Guillain-Barré Syndrome.
This article reviews the current state of Guillain-Barré syndrome (GBS), including its clinical presentation, evaluation, pathophysiology, and treatment. GBS is an acute/subacute-onset polyradiculoneuropathy typically presenting with sensory symptoms and weakness over several days, often leading to quadriparesis. Approximately 70% of patients report a recent preceding upper or lower respiratory tract infection or gastrointestinal illness. Approximately 30% of patients require intubation and ventilation because of respiratory failure. Nerve conduction studies in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) form of GBS typically show evidence for a multifocal demyelinating process, including conduction block or temporal dispersion in motor nerves. Sural sparing is a common phenomenon when testing sensory nerves. CSF analysis commonly shows an elevated protein, but this elevation may not be present until the third week of the illness. Patients with AIDP are treated with best medical management and either IV immunoglobulin (IVIg) or plasma exchange. GBS is a common form of acute quadriparesis; a high level of suspicion is needed for early diagnosis. With appropriate therapy, most patients make a very good to complete recovery.


Clinically meaningful response to the EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in non small cell lung cancer.
Preclinical research and ongoing clinical trials are validating epidermal growth factor receptor (EGFR) as a suitable molecular target in cancer therapy. Here we report the case of a 39-year-old non-smoking man with heavily pretreated stage IV bronchioloalveolar NSCLC who was treated with gefitinib ('Iressa', ZD1839) at the dose of 250 mg/day, orally. Symptomatic relief was already detectable after 2 weeks of gefitinib therapy, pulmonary function tests readily improved, performance status went from 2 to 0 within 8 weeks, CT scan performed after 10 weeks of treatment showed nearly complete resolution of the clinical picture, and clinical remission was maintained up to 32 weeks. This case-report illustrates the potential of EGFR tyrosine kinase inhibition to induce clinically meaningful responses in heavily pretreated, advanced NSCLC patients and suggests that participation of such patients into clinical trials of signal transduction inhibitors should be encouraged.


Preliminary Reporting Patterns of Suicide Ideation and Attempt Among Native American Adolescents in Two Samples.
Native American adolescents are disproportionately burdened by suicidality. Here, we examine patterns of reporting of suicide ideation and suicide attempt among Native American youth compared to those from other ethnoracial backgrounds, as this data is important for grounding commonly subscribed to frameworks of suicide risk (e.g., ideation-to-action). Data are from the Youth Risk Behavior Surveillance Survey (N = 54,243; grades 9-12; 51.0% female) and Minnesota Student Survey (N = 335,151; grades 8, 9, 11; 50.7% female). Comparing Native American youth to peers from other ethnoracial backgrounds, we examined two suicide reporting patterns: 1) odds of reporting suicide attempt among those who reported ideation and 2) odds of reporting suicide ideation among those who reported an attempt. Across both samples, when reporting suicide ideation, youth from other ethnoracial backgrounds were 20-55% less likely than Native American youth to also report attempt. While few consistent differences were observed between Native American youth and those from other racial minority backgrounds in patterns of co-reporting suicide ideation and attempt across samples, White youth were between 37% and 63% less likely than Native American youth to report a suicide attempt without also reporting ideation. The increased odds of engaging in a suicide attempt with or without reporting ideation question the generalizability of widely held frameworks of suicide risk to Native American youth and have important implications for suicide risk monitoring. Future research is needed to illuminate how these behaviors unfold over time and the potential mechanisms of risk for engaging in suicide attempts in this disproportionately burdened group.Abbreviations: YRBSS: Youth Risk Behavior Surveillance Survey; MSS: Minnesota Student Survey.


A motif in the clathrin heavy chain required for the Hsc70/auxilin uncoating reaction.
The 70-kDa heat-shock cognate protein (Hsc70) chaperone is an ATP-dependent "disassembly enzyme" for many subcellular structures, including clathrin-coated vesicles where it functions as an uncoating ATPase. Hsc70, and its cochaperone auxilin together catalyze coat disassembly. Like other members of the Hsp70 chaperone family, it is thought that ATP-bound Hsc70 recognizes the clathrin triskelion through an unfolded exposed hydrophobic segment. The best candidate is the unstructured C terminus (residues 1631-1675) of the heavy chain at the foot of the tripod below the hub, containing the sequence motif QLMLT, closely related to the sequence bound preferentially by the substrate groove of Hsc70 (Fotin et al., 2004b). To test this hypothesis, we generated in insect cells recombinant mammalian triskelions that in vitro form clathrin cages and clathrin/AP-2 coats exactly like those assembled from native clathrin. We show that coats assembled from recombinant clathrin are good substrates for ATP- and auxilin-dependent, Hsc70-catalyzed uncoating. Finally, we show that this uncoating reaction proceeds normally when the coats contain recombinant heavy chains truncated C-terminal to the QLMLT motif, but very inefficiently when the motif is absent. Thus, the QLMLT motif is required for Hsc-70-facilitated uncoating, consistent with the proposal that this sequence is a specific target of the chaperone.


