Folate receptor-mediated boron-10 containing carbon nanoparticles as potential delivery vehicles for boron neutron capture therapy of nonfunctional pituitary adenomas.
Invasive nonfunctional pituitary adenomas (NFPAs) are difficult to completely resect and often develop tumor recurrence after initial surgery. Currently, no medications are clinically effective in the control of NFPA. Although radiation therapy and radiosurgery are useful to prevent tumor regrowth, they are frequently withheld because of severe complications. Boron neutron capture therapy (BNCT) is a binary radiotherapy that selectively and maximally damages tumor cells without harming the surrounding normal tissue. Folate receptor (FR)-targeted boron-10 containing carbon nanoparticles is a novel boron delivery agent that can be selectively taken up by FR-expressing cells via FR-mediated endocytosis. In this study, FR-targeted boron-10 containing carbon nanoparticles were selectively taken up by NFPAs cells expressing FR but not other types of non-FR expressing pituitary adenomas. After incubation with boron-10 containing carbon nanoparticles and following irradiation with thermal neutrons, the cell viability of NFPAs was significantly decreased, while apoptotic cells were simultaneously increased. However, cells administered the same dose of FR-targeted boron-10 containing carbon nanoparticles without neutron irradiation or received the same neutron irradiation alone did not show significant decrease in cell viability or increase in apoptotic cells. The expression of Bcl-2 was down-regulated and the expression of Bax was up-regulated in NFPAs after treatment with FR-mediated BNCT. In conclusion, FR-targeted boron-10 containing carbon nanoparticles may be an ideal delivery system of boron to NFPAs cells for BNCT. Furthermore, our study also provides a novel insight into therapeutic strategies for invasive NFPA refractory to conventional therapy, while exploring these new applications of BNCT for tumors, especially benign tumors.


RNA polymerase sigma factor determines start-site selection but is not required for upstream promoter element activation on heteroduplex (bubble) templates.
Sequence-selective transcription by bacterial RNA polymerase (RNAP) requires sigma factor that participates in both promoter recognition and DNA melting. RNAP lacking sigma (core enzyme) will initiate RNA synthesis from duplex ends, nicks, gaps, and single-stranded regions. We have used DNA templates containing short regions of heteroduplex (bubbles) to compare initiation in the presence and absence of various sigma factors. Using bubble templates containing the sigmaD-dependent flagellin promoter, with or without its associated upstream promoter (UP) element, we demonstrate that UP element stimulation occurs efficiently even in the absence of sigma. This supports a model in which the UP element acts primarily through the alpha subunit of core enzyme to increase the initial association of RNAP with the promoter. Core and holoenzyme do differ substantially in the template positions chosen for initiation: sigmaD restricts initiation to sites 8-9 nucleotides downstream of the conserved -10 element. Remarkably, sigmaA also has a dramatic effect on start-site selection even though the sigmaA holoenzyme is inactive on the corresponding homoduplexes. The start sites chosen by the sigmaA holoenzyme are located 8 nucleotides downstream of sequences on the nontemplate strand that resemble the conserved -10 hexamer recognized by sigmaA. Thus, sigmaA appears to recognize the -10 region even in a single-stranded state. We propose that in addition to its described roles in promoter recognition and start-site melting, sigma also localizes the transcription start site.


Protease inhibitors potentiate chemotherapy-induced neutropenia.
Pharmacokinetic interactions between chemotherapy and highly active antiretroviral therapy (HAART) are described, but there are few data on their clinical relevance. Patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) were treated with concomitant HAART and infusional cyclophosphamide-doxorubicin-etoposide (CDE) chemotherapy. We compared neutropenia according to whether patients received protease inhibitor (PI)-based HAART or non-PI regimens. Differences in survival, response rates, immunologic parameters, and virologic parameters were also investigated. The day-10 (Mann-Whitney U test; P = .012) and day-14 (P = .025) neutrophil counts were significantly lower in patients receiving PIs, though there were no differences in the number of days of granulocyte colony-stimulating factor (G-CSF) administered between groups (P = .16). Grade 3 or 4 infections requiring hospitalization were recorded for a total of 58 (31%) of 190 cycles of CDE: 23 (48%) of 48 when prescribed PIs and 35 (25%) of 142 with concomitant PI-sparing HAART (chi(2) test; P = .0025). There were no statistically significant differences in the response rates, relapse-free survival, or disease-free survival between patients receiving PIs and those not receiving PIs. PI-based HAART appears to significantly potentiate the myelotoxicity of CDE chemotherapy. This potentiation may be a consequence of microsomal enzyme inhibition reducing the metabolism of cytotoxics in this regimen.


Clinician-generated torque on abutment screws using different hand screwdrivers.
Many clinicians use hand screwdrivers to tighten prosthetic and abutment screws. The impact of the screwdriver type, the location of the implant, and the sex of the practitioner on the generated torque is not well understood. The purpose of this in vitro study was to compare the torque generated by different hand screwdrivers when used in the anterior and posterior regions and to evaluate the correlation between the applied torque and the sex and body mass index (BMI) of the practitioner. A mandibular typodont with anterior and posterior implants was mounted in a mannequin head. Fifty clinicians (6 prosthodontists, 8 graduate prosthodontic students, and 36 dental students) used their maximum force to tighten the abutment screws in the anterior and posterior regions, using 3 different hand screwdrivers, with handles of different shapes and sizes (small, medium, and large). The torque values generated were measured using torque meters connected to the implants. The generated torque, sex, age, height, and weight were also recorded for each clinician. A generalized linear model was used to find correlations between the different factors and the generated torque (α=.05). Significant differences were observed among the applied torque values when different screwdrivers were used (P<.001). Higher torque values were generated in the anterior region than in the posterior region (P<.001). The interaction of the sex and BMI of the participants significantly affected the generated torque values (P=.044). The type of screwdriver and location of the implant affected the generated torque. Torque values generated by the large screwdriver were higher than those of small and medium screwdrivers. Higher torque was applied in the anterior region.


Calcium-Free and Cytochalasin B Treatment Inhibits Blastomere Fusion in 2-Cell Stage Embryos for the Generation of Floxed Mice via Sequential Electroporation.
The generation of conditional knockout mice using the Cre-loxP system is advantageous for the functional analysis of genes. Flanked by two loxP sites (floxed) mice can be directly obtained from fertilized eggs by the CRISPR/Cas9 genome editing system. We previously reported that sequential knock-in (KI) of each loxP site by electroporation (EP) at the 1- and 2-cell embryonic stages increases the number of mice with floxed alleles compared with simultaneous KI. However, EP at the 2-cell stage frequently induced blastomere fusion. These fused embryos cannot develop to term because they are tetraploidized. In this study, we examined the following three conditions to inhibit blastomere fusion by EP at the 2-cell stage: (1) hypertonic treatment, (2) Calcium (Ca2+)-free treatment, and (3) actin polymerization inhibition. Hypertonic treatment of 2-cell stage embryos prevented blastomere fusion and facilitated blastocyst development; however, KI efficiency was decreased. Ca2+-free treatment and actin polymerization inhibition by cytochalasin B (CB) reduced fusion rate, and did not have negative effects on development and KI efficiency. These results suggest that Ca2+-free and CB treatment at the 2-cell stage is effective to generate floxed mice in combination with a sequential EP method.


Age-related differences in pulmonary inflammatory responses to JP-8 jet fuel aerosol inhalation.
Our previous studies have demonstrated that JP-8 jet fuel aerosol inhalation induced lung injury and dysfunction. To further examine JP-8 jet fuel-induced inflammatory mechanisms, a total of 40 male C57BL/6 mice (young, 3.5 months; adult, 12 months; half in each age group) were randomly assigned to the exposure or control groups. Mice were nose-only exposed to room air or atmospheres of 1000 mg/m3 JP-8 jet fuel for 1 h/day for 7 days. Lung injury was assessed by pulmonary mechanics, respiratory permeability, lavaged cell profile, and chemical mediators in bronchoalveolar lavage fluid (BALF). The young and adult mice exposed to JP-8 jet fuel had similar values with regards to increased lung dynamic compliance, lung permeability, BALF cell count, and decreased PGE2. However, there were several different responses between the young-versus-adult mice with respect to BALF cell differential, TNF-alpha, and 8-iso-PGF2,, levels after exposure to JP-8 jet fuel. These data suggest that JP-8 jet fuel may have different inflammatory mechanisms leading to lung injury and dysfunction in the younger-versus-adult mice.


Detection of early onset of hypophysitis by (18)F-FDG PET-CT in a patient with advanced stage melanoma treated with ipilimumab.
Ipilimumab is a human monoclonal antibody directed against a receptor expressed on activated T-lymphocytes (CTLA-4). Binding to this receptor induces T-cell activation against tumor cells. A 77-year-old man with a stage IV metastatic melanoma was treated with ipilimumab. F-FDG PET-CT performed for response evaluation revealed intense uptake in the pituitary gland. Two weeks later, biochemical parameters altered confirming hypophysitis. Treatment of the hypophysitis was started, and shortly thereafter, biochemical parameters normalized. Follow-up PET-CT revealed normalization of F-FDG uptake in the pituitary gland. In this case, we present a patient with ipilimumab-induced hypophysitis initially diagnosed on F-FDG PET-CT.


A retrospective analysis and review of an institution's experience with the complications of cranioplasty.
Cranial reconstruction with a cranioplasty is performed to repair skull defects after decompressive craniectomies. To retrospectively review all cranioplasties performed in our institution over 10 years and analyse the complications and the factors that cause complications. Two hundred and forty-three cranioplasties were performed from 2000 to 2010, with a follow-up of at least 1 year. Age, sex, comorbidities, material, site of skull defect, time between decompression and cranioplasty, and rate of complications were collected from our database. Fischer's T-test and direct logistical regression were performed to identify factors that contributed to the rate of complications. p < 0.05 was considered significant. Post-cranioplasty seizures (14.81%), infection and exposed implant (9.05%), haemorrhage (1.65%) and others (0.82%) were identified complications. Total percentage of complications was 25.92%. Previous trauma (p = 0.034) and intracranial haemorrhage (p = 0.019) as well as pre-cranioplasty neurological deficit (p = 0.046) were related to seizures, while pre-cranioplasty neurological deficit (p = 0.036) and exposed implant extrusion (p = 0.048) contributed to infection of cranioplasties. Most of the seizures may be post-traumatic seizures or scar epilepsy from intracranial haemorrhage. Implant extrusions were found to be associated with infection of the implant, and they should therefore be treated early. Patient selection is important as patients with neurological deficits were susceptible to seizures and infection. Intracranial haemorrhage was caused by persistant bleeding, trauma or shunt overdrainge. Cranioplasty has significant complications. A thorough understanding of factors that contribute to the different types of complications will benefit the management of cranioplasty patients.


