunction in MS, using the LASSI-L, a novel memory-based cognitive stress test that uses a new paradigm that capitalizes on semantic interference. Methods: Cross-sectional study in which 93 patients with MS (relapsing-remitting) and 124 healthy controls were included. The LASSI-L test was administered to all participants, as well as a comprehensive neuropsychological battery including a selective reminding test. MS patients were divided into two groups, with cognitive impairment (CI-MS) and cognitively preserved (CP-MS). Results: Reliability of the LASSI-L test was high (Cronbach's alpha 0.892) and there were less ceiling effects. MS patients scored lower than controls on all LASSI-L subtests, except for maximum storage of the initial target items (CRA2). Effect sizes were moderate-large. A delay in learning, difficulties in retroactive semantic interference, failure to recover from proactive semantic interference, and delayed recall were the most frequent findings in MS patients. Scores associated with maximum storage capacity, and retroactive semantic interference were the most strongly associated with cognitive impairment and employment status. Conclusion: We found that deficits in maximum learning, difficulties in recovery from the effects of proactive semantic interference and retroactive semantic interference are three important breakdowns in episodic memory deficits among patients with MS. The LASSI-L showed good psychometric and diagnostic properties. Overall, our study supports the utility of the LASSI-L, as a new cognitive test, useful for neuropsychological assessment in MS in clinical and research settings.


Use of the LUCAS mechanical chest compression device for percutaneous coronary intervention during cardiac arrest: is it really a game changer?
Cardiopulmonary support including closed chest compression is a mainstay in the management of cardiac arrest. However, traditional means (i.e. manual) chest compression may be logistically challenging, especially in patients requiring emergent invasive procedures such as percutaneous coronary intervention for cardiac arrest due to acute myocardial infarction. The LUCAS mechanical chest compression device provides external and automated closed chest compression, thus enabling even complex invasive procedures without interrupting cardiopulmonary support. Nonetheless, no randomized trial has proved to date its benefit in comparison to standard manual chest compression, and to date only observational studies and consensus opinion support its clinical use.


Behavioral family management for serious psychiatric illness.
A description of the various elements that characterize a behavioral family management approach is presented in this chapter. The goal is to teach techniques to families for reducing the stress that their vulnerable relative might face.


Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d I.
T cells control the majority of antigen-specific immune responses. Therefore, influencing the activation of the T-cell response in order to modify immune responsiveness is an obvious therapeutic goal. We have used a mouse model of response to Fel d I, the major cat protein allergen in humans, to explore the ability of peptides derived from Fel d I to inhibit T-cell-dependent immune responses to the peptides themselves and to larger polypeptides. T cells from B6CBAF1 mice respond to the Fel d I peptide IPC-2 after challenge with IPC-2. However, subcutaneous tolerization with IPC-2 prevents this response as measured by production of interleukins 2 and 4 and interferon gamma. Fel d I immunization of B6D2F1 mice results in T-cell responses primarily to one peptide derived from Fel d I. Injecting this peptide in soluble form inhibits T-cell activation (as measured by interleukin 2 production) and antibody production in Fel d I-primed animals when they are subsequently challenged with peptide in adjuvant. Most of the cat-allergic human T-cell response to Fel d I is specific for two peptides on one of its two chains. Immunization of B6CBAF1 mice with recombinant Fel d I chain 1 results in T-cell responses to the same peptides. Subcutaneous administration of these two peptides, which contain some, but not all, of the T-cell epitopes from Fel d I chain I, decreases the T-cell response to the entire recombinant Fel d I chain 1. The ability to tolerize T-cell responses with subcutaneous injections suggests a practical approach to treating human diseases with peptides containing T-cell epitopes.


Corticothalamic connections of auditory-related areas of the temporal lobe in the rhesus monkey.
Corticothalamic connections of auditory areas of the superior temporal regions (STR) were investigated in the rhesus monkey. These connections are organized according to the recently described architectonic parcellation of the STR. The core line regions of the supratemporal plane (STP) project to the medial geniculate nucleus (MGN). All regions except the primary auditory area also have projections to additional thalamic nuclei. The rostral STP has strong connections with the caudal part of the ventral subdivision (MGv) of MGN as well as with medial pulvinar (PM). In contrast the primary auditory area projects mainly to rostral MGv. The caudalmost STP projects mainly to the dorsal subdivision (MGd) and to the magnocellular subdivision (MGmc) as well as to the PM and the lateral (PL) and oral (PO) pulvinar, nucleus limitans (Li), and mediodorsal (MD) nucleus. The belt line regions of the superior temporal gyrus (STG) project mainly to the pulvinar but also have projections to MGd and MGmc. Specifically, rostral STG projects to the caudal part of PM, to MGmc, and to the suprageniculate (SG) nucleus, whereas caudal STG projects to the rostral part of PM and to PL, PO, MGd, MGmc, SG-Li and MD nuclei. The root line areas in the circular sulcus of the Sylvian fissure project mainly to MGmc but also to MGd, PM, and SG-Li nuclei. These connections originate mainly from neurons in cortical layer VI, with some from layer Vb. It is suggested that these connections may be involved in different aspects of auditory information processing.


Why viruses sometimes disperse in groups?†.
Many organisms disperse in groups, yet this process is understudied in viruses. Recent work, however, has uncovered different types of collective infectious units, all of which lead to the joint delivery of multiple viral genome copies to target cells, favoring co-infections. Collective spread of viruses can occur through widely different mechanisms, including virion aggregation driven by specific extracellular components, cloaking inside lipid vesicles, encasement in protein matrices, or binding to cell surfaces. Cell-to-cell viral spread, which allows the transmission of individual virions in a confined environment, is yet another mode of clustered virus dissemination. Nevertheless, the selective advantages of dispersing in groups remain poorly understood in most cases. Collective dispersal might have emerged as a means of sharing efficacious viral transmission vehicles. Alternatively, increasing the cellular multiplicity of infection may confer certain short-term benefits to viruses, such as overwhelming antiviral responses, avoiding early stochastic loss of viral components required for initiating infection, or complementing genetic defects present in different viral genomes. However, increasing infection multiplicity may also entail long-term costs, such as mutation accumulation and the evolution of defective particles or other types of cheater viruses. These costs and benefits, in turn, should depend on the genetic relatedness among collective infectious unit members. Establishing the genetic basis of collective viral dispersal and performing controlled experiments to pinpoint fitness effects at different spatial and temporal scales should help us clarify the implications of these spread modes for viral fitness, pathogenicity, and evolution.


[Cardiac arrhythmias in the elderly].
In the elderly, cardiac arrhythmias and conduction disturbances are characterized by their high frequency, diagnostic difficulties, low tolerance, and delicate treatment. Atrial fibrillation, the prevalence of which exceeds 10% after 80 years, is usually related to hypertensive or ischemic heart disease, and is the cause or the consequence of heart failure. It is first and foremost a cause of thromboembolic events, and especially cerebrovascular embolism. In elderly patients, sinus node dysfunction and AV block are often induced or aggravated by drugs. The iatrogenic risk associated with antiarrhythmic drugs (especially class I) and antithrombotic drugs is elevated in the elderly, and these agents must thus be used with great care. Ventricular rate control is often a safer option than sinus rhythm control for atrial fibrillation. Ablative methods and cardiac pacing techniques are other therapeutic options.


Irradiation-induced translocation of p53 to mitochondria in the absence of apoptosis.
The tumor suppressor protein p53 promotes apoptosis in response to death stimuli by transactivation of target genes and by transcription-independent mechanisms. Recently, it was shown that during apoptosis p53 can specifically translocate to mitochondria, where it physically interacts with and inactivates prosurvival Bcl-2 proteins. In the present study, we therefore investigated the role of mitochondrial translocation of p53 for the stress response of tumor cells. In various cell lines, DNA damage induced by either ionizing irradiation or topoisomerase inhibitors triggered a robust translocation of a fraction of p53 to mitochondria to a similar extent. Nevertheless, the cells succumbed to apoptosis only in response to topoisomerase inhibitors, but remained resistant to apoptosis induced by ionizing radiation. Irradiated cells became senescent, although irradiation triggered a functional p53 response and induced expression of p21, Bax, and Puma. Interestingly, even the targeted expression of p53 to mitochondria was insufficient to launch apoptosis, whereas overexpression of wild-type p53 induced Bax activation and apoptotic alterations. Together, these results suggest that, in contrast to previous reports, mitochondrial translocation of p53 does not per se lead to cell death and that this might constitute a mechanism that contributes to the resistance of tumor cells to ionizing radiation-induced apoptosis.