A case of antibacterial-responsive mucocutaneous disease in a seven-year-old dwarf lop rabbit (Oryctolagus cuniculus) resembling mucocutaneous pyoderma of dogs.
A seven-year-old, ovariohysterectomised female dwarf lop rabbit (Oryctolagus cuniculus) was referred with severe swelling and erythema of the mucocutaneous junctions of the lips, nares and vulva. Bilateral, severe periocular dermatitis was also present. Heavy pure growths of a member of the Staphylococcus intermedius group were cultured from nasal and aural swabs and skin biopsies. Other possible differential diagnoses were eliminated by standard tests. The clinical features and histopathological characteristics of the biopsies were most consistent with mucocutaneous pyoderma, a dermatosis previously reported in dogs but not in rabbits. Treatment of the bacterial infection with oral marbofloxacin and topical ofloxacin eye drops together with supportive therapy resulted in resolution of the lesions. To the authors' knowledge, this is the first report of mucocutaneous bacterial pyoderma, similar to mucocutaneous pyoderma of dogs, in a rabbit.


Vocational Rehabilitation for Patients with Chronic Musculoskeletal Pain With or Without a Work Module: An Economic Evaluation.
Purpose Vocational rehabilitation (VR) is a widely used intervention aimed to optimize work participation for patients on sick leave due to chronic musculoskeletal pain (CMP). Economic evaluations of care as usual VR are scarce, and may provide relevant information to guide clinical, reimbursement and policy decisions. The aim of this study was to evaluate the short-term cost-effectiveness and return on investment (ROI) of VR for patients on sick leave due to CMP with an additional work module (VR+) compared to VR without work module, from a societal and employers' perspective. Methods A retrospective longitudinal cohort study within a Dutch care as usual context was applied. Participants with CMP and decreased work participation originating from seven Dutch rehabilitation centers were included in this study. Participants underwent VR or VR+. Main data sources at baseline and discharge: Quality-adjusted life year (QALY) based on EQ-5D, intervention costs, self-reported productivity and health care utilization. Main analyses cost-effectiveness, including incremental cost-effectiveness ratio (ICER) and a cost-effectiveness acceptability curve (CEAC); and ROI analyses with use of the human capital method. Results N = 324 participants were analyzed. The results show that VR+ was cost-effective compared to VR: mean cost savings of €820 per 0.012 QALY gained. CEAC suggests probability of VR+ being cost-effective is > 0.91 for thresholds of €20.000 and higher. The mean ROI of VR+ for employers was 38%. Conclusion It was concluded that at discharge, VR+ was cost-effective compared to VR. ROI was positive for employers.


Factors and mechanism of "EPR" effect and the enhanced antitumor effects of macromolecular drugs including SMANCS.
Both enhanced vascular permeability and angiogenesis of tumor sustain rapid growth of tumor involving many vascular mediators and high vascular density. On the contrary, however, they can be utilized for macromolecular drug delivery to tumor. Impaired reticuloendothelial/lymphatic clearance of macromolecules from the tumor, or lack of such clearance, is another unique characteristic of tumor tissue, which results intratumor retention of macromolecular drugs thus delivered (Figure 1). Consequently, enhanced permeability and retention (EPR) effect is the basis for the selective targeting of macromolecular drugs to tumor, and the EPR concept is now utilized for selective delivery of many macromolecular anticancer agents in aqueous formation for i.v. or i.a. as well as oily formation for i.a. dosing, which is not possible for low-molecular-weight drugs because of rapid washout by capillary vascular blood flow. This EPR concept has been validated in clinical settings with hepatoma and other solid tumors. In our laboratories, several promising macromolecular anticancer drugs after SMANCS, such as PEG-XO, PEG-DAO, PEG-ZnPP, were developed, warranting further investigation for clinical application. More efficient drug delivery to tumor, especially of macromolecular drugs, may be possible by enhancing the EPR effect with the use of various vascular permeability mediators or potentiators. Suppression of the EPR effect by the use of appropriate inhibitors or antidotes, such as the bradykinin antagonist HOE 140 and protease inhibitors or NOS inhibitors, may also be possible. Thus, one may be able to suppress or retard tumor growth and tumor metastasis. Also, by suppressing vascular permeability with antidotes such as the bradykinin antagonist HOE 140, pleural fluid in lung cancer and ascitic fluid in abdominal carcinomatosis may be controlled and the clinical course of cancer patients may be improved. In summary, tumor vasculature can be an excellent target for delivery of macromolecular anticancer drugs; the most beneficial class of drugs in view of tumor-selective targeting based on the EPR effect in solid tumor as well as compliance of patients and ultimate therapeutic efficacy.