Multinucleated giant cells in periretinal silicone granulomas are associated with progressive proliferative vitreoretinopathy.
To determine the histologic features of granulomatous reactions in persilicone periretinal proliferation. This retrospective study included 12 patients with recurrent retinal detachment and persilicone granulomatous proliferation after vitrectomy for proliferative vitreoretinopathy (PVR). All patients underwent reoperation for membrane surgery. Immunohistochemical study of the excised periretinal membranes was performed with cytokeratins, GFAP, vimentin, CD68, CD45, and lysozyme antibodies. The cellular characteristics of periretinal granulomas allow differentiation of two types of tissue. Spongy tissue (nine cases) showed an accumulation of mature vacuolated macrophages that contained silicone without multinucleated giant cells (MGC). The second type (three cases) consisted of an accumulation of sparsely vacuolated macrophages, epithelioid cells, and MGC. The MGC corresponded to transition forms of foreign body giant cells (FBGC). Spongy tissue was associated with anatomic success (58.3% of cases) and with stabilized PVR (66.7% of cases) at the time of the membrane surgery. MGC were associated with prolonged silicone oil tamponade, recurrent retinal detachment, and progressive PVR. Intraocular silicone oil can lead to periretinal foreign body granulomas. FBGC are occasionally observed and were associated with progressive PVR.


E3 Ubiquitin Ligases: Ubiquitous Actors in Plant Development and Abiotic Stress Responses.
Understanding the precise regulatory mechanisms of plant development and stress responses at the post-translational level is currently a topic of intensive research. Protein ubiquitination, including the sequential performances of ubiquitin-activating (E1), ubiquitin-conjugating (E2) and ubiquitin ligase (E3) enzymes, is a refined post-translational modification ubiquitous in all eukaryotes. Plants are an integral part of our ecosystem and, as sessile organisms, the ability to perceive internal and external signals and to adapt well to various environmental challenges is crucial for their survival. Over recent decades, extensive studies have demonstrated that protein ubiquitination plays key roles in multiple plant developmental stages (e.g. seed dormancy and germination, root growth, flowering time control, self-incompatibility and chloroplast development) and several abiotic stress responses (e.g. drought and high salinity), by regulating the abundance, activities or subcellular localizations of a variety of regulatory polypeptides and enzymes. Importantly, diverse E3 ligases are involved in these regulatory pathways by mediating phytohormone and light signaling or other pathways. In this updated review, we mainly summarize recent advances in our understanding of the regulatory roles of protein ubiquitination in plant development and plant-environment interactions, and primarily focus on different types of E3 ligases because they play critical roles in determining substrate specificity.


[Correction of local and central disorders in patients with chronic abacterial prostatitis in usage of amus-01-intramag unit].
Combined use of dynamic magnetotherapy of local and central action in combination with antibacterial endourethral therapy and rectal administration of vitaprost arrests symptoms of chronic prostatitis. Combination of local and total dynamic magnetotherapy with application of AMUS-01-INTRAMAG unit improves erection quality in 81.8% males with psychogenic form of erectile dysfunction. There was also improvement of spermogram parameters and relieve of asthenovegetative syndrome.


The genetics of osteosarcoma.
Osteosarcoma is a primary bone malignancy with a particularly high incidence rate in children and adolescents relative to other age groups. The etiology of this often aggressive cancer is currently unknown, because complicated structural and numeric genomic rearrangements in cancer cells preclude understanding of tumour development. In addition, few consistent genetic changes that may indicate effective molecular therapeutic targets have been reported. However, high-resolution techniques continue to improve knowledge of distinct areas of the genome that are more commonly associated with osteosarcomas. Copy number gains at chromosomes 1p, 1q, 6p, 8q, and 17p as well as copy number losses at chromosomes 3q, 6q, 9, 10, 13, 17p, and 18q have been detected by numerous groups, but definitive oncogenes or tumour suppressor genes remain elusive with respect to many loci. In this paper, we examine studies of the genetics of osteosarcoma to comprehensively describe the heterogeneity and complexity of this cancer.


[Prenatal diagnosis].
There is probably no other medical field which has undergone such rapid development during the past 20 years as prenatal diagnosis. The number of women who desire this assistance is steadily increasing and more and more techniques have become available which enable a growing number of genetic defects to be diagnosed with certainty prior to birth. Prenatal diagnosis is a significant tool of genetic counselling.


Assessment of Aerobic Exercise Adverse Effects during COPD Exacerbation Hospitalization.
Introduction. Aerobic exercise performed after hospital discharge for exacerbated COPD patients is already recommended to improve respiratory and skeletal muscle strength, increase tolerance to activity, and reduce the sensation of dyspnea. Previous studies have shown that anaerobic activity can clinically benefit patients hospitalized with exacerbated COPD. However, there is little information on the feasibility and safety of aerobic physical activity performed by patients with exacerbated COPD during hospitalization. Objective. To evaluate the effects of aerobic exercise on vital signs in hospitalized patients with exacerbated COPD. Patients and Methods. Eleven COPD patients (63% female, FEV1: 34.2 ± 13.9% and age: 65 ± 11 years) agreed to participate. Aerobic exercise was initiated 72 hours after admission on a treadmill; speed was obtained from the distance covered in a 6-minute walk test (6MWT). Vital signs were assessed before and after exercise. Results. During the activity systolic blood pressure increased from 125.2 ± 13.6 to 135.8 ± 15.0 mmHg (p = 0.004) and respiratory rate from 20.9 ± 4.4 to 24.2 ± 4.5 rpm (p = 0.008) and pulse oximetry (SpO2) decreased from 93.8 ± 2.3 to 88.5 ± 5.7% (p < 0.001). Aerobic activity was considered intense, heart rate ranged from 99.2 ± 11.5 to 119.1 ± 11.1 bpm at the end of exercise (p = 0.092), and patients reached on average 76% of maximum heart rate. Conclusion. Aerobic exercise conducted after 72 hours of hospitalization in patients with exacerbated COPD appears to be safe.


White up-conversion luminescence power and efficiency in Yb(3+)-, Er(3+)- and Tm(3+)-doped BaIn6Y2O13.
A series of BaIn6Y2O13:Yb(3+), Er(3+), Tm(3+) phosphors with different dopant concentrations have been successfully synthesized by a sol-gel method. In order to obtain efficient white light emitting samples, tri-doped and biphasic samples were prepared. Afterwards, we carried out a systematic study on the up-conversion luminescence (UCL) properties of the samples as functions of doping concentrations and excitation densities. The up-conversion (UC) white light emission powers and efficiencies of samples with different dopant concentrations at different excitation power densities were obtained. The highest white UCL efficiency of up to 0.38% was achieved at excitation densities down to 17.5 W cm(-2) in the biphasic samples. More importantly, we demonstrated that the UC materials with higher efficiency do not necessarily have stronger emission power, and the emission power is the most important parameter. A maximum emission power of up to 1.23 mW was obtained. Furthermore, the impact of temperature on the white UCL was studied, and transparent polymer composites that can emit white light were synthesized by doping BaIn6Y2O13 samples into polymethylmethacrylate (PMMA).


Goat and cow milk differ in altering microbiota composition and fermentation products in rats with gut dysbiosis induced by amoxicillin.
Antibiotics are effective treatments for bacterial infections, however, their oral administration can have unintended consequences and may alter the gut microbiota composition. In this study, we examined the influence of antibiotics on the induction of gut dysbiosis and then evaluated the potential of cow and goat milk to restore the microbiota composition and metabolism in newly weaned rats. In the first study (gut dysbiosis model), rats were treated with amoxicillin, a mixture of antibiotics (ampicillin, gentamicin and metronidazole) or no antibiotics (control). Antibiotics reduced the rat body weights, food intakes and faecal outputs compared to the control group. Gut length was significantly decreased after the antibiotic intake. The bacterial populations (Bifidobacterium spp., Lactobacillus spp. and total bacteria) and short-chain fatty acids (SCFAs; acetic, butyric and propionic) concentrations in rat caecum, colon and faeces were significantly altered by the antibiotic treatments. In the second study, we examined the effects of cow and goat milk in restoring bacterial populations and metabolism in rats with gut dysbiosis induced by amoxicillin. Goat milk significantly increased the numbers of Bifidobacterium spp. and Lactobacillus spp. and decreased the numbers of Clostridium perfringens in the caecum and colon of rats treated with amoxicillin. Whereas, rats fed cow milk had higher Lactobacillus spp. and lower C. perfringens in the gut. Caecal and colonic SCFAs (acetic, butyric and propionic) concentrations differed significantly between rats fed cow and goat milk diets. Overall, goat and cow milk varied in their effects on the immature gut following antibiotic-induced dysbiosis in a rat model.