Predicting nose projection and pronasale position in facial approximation: a test of published methods and proposal of new guidelines.
Many prediction guidelines exist in facial approximation for determining the soft-tissue features of the face, and the reliability of each is generally unknown. This study examines four published and commonly used soft-tissue prediction guidelines for estimating nose projection, two of which also estimate the position of the pronasale. The methods tested are those described by: 1) Gerasimov ([1971] The Face Finder; London: Hutchinson & Co.), using the distal third of the nasal bones and the nasal spine; 2) Krogman ([1962] The Human Skeleton in Forensic Medicine; Springfield: Charles C. Thomas), using the average soft-tissue depth at midphiltrum, plus three times the length of the nasal spine (and a variation of this technique: plus three times the distance of the tip of the nasal spine from the nasal aperture); 3) Prokopec and Ubelaker ([2002] Forensic Sci Commun 4:1-4), using the reflected profile line of the nasal aperture; and 4) George ([1987] J Forensic Sci 32:1305-1330), using a variation of the Goode method. Four identical hard-tissue tracings were made of 59 adult lateral head cephlograms (29 males, mean age 24, SD 10 years; 30 females, mean age 23, SD 5 years) on separate sheets of tracing paper. One soft-tissue tracing was also made for each radiograph. All tracings were marked with three identical reference points. Soft-tissue tracings were isolated from one of us (C.N.S.), who attempted under blind conditions to predict pronasale position and nose projection on the hard-tissue tracings, using the soft-tissue prediction guides above. Actual soft-tissue tracings were then compared to each of the predicted tracings, and differences in projection/pronasale position were measured. Results indicate that for nose projection, methods 3 and 4 performed well, while methods 1 and 2 performed poorly. Features which are most related to nose projection/pronasale are described in this paper, as are regression equations generated from these variables that predict pronasale/nose projection better than the traditional methods mentioned above. The results of this study are significant because they: 1) indicate that the popular facial approximation methods used to build the nose are inaccurate and produce incorrect nose anatomy; and 2) indicate that the new pronasale prediction methods developed here appear to have less error than traditional methods.


The effect of legislation on injuries sustained by rear seat car passengers.
A study of 206 injured rear seat passengers was undertaken over two 4-month periods before and after the introduction of legislation enforcing use of rear seat-belts on 1 July 1991. The proportion of both adults and children using rear seat-belts increased after the law. Those wearing belts were less likely to suffer serious injury. The majority of passengers comply with the law but many rear seat passengers remain unrestrained because cars are not fitted with belts.


Selective inhibitory effects of suberosin on CYP1A2 in human liver microsomes.
Suberosin is a natural phytoconstituent isolated from Citropsis articulata, especially employed for its anticoagulant properties. Although metabolic studies assessing suberosin have been conducted, it is possible interactions with drugs and food have not yet been investigated. In the present study, we analyzed the selective inhibitory effects of suberosin on cytochrome P450 (CYP) enzymes using a cocktail probe assay. Various concentrations of suberosin (0-50 μM) were incubated with isoform-specific CYP probes in human liver microsomes (HLMs). We found that suberosin significantly inhibited CYP1A2-catalyzed phenacetin O-deethylation, exhibiting IC50 values of 9.39 ± 2.05 and 3.07 ± 0.45 μM with and without preincubation in the presence of β-NADPH, respectively. Moreover, suberosin showed concentration-dependent, but not time-dependent, CYP1A2 inhibition in HLMs, indicating that suberosin acts as a substrate and reversible CYP1A2 inhibitor. Using a Lineweaver-Burk plot, we found that suberosin competitively inhibited CYP1A2-catalyzed phenacetin O-deethylation. Furthermore, suberosin showed similar inhibitory effects on recombinant human CYP1A1 and 1A2. In conclusion, suberosin may elicit herb-drug interactions by selectively inhibiting CYP1A2 during the concurrent administration of drugs that act as CYP1A2 substrates.


Effect of the addition of rocuronium to local anesthetics for peribulbar block.
To test the hypothesis that rocuronium added to a mixture of local anaesthetics could improve akinesia in Peribulbar Block (PB) we designed this prospective, randomized, double-blinded study. Sixty ASA physical status I and II patients presenting for cataract surgery (manual extracapsular lens extraction) under PB were included. Patients were randomized to 2 groups: rocuronium group (n = 30) received PB with a local anesthetic mixture (Lidocaine 2% + Bupivacaine 0.5%) to which was added 0.06 mg/Kg of rocuronium and control group (n = 30) received PB with the same mixture to which was added saline. Akinesia was assessed with a 12-point scale at 2, 5 and 10 minutes after injection (each of the four rectus muscles and each lid was scored from 0 to 2; 0 = total akinesia, 1 = partial akinesia, 2 = no akinesia). The need for supplementary injection, adverse effects and complications were also recorded. Rocuronium group demonstrated significantly better akinesia scores than control group at 2, 5 and 10 minutes post PB (p < 0.05). Supplementary injection was necessary in 4 patients (13%) in rocuronium group versus 12 patients (40%) in control group (p = 0.039). No significant complications were recorded. Rocuronium added to a mixture of local anaesthetics at a dose of 0.06 mg/Kg improved the quality of akinesia in PB and reduced the need for supplementary injections.


[Pancreatic tumour in a child].
Abdominal pain is a common symptom in children and recurrent abdominal pain (RAP) has a prevalence of 8.4% in childhood. In 90-95% of RAPs no organic disease is identified. Thus, it is important that the few of somatic origin are diagnosed. We describe a case concerning a 12-year-old girl, diagnosed with a solid pseudopapillary tumour of the pancreas. The symptoms were RAP and postprandial vomiting. The purpose of this article is to increase the knowledge of "alarm findings" indicating an organic disease in children with RAP.


Distributed Coordination for Optimal Energy Generation and Distribution in Cyber-Physical Energy Networks.
This paper proposes three coordination laws for optimal energy generation and distribution in energy network, which is composed of physical flow layer and cyber communication layer. The physical energy flows through the physical layer; but all the energies are coordinated to generate and flow by distributed coordination algorithms on the basis of communication information. First, distributed energy generation and energy distribution laws are proposed in a decoupled manner without considering the interactive characteristics between the energy generation and energy distribution. Second, a joint coordination law to treat the energy generation and energy distribution in a coupled manner taking account of the interactive characteristics is designed. Third, to handle over- or less-energy generation cases, an energy distribution law for networks with batteries is designed. The coordination laws proposed in this paper are fully distributed in the sense that they are decided optimally only using relative information among neighboring nodes. Through numerical simulations, the validity of the proposed distributed coordination laws is illustrated.


Alpha 1-microglobulin, beta 2-microglobulin and retinol binding protein in childhood febrile illness and renal disease.
Serum and urinary levels of alpha-1-microglobulin (A1M), beta-2-microglobulin (B2M) and retinol binding protein (RBP) were measured using a Mancini radial immunodiffusion technique in 52 children with renal disease, 36 with non-renal febrile illness and 29 controls. In controls the mean serum level for A1M was 25 +/- 4.6 (SD) mg/l for B2M 1.7 +/- 0.5 mg/l and for RBP 31 +/- 8 mg/l. A1M levels were not significantly altered by febrile illness while B2M was elevated and RBP markedly depressed. Serum A1M and B2M were elevated in the nephrotic syndrome, while serum B2M was also raised during infancy. Coefficients of log-transformed data with creatinine-derived glomerular filtration rate (GFR) were -0.87 for B2M, -0.71 for RBP, and -0.62 for A1M. In the urine A1M was always measurable in controls while B2M and RBP were undetectable in all but a small number. The urine levels of all three proteins increased in response to non-renal febrile illness, and rose invariably when GFR fell to below 40-50 ml/min per 1.73 m2. Of the three proteins A1M was most frequently elevated in the urine with febrile and renal illness. RBP was rarely detectable when the other two proteins were not. Urinary A1M was consistently elevated in the nephrotic syndrome in contrast to B2M, possibly as a reflection of the increased glomerular permeability. We conclude that serum B2M is superior to A1M and RBP as an index of glomerular filtration, although its levels should be interpreted with caution in febrile disease.(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacokinetics and protein binding of cis-dichlorodiammine platinum (II) administered as a one hour or as a twenty hour infusion.
The pharmacokinetics of cis-dichlorodiam-minoplatinum (II) (cisplatin) have been studied in seven patients, of whom four received the drug as a one hour infusion and three received it as a 20 h infusion. The patients receiving the drug over one hour exhibited biphasic clearance of total platinum with a rapid initial phase (8.7-22.5 min) and a prolonged second phase (30.5-106 h). Free (ultrafilterable) cisplatin was readily detectable in this group and was rapidly cleared (half-life about 22 min). The volume of distribution of the drug was 50.3-65.6 liters and it was 26.6-50% excreted in the urine in 48 h. In the patients receiving the 20 h infusion, a more complex plasma elimination curve was seen, with the appearance of a secondary peak. Free drug was not detectable in these patients and they showed less urinary excretion (21.4-25.9% at 48 h) than the one hour group. Cisplatin was bound to several plasma proteins, including albumin, transferrin, and gamma-globulin. The data indicate that cisplatin is retained in the body more extensively after a 20 h infusion than after a one hour infusion.


A Cretaceous eutriconodont and integument evolution in early mammals.
The Mesozoic era (252-66 million years ago), known as the domain of dinosaurs, witnessed a remarkable ecomorphological diversity of early mammals. The key mammalian characteristics originated during this period and were prerequisite for their evolutionary success after extinction of the non-avian dinosaurs 66 million years ago. Many ecomorphotypes familiar to modern mammal fauna evolved independently early in mammalian evolutionary history. Here we report a 125-million-year-old eutriconodontan mammal from Spain with extraordinary preservation of skin and pelage that extends the record of key mammalian integumentary features into the Mesozoic era. The new mammalian specimen exhibits such typical mammalian features as pelage, mane, pinna, and a variety of skin structures: keratinous dermal scutes, protospines composed of hair-like tubules, and compound follicles with primary and secondary hairs. The skin structures of this new Mesozoic mammal encompass the same combination of integumentary features as those evolved independently in other crown Mammalia, with similarly broad structural variations as in extant mammals. Soft tissues in the thorax and abdomen (alveolar lungs and liver) suggest the presence of a muscular diaphragm. The eutriconodont has molariform tooth replacement, ossified Meckel's cartilage of the middle ear, and specialized xenarthrous articulations of posterior dorsal vertebrae, convergent with extant xenarthran mammals, which strengthened the vertebral column for locomotion.