A comparison of two-dimensional electrophoresis data with phenotypical traits in Arabidopsis leads to the identification of a mutant (cri1) that accumulates cytokinins.
Total proteins extracted from developmental mutants of Arabidopsis thaliana (L.) Heyhn. and from wild-type plants cultivated in the presence of various hormones were analyzed by two-dimensional (2-D) gel electrophoresis. Computer analysis of 2-D gels followed by a statistical treatment of data allowed us to build a phenogram that describes the biochemical distances between the different genotypes. Analysis of the 2-D electrophoresis data allowed us to discriminate mutants in agreement with phenotypical and physiological traits. This biochemical analysis helped us to develop a working hypothesis which led us to show that one developmental mutant (cri1) overaccumulates cytokinins.


From Boreli (1680) and Bell (1826) to the Dynamics of Action and Perception.
Recent developments in the study of action and perception have their roots in the contemplations of Giovanni Borelli, a 17th-century Italian mathematician and physicist, and Sir Charles Bell, and 18th-century English physiologist and neuroanatomist. When Borelli looked at muscle and its functional achievements, he saw dynamics with its attendant laws and principles; when Bell looked at muscle, he saw information about muscular states and a smart mechanism for its measurement. Research and theory on the dynamics of coordination and locomotion, and on the perceptual achievements of the haptic subsystem of dynamic touch, are providing affirmation of these visions of Borelli and Bell.


Neonatal infraorbital nerve transection in the rat: comparison of effects on substance P immunoreactive primary afferents and those recognized by the lectin Bandierea simplicifolia-I.
Retrograde tracing, immunocytochemical, and histochemical methods were used to determine the manner in which different classes of trigeminal (V) ganglion cells respond to transection of their axons during infancy. Retrograde tracing with true blue (TB), histochemistry using the plant lectin Bandieraea simplicifolia-I (BS-I), and immunocytochemistry using an antiserum directed against substance P (SP) were carried out in the V ganglion and V brainstem complex of normal adult rats. In the adult V ganglion, 11.9 +/- 1.9% of the cells that sent axons into the infraorbital nerve (ION) contained SP-like immunoreactivity (SPLI) and 26.9 +/- 3.6% bound the lectin BS-I. Only 2.7 +/- 1.6% of ION cells were labelled by both the SP antiserum and BS-I. Transection of the ION on the day of birth had very different effects upon primary afferent neurons containing SPLI and those labelled by BS-I. We have previously shown that such lesions result in a significant expansion of the portion of SpC innervated by primary afferents containing SPLI and we have also provided data consistent with the proposal that ganglion cells recognized by an antiserum directed against SP are more likely than other primary afferent neurons to survive neonatal axotomy. In the present study, combination of retrograde tracing with TB and lectin binding histochemistry showed that cells recognized by BS-I were selectively lost after neonatal ION transection. Only 14.2 +/- 4.4% of the ION ganglion cells that projected into this nerve at the time of the lesion and that survived neonatal axotomy were BS-I positive when the animals reached adulthood. Neonatal ION transection also resulted in a permanent reduction in the density of BS-I binding in SpC. Bandieraea simplicifolia-I binding in the brainstem ipsilateral to the damaged nerve was almost completely gone within 1 day of the nerve transection and recovered only partially by the time the rats were 2 months of age. In alternate sections tested with the SP antiserum, there was a slight reduction in the density of SPLI in the deafferented SpC on postnatal days 4 and 5, but this change never approached that observed for BS-I binding.


Early Sonographic Evaluation of Intrarenal Arterial Resistive Index and Long-term Renal Function in Renal Transplant Recipients in South Western Nigeria.
Color Doppler ultrasonography of intrarenal arterial Resistive Index (RI), performed early after kidney transplant, has proven to reliably predict short-term allograft function. The aim of this study was to assess whether early Doppler assessment could correlate with long-term renal function. This was a retrospective study of intrarenal RI using ultrasound in 41 stable kidney transplant patients who underwent RI assessment within 1 month after the transplant. Color Doppler ultrasonography was done to calculate the intrarenal RI within the first 4 weeks after transplant. The mean values of the intrarenal RI of the interlobar arteries of the allograft kidneys were measured and recorded. The data were analyzed with the aid of computer-based SPSS 20.0 software for windows (IBM, International Business Machines Corporation, Company, Armonk, New York, USA). Older recipient age, active smoking, and proteinuria were associated with a higher intrarenal RI. Multivariate analyses showed that renal RI and donor age were independent predictors of allograft outcome. Kaplan-Meier estimates of cumulative graft survival were significantly worse in patients who had the values of the RI of 0.7 or more than they were in patients who had the values of the RI of <0.7. This study reveals that renal RI determined within the 1st month after renal transplant correlates with long-term allograft function in kidney transplant recipients.