Antinociceptive and anti-inflammatory activities of the ethanolic extract, fractions and 8-methoxylapachenol from Sinningia allagophylla tubers.
This study investigated the antinociceptive and anti-inflammatory activities of the ethanolic extract (EESAl), fractions and the compound 8-methoxylapachenol (8ML) obtained from the tubers of Sinningia allagophylla. Male Swiss mice were treated with EESAl (3-300 mg/kg) or vehicle by oral route (p.o.) 1 hr before the injection of formalin 2.5% or carrageenan (Cg) into the hind paw. EESAl (3-30 mg/kg) reduced the inflammatory phase of the nociceptive behaviour induced by formalin (around 65% for all doses). EESAl (3-300 mg/kg, p.o.) also reduced Cg-induced mechanical hyperalgesia and oedema in a dose-dependent fashion but did not change the hot-plate latency or the motor performance of the animals. Oral administration of petroleum ether fraction (PE, 3 mg/kg), but not in the methanolic fraction (30 mg/kg), reduced both Cg-induced oedema and hyperalgesia. Compound 8ML isolated from PE (1.8 mg/kg, p.o.) abolished Cg-induced hyperalgesia but also did not change hot-plate latency or motor performance of the animals. 8ML administration into the paw (0.75-750 pg) dose-dependently reduced Cg-induced hyperalgesia. 8ML (750 pg) also blocked the hyperalgesia induced by tumour necrosis factor (TNF-α), interleukin-1β (IL-1β) and prostaglandin E2 (PGE2 ) but failed to change the hyperalgesia induced by cytokine-induced neutrophil chemoattractant-1 (CINC-1) and dopamine (Dopa). These results suggest that EESAl has an important antinociceptive and anti-inflammatory activity, the former one related, at least in part, to the reduction in the hyperalgesia. Similarly, 8ML reduced Cg-induced oedema and mechanical hyperalgesia and seems to act in peripheral sites and on the prostaglandin rather than on the sympathetic component of the Cg-inflammatory hyperalgesia.


Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.
Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies.


Research on Adaptive Multi-Source Information Fault-Tolerant Navigation Method Based on No-Reference System Diagnosis.
In order to obtain accurate and optimized navigation sensor information, it is necessary to study information fusion and fault diagnosis with high reliability, high precision and high autonomy, and then to propose a rapid and accurate intelligent decision-making scheme based on multi-source and heterogeneous navigation information. In view of the existing fault-tolerant navigation federated filter structure, the method of assuming the reference system (inertial navigation system) to be fault-free and then diagnosing the measuring sensor fault is generally adopted. Considering that the structure of the filter can't detect and isolate the faults of the inertial navigation system, the performance of the MEMS inertial navigation system declines due to complex environments resulting from vibrations and temperature changes; additionally, external interference may lead to the direct failure of the MEMS inertial device. Therefore, this paper studies a fault-tolerant navigation method based on a no-reference system. For the sensor sub-system of a custom micro air vehicle (MAV), a fault detection method based on a reference-free system is proposed. Based on the fault type analysis, some improvements have been made to the existing residual chi-square detection method, and an interactive residual fault detection method with distributed states is proposed. On this basis, aiming at the characteristics of a reference-free system, the weight distribution scheme of the reference system and the tested systems are studied, and a self-regulation filter fusion and fault detection method based on reference-free system is designed.


Spinal anesthesia for elective ceasarean section: use of different doses of hyperbaric bupivacaine associated with morphine and clonidine.
To comparatively study the efficacy and maternal and fetal side-effects of two doses of bupivacaine associated with morphine and clonidine, administered by the subarachnoid route for cesarean section. The study included 66 pregnant women at term, distributed into two groups. GI: bupivacaine 8.0 mg (1.6 mL) + clonidine 75 µg (0.5 mL) + morphine 100 µg (1.0 mL) and GII: bupivacaine 10 mg (2.0 mL) + clonidine 75 µg (0.5 mL) + morphine 100 µg (1.0 mL). The following parameters were assessed: onset and maximum level of sensory block; quality of intraoperative and postoperative analgesia; degree and duration of motor block; maternal repercussions and Apgar score. The onset of sensory block, quality of intraoperative analgesia and total duration of analgesia were similar in both groups; maximum extent of sensory block predominated in T4; maximum degree of motor block (Bromage 3); time motor block regression was significantly longer in GII; Hemodynamic, respiratory repercussions, adverse maternal effects and Apgar scores were similar between groups. In both groups, there was a predominance of drowsy or sleeping patients. The addition of morphine and clonidine to low doses of hyperbaric bupivacaine produced adequate anesthesia for cesarean section and good postoperative analgesia, without any maternal and fetal repercussions.


Spontaneous regression of a metastatic carcinoma transmitted by a kidney graft.
Transmission of a malignancy from a donor's organ to the recipient of the graft is a rare event, though it is a severe complication that can result in a poor outcome. Usually, immunosuppressive therapy is discontinued and the allograft is removed. However, treatment of patients with the disseminated cancers implies that after the graft removal and cessation of the immunosuppression, radiotherapy, chemotherapy, or immunotherapy with alpha-interferon (INF-α) or interleukin-2 (IL-2) are required. The case report presents a clinical case of a transmitted kidney graft with multiple metastases (MTS) in a 31-year-old woman with the spontaneous regression of the metastatic cancer after transplantectomy and cancellation of the immunosuppressive therapy. Obviously, the determining factor is the recognition of the tumor by the effectors of the antitumor immunity due to the human leukocyte antigen (HLA) mismatch between the donor and the recipient. Therefore, cancellation of the immunosuppressive therapy in cases of transferal of a malignancy with a transplanted organ allows the effectors of the immune system to distinguish the tumor as a foreign tissue and effectively eliminate this neoplasm.


A Novel Mutation on RAF1 in Association with Fetal Findings Suggestive of Noonan Syndrome.
Noonan syndrome is a multisystem genetic disorder caused by genes encoding proteins involved in the RAS-MAPK pathway. Affected fetuses have variable presentations ranging from the absence of prenatal findings to increased nuchal fold, cystic hygromas, pleural effusions, cardiac malformations, or skin edema. We describe a male fetus who had features consistent with Noonan syndrome at the time of fetal anatomic survey, including hydrops and a possible cardiac defect. Subsequent scan revealed persistent bilateral pleural effusions (with predominance of lymphocytes). After bilateral thoracoamniotic shunt placement, the fetus did well and delivered at term. Prenatal testing revealed an S650F missense mutation in the RAF1 gene, which had not previously been associated with Noonan syndrome.


CHAC1 exacerbates arsenite cytotoxicity by lowering intracellular glutathione levels.
We here examined whether CHAC1 is implicated in arsenite (As(III))-induced cytotoxicity in HaCaT cells. We found that HaCaT cells in which the intracellular GSH levels were elevated by transfection with CHAC1 siRNA showed decreased sensitivity to As(III) compared to the control cells. Treatment with BSO (an inhibitor of GSH biosynthesis) abolished the decrease in sensitivity to As(III), suggesting that an increase in intracellular GSH levels was involved in the decrease in sensitivity to As(III) due to the decrease in the levels of CHAC1 expression. When we examined the expression of CHAC1 after exposure of HaCaT cells to As(III), the levels of CHAC1 were increased. Since CHAC1 is a proapoptotic factor, we examined appearance of apoptotic cells and cleavage of caspase-3 after exposure to As(III) to determine whether As(III)-induced CHAC1 up-regulation was involved in apoptosis induction. The results showed that induction of apoptosis by As(III) exposure was not detected in CHAC1 siRNA-transfected cells. Together, our findings indicate that CHAC1 is involved in the sensitivity of HaCaT cells to As(III) by regulating the intracellular GSH levels, and in particular, CHAC1 is involved in As(III)-induced apoptosis.


Temporomandibular disorders in a sample population of the Brazilian northeast.
Temporomandibular disorder (TMD) is a common condition. This study is part of a research group and it investigated the prevalence of TMD and myofascial pain and its association with gender, age and socioeconomic class. The sample comprised 100 subjects, aged 15 to 70, users of the Family Health Units' services, in the city of Recife, PE, Brazil. The TMD degree was evaluated using the Research Diagnostic Criteria for TMD and socioeconomic class by the Economic Classification Criteria Brazil. Categorical variables were analyzed by chi-square test for proportions and Fisher's exact test for 2x2 tables, and binary logistic analysis to track the relationship between the independent and dependent variables. According to the results, 42% of the subjects had TMD and 14% myofascial pain. No statistically significant association could be found between TMD and gender or socioeconomic class, but it was found to have statistically significant association with age, and myofascial pain was associated with socioeconomic class. Considering that the results of the present study should be confirmed by further studies and the fact that this was a pilot study, the prevalence must be analyzed with caution.


Recall of surgery for major trauma.
Major traumatic injury frequently causes hemodynamic instability that necessitates reducing the usual dose of anesthetic given for surgery. Nevertheless, a lower dose may be sufficient to provide anesthesia because of conditions present in trauma victims that are known to reduce anesthetic requirement (hypotension, hypothermia, and acute alcohol intoxication). To determine the incidence and patient perception of recall of surgery, 51 patients were interviewed after surgery for major trauma. Patients were assigned to one of two groups. Thirty-seven patients were given an anesthetic for endotracheal intubation and had continuous or almost continuous anesthesia during surgery. Of the four who recalled surgery (11%), two considered this awareness their worst hospital experience. Fourteen other patients, who were more severely injured, were not given an anesthetic for endotracheal intubation and/or for 20 or more consecutive minutes during surgery. Of the six patients in this group who recalled surgery (43%), two considered this awareness their worst hospital experience. No condition known to reduce anesthetic requirement did so reliably enough that recall of surgery did not occur when the anesthetic dose had to be reduced because of major trauma. The authors conclude that the incidence of recall of surgery in victims of major trauma is considerable, and that reducing the dose of anesthetic increases this incidence, despite the presence of conditions known to reduce anesthetic requirement.