Assessment of the Global Variance Effective Size of Subdivided Populations, and Its Relation to Other Effective Sizes.
The variance effective population size ([Formula: see text]) is frequently used to quantify the expected rate at which a population's allele frequencies change over time. The purpose of this paper is to find expressions for the global [Formula: see text] of a spatially structured population that are of interest for conservation of species. Since [Formula: see text] depends on allele frequency change, we start by dividing the cause of allele frequency change into genetic drift within subpopulations (I) and a second component mainly due to migration between subpopulations (II). We investigate in detail how these two components depend on the way in which subpopulations are weighted as well as their dependence on parameters of the model such a migration rates, and local effective and census sizes. It is shown that under certain conditions the impact of II is eliminated, and [Formula: see text] of the metapopulation is maximized, when subpopulations are weighted proportionally to their long term reproductive contributions. This maximal [Formula: see text] is the sought for global effective size, since it approximates the gene diversity effective size [Formula: see text], a quantifier of the rate of loss of genetic diversity that is relevant for conservation of species and populations. We also propose two novel versions of [Formula: see text], one of which (the backward version of [Formula: see text]) is most stable, exists for most populations, and is closer to [Formula: see text] than the classical notion of [Formula: see text]. Expressions for the optimal length of the time interval for measuring genetic change are developed, that make it possible to estimate any version of [Formula: see text] with maximal accuracy.


Prevalence of feline leukemia virus infection in random source laboratory cats.
Three years of quarantine data involving the prevalence of Feline Leukemia Virus (FeLV) in laboratory cats (Felis catus) was evaluated. Testing was performed using a commercially available ELISA system. Annual prevalence of infection ranged from 5.4 to 10.7% of the 937 cats tested. Results obtained with the enzyme linked immunosorbent assay (ELISA) system compared well with tests performed using an immunofluorescent antibody assay system (IFA). Seasonal periodicity was noted with higher infection rates among animals received in April. Holding period at the supplier and gender did not influence disease prevalence. The availability of a simple test system, the unacceptability of FeLV infected cats for research, the danger of transmission and a higher prevalence of infection than earlier reports indicated that supplier and user evaluation of research cats for FeLV would be prudent.


Effects of an anticoagulant and a lipid-lowering agent on the prevention of steroid-induced osteonecrosis in rabbits.
This study was designed to evaluate the effects of the combined treatment with an anti-coagulant (enoxaparin) agent and a lipid-lowering agent (lovastatin) on prevention or decrease in the occurrence of steroid-induced osteonecrosis in rabbits. A total of 112 rabbits, which were injected intramuscularly with 20 mg/kg of methylprednisolone acetate were divided into four groups and treated as follows: one group received enoxaparin combined with lovastatin (EL; n = 30), another received enoxaparin alone (EA; n = 28), another received lovastatin alone (LA; n = 28) and the last received no treatment (non-prophylactic; NP, n = 26). Haematological examination for serum lipid levels and prothrombin time was carried out and both femora and humeri were examined histopathologically for the presence of osteonecrosis (ON) before injection and at 2, 4, 8 and 12 weeks after the injection. The incidence of ON in the EL group (15%) was significantly lower than that observed in the NP group (68%). The incidence in the EA and LA groups was also significantly lower than that in the NP group (31%, 35%vs. 68%). The fat cell sizes of the bone marrow in both EL (46.49 +/- 1.27 microm) and LA (50.8 +/- 2.31 microm) groups were lower than in the NP group (59.89 +/- 6.33 microm). The prothrombin time was prolonged and plasma lipid levels were reduced in the EL group during the study. Combination treatment with an anti-coagulant agent and a lipid-lowering agent can reduce the incidence of steroid-induced ON in rabbits. Future evaluation in clinical practice is necessary.


[W6S8] octahedral tungsten clusters functionalized with thiophene derivatives: toward polymerizable building blocks.
The functionalization of octahedral [W(6)S(8)] clusters with a family of phosphino-thiophene ligands has been investigated with the goal of synthesizing extended networks of [W(6)S(8)] units covalently linked to one another through thiophene-conjugated bridges. In addition to new phosphino-thiophene ligands, eight clusters were synthesized and characterized by (1)H and (31)P NMR spectroscopies, elemental analysis, and UV-vis absorption. These clusters are formulated [W(6)S(8)(T-PPh(2))6] (1a), [W(6)S(8)(T-PEt(2))(6)] (1b), [W(6)S(8)(2T-PPh(2))(6)] (2a), [W(6)S(8)(2T-PEt(2))(6)] (2b), [W(6)S(8)(3T-PPh(2))(6)] (3a), [W(6)S(8)(3T-PEt(2))(6)] (3b), [W(6)S(8)((2T)(3)P)(6)] (4), and [W(6)S(8)(2EDOT-PEt(2))(6)] (5) (T = thiophene and EDOT = 3,4-ethylenedioxythiophene). The molecular structure of six of them has been obtained by single-crystal X-ray diffraction analysis. All of them crystallize in the P1 triclinic space group except 3b, which has the P2(1)/c monoclinic symmetry. The redox behavior of both the ligands and the corresponding functionalized clusters has been investigated by cyclic voltammetry. An attempt to electropolymerize these species is also reported.


Functionally relevant white matter degradation in multiple sclerosis: a tract-based spatial meta-analysis.
To identify statistical consensus between published studies for distribution and functional relevance of tract white matter (WM) degradation in multiple sclerosis (MS). By systematically searching online databases, tract-based spatial statistics studies were identified that compared fractional anisotropy (FA; a marker for WM integrity) in MS patients to healthy control subjects, correlated FA in MS patients with physical disability, or correlated FA in MS patients with cognitive performance. Voxelwise meta-analysis was performed by using the Signed Differential Mapping method for each comparison. Moderating effects of mean age, mean physical disability score, imager magnet strength, lesion load, and number of diffusion directions were assessed by means of meta-regression. Meta-analysis was performed on data from 495 patients and 253 control subjects across 12 studies. MS diagnosis was significantly associated with widespread lower tract FA (nine studies; largest cluster, 4379 voxels; z = 7.1; P < .001). Greater physical disability was significantly associated with lower FA in the right posterior cingulum, left callosal splenium, right inferior fronto-occipital fasciculus, and left fornix crus (six studies; 323 voxels; z = 1.7; P = .001). Impaired cognition was significantly associated with lower FA in the callosal genu, thalamus, right posterior cingulum, and fornix crus (seven studies; largest cluster, 980 voxels; z = 2.5; P < .001). WM damage is widespread in MS with differential and only minimally overlapping distributions of low FA that relates to physical disability and cognitive impairment. The higher number of clusters of lower FA in relation to cognition and their higher z scores suggest that cerebral WM damage may have a greater relevance to cognitive dysfunction than physical disability in MS, and that low anterior callosal and thalamic FA have specific importance to cognitive status.


Multi-spectroscopic and molecular modelling approach to investigate the interaction of riboflavin with human serum albumin.
Riboflavin (RF) plays an important role in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Human serum albumin (HSA) is an important protein involved in the transportation of drugs, hormones, fatty acid and other molecules which determine the biodistribution and physiological fate of these molecules. In this study, we have investigated the interaction of riboflavin RF with HSA under simulative physiological conditions using various biophysical, calorimetric and molecular docking techniques. Results demonstrate the formation of riboflavin-HSA complex with binding constant in the order of 104 M-1. Fluorescence spectroscopy confirms intermediate strength having a static mode of quenching with stoichiometry of 1:1. Experimental results suggest that the binding site of riboflavin mainly resides in sub-domain IIA of HSA and that ligand interaction increases the α-helical content of HSA. These parameters were further verified by isothermal titration calorimetry ITC which confirms the thermodynamic parameters obtained by fluorescence spectroscopy. Molecular docking was employed to suggest a binding model. Based on thermodynamic, spectroscopic and computational observations it can be concluded that HSA-riboflavin complex is mainly stabilized by various non-covalent forces with binding energy of -7.2 kcal mol-1.


[Condensed and dispersed chromatin in the nuclei of thyroid follicular cells under normal conditions and following thyrotropic stimulation].
The author examined the changes in the nuclear size, in its form and optical density as well as the changes in the condensed and dispersed chromatin of the follicular cells of the thyroid gland after thyroid stimulation by means of the method of scanning cytophotometry. He found that after a 20-day treatment of the animals with methythyouracyl-an agent, which blocks thyroid hormonal synthesis and in this way raised the level of the thyreothropic hormone in circulation, the size of the cell nuclei was increased and at the same time its concentration of DNA was reduced. The amount of the particles of the condensed chromatin after thyreotropic stimulation diminished, but the integral space remained unchanged and the area of the dispersed chromatine was mainly increased. The obtained data are discussed in view of the possibilities of the scanning cytophotometry for evaluation of the functional activity of the cell.