Nicotine Inhibits the Cytotoxicity and Genotoxicity of NNK Mediated by CYP2A13 in BEAS-2B Cells.
Both tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and nicotine can be metabolized by cytochrome P450 2A13 (CYP2A13). Previous studies have shown that nicotine has a potential inhibitory effect on the toxicity of NNK. However, due to the lack of CYP2A13 activity in conventional lung cell lines, there had been no systematic in vitro investigation for the key target organ, the lung. Here, BEAS-2B cells stably expressing CYP2A13 (B-2A13 cells) were constructed to investigate the effects of nicotine on the cytotoxicity and genotoxicity of NNK. The results showed more sensitivity for NNK-induced cytotoxicity in B-2A13 cells than in BEAS-2B and B-vector cells. NNK significantly induced DNA damage, cell cycle arrest, and chromosomal damage in B-2A13 cells, but had no significant effect on BEAS-2B cells and the vector control cells. The combination of different concentration gradient of nicotine without cytotoxic effects and a single concentration of NNK reduced or even counteracted the cytotoxicity and multi-dimensional genotoxicity in a dose-dependent manner. In conclusion, CYP2A13 caused the cytotoxicity and genotoxicity of NNK in BEAS-2B cells, and the addition of nicotine could inhibit the toxicity of NNK.


SERT and NET polymorphisms, temperament and antidepressant response.
The genetic variations in norepinephrine transporter (NET) and serotonin transporter (SERT) genes have been associated with personality traits, several psychiatric disorders and the efficacy of antidepressant treatment. We investigated the separate effects and possible interactions between NET T-182C (rs2242446) and SERT 5-HTTLPR (rs4795541) polymorphisms on selective serotonin reuptake inhibitors (SSRI) treatment response and temperamental traits assessed by the Temperament and Character Inventory (TCI) in a clinical sample of subjects with major depressive disorder (MDD). Our sample of 97 patients with major depression completed the 107-item TCI temperament questionnaire (version IX) at the initial assessment of the study and after 6 weeks of follow-up. All subjects received selective SSRI medications. Temperament dimension scores at baseline ( 1 ) and endpoint ( 2 ) during antidepressant treatment were analyzed between NET and SERT genotypes. SS-genotype of 5-HTTLPR was associated with higher baseline Persistence scores than SL- or LL-genotype. A corresponding but weaker association was found at endpoint. No differences were found between 5-HTTLPR genotypes and other temperament dimensions and 5-HTTLPR genotypes had no effect on treatment response. Our results suggest that the SS-genotype of 5-HTTLPR is associated with Persistence scores in patients with MDD. Higher Persistence could be viewed as a negative trait when recovering from stress and its association with short and "weaker" S-allele may be related to less efficient serotonin neurotransmission, possibly resulting in less effective coping strategies on a behavioral level.


Management of Hyperglycemia in the Noncritical Care Setting: A Real-World Case-Based Approach With Alternative Insulin- and Noninsulin-Based Strategies.
Insulin remains the mainstay of treatment for inpatient hyperglycemia in the United States and Canada. However, some other countries commonly use noninsulin agents such as metformin and sulfonylureas, and several trials have demonstrated the efficacy and safety of incretin-based agents in patients with type 2 diabetes who are admitted to noncritical care medicine and surgery services. There is a high degree of interest in alternative glucose-lowering strategies to achieve favorable glycemic outcomes with lower risks of hypoglycemia. In this case series, we highlight the challenges of inpatient glycemic management and the need for alternatives to the traditional basal-bolus insulin regimen. Additional investigation will be imperative to validate the safety and efficacy of appropriate insulin and noninsulin treatments and to further develop guidelines that are applicable in real-world hospital settings.


The treatment of primary and metastatic renal cell carcinoma (RCC) with image-guided stereotactic body radiation therapy (SBRT).
Brain metastases from renal cell carcinoma (RCC) have been successfully treated with stereotactic radiosurgery (SRS). Metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high-dose radiation in a few fractions. This paper reports the authors' initial experience with image-guided SBRT in treating primary and metastatic RCC. The image-guided Brainlab Novalis stereotactic system was used. Fourteen patients with 23 extra-cranial metastatic RCC lesions (orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine and abdominal wall) and two patients with biopsy-proven primary RCC (not surgical candidates) were treated with SBRT (24-40 Gy in 3-6 fractions over 1-2 weeks). All patients were immobilised in body cast or head and neck mask. Image-guidance was used for all fractions. PET/CT images were fused with simulation CT images to assist in target delineation and dose determination. SMART (simultaneous modulated accelerated radiation therapy) boost approach was adopted. 4D-CT was utilised to assess tumour/organ motion and assist in determining planning target volume margins. Median follow-up was nine months. Thirteen patients (93%) who received SBRT to extra-cranial metastases achieved symptomatic relief. Two patients had local progression, yielding a local control rate of 87%. In the two patients with primary RCC, tumour size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There were no significant treatment-related side effects. Image-guided SBRT provides excellent symptom palliation and local control without any significant toxicity. SBRT may represent a novel, non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC.