Travel Burden and Clinical Profile of Cancer Patients Admitted to the Cancer Institute of Iran in 2012.
Burden of cancer is increasing in developing countries, where healthcare infrastructures and resources are limited. Evaluating the pattern of care would provide evidence for planning and improvement of the situation. We studied the pattern of residential place and clinical information of cancer patients who were admitted to the Cancer Institute of Iran from January 1, to May 31, 2012. We studied 1,705 consecutive cancer patients admitted to the Cancer Institute in the study period. The most common cancers were breast (29.2%), colorectal (9.0%), stomach (8.3%), head & neck (8.0%) and esophageal (3.8%) cancers. Radiotherapy was the main treatment (52.1%) followed by chemotherapy (43.8%) and surgery (29.1%). We found that 60% of the patients presented in the loco-regional or advanced stages. About 35% of patients travelled from other provinces mainly from Mazandaran (13.4%), Lorestan (10.6%), Zanjan (7.8%) and Ghazvin (6.6%). On average, the cancer patients travelled about 455 kilometers to receive care in the cancer institute. We found more than 38% patients who were referred from other provinces had an early stage tumor. Establishment of comprehensive cancer centers in different geographical regions and implementation of a proper referral system for advanced cancer patients is needed to improve the patient outcomes and mitigate the burden of travel of patients for cancer care.


Designing Morphotropic Phase Composition in BiFeO3.
In classical morphotropic piezoelectric materials, rhombohedral and tetragonal phase variants can energetically compete to form a mixed phase regime with improved functional properties. While the discovery of morphotropic-like phases in multiferroic BiFeO3 films has broadened this definition, accessing these phase spaces is still typically accomplished through isovalent substitution or heteroepitaxial strain which do not allow for continuous modification of phase composition postsynthesis. Here, we show that it is possible to use low-energy helium implantation to tailor morphotropic phases of epitaxial BiFeO3 films postsynthesis in a continuous and iterative manner. Applying this strain doping approach to morphotropic films creates a new phase space based on internal and external lattice stress that can be seen as an analogue to temperature-composition phase diagrams of classical morphotropic ferroelectric systems.


Drug-set enrichment analysis: a novel tool to investigate drug mode of action.
Automated screening approaches are able to rapidly identify a set of small molecules inducing a desired phenotype from large small-molecule libraries. However, the resulting set of candidate molecules is usually very diverse pharmacologically, thus little insight on the shared mechanism of action (MoA) underlying their efficacy can be gained. We introduce a computational method (Drug-Set Enrichment Analysis-DSEA) based on drug-induced gene expression profiles, which is able to identify the molecular pathways that are targeted by most of the drugs in the set. By diluting drug-specific effects unrelated to the phenotype of interest, DSEA is able to highlight phenotype-specific pathways, thus helping to formulate hypotheses on the MoA shared by the drugs in the set. We validated the method by analysing five different drug-sets related to well-known pharmacological classes. We then applied DSEA to identify the MoA shared by drugs known to be partially effective in rescuing mutant cystic fibrosis transmembrane conductance regulator (CFTR) gene function in Cystic Fibrosis. The method is implemented as an online web tool publicly available at http://dsea.tigem.it. email@example.com Supplementary data are available at Bioinformatics online.


SELECTION OF BENEVOLENCE IN A HOST-PARASITE SYSTEM.
A paradigm for the evolution of cooperation between parasites and their hosts argues that the mode of parasite transmission is critical to the long-term maintenance of cooperation. Cooperation is not expected to be maintained whenever the chief mode of transmission is horizontal: a parasite's progeny infect hosts unrelated to their parent's host. Cooperation is expected to be maintained if the chief mode of transmission is vertical: a parasite's progeny infect only the parent's host or descendants of that host. This paradigm was tested using bacteria and filamentous bacteriophage (f1). When cells harboring different variants of these phage were cultured so that no infectious spread was allowed, ensuring that all parasite transmission was vertical, selection favored the variants that were most benevolent to the host-those that least harmed host growth rate. By changing the culture conditions so that horizontal spread of the phage was allowed, the selective advantage of the benevolent forms was lost. These experiments thus support the theoretical arguments that mode of transmission is a major determinant in the evolution of cooperation between a parasite and its host.


Lancisi's sign and central venous catheter tip position: a case report.
Valvular disease and pulmonary hypertension are common conditions in haemodialysis patients. In presence of tricuspid regurgitation, an increased retrograde blood flow into the right atrium during ventricle systole results in a typical modification of the normal venous waveform, creating a giant c-v wave. This condition clinically appears as a venous palpable pulsation within the internal jugular vein, also known as Lancisi's sign. An 83-year-old woman underwent haemodialysis for 9 years. After arteriovenous fistula thrombosis, a right internal jugular vein non-tunnelled central venous catheter (CVC) was placed. About one month later, the patient was referred to our facility for the placement of a tunnelled CVC. Neck examination revealed an elevated jugular venous pulse, the Lancisi's sign. Surprisingly, chest x-ray posteroanterior view showed the non-tunnelled catheter tip in correspondence with the right ventricle. She underwent surgery for temporary to tunnelled CVC conversion using the same venous insertion site (Bellcath®10Fr-length 25 cm to Mahurkar®13.5Fr-length 19 cm). In the postoperative period, we observed a significant reduction of the jugular venous pulse. The inappropriate placement of a 25-cm temporary CVC in the right internal jugular vein worsened the tricuspid valve regurgitation, which became evident by the Lancisi's sign. Removal of the temporary CVC from the right ventricle resulted in improved right cardiac function. Safe approaches recommended by guidelines for the CVC insertion technique and for checking the tip position should be applied in order to avoid complications.


Preparation of carbon quantum dots from ionic liquid modified biomass for the detection of Fe3+ and Pd2+ in environmental water.
A new type of green carbon quantum dots (ILB-CQDs) was prepared by hydrothermal method using ionic liquid as a modifier and grape skin as carbon source, and was obtained from hydrogen-bonded lattice structure ionic liquid preparation, which makes the CQDs in a ring-like stable structure with a stability period of more than 90 day. There is also the catalytic effect of the ionic liquid on cellulose, which makes the prepared CQDs show good advantages, such as uniform particle size, high quantum yield (26.7%), and very good fluorescence performance. This is a smart material for the selective detection of Fe3+ and Pd2+. It has a detection limit of 0.001 nM for Fe3+ and 0.23 µM for Pd2+ in pure water. It has a detection limit of 3.2 nmol/L for Fe3+ and 0.36 µmol/L for Pd2+ in actual water, both of which meet the requirements of WHO drinking water standards. And there is to achieve more than 90% of water restoration effect.


Intensive cyclophosphamide (NSC-26271) therapy for solid tumors.
Cyclophospamide was given in two dose schedules to 25 patients with a variety of nonlymphoid solid tumors. Eleven patients were given 18 courses of cyclophosphamide at a total dose of 60 mg/kg. Sixteen patients received 26 courses at a total dose of 100 mg/kg. Two patients were treated with both regimens. Partial responses were achieved in two patients treated with 60-mg/kg dose of cyclophosphamide. One of these patients had osteogenic sarcoma and the other had renal carcinoma. The higher dose also produced two partial responses, one in a patient with anaplastic carcinom a of the lung and the other in a patient with anaplastic carcinoma of the lung and the other in a patient with embryonal testicular carcinoma. Mean leukocyte counts fell to a nadir of 1400 cells/mm after 60 mg/kg while they dropped to below 1000 cells/mm for 5 days after 100 mg/kg of cyclophosphamide. Mean platelet counts remained above 150,000 platelets/mm after both cyclophosphamide schedules. In fective complications were documented aftter three of the 18 courses at 60 mg/kg and after ten of the 26 courses at 100 mg5kg. In the latter group, there were three episodes of bacteremia, including one death from pseudomonas sepsis. Nonhematologic toxicity noted with the 100-mg/kg dose of cyclophosphamide included rare instances of electrocardiogram changes and serum enzyme alterations compatible with myocardial toxicity. The intensive cyclophosphamide therapy did not appear to result in an increased antitumor response in malignancies usually considered to be refractory to alkylating agents.


Identification of circRNA Biomarker for Gastric Cancer through Integrated Analysis.
Gastric cancer (GC) is one of the most common malignant tumors and ranks third in cancer mortality globally. Although, a lot of advancements have been made in diagnosis and treatment of gastric cancer, there is still lack of ideal biomarker for the diagnosis and treatment of gastric cancer. Due to the poor prognosis, the survival rate is not improved much. Circular RNAs (circRNAs) are single-stranded RNAs with a covalently closed loop structure that don't have the 5'-3' polarity and a 3' polyA tail. Because of their circular structure, circRNAs are more stable than linear RNAs. Previous studies have found that circRNAs are involved in several biological processes like cell cycle, proliferation, apoptosis, autophagy, migration and invasion in different cancers, and participate in some molecular mechanisms including sponging microRNAs (miRNAs), protein translation and binding to RNA-binding proteins. Several studies have reported that circRNAs play crucial role in the occurrence and development of different types of cancers. Although, some studies have reported several circRNAs in gastric cancer, more studies are needed in searching new biomarkers for gastric cancer diagnosis and treatment. Here, we investigated potential circRNA biomarkers for GC using next-generation sequencing (NGS) data collected from 5 paired GC samples. A total of 45,783 circRNAs were identified in all samples and among them 478 were differentially expressed (DE). The gene ontology (GO) analysis of the host genes of the DE circRNAs showed that some genes were enriched in several important biological processes, molecular functions and cellular components. The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that some host genes were enriched in several GC related pathways. The circRNA-miRNA-gene interaction network analysis showed that two circRNAs circCEACAM5 and circCOL1A1 were interacted with gastric cancer related miRNAs, and their host genes were also the important therapeutic and prognostic biomarkers for GC. The experimental results also validated that these two circRNAs were DE in GC compared to adjacent normal tissues. Overall, our findings suggest that these two circRNAs circCEACAM5 and circCOL1A1 might be the potential biomarkers for the diagnosis and treatment of GC.


Nickel allergy and hand dermatitis in a stratified sample of the Danish female population: an epidemiological study including a statistic appendix.
The occurrence of nickel allergy and hand eczema has been investigated in a stratified sample (2 500) of the Danish female population by an interview technique. The incidence density (allergy intensity) has been estimated by standard maximum likelihood methods. The age-specific prevalence rates have been calculated by life table techniques. The incidence density has doubled in all age groups from 1948 to 1973. The highest prevalence rate of nickel allergy was found in the 45-year-olds (0.189 +/- 0.023). The possible interaction between nickel allergy and hand eczema was analysed by a Markov chain model. Compared with non-nickel-sensitive women, a woman who has become nickel sensitized ran an increased risk of developing hand eczema. And those who had first developed hand eczema ran an increased risk of subsequently developing nickel allergy. In future efforts to reduce direct skin contact with nickel, the close relation between nickel allergy and hand eczema should be the main argument. Statistical methods based on the incidence density will be useful in the evaluation of these efforts.