Carbon microfibers sheathed with aligned carbon nanotubes: towards multidimensional, multicomponent, and multifunctional nanomaterials.
Multicomponent and multifunctional hybrid structures based on microsized carbon fibers sheathed with aligned carbon nanotubes and their derivatives have been successfully prepared, and have been demonstrated to be an effective means for connecting nanoscale entities to the outside world and to possess interesting electrochemical properties attractive for a wide range of potential applications, including in methanol direct fuel cells and highly sensitive biological and chemical sensors. Judicious modification of the carbon-fiber-supported aligned carbon nanotubes with various functional moieties could lead to a class of novel multidimensional, multicomponent, and multifunctional materials of practical significance.


Food choice by people with intellectual disabilities at day centres: A qualitative study.
People with intellectual disabilities experience a range of health inequalities. It is important to investigate possible contributory factors that may lead to these inequalities. This qualitative study identified some difficulties for healthy eating in day centres. (1) Service users and their family carers were aware of healthy food choices but framed these as diets for weight loss rather than as everyday eating. (2) Paid carers and managers regarded the principle of service user autonomy and choice as paramount, which meant that they felt limited in their capacity to influence food choices, which they attributed to the home environment. (3) Carers used food as a treat, a reward and for social bonding with service users. (4) Service users' food choices modelled other service users' and carers' choices at the time. It is suggested that healthy eating should be made more of a priority in day care, with a view to promoting exemplarily behaviour that might influence food choice at home.


Antiferromagnetic spin correlations between corner-shared [FeO5]7- and [FeO6]9- units, in the novel iron-based compound: BaYFeO4.
A novel quaternary compound in the Ba-Y-Fe-O phase diagram was synthesized by solid-state reaction and its crystal structure was characterized using powder X-ray diffraction. The crystal structure of BaYFeO4 consists of a unique arrangement of Fe(3+) magnetic ions, which is based on alternate corner-shared units of [FeO5](7-) square pyramids and [FeO6](9-) octahedra. This results in the formation of stairwise channels of FeO polyhedra along the b crystallographic axis. The structure is described in an orthorhombic crystal system in the space group Pnma with lattice parameters a = 13.14455(1) Å, b = 5.694960(5) Å, and c = 10.247630(9) Å. The temperature-dependent magnetic susceptibility data reveal two antiferromagnetic (AFM) transitions at 33 and 48 K. An upturn in the magnetic susceptibility data above these transitions is observed, which does not reach its maximum even at 390 K. The field-dependent magnetization data at both 2 and 300 K show a nearly linear dependence and do not exhibit significant hysteresis. Heat capacity measurements between 2 and 200 K reveal only a broad anomaly without any indication of long-range ordering. The latter data set is not in good agreement with the magnetic susceptibility data, which makes it difficult to exactly determine the magnetic ground state of BaYFeO4. Accordingly, a temperature-dependent neutron diffraction study is in order, which will enable resolving this issue. The theoretical study of the relative strengths of magnetic exchange interactions along various possible pathways, using extended Hückel spin dimer analysis, shows that only interactions between square pyramidal and octahedral centers are significant, and among them, the intrachannel correlations are stronger than interchannel interactions. This is the first physical property study in such a magnetic ion substructure.


Infections and inflammatory bowel disease: challenges in Asia.
The diagnosis and management of inflammatory bowel disease (IBD) in Asia can be challenging as certain infections can mimic IBD and lead to a misdiagnosis. Colitis can be caused by bacterial infections, ileitis can result from Yersinia and Salmonella infections and ileocolonic ulcers can be seen in intestinal tuberculosis and amebiasis. In addition, cytomegalovirus and Clostridium difficile infection may mimic a flare of IBD and their presence is associated with an increased risk of colectomy and mortality. Because of the increasing use of corticosteroids, immunosuppressive drugs and biological agents the risk of opportunistic infection and the reactivation of latent infection including tuberculosis and hepatitis B, are also higher in IBD patients. Screening and prevention of infection, timely vaccination and the education of the patient is paramount before initiating immunosuppressive drugs. The role of the physician lies not only in the diagnosis and management of IBD but also in the ability to prevent, recognize and treat infections.


Seasonal Movement Patterns and Long-Range Dispersal of Asian Citrus Psyllid in Florida Citrus.
The Asian citrus psyllid, Diaphorina citri Kuwayama, is the vector of the bacterial pathogen, Candidatus Liberibacter asiaticus, which is the causal agent of huanglongbing (HLB) in the United States. Both short-range and long-range dispersal of D. citri adults affect the spread of HLB; however, little is known about the long-range dispersal capabilities of D. citri in the field or the seasonality of flight behavior. In the present study, an in situ protein marking technique was used to determine the dispersal of D. citri by trapping marked adults under natural field conditions. D. citri movement from abandoned citrus groves to adjacent managed citrus groves was greatest during the spring and summer months and decreased significantly during the colder months (September-March). D. citri were able to traverse potential geographic barriers such as roads and fallow fields. In an experiment conducted to determine long-range dispersal capacity in the absence of severe weather events, D. citri were able to disperse at least 2 km within 12 d. Wind direction was not correlated with the number of marked psyllids captured, indicating substantial flight capability by D. citri. Finally, the number of marked psyllids captured increased with the density of emerging young leaves on surrounding trees. The results confirm that abandoned citrus groves in Florida serve as reservoirs for D. citri, which can disperse across long distances despite geographical barriers.


Superoxide Dismutase Mimic, MnTE-2-PyP Enhances Rectal Anastomotic Strength in Rats after Preoperative Chemoradiotherapy.
Rectal cancer is one of the malignant diseases with high morbidity and mortality in the world. Currently, surgical resection is the main treatment method, and preoperative chemoradiotherapy (CRT) is widely used in clinical application to increase resectability and decrease the local recurrence rate. However, CRT increases the risk of colon anastomotic leak, and currently, there are no FDA approved treatments against this side effect. It is essential to develop new drugs to reduce postoperative anastomotic leak after preoperative CRT. 90 rats underwent standard resection and intestine anastomosis treatment and were divided into six groups for different treatments. During the relaparotomy, bursting pressure of anastomosis was measured and intestinal segments were taken for histopathologic examination and biochemical analyses. RT-PCR and ELISA were applied to measure matrix metalloproteinase (MMP) mRNA and protein levels. Blood vessels were observed by immunohistochemistry, and collagen deposition was observed by Picrosirius Red staining. Preoperative CRT reduced the postoperative anastomotic strength. MnTE-2-PyP increased the bursting pressure and hydroxyproline levels of intestine anastomosis after CRT treatment. Mechanically, MnTE-2-PyP decreased the MMP levels and increased microvessel density (MVD) and collagen deposition. The MMP inhibitor doxycycline had a positive effect on anastomosis healing, but was inferior to MnTE-2-PyP. MnTE-2-PyP enhanced intestine anastomotic strength in rats with preoperative CRT. Specifically, MnTE-2-PyP decreased MMP levels and increased MVD in anastomosis. Therefore, MnTE-2-PyP may be helpful in the prevention of anastomotic leak after preoperative CRT.


Pediatric emergency department suicidal patients: two-site evaluation of suicide ideators, single attempters, and repeat attempters.
Reducing youth suicide and suicide attempts are national priorities. Suicidal youth emergency department (ED) patients are at high risk for repeat and fatal attempts, yet information is lacking to guide service delivery. In one of the largest clinical studies of youth ED patients presenting with suicidality, we examine ideators, single attempters, and repeat attempters with the aim of clarifying optimal strategies for ED management and risk assessment. Consecutively admitted suicidal youths (10-18 years) from two EDs (N = 210) completed a questionnaire assessing sociodemographic, clinical, service use, and environmental stress variables. Despite differences in background characteristics, high levels of depression, externalizing behavior, posttraumatic stress symptoms, substance use, and thought problems were observed across sites. Suicide attempt risk, defined along a continuum ranging from ideation to single attempts to repeat attempts, was predicted by higher levels of clinical symptoms, service use, and environmental stress. Specific stresses associated with increased suicide attempt risk were romantic breakups, exposure to suicide/suicide attempts, and pregnancy in self or partner. Significant predictors of attempt risk in the male-only subgroup were depression, thought problems, previous ED visits, and romantic breakups. Pediatric ED patients presenting with suicidal ideation, single attempts, and repeat attempts fall along a continuum of increasing risk. Suicide attempt risk in males is associated with high levels of depression, but not with increased treatment rates, suggesting undertreatment in males, a group with particularly high risk for death by suicide. Treatment barriers must be addressed to achieve our national goal of reducing suicide/suicide attempts in youths.


Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial.
The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. clinicaltrials.gov Identifier: NCT01426880.


Reliability and validity of the Spielberger State-Trait Anxiety Inventory (STAI) among urological patients: a Malaysian study.
To validate the English version of the Spielberger State-Trait Anxiety Inventory (STAI) in a sample of Malaysia patients with and without urinary symptoms. Validity and reliability were studied in patients with lower urinary tract symptoms (LUTS) and patients without LUTS. Reliability was evaluated using the test-retest method and internal consistency was assessed using Cronbach's alpha. Sensitivity to change was expressed as the effect size in the pre-intervention versus post-intervention score in additional patients with LUTS who underwent transurethral resection of the prostate (TURP). Internal consistency was excellent. A high degree of internal consistency was observed for each of the 40 items with Cronbach's alpha value = 0.38 to 0.89 while the Cronbach's alpha for the total scores was 0.86. Test-retest correlation coefficients for the 40 items score were highly significant. Intraclass correlation coefficient was high (ICC=0.39 to 0.89). A high degree of sensitivity and specificity to the effects of treatment was observed. A high degree of significant level between baseline and post-treatment scores was observed across nearly half of the items in surgical group but not in the non-LUTS group (control subjects). The STAI is reliable, valid and sensitive to clinical change in a sample of Malaysian patients with and without urinary symptoms.