Levels of malondialdehyde and superoxide dismutase in subclinical hyperthyroidism.
We aimed to determine whether patients with subclinical hyperthyroidism (SH) are subject to oxidative stress. Twenty-two women and 8 men having endogenous subclinical hyperthyroidism for a duration of at least 6 months, and 21 women and 9 men healthy controls were included in this study. We measured the level of plasma malondialdehyde, as one of the lipid peroxidation markers, and the activity of erythrocyte superoxide dismutase, which is an antioxidant enzyme. The activity of erythrocyte superoxide dismutase and plasma malondialdehyde levels were found to be significantly higher in subjects with subclinical hyperthyroidism than the control group (P < .01). The results of this study suggest that oxidative stress and antioxidative response could be increased in patients having subclinical hyperthyroidism.


Modeling genetic benefits and financial costs of integrating biobanking into the conservation breeding of managed marsupials.
Managed breeding programs are an important tool in marsupial conservation efforts but may be costly and have adverse genetic effects in unavoidably small captive colonies. Biobanking and assisted reproductive technologies (ARTs) could help overcome these challenges, but further demonstration of their potential is required to improve uptake. We used genetic and economic models to examine whether supplementing hypothetical captive populations of dibblers (Parantechinus apicalis) and numbats (Myrmecobius fasciatus) with biobanked founder sperm through ARTs could reduce inbreeding, lower required colony sizes, and reduce program costs. We also asked practitioners of the black-footed ferret (Mustela nigripes) captive recovery program to complete a questionnaire to examine the resources and model species research pathways required to develop an optimized biobanking protocol in the black-footed ferret. We used data from this questionnaire to devise similar costed research pathways for Australian marsupials. With biobanking and assisted reproduction, inbreeding was reduced on average by between 80% and 98%, colony sizes were on average 99% smaller, and program costs were 69- to 83-fold lower. Integrating biobanking made long-standing captive genetic retention targets possible in marsupials (90% source population heterozygosity for a minimum of 100 years) within realistic cost frameworks. Lessons from the use of biobanking technology that contributed to the recovery of the black-footed ferret include the importance of adequate research funding (US$4.2 million), extensive partnerships that provide access to facilities and equipment, colony animals, appropriate research model species, and professional and technical staff required to address knowledge gaps to deliver an optimized biobanking protocol. Applied research investment of A$133 million across marsupial research pathways could deliver biobanking protocols for 15 of Australia's most at-risk marsupial species and 7 model species. The technical expertise and ex situ facilities exist to emulate the success of the black-footed ferret recovery program in threatened marsupials using these research pathways. All that is needed now for significant and cost-effective conservation gains is greater investment by policy makers in marsupial ARTs.


Hemodynamic failure and graft dysfunction after lung transplant: A possible clinical continuum with immediate and long-term consequences.
The postoperative hemodynamic management after lung transplant (LUTX) is guided by limited evidence. We aimed to describe and evaluate risk factors and outcomes of postoperative vasoactive support of LUTX recipients. In a single-center retrospective analysis of consecutive adult LUTX, two cohorts were identified: (1) patients needing prolonged vasoactive support (>12 h from ICU admission) (VASO+); (2) or not (VASO-). Postoperative hemodynamic characteristics were thoroughly analyzed. Risk factors and outcomes of VASO+ versus VASO- cohorts were assessed by multivariate logistic regression and propensity score matching. One hundred and thirty-eight patients were included (86 (62%) VASO+ versus 52 (38%) VASO-). Vasopressors (epinephrine, norepinephrine, dopamine) were used in the first postoperative days (vasoactive inotropic score at 12 h: 6 [4-12]), while inodilators (dobutamine, levosimendan) later. Length of vasoactive support was 3 [2-4] days. Independent predictors of vasoactive use were: LUTX indication different from cystic fibrosis (p = .003), higher Oto score (p = .020), longer cold ischemia time (p = .031), but not preoperative cardiac catheterization. VASO+ patients showed concomitant hemodynamic and graft impairment, with longer mechanical ventilation (p = .010), higher primary graft dysfunction (PGD) grade at 72 h (PGD grade > 0 65% vs. 31%, p = .004, OR 4.2 [1.54-11.2]), longer ICU (p < .001) and hospital stay (p = .013). Levosimendan as a second-line inodilator appeared safe. Vasoactive support is frequently necessary after LUTX, especially in recipients of grafts of lesser quality. Postoperative hemodynamic dysfunction requiring vasopressor support and graft dysfunction may represent a clinical continuum with immediate and long-term consequences. Further studies may elucidate if this represents a possible treatable condition.