Evolutionary ecology of opsin gene sequence, expression and repertoire.
Linking molecular evolution to biological function is a long-standing challenge in evolutionary biology. Some of the best examples of this involve opsins, the genes that encode the molecular basis of light reception. In this issue of Molecular Ecology, three studies examine opsin gene sequence, expression and repertoire to determine how natural selection has shaped the visual system. First, Escobar-Camacho et al. () use opsin repertoire and expression in three Amazonian cichlid species to show that a shift in sensitivity towards longer wavelengths is coincident with the long-wavelength-dominated Amazon basin. Second, Stieb et al. () explore opsin sequence and expression in reef-dwelling damselfish and find that UV- and long-wavelength vision are both important, but likely for different ecological functions. Lastly, Suvorov et al. () study an expansive opsin repertoire in the insect order Odonata and find evidence that copy number expansion is consistent with the permanent heterozygote model of gene duplication. Together these studies emphasize the utility of opsin genes for studying both the local adaptation of sensory systems and, more generally, gene family evolution.


Gonadotropin-releasing hormone agonist for ovulation trigger - OHSS prevention and use of modified luteal phase support for fresh embryo transfer.
The introduction of gonadotrophin-releasing hormone agonist (GnRHa) trigger greatly impacted modern IVF treatment. Patients at low risk of ovarian hyperstimulation syndrome (OHSS) development, undergoing fresh embryo transfer and GnRHa trigger can be offered a virtually OHSS-free treatment with non-inferior reproductive outcomes by using a modified luteal phase support in terms of small boluses of human chorionic gonadotrophin (hCG), daily recombinant luteinizing hormone LH (rLH) or GnRHa. In the OHSS risk patient, GnRHa trigger can safely be performed, followed by a 'freeze-all' policy with a minimal risk of OHSS development and high live birth rates in the subsequent frozen embryo transfer cycle. Importantly, GnRHa trigger opened the 'black box' of the luteal phase, promoting research in the most optimal steroid levels during the luteal phase. GnRHa trigger allows high-dose gonadotropin stimulation to achieve the optimal number of oocytes and embryos needed to ensure the highest chance of live birth. This review thoroughly discusses how the GnRHa trigger concept adds safety and efficacy to modern IVF in terms of OHSS prevention. Furthermore, the optimal luteal phase management after GnRHa trigger in fresh embryo transfer cycles is discussed.


Microsatellites and petal morphology reveal new patterns of admixture in Orchis hybrid zones.
The genetic structure of hybrid zones provides insight into the potential for gene flow to occur between plant taxa. Four closely related European orchid species (Orchis anthropophora, O. militaris, O. purpurea, and O. simia) hybridize when they co-occur. We aimed to characterize patterns of hybridization in O. militaris-O. purpurea, O. purpurea-O. simia, and O. anthropophora-O. simia hybrid zones using molecular and morphological data. We used 11 newly isolated nuclear microsatellites to genotype 695 individuals collected from seven hybrid zones and six allopatric parental populations in France. Geometric morphometric analysis was conducted using 15 labellum landmarks to capture the main aspects of petal shape. Backcrossing was asymmetric toward O. militaris in multiple O. militaris-O. purpurea hybrid zones. Hybrids in O. purpurea-O. simia and O. anthropophora-O. simia hybrid zones were largely limited to F1 and F2 generations, but further admixture had occurred. These patterns were reflected in labellum geometric morphometric data, which correlated strongly with nuclear microsatellite data in all three species combinations. The coexistence of parental and admixed individuals in these Orchis hybrid zones implies they are likely to be tension zones being maintained by a balance between gene flow into the hybrid zone and selection acting against admixed individuals. The pattern of admixture in the three species combinations suggests intrinsic selection acting on the hybrids is weaker in more closely related taxa.


Developing a mid-range theory of patient advocacy through concept analysis.
The aim of this paper is to clarify and refine the concept of patient advocacy through synthesizing the advocacy literature in nursing and to establish a theoretical basis for future studies on patient advocacy in nursing. Patient advocacy is an essential component of the Registered Nurse professional role. During the past 30 years, the patient advocacy role has become more important, but the concept of patient advocacy lacks a consistent definition and research into nurses' patient advocacy roles is limited. There have been few quantitative empirical studies on patient advocacy in nursing. Walker and Avant's method of concept analysis was used as a guideline in examining the concept of patient advocacy through synthesizing the advocacy literature in English (1974-2006). A mid-range theory of patient advocacy emerges during the process of synthesizing and analysing the advocacy literature. Three core attributes of the concept of patient advocacy are identified: (1) safeguarding patients' autonomy; (2) acting on behalf of patients; and (3) championing social justice in the provision of health care. They reflect nurses' patient advocacy roles at both macro- and micro-social levels. Antecedents of patient advocacy occur at both macro- and micro-social levels and call for nurses' advocacy roles in the healthcare system. Consequences produced by nurses' patient advocacy behaviours are contextual. Nurses' patient advocacy behaviours not only can positively influence the patients, other nurses and the nursing profession, but also can cause negative consequences for nurses who take action to advocate for patients. The proposed mid-range theory may be useful in guiding advocacy practice in nursing and in guiding research in the advocacy area. The proposed theory needs to be furthered refined and tested in the future.


Cannabis use and anxiety: is stress the missing piece of the puzzle?
Comorbidity between anxiety and cannabis use is common yet the nature of the association between these conditions is not clear. Four theories were assessed, and a fifth hypothesis tested to determine if the misattribution of stress symptomology plays a role in the association between state-anxiety and cannabis. Three-hundred-sixteen participants ranging in age from 18 to 71 years completed a short online questionnaire asking about their history of cannabis use and symptoms of stress and anxiety. Past and current cannabis users reported higher incidence of lifetime anxiety than participants who had never used cannabis; however, these groups did not differ in state-anxiety, stress, or age of onset of anxiety. State-anxiety and stress were not associated with frequency of cannabis use, but reported use to self-medicate for anxiety was positively associated with all three. Path analyses indicated two different associations between anxiety and cannabis use, pre-existing and high state-anxiety was associated with (i) higher average levels of intoxication and, in turn, acute anxiety responses to cannabis use; (ii) frequency of cannabis use via the mediating effects of stress and self-medication. None of the theories was fully supported by the findings. However, as cannabis users reporting self-medication for anxiety were found to be self-medicating stress symptomology, there was some support for the stress-misattribution hypothesis. With reported self-medication for anxiety being the strongest predictor of frequency of use, it is suggested that researchers, clinicians, and cannabis users pay greater attention to the overlap between stress and anxiety symptomology and the possible misinterpretation of these related but distinct conditions.


[Evaluation of mesial displacement of mandibular complete dentures with long-centric occlusal pattern].
To evaluate whether the mesial displacement of the mandibular complete dentures with long-centric occlusal pattern could meet the long centric of edentulous patients and to verify the design theory of the long-centric occlusal pattern of complete dentures. Complete dentures with three different occlusal patterns were made for each of 10 edentulous patients. Gothic arch tracing apparatus was used to record the long centric of edentulous patients. Three-dimensional measuring apparatus was used to measure the mesial displacement of mandibular dentures with three occlusal patterns. Comparison of the mesial displacement of three occlusal pattern dentures was made each other and with the long centric of the patients respectively. The mean of long centric was (1.02 +/- 0.36) mm. The means of mesial displacement of mandibular complete dentures were as follows: the long-centric occlusal pattern dentures (1.016 +/- 0.348) mm, the linear occlusal dentures (1.092 +/- 0.448) mm, the anatomic occlusal dentures (0.409 +/- 0.253) mm. The mandibular complete dentures with long-centric occlusal pattern can meet the physiological requirement for the long centric of edentulous patients and achieve a free slide from the centric relation position to the muscular contact position of the mandible.


Anaphase promoting complex or cyclosome?
The anaphase promoting complex/cyclosome (APC/C) was initially described as a multi-subunit protein complex that ubiquitinates anaphase inhibitors thus targeting them for destruction by proteasomes to initiate loss of sister chromatid cohesion. However, recent studies have identified important new functions of the APC/C. Moreover, sister centromere separation can occur in the absence of APC/C activity in mammals, indicating that anaphase onset might be triggered by multiple factors. Here we discuss whether the APC/C functions primarily as the anaphase trigger, or whether it has more general properties, relevant for cell cycle control at multiple developmental and cell cycle stages. Additionally, we discuss the validity of the APC-dependent model for sister segregation in mammals.


Acute effects of intravenously administered hypertonic saline solution on transruminal rehydration in dairy cows.
To determine the effect of IV administered hypertonic saline solution (HSS) on transruminal rehydration in clinically normal dairy cows. 10 Holstein cows. Cows in a 2-way randomized cross-over design study were given nothing per os for 36 hours, then were randomly assigned to receive either an oral water load (OWL; 40 ml/kg of body weight) by ruminal gavage or HSS IV (5 ml/kg of body weight) plus OWL; 10 days later, each cow received the other treatment. Outcome measures included serum and urine osmolality, electrolyte (Ca, P, Na, K, and Cl), creatinine, blood glucose, hemoglobin (Hgb), and plasma total protein (PTP) concentrations; serum colloid osmotic pressure (SCOP); urine volume; PCV; and blood gas analytes (pH, P(CO2), P(O2), HCO3-, base excess [BE], and O2 saturation). IV administered HSS plus OWL caused Hgb, PCV, PTP, SCOP, blood pH, BE, HCO3-, and urine osmolality values to decrease and fractional excretion (FE) of electrolytes, serum osmolality, and urine volume to increase. Blood glucose concentration was different between treatments at 0 and 150 minutes, and FEK, FECl, and FECa were similar by 180 minutes after OWL alone, but absolute excretion of Na and P and FENa and FE(P) remained high after HSS administration. Oral water load caused Hgb, PCV, PTP, serum electrolyte and creatinine, SCOP, and urine osmolality values to remain unchanged or decrease slowly and pH, BE, HCO3-, FECa values to increase slightly by 180 minutes. IV administration of HSS plus OWL, unlike OWL alone, increases circulatory volume rapidly, induces slight metabolic acidosis, increases renal perfusion and glomerular filtration rate, and effects changes in serum Ca and P homeostasis that may be useful in treating sick dairy cows.