Interferon gamma, IL-12, IL-12R and STAT-1 immunodeficiency diseases: disorders of the interface of innate and adaptive immunity.
Susceptibility to mycobacterial infection has long been associated with defects in T cell immunity, such as those conferred by HIV infection or iatrogenic immune suppression. However, despite these well-recognized predispositions to clinical disease with tuberculosis and nontuberculous mycobacteria, the genetic disorders that are relatively specific for mycobacterial infection with nontuberculous bacteria and bacille Calmette Guerin (BCG) involve the innate immune pathways, and all engage interferon gamma and IL-12 production, signaling, and availability.


Cystic fibrosis (CF) care through the patients' eyes - a nationwide survey on experience and satisfaction with services using a disease-specific questionnaire.
The patients' perspective is an important aspect of quality management. A newly developed disease-specific questionnaire was used to assess the patients' experiences with care provided in specialised cystic fibrosis (CF) care centres. 90 CF centres in Germany were invited to participate. Centre staff collected patient consent forms and sent the patients' addresses to the study centre. The questionnaires for adults and parents had 100 and 104 items respectively, with 3-6 response categories each. Items were dichotomised into "problem scores" (PS), indicating the presence or absence (PS 0%) of a reported problem. 56 CF centres took part in the survey and recruited 1642 adults with CF and 1205 parents. The response rates were 74% in each group, with 1221 completed questionnaires from adults and 891 from parents. Participants reported good experiences with care. Factor analysis revealed 10 factors covering 70 items. Participants reported the best results for the factors "Physiotherapists" (PS 6%) and "Physician-Patient Relationship" (PS 9%). Factors with the highest problem scores were inpatient and outpatient "Facilities, Hygiene and Services". CF centres received reports of their own results and mean problem scores of all participating institutions. The problem scores differed considerably between CF centres. The nation-wide CF-specific patient experience survey identified specific shortcomings which were mainly related to communication, centre organisation, and facilities. Centre staff can use the results to improve the quality of care. We suggest that patients' views should become an integral component of efforts to promote patient-centred care.


Diagnosing Necrotizing Fasciitis Using Procalcitonin and a Laboratory Risk Indicator: Brief Overview.
Necrotizing fasciitis is a progressive inflammatory disease that requires an early diagnosis to avoid limb salvage and other deadly manifestations. The current protocol is the microbiological and histopathological sampling of the tissue. Once the diagnosis is made, it should be managed with antimicrobial therapy, debridement, and surgical interventions. Such interventions can be invasive and increase the time to treat, which may increase morbidity. Our article discusses procalcitonin, C-reactive protein, and other markers, such as "pain out of proportion," lactate, creatinine, and creatine kinase, to make a quicker diagnosis before proceeding with invasive procedures. We discussed a similar non-invasive approach called the "Laboratory Risk Indicator for Necrotizing Fasciitis" scoring system that can aid in the early diagnosis of necrotizing fasciitis, which can prompt rapid empiric therapy, reducing the chances of morbidity. This scoring system comprises C-reactive protein, white blood cell count, hemoglobin level, creatinine, sodium, and glucose. Such non-invasive, bedside, and quick tests can help in reducing the time required to make the diagnosis and can affect the course of the disease, hence, improving patient outcomes.


Regulation of Salmonella-induced membrane ruffling by SipA differs in strains lacking other effectors.
The Salmonella pathogenicity island 1 (SPI-1) type three secretion system (TTSS) is essential for Salmonella invasion of host cells through its triggering of actin-dependent membrane ruffles. The SPI-1 effectors SipA, SopE, SopE2 and SopB all have actin regulating activities and contribute to invasion. The precise role of actin regulation by SipA in Salmonella invasion remains controversial since divergent data have been presented regarding the relationship between SipA and membrane ruffling. We hypothesized that the contribution of SipA to membrane ruffling and invasion might vary between Salmonella strains. We compared the effects of SipA deletion on Salmonella enterica serovar Typhimurium (S. Typhimurium) strains that possess or lack SopE. Loss of SipA reduced invasion in the early stages of infection by SopE(+) and SopE(-) strains but the number of membrane ruffles elicited was unaffected. Salmonella strains lacking both SipA and SopE induced ruffles with very different morphology from those induced by wild-type strains or ones lacking single effectors, including the presence of highly dynamic finger-like protrusions and numerous filopodia. A similar phenotype was found for sipA(-)sopE(-), sipA(-)sopE2(-) and sipA(-)sopB(-) mutants. Thus, SipA plays a more prominent role in induction of invasion-competent membrane ruffles by Salmonella lacking a full complement of SPI-1 effectors.


The performance of selected semi-empirical and DFT methods in studying C₆₀ fullerene derivatives.
The capability of reproducing the open circuit voltages (V(oc)) of 15 representative C60 fullerene derivatives was tested using the selected quantum mechanical methods (B3LYP, PM6, and PM7) together with the two one-electron basis sets. Certain theoretical treatments (e.g. PM6) were found to be satisfactory for preliminary estimates of the open circuit voltages (V(oc)), whereas the use of the B3LYP/6-31G(d) approach has been proven to assure highly accurate results. We also examined the structural similarity of 19 fullerene derivatives by employing principle component analysis (PCA). In order to express the structural features of the studied compounds we used molecular descriptors calculated with semi-empirical (PM6 and PM7) and density functional (B3LYP/6-31G(d)) methods separately. In performing PCA, we noticed that semi-empirical methods (i.e. PM6 and PM7) seem satisfactory for molecules, in which one can distinguish the aromatic and the aliphatic parts in the cyclopropane ring of PCBM (phenyl-C61-buteric acid methyl ester) and they significantly overestimate the energy of the highest occupied molecular orbital (E(HOMO)). The use of the B3LYP functional, however, is recommended for studying methanofullerenes, which closely resemble the structure of PCBM, and for their modifications.


A Comparison of E6H4 and G175-405 p16-specific Monoclonal Antibodies in Oropharyngeal Squamous Cell Carcinoma.
The purpose of this investigation is to directly compare G175-405 and E6H4 p16-specific antibodies as immunomarkers of HPV-driven oropharyngeal carcinoma. The investigators designed a retrospective analysis using specimens from an archived tissue bank with known in situ hybridization and polymerase chain reaction status for HPV DNA. Fifty randomly selected oropharyngeal specimens were evaluated with both the G175-405 and E6H4 p16-specific monoclonal antibodies. Two pathologists, blinded to the HPV-specific testing status, evaluated p16 positivity for both antibody clones. Interrater agreement was determined using a Cohen κ coefficient. Sensitivity and specificity values were calculated using a standard 2×2 contingency table, then compared using McNemar test. Interrater agreement for interpretation of p16 expression was 92% (κ=0.84) for the G175-405 clone and 100% for the E6H4 clone (κ=1.0). The G175-405 stain had a sensitivity of 0.917 and specificity of 0.846. The E6H4 stain had a sensitivity of 1.000 and specificity of 0.769. Using McNemar test, there were no significant differences found for sensitivity (P=0.480) or specificity (P=0.480) values. The results of this study suggest that though both G175-405 and E6H4 antibody stains are statistically comparable immunomarkers for HPV-driven oropharyngeal carcinoma, the E6H4 clone offers improved interobserver reliability.


High prevalence of peripheral arterial disease in Korean patients with coronary or cerebrovascular disease.
This prospective study surveyed the prevalence of peripheral arterial disease (PAD) in Korean patients with coronary arterial disease (CAD) or cerebrovascular disorder (CVD). From March 2010, 576 hospitalized patients in cardiovascular or stroke center were enrolled as the study group. Ankle-brachial index (ABI) was measured and the cut-off point for diagnosing PAD was ≤ 0.9 at rest. A total of 424 hospitalized patients in the Department of Surgery and aged ≥ 50 yr was enrolled as the control group. The prevalence of PAD was significantly higher in the study group than the control group (7.6% vs 1.7%; P < 0.001). To analyze the relationship of other vascular diseases and PAD, the patients were regrouped; group A (no CAD or CVD), group B (CAD only), group C (CVD only), and group D (CAD and CVD). Compared with group A, those with other vascular diseases (group B, C, D) had significantly higher prevalence of PAD, diabetes, dyslipidemia, renal insufficiency and claudication. The trend that patients with CAD or CVD are at risk of PAD is observed in this cross-sectional study in Koreans. Routine ABI measurement is recommended in these high-risk groups for early detection and proper management of PAD.