Reverse prostheses in arthropathies with cuff tear: are survivorship and function maintained over time?
The use of reverse shoulder arthroplasty has considerably increased since first introduced in 1985. Despite demonstrating early improvement of function and pain, there is limited information regarding the durability and longer-term outcomes of this prosthesis. We determined complication rates, functional scores over time, survivorship, and whether radiographs would develop signs of loosening. We retrospectively reviewed 527 reverse shoulder arthroplasties performed in 506 patients between 1985 and 2003. Clinical and radiographic assessment was performed in 464 patients with a minimum followup of 2 years and 148 patients with a minimum followup of 5 years (mean, 7.5 years; range, 5-17 years). Cumulative survival curves were established with end points being prosthesis revision and Constant-Murley score of less than 30 points. Eighty-nine of 489 had at least one complication for a total of 107 complications. Survivorship free of revision was 89% at 10 years with a marked break occurring at 2 and 9 years. Survivorship to a Constant-Murley score of less than 30 was 72% at 10 years with a marked break observed at 8 years. We observed progressive radiographic changes after 5 years and an increasing frequency of large notches with long-term followup. Although the need for revision of reverse shoulder arthroplasty was relatively low at 10 years, Constant-Murley score and radiographic changes deteriorated with time. These findings are concerning regarding the longevity of the reverse shoulder arthroplasty, and therefore caution must be exercised when recommending reverse shoulder arthroplasty, especially in younger patients. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Altered Organization of GABA(A) Receptor mRNA Expression in the Depressed Suicide Brain.
Inter-relationships ordinarily exist between mRNA expression of GABA(A) subunits in the frontopolar cortex (FPC) of individuals that had died suddenly from causes other than suicide. However, these correlations were largely absent in persons that had died by suicide. In the present investigation, these findings were extended by examining GABA(A) receptor expression patterns (of controls and depressed individuals that died by suicide) in the orbital frontal cortex (OFC), hippocampus, amygdala. locus coeruleus (LC) and paraventricular nucleus (PVN), all of which have been implicated in either depression, anxiety or stress responsivity. Using QPCR analysis, we found that in controls the inter-relations between GABA(A) subunits varied across brain regions, being high in the hippocampus and amygdala, intermediate in the LC, and low in the OFC and PVN. The GABA(A) subunit inter-relations were markedly different in persons that died by suicide, being reduced in hippocampus and amygdala, stable in the LC, but more coordinated in the OFC and to some extent in the PVN. It seems that altered brain region-specific inhibitory signaling, stemming from altered GABA(A) subunit coordination, are associated with depression/suicide. Although, it is unknown whether GABA(A) subunit re-organization was specifically tied to depression, suicide, or the accompanying distress, these data show that the coordinated expression of this transcriptome does vary depending on brain region and is plastic.


Reanalysis of multislice (1)H MRSI in amyotrophic lateral sclerosis.
The goal of this work was to reexamine previously published (1) brain spectroscopy data of abnormal metabolite ratios in amyotrophic lateral sclerosis (ALS). Toward this goal, (1)H MR spectroscopic imaging data from 10 ALS and nine control subjects were reanalyzed using improved data analysis techniques, including automated curve fitting and tissue-volume correction. In the motor cortex of ALS, N-acetyl aspartate (NAA) was 23% (P = 0.004) lower than in controls, and in the posterior internal capsule of ALS choline compounds (Cho) were 20% (P = 0.02) higher. This demonstrates that the metabolite ratio changes in ALS were due to NAA loss in the motor cortex (as expected) and Cho increase in the posterior internal capsule (not expected). Magn Reson Med 45:513-516, 2001.


Development of an In Vitro Method of Propagation for Artemisia tridentata subsp. tridentata to Support Genome Sequencing and Genotype-by-Environment Research.
Basin big sagebrush (Artemisia tridentata subsp. tridentata) is a keystone species of the sagebrush steppe, a widespread ecosystem of western North America threatened by climate change. The study's goal was to develop an in vitro method of propagation for this taxon to support genome sequencing and genotype-by-environment research on drought tolerance. Such research may ultimately facilitate the reintroduction of big sagebrush in degraded habitats. Seedlings were generated from two diploid mother plants (2n = 2x = 18) collected in environments with contrasting precipitation regimes. The effects of IBA and NAA on rooting of shoot tips were tested on 45 individuals and 15 shoot tips per individual. Growth regulator and individual-seedling effects on percent rooting and roots per shoot tip were evaluated using statistical and clustering analyses. Furthermore, rooted shoot tips were transferred into new media to ascertain their continued growth in vitro. The results suggest that A. tridentata is an outbred species, as shown by individuals' effect on rooting and growth. IBA addition was the most effective method for promoting adventitious rooting, especially in top-performing individuals. These individuals also have high survival and growth rates upon transferring to new media, making them suitable candidates for generating biomass for genome sequencing and producing clones for genotype-by-environment research.