Testing for drug use, Part 1: Analytical methods.
Issues surrounding the screening and testing of individuals for drug use, including analytical and legal aspects of the procedures and social, political, and ethical problems and concerns, are reviewed. Historically, professional and societal debate regarding drug taking, drug-use problems, and the utility of drug testing programs occurs in cycles. Analytical methods commonly used to test for drug use include breath analysis for alcohol and urine drug assays. Blood alcohol concentrations are determined by laboratory assay methods or by portable devices used in the field. While poor laboratory procedures can invalidate test results for both breath and urine tests, urine screening test results can be further invalidated by improper handling of specimens or by tampering on the part of the subject. Also, test results are meaningful only if they are correlated with a clinical state. Legal issues have been raised concerning the validity of testing procedures used and the reliability of evidence obtained, especially in relation to pre-employment drug screening. From an ethical standpoint, drug testing tends to focus efforts to combat drug abuse on the drugs themselves instead of on the social context of the problem. With a recycled interest in drug-use testing and screening, primarily attributable to technological advances, little attention is being given to other approaches to controlling drug use. Additional research is needed to better describe the nature and extent of our drug-use problems and their impact on society.


Kinetic analysis reveals successive steps leading to miRNA-mediated silencing in mammalian cells.
MicroRNAs (miRNAs) regulate most cellular functions, acting by posttranscriptionally repressing numerous eukaryotic mRNAs. They lead to translational repression, deadenylation and degradation of their target mRNAs. Yet, the relative contributions of these effects are controversial and little is known about the sequence of events occurring during the miRNA-induced response. Using stable human cell lines expressing inducible reporters, we found that translational repression is the dominant effect of miRNAs on newly synthesized targets. This step is followed by mRNA deadenylation and decay, which is the dominant effect at steady state. Our findings have important implications for understanding the mechanism of silencing and reconcile seemingly contradictory data.


The effects of sleep debt and monotonous work on sleepiness and performance during a 12-h dayshift.
The study examined the effects of the amount of preceding sleep and work pace on sleepiness and cognitive performance during a 12-h dayshift. Twelve process operators (aged 28-56 years) completed a study with four single 12-h dayshifts and preceding night sleep in the laboratory. A simulated distillation process served as a work task. The 12-h shifts differed from each other in terms of the amount of preceding night sleep (23:00-06:30 hours or 2:30-6:30 hours) and work pace (slow or fast). All shifts contained four work simulation sessions of 1.5 h, and each of them included a 15-min alarm session. Cognitive performance was also measured with a 10-choice reaction time test and a mental subtraction test. Objective sleepiness was measured with a continuous electroencephalography/electro-oculography (EEG/EOG) recording during the work periods and with a sleep latency test. Subjective sleepiness at work was measured with the Karolinska Sleepiness Scale. Sleep debt increased the proportion of EEG/EOG-defined and subjective sleepiness at work, but did not impair work or test performance. The fatiguing effect of monotonous work as indicated by EEG/EOG-defined sleepiness was comparable with the effect of sleep debt. The alarm epochs in the middle of monotonous work temporarily decreased EEG/EOG-defined sleepiness. Sleep debt or monotonous work did not have a significant effect on the results of the sleep latency test. None of the sleepiness or performance measures indicated the impairment of a subject's functional capacity at the end of the 12-h shift. Our results suggest that monotonous work is at least as harmful as moderate sleep debt for alertness at work. The results support the view that the last hours of a single 12-h dayshift with frequent pauses are not associated with an increase in sleepiness or performance errors.


An ab initio study of structural properties and single vacancy defects in Wurtzite AlN.
The cell parameters, bulk moduli and electronic densities-of-states (DOS) of pure and vacancy defect AlN were computed using generalized-gradient approximation (GGA) and hybrid functional (B3LYP) computational methods within both plane wave-pseudopotential and localized Gaussian basis set approaches. All of the methods studied yielded cell parameters and bulk moduli in reasonable agreement with experiment. The B3LYP functional was also found to predict an optical band gap in excellent agreement with experiment. These methods were subsequently applied to the calculation of the geometry, defect state positions and formation energies of the cation (V(Al)) and anion (V(N)) single vacancy defects. For the V(Al) defect, the plane wave-pseudopotential predicted a significant retraction of the neighboring N away from the vacancy, while for the V(N) defect, only slight relaxations of the surrounding Al atoms towards the vacancy were predicted. For the computed DOS of both vacancy defects, the GGA methods yielded similar features and defect level positions relative to the valence band maximum, while the B3LYP method predicted higher separations between the defect levels and the valence and conduction bands, leading to higher energy occupied defect levels.


The expanded collagen VI family: new chains and new questions.
Collagen VI is a component of the extracellular matrix of almost all connective tissues, including cartilage, bone, tendon, muscles and cornea, where it forms abundant and structurally unique microfibrils organized into different suprastructural assemblies. The precise role of collagen VI is not clearly defined although it is most abundant in the interstitial matrix of tissues and often found in close association with basement membranes. Three genetically distinct collagen VI chains, α1(VI), α2(VI) and α3(VI), encoded by the COL6A1. COL6A2 and COL6A3 genes, were first described more than 20 years ago. Their molecular assembly and role in congenital muscular dystrophy has been broadly characterized. In 2008, three additional collagen VI genes arrayed in tandem at a single gene locus on chromosome 3q in humans, and chromosome 9 in mice, were described. Following the naming scheme for collagens the new genes were designated COL6A4. COL6A5 and COL6A6 encoding the α4(VI), α5(VI) and α6(VI) chains, respectively. This review will focus on the current state of knowledge of the three new chains.


Novel cerebroprotective agents with central nervous system stimulating activity. 1. Synthesis and pharmacology of 1-amino-7-hydroxyindan derivatives.
To develop a novel cerebroprotective agent with central nervous system (CNS) stimulating activity, a series of 1-amino-7-hydroxyindan derivatives was synthesized, and their effects on the survival time of mice under hypoxic conditions were tested. CNS-stimulating activity was also evaluated by examining the promotional effect on the recovery from cerebral concussion induced coma in mice. Several compounds prolonged the survival time of mice in hypoxic conditions at a dose of 30 mg/kg (sc or ip) and 100 mg/kg (po). They also exhibited the promotional effects on recovery from coma at a dose of 100 mg/kg po. The three most potent compounds in both tests, 1-amino-7-hydroxy-6-(1-methylpropyl)indan, 1-amino-7-hydroxy-4, 6-dimethyl-2-phenylindan, and 1-amino-7-hydroxy-2,2,4,6-tetramethylindan were selected for further investigations. Structure-activity relationships were also discussed.


Occult causes of hypokalemia.
Most causes of hypokalemia are obvious from the clinical picture and the values for plasma electrolytes. In cases with obscure etiology, a pretreatment estimation of urinary potassium and chloride often helps lead the clinician into new and fruitful avenues of clinical investigation. Here we present four cases of hypokalemia in which the pathogenesis was initially enigmatic but was clarified somewhat by the determination of the urinary electrolytes. These simple, inexpensive investigations were initiated by the clinical chemistry laboratory in each case. The results encouraged the physicians to consider further clinical investigations, which led to a definitive diagnosis, before invoking expensive hormonal analyses.


Identification of Novel Viruses in Amblyomma americanum, Dermacentor variabilis, and Ixodes scapularis Ticks.
Ticks carry a wide range of known human and animal pathogens and are postulated to carry others with the potential to cause disease. Here we report a discovery effort wherein unbiased high-throughput sequencing was used to characterize the virome of 2,021 ticks, including Ixodes scapularis (n = 1,138), Amblyomma americanum (n = 720), and Dermacentor variabilis (n = 163), collected in New York, Connecticut, and Virginia in 2015 and 2016. We identified 33 viruses, including 24 putative novel viral species. The most frequently detected viruses were phylogenetically related to members of the Bunyaviridae and Rhabdoviridae families, as well as the recently proposed Chuviridae. Our work expands our understanding of tick viromes and underscores the high viral diversity that is present in ticks. IMPORTANCE The incidence of tick-borne disease is increasing, driven by rapid geographical expansion of ticks and the discovery of new tick-associated pathogens. The examination of the tick microbiome is essential in order to understand the relationship between microbes and their tick hosts and to facilitate the identification of new tick-borne pathogens. Genomic analyses using unbiased high-throughput sequencing platforms have proven valuable for investigations of tick bacterial diversity, but the examination of tick viromes has historically not been well explored. By performing a comprehensive virome analysis of the three primary tick species associated with human disease in the United States, we gained substantial insight into tick virome diversity and can begin to assess a potential role of these viruses in the tick life cycle.


Differences among antimicrobial properties of carrion beetle secretions reflect phylogeny and ecology.
Carrion beetles (Coleoptera: Silphidae) consist of two subfamilies in North America. Members of the Silphinae arrive at carcasses during the mid-stage of decay and their larvae feed on developing maggots, while members of the Nicrophorinae bury and tend carcasses upon which their developing larvae feed. The Nicrophorinae maintain the condition of the carcass by applying oral and anal secretions that reduce carcass decay apparently through bacterial inhibition, although quantification has not been made. We hypothesized that enzymes in the oral and anal secretions of the subfamily Nicrophorinae would inhibit bacterial growth, while secretions from the subfamily Silphinae would not. The secretions were assayed for inhibitory effects with a Microtox Analyzer that monitors the decrease in bioluminescence from the bacterium Vibrio fischerii. We found a significant difference of bioluminescence in the control compared to secretions of 8 out of 10 tested Nicrophorinae (with oral secretions being most active), while only anal secretions from Necrodes surinimensis of the Siphinae significantly reduced bacterial survival. These data follow the known phylogenic relationship in which Necrodes is the closest genus to the Nicrophorinae. The two species of Nicrophorinae, which did not show significant reductions in bacterial growth, differ ecologically from the others. Thus, the presence of antimicrobial compounds in most Nicrophorinae secretions, but not in most other Silphinae, represents an adaptation to preserve the buried carcass.