A discrete Fourier-encoded, diagonal-free experiment to simplify homonuclear 2D NMR correlations.
Nuclear magnetic resonance (NMR) spectroscopy has long served as an irreplaceable, versatile tool in physics, chemistry, biology, and materials sciences, owing to its ability to study molecular structure and dynamics in detail. In particular, the connectivity of chemical sites within molecules, and thereby molecular structure, becomes visible by multi-dimensional NMR. Homonuclear correlation experiments are a powerful tool for identifying coupled spins. Generally, diagonal peaks in these correlation spectra display the strongest intensities and do not offer any new information beyond the standard one-dimensional spectrum, whereas weaker, symmetrically placed cross peaks contain most of the coupling information. The cross peaks near the diagonal are often affected by the tails of strong diagonal peaks or even obscured entirely by the diagonal. In this paper, we demonstrate a homonuclear encoding approach based on imparting a discrete phase modulation of the targeted cross peaks and combine it with a site-selective sculpting scheme, capable of simplifying the patterns arising in these 2D correlation spectra. The theoretical principles of the new methods are laid out, and experimental observations are rationalized on the basis of theoretical analyses. The ensuing techniques provide a new way to retrieve 2D coupling information within homonuclear spin systems, with enhanced sensitivity, speed, and clarity.


All-terrain vehicle rules and regulations: impact on pediatric mortality.
All-terrain vehicles (ATV) use by children leads to severe injury and death. Since the US Consumer Product Safety Commission consent decree expired in 1998, there has been little movement in regulating ATV use for children (<16 yr). The authors hypothesized that states with laws and regulations restricting pediatric ATV use may abrogate excess death compared with states without such restrictions. Pediatric mortality data reported to the consumer product safety commission from 1982 to 1998 were analyzed as well as state all-terrain vehicle requirements compiled by the Specialty Vehicle Institute of America in August 2001. The authors calculated ATV mortality rate by dividing ATV mortality frequency by 1980-2000 pediatric census results. They compared the top 26 states with the highest ATV mortality rates (TOP) with those of all other states (OTH) in terms of age, ATV type, ATV occupancy, and ATV laws. Chi-square analysis was performed. There were 1,342 ATV pediatric deaths during the 16-year period. The TOP states averaged approximately a 2-fold increase in adjusted ATV mortality rate compared with the national ATV pediatric mortality rate. Ninety-two percent of TOP states have no licensing laws compared with 73% of the OTH states (P <.07). There is no difference between groups with regard to minimum age requirements and safety certification. Current legal and regulatory standards have low probability of decreasing ATV-related pediatric mortality. States should adopt laws that restrict the use of ATV's for children less than 16 years of age and potentially prevent excess ATV-related pediatric mortality.


Modified In-Office Maxillary Balloon Sinus Dilation for Post-Procedure Sinus Monitoring and Access.
Introduction As experience grows with in-office balloon sinus dilation (BSD) procedures, technique modifications will evolve to meet specific needs. The major disadvantage with the maxillary BSD procedure is that the intact uncinate process prevents visualization of and instrument access into the maxillary sinus both intraoperatively and postoperatively. Combining a partial or complete uncinectomy procedure with maxillary BSD could be beneficial in selected patients with certain maxillary sinus problems. Objective The primary objective of this study was to see if, in selected patients, combining an uncinectomy and maxillary sinus BSD together allowed visualization of and access to the maxillary sinus cavity at the time of the procedure and at follow-up visits. Method A chart review was completed for BSD cases performed from 2013 through mid-2015 identifying patients who underwent partial or complete uncinectomy with in-office maxillary sinus BSD. A total of 14 patients were identified, with 26 sinuses treated. The data collected included: difficulty or problems in performing an uncinectomy with the maxillary sinus BSD; visualization and access to the maxillary sinus cavity both intraoperatively and at follow-up visits; and occurrence of complications or late adverse sequelae. All patients completed a minimum 6-month follow-up. Results Combined uncinectomy and maxillary sinus BSD procedures were easily completed for all patients without complications, and no late adverse sequelae were encountered. The maxillary sinuses could be visualized and accessed, if needed, intraoperatively and at all follow-up visits. Conclusions In selected subsets of maxillary sinus conditions this procedure modification can provide significant benefits. A case is presented for illustration.


[A case report of primary repair for thoracic and thoracoabdominal and iliac artery aneurysms associated with severe visceral artery occlusive diseases--a redo operation for thoracoabdominal aortic aneurysm after infrarenal abdominal aortic aneurysm repair].
Abdominal aortic aneurysms can now be successfully repaired with low mortality and few early complications. On the other hand, the cases that required operations for recurrent aneurysms have been increased during long term follow-up period. In such cases, there are many difficulties for operative procedures compared to their first operations and many risk factors. A case of successful operation for the thoracoabdominal aortic aneurysm associated with severe stenotic lesions of the visceral arteries and descending thoracic aneurysm and left common iliac artery aneurysm are reported. A 74-year-old man who underwent operation for infrarenal abdominal aortic aneurysm and left nephrectomy 7 years and 9 months ago at our institution developed an aneurysm just above the proximal anastomosis with severe stenotic lesions of the visceral arteries. At the same time, descending thoracic aortic aneurysm and left common iliac artery aneurysm were associated. And he had ischemic heart disease. Under selective perfusion of the visceral arteries, graft replacement of these aneurysms and reconstruction of superior mesenteric artery and right renal artery were done. The patient had good post operative course and started oral feeding at 3 post operation day. He returned to his occupation and is doing well with no trouble one and half year after operation.


[99 percent of history].
This text is a slightly edited version of a lecture given when the author was installed as professor of environmental history at Umeå University on October 9, 1993. The author sketches tendencies in historical research--the Annales-school and the historiography of the West in the United States--leading up to the formation of environmental history as an independent field of research during the last quarter century. He comments on some recent examples of excellent scholarship--works by Alfred Crosby, Carolyn Merchant, Donald Worster--before turning to an older tradition of environmental description in 19th century geography, geology and the life sciences. He then puts environmental investigations into the framework of a general history of science starting with John Evelyn's study of the quality of the London air, published in 1661, but also mentioning major naturalists and thinkers such as Pascal, Linnaeus, Haeckel, and Humboldt. The author finally takes up the theme of biodiversity, indicating that a history of the environment and of the environmental sciences also has implications for how nature is treated today and how it will be treated in the future.


Deceleration of fetal growth rate as alternative predictor for childhood outcomes: a birth cohort study.
Small for gestational age (SGA) is frequently used to define fetal growth restriction (FGR). However, FGR describes a slowdown in fetal growth and is not synonymous with SGA, which may introduce misclassification. We investigated the effect of both on delivery and childhood outcomes. From a prospective population-based cohort study we included 7959 live singleton births with data available on second trimester estimated fetal weight (EFW) and birth weight. We used a decrease in growth of > 40 percentiles between second trimester EFW and birthweight to define a deceleration in growth. SGA was defined as birthweight <p5. Deceleration of growth occurred in 27,2% in SGA neonates and in 10,3% of neonates with an appropriate for gestational age (AGA) birthweight. Of all fetuses with decelerated growth, 90% was born AGA. SGA neonates were more often delivered by instrumental delivery or cesarean section and admitted to NICU. Both decelerated growth and SGA were associated with accelerated growth at 2 years, a smaller aortic diameter and lower left ventricular mass at 6 years. Both decelerated growth and SGA are associated with unfavorable clinical outcomes in childhood. In addition to SGA, neonates with deceleration of growth should be considered a high-risk group.


Serum neuron specific enolase level as a prognostic factor in non-small cell lung cancer.
In 93 patients with inoperable non-small cell lung carcinoma who underwent chemotherapy including cisplatin, the prognostic value of 9 factors were determined using Cox's proportional hazard model. Univariate analysis revealed that patients with a performance status of grade 2 (p < 0.01) or 3 (p < 0.05), those with stage IV disease (p < 0.05), those with a serum neuron specific enolase (NSE) level > 7.0 ng/ml (p < 0.001), and those with a low serum albumin level (p < 0.05) had a significantly worse prognosis. Multivariate analysis showed that a performance status of 2 or 3 and a high NSE serum level were associated with a significantly worse prognosis. More attention should be paid to the serum NSE level in patients with non-small cell lung carcinoma, because it not only reflects the tumor volume, but is also a prognostic factor which is dependent on individual tumor characteristics.


Female choice impacts residential male takeover in golden snub-nosed monkeys (Rhinopithecus roxellana).
In primate species with social systems consisting of one-male breeding units (OMUs), resident male takeover represents a major challenge to individual reproductive success and mating strategies. The golden snub-nosed monkey (Rhinopithecus roxellana) is characterized by large multilevel societies (MLS) comprised of several OMUs and all-male units (AMUs); however, the factors and mechanisms associated with resident male takeover, which offer important insight into primate reproduction and social strategies, are still poorly understood. Based on 5-year monitoring data from a free-ranging herd of golden monkeys from the Qinling Mountains in China, we categorized three phases of an OMU, that is, a rising phase, developing phase, and declining phase. The rising and declining phases were unstable periods in which male takeover in an OMU might occur. Factors causing takeover, such as leader male rank, fighting ability, reproduction rate, and affiliation (proximity, allogrooming), were analyzed for males and females and for different OMUs. Results indicated that the new resident male's fighting ability was lower than that of the former resident male in 23 cases. After replacement, the rank order of the new resident male significantly declined. Females involved in a takeover increased their distance from the resident male and decreased mating frequency during the three months prior to takeover. Females with infants under one-year-old had a marked effect on the specific time of takeover occurrence. These results suggested that female choice was the main factor deciding whether a takeover attempt was successful. Furthermore, rather than male conflict, females more often initiated and affected takeover and outcome, implying that the social status and competitive ability of the males played lesser roles during takeover.