Solution structure of ileal lipid binding protein in complex with glycocholate.
Ileal lipid binding protein (ILBP) is a cytosolic lipid-binding protein that binds both bile acids and fatty acids. We have determined the solution structure of porcine ILBP in complex with glycocholate by homonuclear and heteronuclear two-dimensional NMR spectroscopy. The conformation of the protein-ligand complex was determined by restrained energy minimization and simulated annealing calculations after docking the glycocholate ligand into the protein structure. The overall tertiary structure of ILBP is highly analogous to the three-dimensional structures of several other intracellular lipid binding proteins (LBPs). Like the apo-structure, the bile-acid complex of ILBP is composed of 10 anti-parallel beta-strands that form a water-filled clam-shell structure, and two short alpha-helices. Chemical shift data indicated that the bile acid ligand is bound inside the protein cavity. Furthermore, 13C-edited heteronuclear single-quantum correlation-NOESY experiments showed NOE contacts between several aromatic residues located in the proposed bile acid portal region and the 13C-labeled ligand. A single bile acid molecule is bound inside the protein, with the steroid moiety penetrating deep into the water-accessible internal cavity, such that ring A is located right above the plane of the Trp49 indole ring. The carboxylate tail of the ligand is protruding from the proposed bile acid portal into the surrounding aqueous solution. The body of the steroid moiety is oriented with the nonpolar face in contact with the mostly hydrophobic residues of beta-strands C, D and E, while the polar face shows contacts with the side-chains of Tyr97, His99, Glu110 and Arg121 in beta-strands H, I and J. Thus, the conformational arrangement of the ligand complex suggests that the binding affinity of ILBP for bile acid molecules is based mainly on strong hydrophobic interactions inside the protein cavity. Furthermore, this binding mode explains how ILBP can transport unconjugated and conjugated bile acids.


Redundancy of C/EBP alpha, -beta, and -delta in supporting the lipopolysaccharide-induced transcription of IL-6 and monocyte chemoattractant protein-1.
C/EBP alpha, -beta, and -delta are members of the CCAAT/enhancer binding protein family of transcriptional regulators. All three of these factors are expressed by bone marrow-derived macrophages, with the DNA binding activity of C/EBP beta and -delta increased by treatment with LPS while that of C/EBP alpha is decreased. We have ectopically expressed each C/EBP protein in P388 lymphoblasts. The expression of any of these transcription factors is sufficient to confer the LPS-inducible expression of IL-6 and monocyte chemoattractant protein-1 to lymphoblasts, which normally lack C/EBP factors and do not display LPS induction of proinflammatory cytokines. Thus, the activities of C/EBP alpha, -beta, and -delta are redundant in regard to the expression of IL-6 and monocyte chemoattractant protein-1. Since C/EBP beta-deficient mice have been reported to be largely normal in their expression of proinflammatory cytokines, it is likely that the lack of C/EBP beta is compensated for by the induction of C/EBP delta upon LPS treatment.


Bacillus curdlanolyticus sp. nov. and Bacillus kobensis sp. nov., which hydrolyze resistant curdlan.
Taxonomic characteristics of seven bacterial strains which were isolated from soil and hydrolyze resistant curdlan were studied. These bacteria were aerobic, spore-forming rods, contained menaquinone 7 as a major quinone, contained anteiso-C15:0 and iso-C16:0 as major cellular fatty acids, had guanine-plus-cytosine contents of 50 to 52 mol%, and could be divided into two groups on the basis of physiological and chemotaxonomic characteristics and DNA-DNA hybridization data. We propose the following two new species: Bacillus curdlanolyticus for strains YK9, YK121, YK161, YK201, and YK203, with type strain YK9 (= IFO 15724); and Bacillus kobensis for strains YK205 and YK207, with type strain YK205 (= IFO 15729).


Synthesis and chromatographic evaluation of molecularly imprinted polymers prepared by the substructure approach for the class-selective recognition of glucuronides.
Two series of molecularly imprinted polymers (MIPs) for the class-selective recognition of glucuronides have been prepared by using lipophilic substructures of the target analyte as template molecule and potent host monomers against oxyanions, that are expected to establish a strong stoichiometric interaction with the single carboxylic group of the template. The polymers were tested as stationary phases in liquid chromatography for specific recognition. A preliminary investigation of the imprinting properties of eleven MIPs was carried out, by comparing the retention time of the template and of structurally related compounds on the MIP column with that on the corresponding non-imprinted polymer (NIP). The two polymers showing the best performance were selected to further test cotinine, mycophenolic acid, testosterone and their respective glucuronides as model compounds. The high specificity obtained against glucuronides and the different chemical structure of the parent drug make the two MIPs class-selective imprinted receptors, also suitable for SPE application.