Isotope effects in aqueous solvation of simple halides.
We present a path-integral-molecular-dynamics study of the thermodynamic stabilities of DOH⋯ X- and HOD⋯ X- (X = F, Cl, Br, I) coordination in aqueous solutions at ambient conditions. In agreement with experimental evidence, our results for the F- case reveal a clear stabilization of the latter motif, whereas, in the rest of the halogen series, the former articulation prevails. The DOH⋯ X- preference becomes more marked the larger the size of the ionic solute. A physical interpretation of these tendencies is provided in terms of an analysis of the global quantum kinetic energies of the light atoms and their geometrical decomposition. The stabilization of the alternative ionic coordination geometries is the result of a delicate balance arising from quantum spatial dispersions along parallel and perpendicular directions with respect to the relevant O-H⋯X- axis, as the strength of the water-halide H-bond varies. This interpretation is corroborated by a complementary analysis performed on the different spectroscopic signals of the corresponding IR spectra.


Engineered promoters enable constant gene expression at any copy number in bacteria.
The internal environment of growing cells is variable and dynamic, making it difficult to introduce reliable parts, such as promoters, for genetic engineering. Here, we applied control-theoretic ideas to design promoters that maintained constant levels of expression at any copy number. Theory predicts that independence to copy number can be achieved by using an incoherent feedforward loop (iFFL) if the negative regulation is perfectly non-cooperative. We engineered iFFLs into Escherichia coli promoters using transcription-activator-like effectors (TALEs). These promoters had near-identical expression in different genome locations and plasmids, even when their copy number was perturbed by genomic mutations or changes in growth medium composition. We applied the stabilized promoters to show that a three-gene metabolic pathway to produce deoxychromoviridans could retain function without re-tuning when the stabilized-promoter-driven genes were moved from a plasmid into the genome.


Differential roles of regulatory T cells in acute respiratory infections.
Acute respiratory infections trigger an inflammatory immune response with the goal of pathogen clearance; however, overexuberant inflammation causes tissue damage and impairs pulmonary function. CD4+FOXP3+ regulatory T cells (Tregs) interact with cells of both the innate and the adaptive immune system to limit acute pulmonary inflammation and promote its resolution. Tregs also provide tissue protection and coordinate lung tissue repair, facilitating a return to homeostatic pulmonary function. Here, we review Treg-mediated modulation of the host response to respiratory pathogens, focusing on mechanisms underlying how Tregs promote resolution of inflammation and repair of acute lung injury. We also discuss potential strategies to harness and optimize Tregs as a cellular therapy for patients with severe acute respiratory infection and discuss open questions in the field.


Molecular differences in the mitochondrial cytochrome oxidase I (mtCOI) gene and development of a species-specific marker for onion thrips, Thrips tabaci Lindeman, and melon thrips, T. palmi Karny (Thysanoptera: Thripidae), vectors of tospoviruses (Bunyaviridae).
A quick and developmental-stage non-limiting method of the identification of vectors of tospoviruses, such as Thrips tabaci and T. palmi, is important in the study of vector transmission, insecticide resistance, biological control, etc. Morphological identification of these thrips vectors is often a stumbling block in the absence of a specialist and limited by polymorphism, sex, stage of development, etc. Molecular identification, on the other hand, is not hampered by the above factors and can easily be followed by a non-specialist with a little training. The mitochondrial cytochrome oxidase I (mtCOI) exhibits reliable inter-species variations as compared to the other markers. In this communication, we present the differences in the mtCOI partial sequence of morphologically identified specimens of T. tabaci and T. palmi collected from onion and watermelon, respectively. Species-specific markers, identified in this study, could successfully determine T. tabaci and T. palmi, which corroborated the morphological identification. Phylogenetic analyses showed that both T. tabaci and T. palmi formed different clades as compared to the other NCBI accessions. The implication of these variations in vector efficiency has to be investigated further. The result of this investigation is useful in the quick identification of T. tabaci and T. palmi, a critical factor in understanding the epidemiology of the tospoviruses, their management and also in quarantine.


Cancer incidence and mortality in China, 2014.
National Central Cancer Registry of China (NCCRC) updated nationwide cancer statistics using population-based cancer registry data in 2014 collected from all available cancer registries. In 2017, 449 cancer registries submitted cancer registry data in 2014, among which 339 registries' data met the criteria of quality control and were included in analysis. These cancer registries covered 288,243,347 population, accounting for about 21.07% of the national population in 2014. Numbers of nationwide new cancer cases and deaths were estimated using calculated incidence and mortality rates and corresponding national population stratified by area, sex, age group and cancer type. The world Segi's population was applied for age-standardized rates. A total of 3,804,000 new cancer cases were diagnosed, the crude incidence rate was 278.07/100,000 (301.67/100,000 in males, 253.29/100,000 in females) and the age-standardized incidence rate by world standard population (ASIRW) was 186.53/100,000. Calculated age-standardized incidence rate was higher in urban areas than in rural areas (191.6/100,000 vs. 179.2/100,000). South China had the highest cancer incidence rate while Southwest China had the lowest incidence rate. Cancer incidence rate was higher in female for population between 20 to 54 years but was higher in male for population younger than 20 years or over 54 years. A total of 2,296,000 cancer deaths were reported, the crude mortality rate was 167.89/100,000 (207.24/100,000 in males, 126.54/100,000 in females) and the age-standardized mortality rate by world standard population (ASMRW) was 106.09/100,000. Calculated age-standardized mortality rate was higher in rural areas than in urban areas (110.3/100,000 vs. 102.5/100,000). East China had the highest cancer mortality rate while North China had the lowest mortality rate. The mortality rate in male was higher than that in female. Common cancer types and major causes of cancer death differed between age group and sex. Heavy cancer burden and its disparities between area, sex and age group pose a major challenge to public health in China. Nationwide cancer registry plays a crucial role in cancer prevention and control.


Structure and development of the subesophageal zone of the Drosophila brain. I. Segmental architecture, compartmentalization, and lineage anatomy.
The subesophageal zone (SEZ) of the Drosophila brain houses the circuitry underlying feeding behavior and is involved in many other aspects of sensory processing and locomotor control. Formed by the merging of four neuromeres, the internal architecture of the SEZ can be best understood by identifying segmentally reiterated landmarks emerging in the embryo and larva, and following the gradual changes by which these landmarks become integrated into the mature SEZ during metamorphosis. In previous works, the system of longitudinal fibers (connectives) and transverse axons (commissures) has been used as a scaffold that provides internal landmarks for the neuromeres of the larval ventral nerve cord. We have extended the analysis of this scaffold to the SEZ and, in addition, reconstructed the tracts formed by lineages and nerves in relationship to the connectives and commissures. As a result, we establish reliable criteria that define boundaries between the four neuromeres (tritocerebrum, mandibular neuromere, maxillary neuromere, labial neuromere) of the SEZ at all stages of development. Fascicles and lineage tracts also demarcate seven columnar neuropil domains (ventromedial, ventro-lateral, centromedial, central, centrolateral, dorsomedial, dorsolateral) identifiable throughout development. These anatomical subdivisions, presented in the form of an atlas including confocal sections and 3D digital models for the larval, pupal and adult stage, allowed us to describe the morphogenetic changes shaping the adult SEZ. Finally, we mapped MARCM-labeled clones of all secondary lineages of the SEZ to the newly established neuropil subdivisions. Our work will facilitate future studies of function and comparative anatomy of the SEZ.


[Problems of survey materials in external quality control survey].
In the past over twenty years the Japan Medical Association Quality Control Survey Committee has experienced various types of problems in preparing a large amount of different control survey materials with some matrix effects. This may have caused inappropriate evaluation for some of the participated laboratory. Not only the participated laboratories but also some industrial companies should participate to identify the exact matrix effects, so that the Committee may be able to avoid some inappropriate decisions on evaluation of the reported results. However, at the present time, no standard is available for the identification of matrix effects. The Japanese Committee for Clinical Laboratory Standards, in 1991, organized the research group on external quality control, and suggested a proposal to identify some matrix effects of survey materials for a particular assay system.


In vivo comparison of jellyfish and bovine collagen sponges as prototype medical devices.
Jellyfish have emerged as a source of next generation collagen that is an attractive alternative to existing sources, such as bovine and porcine, due to a plentiful supply and providing a safer source through lack of bovine spongiform encephalopathy (BSE) transmission risk and potential viral vectors, both of which could be transmitted to humans. Here we compare collagen implantable sponges derived for the first time from the Rhizostoma pulmo jellyfish. A further novelty for the research was that there was a comparison for sponges that were either uncrosslinked or crosslinked using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), and an assessment on how this affected resorption, as well as their biocompatibility compared to bovine type I collagen sponges. The scaffolds were prepared and examined using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and scanning electron microscopy (SEM). The samples were implanted in adult male Wistar rats for in vivo experimentation. Both crosslinked and uncrosslinked jellyfish collagen sponges showed a significant reduction in histopathology scores over the course of the study, whereas the bovine collagen sponge scores were not significantly reduced. Both jellyfish collagen sponges and the bovine sponge were tolerated well by the hosts, and a recovery was visible in all samples, suggesting that R. pulmo jellyfish-derived collagen could offer compelling biocompatibility with wound healing applications. We also demonstrate that noncrosslinked samples could be safer with better resorption times than crosslinked samples. © 2017 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1524-1533, 2018.