Large cell carcinoma of the lung.
The diagnosis of large cell carcinoma of the lung on the basis of hematoxylin and eosin (H & E) stains represents a heterogeneous group, both endodermally and non-endodermally derived, totalling about 16% of lung cancers. By the use of special stains, such as Kreyberg and Grimelius stains, this percentage can be sharply reduced, leaving a core group of about 10%, including giant cell and clear cell variants. This core group may show a variety of ultramicroscopic organelles that are insufficiently developed to alter the light microscopic characteristics on which the diagnosis depends. In a study of 1000 slides, large cell carcinoma constituted 6% of the squamous cell carcinoma slides and 21% of the adenocarcinoma slides, which was reduced to 3% by mucin stains. Giant cells predominated in 5% and clear cells in 10% of large cell carcinoma slides. Large cells also occurred in 12% of small cell carcinoma slides.


Concurrent psychological stress and infectious colitis is key to sustaining enhanced peripheral sensory signaling.
The development of postinfectious-irritable bowel syndrome is associated with psychological stress but this relationship is poorly understood. The mouse Citrobacter rodentium model enhances the postinfectious excitability of colonic nociceptors, which can be further amplified by water-avoidance stress (WAS). This study tested whether concurrent infectious colitis and chronic stress enhance and sustain nociceptor excitability more than stress after resolution of infection. Male C57 mice were gavaged with C. rodentium. WAS (1 h/day) was performed at different time-points relative to the infection. After the final session of WAS, T9-T13 colonic-projecting DRG neurons were isolated, cultured overnight and patch-clamped to assess excitability. To investigate potential mechanisms, histological damage scores and colonic cytokine production were assessed. WAS more than 30 days after C. rodentium infection produced no greater DRG excitability than WAS in uninfected mice. However, when overlapped with chronic stress (3 sessions of WAS; 7 days before, 9 days during and 9 days after C. rodentium or sham gavage), C. rodentium significantly enhanced DRG excitability vs saline-gavaged chronically stressed mice. Bodyweights and colonic damage scores were unchanged. Both WAS and C. rodentium gavage were found to significantly alter colonic cytokines at postinfection day 30. Chronic stress and infectious colitis combine in an additive manner to heighten and prolong the sensitivity of visceral nociceptors. The effect relies on temporal coincidence of stress and infection, does not involve substantial exacerbation of inflammation, and may involve combined direct stress hormone and immune signaling on DRG neurons.


Effect of Reduced Tube Voltage on Diagnostic Accuracy of CT Colonography.
The normal tube voltage in computed tomography colonography (CTC) is 120 kV. Some reports indicate that the use of a low tube voltage (lower than 120 kV) technique plays a significant role in reduction of radiation dose. However, to determine whether a lower tube voltage can reduce radiation dose without compromising diagnostic accuracy, an evaluation of images that are obtained while maintaining the volume CT dose index (CTDIvol) is required. This study investigated the effect of reduced tube voltage in CTC, without modifying radiation dose (i.e. constant CTDIvol), on image quality. Evaluation of image quality involved the shape of the noise power spectrum, surface profiling with volume rendering (VR), and receiver operating characteristic (ROC) analysis. The shape of the noise power spectrum obtained with a tube voltage of 80 kV and 100 kV was not similar to the one produced with a tube voltage of 120 kV. Moreover, a higher standard deviation was observed on volume-rendered images that were generated using the reduced tube voltages. In addition, ROC analysis revealed a statistically significant drop in diagnostic accuracy with reduced tube voltage, revealing that the modification of tube voltage affects volume-rendered images. The results of this study suggest that reduction of tube voltage in CTC, so as to reduce radiation dose, affects image quality and diagnostic accuracy.


Schwannoma of the medulla oblongata. Case report.
A case of intraparenchymal schwannoma of the medulla oblongata is presented. The radiographic and pathological characteristics of this rare tumor are discussed, and the world literature regarding intracerebral intraparenchymal schwannomas is reviewed. The current etiological theories of these intra-axial nerve-sheath tumors are reviewed. The importance of early identification and differentiation of these potentially curable tumors from malignant glial tumors is emphasized.


Epstein-Barr virus and nasopharyngeal carcinoma.
Since its discovery 50 years ago, Epstein-Barr virus (EBV) has been linked to the development of cancers originating from both lymphoid and epithelial cells. Approximately 95% of the world's population sustains an asymptomatic, life-long infection with EBV. The virus persists in the memory B-cell pool of normal healthy individuals, and any disruption of this interaction results in virus-associated B-cell tumors. The association of EBV with epithelial cell tumors, specifically nasopharyngeal carcinoma (NPC) and EBV-positive gastric carcinoma (EBV-GC), is less clear and is currently thought to be caused by the aberrant establishment of virus latency in epithelial cells that display premalignant genetic changes. Although the precise role of EBV in the carcinogenic process is currently poorly understood, the presence of the virus in all tumor cells provides opportunities for developing novel therapeutic and diagnostic approaches. The study of EBV and its role in carcinomas continues to provide insight into the carcinogenic process that is relevant to a broader understanding of tumor pathogenesis and to the development of targeted cancer therapies.


Galectins and collectinis expression are increased in Haemonchus contortus-infected corriedale sheep.
Galectins and collectins are proteins classified in the lectin family that have the ability to recognize molecular patterns associated with pathogens. Studies on cattle have demonstrated high expression of these proteins during infection with gastrointestinal nematodes. The aim of this study was to investigate whether the level of Haemonchus contortus infection would alter the expression of galectins (Gal11 and Gal14) and collectins (SPA and CGN) in sheep. Twelve Corriedale sheep exposed to natural infection with nematodes were divided into two groups: group 1 (G1, n = 7) and group 2 (G2, n = 5), with low and high parasite burdens, respectively, based on fecal egg counts and abomasal parasite counts. The fecal egg counts and abomasal parasite counts were significantly different (p < 0.05) between the groups. Galectin and collectin gene expression was observed in all sheep abomasal samples. However, animals with lower infection levels showed lower expression of the genes Gal14, SPA and CGN (p < 0.05). Expression of lectins was associated with the abomasal H. contortus burden, thus suggesting that these proteins may have a role in controlling of this infection.


Corticotectal circuit in the cat: a functional analysis of the lateral geniculate nucleus layers of origin.
1. The dorsal lateral geniculate nucleus (LGN) of the cat is a major thalamic relay between the retina and several visual cortical areas. These cortical areas in turn project to the superior colliculus (SC). The aim of the present experiment was to determine which LGN layers provide a necessary input to the corticotectal circuit. 2. Individual layers of the LGN were reversibly inactivated by microinjection of cobalt chloride during recording of visual responses in the retinotopically corresponding part of the superior colliculus. 3. For cells driven through the contralateral eye, inactivation of layer A or the medial interlaminar nucleus (MIN) had little effect on visual responsiveness in the superior colliculus. In contrast, inactivation of layer C abolished visual responses at one-quarter of the SC recording sites, reduced responses at another quarter, and left half of the recording sites unaffected. 4. For cells driven through the ipsilateral eye, inactivation of layer C1 or the MIN had no effect. Inactivation of layer A1 uniformly reduced visual responses in the superior colliculus and usually abolished them entirely. 5. These results are compatible with previous work showing that cortical input to the SC originates from Y-cells. They indicate that two of the five Y-cell containing layers (A1 and C) provide major inputs to the corticotectal circuit. The results suggest that layer A1 is functionally allied to layer C as well as to layer A.


Elucidation of binding mechanism, affinity, and complex structure between mWT1 tumor-associated antigen peptide and HLA-A*24:02.
We have applied our advanced computational and experimental methodologies to investigate the complex structure and binding mechanism of a modified Wilms' Tumor 1 (mWT1) protein epitope to the understudied Asian-dominant allele HLA-A*24:02 (HLA-A24) in aqueous solution. We have applied our developed multicanonical molecular dynamics (McMD)-based dynamic docking method to analyze the binding pathway and mechanism, which we verified by comparing the highest probability structures from simulation with our experimentally solved x-ray crystal structure. Subsequent path sampling MD simulations elucidated the atomic details of the binding process and indicated that first an encounter complex is formed between the N-terminal's positive charge of the 9-residue mWT1 fragment peptide and a cluster of negative residues on the surface of HLA-A24, with the major histocompatibility complex (MHC) molecule preferring a predominantly closed conformation. The peptide first binds to this closed MHC conformation, forming an encounter complex, after which the binding site opens due to increased entropy of the binding site, allowing the peptide to bind to form the native complex structure. Further sequence and structure analyses also suggest that although the peptide loading complex would help with stabilizing the MHC molecule, the binding depends in a large part on the intrinsic affinity between the MHC molecule and the antigen peptide. Finally, our computational tools and analyses can be of great benefit to study the binding mechanism of different MHC types to their antigens, where it could also be useful in the development of higher affinity variant peptides and for personalized medicine.


A systematic review of the effects of e-cigarette use on lung function.
Given the increasing use of e-cigarettes and uncertainty surrounding their safety, we conducted a systematic review to determine the effects of e-cigarettes on measures of lung function. We systematically searched EMBASE, MEDLINE, and PsycINFO databases via Ovid, the Cochrane CENTRAL database, and the Web of Science Core from 2004 until July 2021, identifying 8856 potentially eligible studies. A total of eight studies (seven studying immediate effects and one long-term effects, 273 total participants) were included. The risk of bias was assessed using the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) and Cochrane risk of bias tools. These studies suggest that vaping increases airway resistance but does not appear to impact forced expiratory volume in one second (FEV1), forced vital capacity (FVC), or FEV1/FVC ratio. However, given the limited size and follow-up duration of these studies, larger, long-term studies are required to further determine the effects of e-cigarettes on lung function.


Using Technology to Improve Access to Mental Health Services.
Mental ill-health is a public health threat that is prevalent throughout the United States. Tens of millions of Americans have been diagnosed along the continuum of mental ill-health, and many more millions of family members and friends are indirectly affected by the pervasiveness of mental ill-health. Issues such as access and the societal stigma related to mental health issues serve as deterrents to patients receiving their necessary care. However, technological advances have shown the potential to increase access to mental health services for many patients.


Mode of action of estra-1,3,5(10)-triene-3, 17 beta-diol, 3-benzoate, 17[4-[4-[bis(2-chloroethyl)amino]phenyl]-1-oxobutoxy] acetate] (KM2210) on MCF-7 human breast tumours transplanted into nude mice.
KM2210 is a benzoate of an estradiol-chlorambucil conjugate with three active metabolites, KM2202, estradiol (E2) and chlorambucil (CBL). The mode of action of this compound was assessed using MCF-7 human breast tumours transplanted into nude mice. The growth of MCF-7 in nude mice was inhibited by KM2210 and enhanced by E2, although the serum levels of E2 in nude mice treated with KM2210 and E2 were similar. The antitumour activity of CBL was completely blocked by extrinsic E2, while KM2210 suppressed the growth of MCF-7 in spite of the presence of E2 in the serum of tumour-bearing nude mice. KM2210 and KM2202 suppressed the expression of cytosol estrogen receptor (ER) of MCF-7 cells detected by the dextran-coated charcoal and fluorescent E2 staining method, although CBL did not affect the ER expression of MCF-7 cells. This inhibitory effect of KM2210 on ER was also corroborated by the fact that the pretreatment with KM2210 prevented the E2-stimulated growth of MCF-7 in nude mice. These results indicated that one of the effects induced by KM2210 is the blockage of ER expression in combination with the alkylating antitumour activity of CBL. KM2210 is thought to be a promising agent with unique modes of action for ER-positive breast carcinomas.


Defining the full therapeutic potential of recombinant growth factors in the post radiation-accident environment: the effect of supportive care plus administration of G-CSF.
Radiation accidents are uncontrolled and ill-defined, the exposure is nonuniform and may be partial body, forecasting a variable dose distribution and sparing of hematopoietic stem cells. We propose that the "best" treatment protocol available now for severely irradiated personnel with acute hematopoietic syndrome is the combination of supportive care and administration of recombinant cytokines as soon as possible after irradiation. Herein, we demonstrate the significant effect of G-CSF administration on lethally irradiated canines. G-CSF administered early and continuously after irradiation increased neutrophil recovery and survival over a lethal and supralethal dose range. The respective LD50/30 for the control, supportive care-alone cohorts of 338 cGy, was increased to 488 cGy with administration of G-CSF. Clearly, the use of supportive care and G-CSF enhanced recovery of myelopoiesis and survival after lethal doses of irradiation.


Fast, simple and calibration-free size characterization and quality control of extracellular vesicles using capillary Taylor dispersion analysis.
This study reports the development of a Taylor Dispersion Analysis (TDA) method for the size characterization of Extracellular Vesicles (EVs), which are highly heterogeneous nanoscale cell-derived vesicles (30-1000 nm). Here, we showed that TDA, conducted in uncoated fused silica capillaries (50 µm i.d.) using a conventional Capillary Electrophoresis instrument, is able to provide absolute sizing (requiring no calibration) of bovine milk-derived EVs in a small sample volume (∼ 7 nL) and over their entire size range, even the smallest ones (< 70 nm) not accessible via other techniques that provide nanoparticle sizing in suspension. TDA size measurements were repeatable (RSD < 10%) and the average EV sizes were found in the range of 120-210 nm, in very good agreement with those measured with Nanoparticle Tracking Analysis, commonly used for EV characterization. TDA allowed quantitative estimation of EVs for concentrations ≥ 2 × 1011 EVs/mL. Furthermore, TDA was able to detect minor changes in EV size (i.e. by ∼25 nm upon interaction with specific anti-CD9 antibodies of ∼150 kDa), and to highlight the impact of extraction methods (i.e. milk pretreatment: freezing, acid precipitation or centrifugation; the type of size-exclusion chromatography column) and of fluorescent labeling (i.e. intravesicular or surface labeling) on the isolated EV population size. In parallel to EV sizing, TDA allowed to detect molecular contaminants (average sizes ∼1-13 nm) present within the sample, rendering this method a valuable tool to assess the quality and quantity of EV isolates.


Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens.
A 48-year-old woman with profound, rapidly progressive dyspnea requested a second opinion regarding the diagnosis and management of an undiagnosed interstitial process. One year prior to this evaluation, she had been placed on therapy with exogenous estrogens for the treatment of osteoporosis. During this therapy, she had a marked deterioration of her pulmonary status. Review of her open lung biopsy, which was obtained five years previously, revealed lymphangioleiomyomatosis. Discontinuation of estrogen therapy and treatment with tamoxifen were successful in stopping the progressive course. This patient's clinical course suggested an association between estrogen therapy and clinical deterioration during the menopause.


Proton-Based Ultrafast Magic Angle Spinning Solid-State NMR Spectroscopy.
Protons are vastly abundant in a wide range of exciting macromolecules and thus can be a powerful probe to investigate the structure and dynamics at atomic resolution using solid-state NMR (ssNMR) spectroscopy. Unfortunately, the high signal sensitivity, afforded by the high natural-abundance and high gyromagnetic ratio of protons, is greatly compromised by severe line broadening due to the very strong 1H-1H dipolar couplings. As a result, protons are rarely used, in spite of the desperate need for enhancing the sensitivity of ssNMR to study a variety of systems that are not amenable for high resolution investigation using other techniques including X-ray crystallography, cryo-electron microscopy, and solution NMR spectroscopy. Thanks to the remarkable improvement in proton spectral resolution afforded by the significant advances in magic-angle-spinning (MAS) probe technology, 1H ssNMR spectroscopy has recently attracted considerable attention in the structural and dynamics studies of various molecular systems. However, it still remains a challenge to obtain narrow 1H spectral lines, especially from proteins, without resorting to deuteration. In this Account, we review recent proton-based ssNMR strategies that have been developed in our laboratory to further improve proton spectral resolution without resorting to chemical deuteration for the purposes of gaining atomistic-level insights into molecular structures of various crystalline solid systems, using small molecules and peptides as illustrative examples. The proton spectral resolution enhancement afforded by the ultrafast MAS frequencies up to 120 kHz is initially discussed, followed by a description of an ensemble of multidimensional NMR pulse sequences, all based on proton detection, that have been developed to obtain in-depth information from dipolar couplings and chemical shift anisotropy (CSA). Simple single channel multidimensional proton NMR experiments could be performed to probe the proximity of protons for structure determination using 1H-1H dipolar couplings and to evaluate the changes in chemical environments as well as the relative orientation to the external magnetic field using proton CSA. Due to the boost in signal sensitivity enabled by proton detection under ultrafast MAS, by virtue of high proton natural abundance and gyromagnetic ratio, proton-detected multidimensional experiments involving low-γ nuclei can now be accomplished within a reasonable time, while the higher dimension also offers additional resolution enhancement. In addition, the application of proton-based ssNMR spectroscopy under ultrafast MAS in various challenging and crystalline systems is also presented. Finally, we briefly discuss the limitations and challenges pertaining to proton-based ssNMR spectroscopy under ultrafast MAS conditions, such as the presence of high-order dipolar couplings, friction-induced sample heating, and limited sample volume. Although there are still a number of challenges that must be circumvented by further developments in radio frequency pulse sequences, MAS probe technology and approaches to prepare NMR-friendly samples, proton-based ssNMR has already gained much popularity in various research domains, especially in proteins where uniform or site-selective deuteration can be relatively easily achieved. In addition, implementation of the recently developed fast data acquisition approaches would also enable further developments in the design and applications of proton-based ultrafast MAS multidimensional ssNMR techniques.


Tunable Magnetic Phases at Fe3O4/SrTiO3 Oxide Interfaces.
We demonstrate the emergence and control of magnetic phases between magnetite (Fe3O4), a ferrimagnetic halfmetal, and SrTiO3, a transparent nonmagnetic insulator considered the bedrock of oxide-based electronics. The Verwey transition ( TV) was detected to persist from bulk-like down to ultrathin Fe3O4 films, decreasing from 117 ± 4 K (38 nm) to 25 ± 4 K (2 nm), respectively. Element-selective electronic and magnetic properties of the ultrathin films and buried interfaces are studied by angle-dependent hard X-ray photoelectron spectroscopy and X-ray magnetic circular dichroism techniques. We observe a reduction of Fe2+ ions with decreasing film thickness, accompanied by an increase of Fe3+ ions in both tetrahedral and octahedral sites and conclude on the formation of a magnetically active ferrimagnetic 2 u.c. γ-Fe2O3 intralayer. To manipulate the interfacial magnetic phase, a postannealing process causes the controlled reduction of the γ-Fe2O3 that finally leads to stoichiometric and ferrimagnetic Fe3O4/SrTiO3(001) heterointerfaces.