Rhabdomyolysis and unilateral renal infarction after a motor vehicle crash.
A 46-year-old man with no previous history of abnormal urinalysis findings or renal dysfunction was admitted to a local hospital because of a motor vehicle crash. An open laparotomy was performed to treat a perforation of the small intestine. After operation, oliguria and renal dysfunction developed, and he was admitted to our hospital because of acute renal failure after trauma. Acute renal failure was assumed to be due to rhabdomyolysis with elevated serum creatinine, blood urea nitrogen, and creatine kinase levels and myoglobinemia. Left flank pain occurred several days after admission, and the serum alkaline phosphatase level increased between days 5 and 12 following admission. Although hemodialysis was performed 9 times and the urine output was satisfactory, the creatinine clearance levels increased only to about 50 mL/min/1.73 m2 (0.84 mL/s/m2) at 6 weeks following admission. As a result, a diagnosis of renal infarction due to acute renal artery occlusion was considered. The left kidney was atrophic on an abdominal computed tomographic scan and was nonfunctioning on a renogram. This case shows the importance of not overlooking the possibility of a renal infarction associated with rhabdomyolysis after a motor vehicle crash. In particular, the changes in the serum alkaline phosphatase levels were important in making a correct diagnosis in this case.


A conformation-dependent epitope of human platelet glycoprotein IIIa.
This study explores conformational states of human platelet glycoprotein IIIa (GP IIIa) and possible mechanisms of fibrinogen receptor exposure. D3GP3 is an IgG1, kappa monoclonal antibody generated against purified GP IIIa and found to be specific for GP IIIa by immunoprecipitation and Western blot analysis. The binding of D3GP3 to resting platelets caused fibrinogen binding (approximately 5,000 molecules/platelet) and platelet aggregation but not secretion. Platelets express 40,000-50,000 GP IIb-IIIa molecules in their surface membranes. However, resting platelets only bound approximately 5,000 D3GP3 molecules/platelet. D3GP3 binding to platelets could be increased 2-3-fold by dissociation of the GP IIb-IIIa complex with 5 mM EDTA or by occupying the fibrinogen receptor with either RGDS peptides or fibrinogen. Platelet stimulation with ADP in the absence of fibrinogen did not cause increased D3GP3 binding above control levels. These data suggest that 1) GP IIb-IIIa can exist in multiple conformations in the platelet membrane, 2) D3GP3 binding to GP IIIa can expose the fibrinogen receptor, 3) the binding of either RGDS peptides or fibrinogen causes exposure of the D3GP3 epitope, and 4) platelet activation in the absence of ligand does not induce the same conformational changes in GP IIb-IIIa as does receptor occupancy by RGDS peptides or fibrinogen.


Highly Selective Synthesis of Pillar[ n]arene ( n = 5, 6).
An efficient and highly selective synthetic method toward the preparation of pillar[ n]arenes ( n = 5, 6) is reported, based upon a high solvent-dependent selectivity found in the condensation reaction between 1,4-dialkyloxybenzene and paraformaldehyde, involving methanesulfonic acid as catalyst. Pillar[6]arene (P6) is obtained as the major product when using chloroform as solvent, while in dichloromethane pillar[5]arene (P5) is the dominant product. Accordingly, a series of P5 and P6 have been selectively synthesized with excellent yield.


Predictors of clinical AIDS in young homosexual men in a high-risk area.
One hundred and sixty-seven homosexual men in Los Angeles characterized by HIV antibody, T-cell numbers, titres to cytomegalovirus (CMV), and specific sexual practices were followed for two years for immune changes and for more than three years for development of clinical AIDS. Thirty-five per cent had antibody to HIV at baseline. The mean level of T-helper (Th) cells was significantly lower and of T-suppressor (Ts) cells significantly higher in HIV seropositives than in seronegatives. The annualized incidence of HIV seroconversion was 7%. Eight men developed AIDS, an attack rate of 14% in those with HIV antibody at baseline. A number of observations were made: T-cell alterations, except a transient elevation in Ts cells, were unusual in the absence of HIV antibody; a seropositive man with a T-cell alteration was significantly less likely to revert to 'within normal limits' than was a seronegative man; a steady decline in the number of Th cells preceded onset of clinical AIDS; the number of Ts cells remained higher in men subsequently developing AIDS than in other seropositive men; clinical AIDS occurred only in men with HIV antibody whose CMV antibody levels were above the median for the group (1:1600); and the attack rate for clinical AIDS was 50% in men with HIV antibody and elevated CMV who at baseline had either: fewer than 325 Th cells/cc, or whose Th/Ts ratio was below 0.8 (but whose levels of Th and Ts cells were within normal limits).(ABSTRACT TRUNCATED AT 250 WORDS)


Understanding the evolution and development of neurosensory transcription factors of the ear to enhance therapeutic translation.
Reconstructing a functional organ of Corti is the ultimate target towards curing hearing loss. Despite the impressive technical gains made over the last few years, many complications remain ahead for the two main restoration avenues: in vitro transformation of pluripotent cells into hair cell-like cells and adenovirus-mediated gene therapy. Most notably, both approaches require a more complete understanding of the molecular networks that ensure specific cell types form in the correct places to allow proper function of the restored organ of Corti. Important to this understanding are the basic helix-loop-helix (bHLH) transcription factors (TFs) that are highly diverse and serve to increase functional complexity but their evolutionary implementation in the inner ear neurosensory development is less conspicuous. To this end, we review the evolutionary and developmentally dynamic interactions of the three bHLH TFs that have been identified as the main players in neurosensory evolution and development, Neurog1, Neurod1 and Atoh1. These three TFs belong to the neurogenin/atonal family and evolved from a molecular precursor that likely regulated single sensory cell development in the ectoderm of metazoan ancestors but are now also expressed in other parts of the body, including the brain. They interact extensively via intracellular and intercellular cross-regulation to establish the two main neurosensory cell types of the ear, the hair cells and sensory neurons. Furthermore, the level and duration of their expression affect the specification of hair cell subtypes (inner hair cells vs. outer hair cells). We propose that appropriate manipulation of these TFs through their characterized binding sites may offer a solution by itself, or in conjunction with the two other approaches currently pursued by others, to restore the organ of Corti.


Baseline Functional Connectivity in Resting State Networks Associated with Depression and Remission Status after 16 Weeks of Pharmacotherapy: A CAN-BIND Report.
Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. So far, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity associated with MDD and pharmacotherapy outcomes in a large, multisite sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression. Symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior cingulate cortex, insula and dorsolateral prefrontal cortex) and all other brain voxels. Partial least squares was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission (MADRS ≤ 10) early (within 8 weeks), late (within 16 weeks), or not at all. We replicated previous findings of altered connectivity in patients. In addition, baseline connectivity of the anterior/posterior cingulate and insula seeds differentiated patients with different treatment outcomes. The stability of these differences was established in the largest single-site subsample. Our replication and extension of altered connectivity highlighted previously reported and new differences between patients and controls, and revealed features that might predict remission prior to pharmacotherapy. Trial registration:ClinicalTrials.gov: NCT01655706.


[Expert opinion on biologic stains. Determination of status, future trends].
In this paper an attempt is made to critically review the literature, with special emphasis on bloodstain analysis. One essential aim is the integration of this field into casework. Three basic components in skillful assessment of stains are described: (1) analysis of stain morphology, (2) discriminating and attributing analyses, (3) individualization. Regarding the first, the analysis of stain morphology is based upon the extensive experimental literature published since 1895--mainly in continental Europe. Since 1971 there have also been publications in the American literature. The large family of stain forms and their dependency on multiple variables are described, especially regarding the modes of formation, the energy of impact, and the physical properties of the substrate. The essential elements for reconstruction of the crime are described. The areas of application are arranged in case groups. Since in case work the stain pattern is complicated by many artifacts and overlaps, forensic pathologists are considered the ideal experts for the analysis of bloodstain patterns, as they have a profound knowledge of the type and sequence of injuries. If this is not the case, the forensic pathologist should at least be integrated into the investigating team. In practical application, the stain form is not always adequately analysed. The education and training of pathologists should be improved to achieve this standard. Analysis of the stain morphology and a subsequent selection of stains are also essential prerequisites for meaningful further investigations. By the use of discriminating and attributing analyses, one can as a rule arrive at a definite answer by using only one test. This is true for basic questions such as the identification of blood type, as well as proof of exclusion. One can distinguish between traditional methods, the new field of immunochemistry and rarely used methods. Immunochemistry has permitted success in recent years in determination of the blood group from hair. It is recommended that reference laboratories be established for training in these rare methods. Individualization analyses are subdivided into two large fields: non-DNA individualization and DNA individualization. It is postulated that in the future stain laboratory both areas will coexist. In non-DNA individualization, essential progress has been made. The detection of protein polymorphisms by blotting and subsequent visualization by antibody-linked enzyme/substrate reactions has led to a considerable increase in sensitivity and specificity.(ABSTRACT TRUNCATED AT 400 WORDS)


A Structural View of Xenophagy, a Battle between Host and Microbes.
The cytoplasm in mammalian cells is a battlefield between the host and invading microbes. Both the living organisms have evolved unique strategies for their survival. The host utilizes a specialized autophagy system, xenophagy, for the clearance of invading pathogens, whereas bacteria secrete proteins to defend and escape from the host xenophagy. Several molecules have been identified and their structural investigation has enabled the comprehension of these mechanisms at the molecular level. In this review, we focus on one example of host autophagy and the other of bacterial defense: the autophagy receptor, NDP52, in conjunction with the sugar receptor, galectin-8, plays a critical role in targeting the autophagy machinery against Salmonella; and the cysteine protease, RavZ secreted by Legionella pneumophila cleaves the LC3-PE on the phagophore membrane. The structure-function relationships of these two examples and the directions of future research will be discussed.


Linaclotide - a secretagogue and antihyperalgesic agent - what next?
Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase-C (GC-C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation- and stress-induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint-induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC-C receptors. Dose-effect relationships of linaclotide were complicated and non-linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC-C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress-induced increased intestinal permeability. However, the data need to be confirmed in humans and in long-term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide's known effects on epithelial GC-C receptors.