GALNT2 expression is reduced in patients with Type 2 diabetes: possible role of hyperglycemia.
Impaired insulin action plays a major role in the pathogenesis of type 2 diabetes, a chronic metabolic disorder which imposes a tremendous burden to morbidity and mortality worldwide. Unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. Down-regulation of GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), causes impaired insulin signaling and action in cultured human liver cells. In addition, GALNT2 mRNA levels are down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats. To investigate the role of GALNT2 in human hyperglycemia, we measured GALNT2 mRNA expression levels in peripheral whole blood cells of 84 non-obese and 46 obese non-diabetic individuals as well as of 98 obese patients with type 2 diabetes. We also measured GALNT2 mRNA expression in human U937 cells cultured under different glucose concentrations. In vivo studies indicated that GALNT2 mRNA levels were significantly reduced from non obese control to obese non diabetic and to obese diabetic individuals (p<0.001). In vitro studies showed that GALNT2 mRNA levels was reduced in U937 cells exposed to high glucose concentrations (i.e. 25 mmol/l glucose) as compared to cells exposed to low glucose concentration (i.e. 5.5 mmol/l glucose +19.5 mmol/l mannitol). In conclusion, our data indicate that GALNT2 is down-regulated in patients with type 2 diabetes and suggest that this association is, at least partly, secondary to hyperglycemia. Further studies are needed to understand whether GALNT2 down-regulation plays a pathogenic role in maintaining and/or aggravating the metabolic abnormalities of diabetic milieu.


Safety of Oral Midazolam as a Perioperative Anxiolytic for Outpatient Dermatologic Procedures.
Perioperative anxiety can negatively impact patient satisfaction and can complicate outpatient dermatologic procedures. Evaluate adverse events associated with oral midazolam as a perioperative anxiolytic during dermatologic surgery and assess whether an enhanced monitoring approach is associated with an increased detection rate. Five hundred cases (250 before and after change in monitoring) where patients were administered oral midazolam between July 2015 and May 2017 were retrospectively reviewed. The number of procedures, type of procedures, dose in milligrams, number of doses, major and minor adverse events, and vital signs were recorded. The difference in number of treatment sites, types of procedures, and total dose administered was not significant. There were minor but significant differences in the mean change in blood pressure, heart rate, respiratory rate, and Richmond Agitation and Sedation Scale score before and after the procedure but not oxygen saturation. These vital sign changes were not clinically significant. There were zero major adverse events in both groups. There were 2 patients who became transiently hypoxic. Oral midazolam administration was not associated with major adverse events including in the more intensively monitored group. This supports its use as an anxiolytic for outpatient dermatologic procedures.


Accidental Intra Arterial Injection And Limb Ischemia.
Accidental intra-arterial drug injections usually occur as an iatrogenic complication but it is also found in drug abusers as a result of attempted intravenous (IV) injections. It is estimated that accidental intra-arterial injections are found in 1:3500-1:56000 patients visiting emergency department. This was cross sectional study performed in cardiovascular department Lady reading Hospital Peshawar from 1.1.2013 to 31.8.2015. Accidental intra-arterial injection was defined as intravenous injection in upper limb for any illness which is followed by sudden severe pain in limb followed by bluish discoloration of any part of limb. Data was analysed using SPSS-20. Frequency and percentage were calculated for categorical variables like while Means±SD was calculated for numerical variables. Chi square test was used to compare Categorical variables. Total 30 patients were studied in whom 17 were male. Mean age of the study population was 43.2±17.9 years. All patients after admission were put on intravenous Heparin alone or in combination with Dexamethason, Beraprost and Nifedifin on discretion of visiting consultant. Injection diclofenac were found more frequently as cause of limb ischemia (43 %). Amputation of digits or part of limb was noted in 7 (23.1 %) cases. Accidental intra-arterial injection can lead to limb ischemia and even limb loss so while injecting IV drugs, care should be taken to use venous site away from arterial sites.


The selective GABAB antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model.
Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.


EARLY: a pilot study on early diagnosis of atrial fibrillation in a primary healthcare centre.
Atrial fibrillation (AF) is associated with high morbidity and mortality. Early diagnosis is likely to improve therapy and prognosis. The study objective was to evaluate the usefulness of a programme for early diagnosis of AF in patients from an urban primary care centre. Participants were recruited from a randomized sample of patients not diagnosed with AF but having relevant risk factors: age ≥ 65 years, ischaemic and/or valvular heart disease, congestive heart failure, hypertension, and/or diabetes. Patients were randomly assigned to the intervention group (IG) or control group (CG). The intervention included (i) initial visit with clinical history, electrocardiogram, and instruction about pulse palpation and warning signs and (ii) electrocardiogram every 6 months during a 2-year follow-up. The main endpoint of the study was the proportion of new cases diagnosed at 6 months. Secondary endpoints were number of new AF diagnoses and complications associated with the arrhythmia in both groups. A total of 928 patients were included (463 IG and 465 CG). At 6 months, AF was diagnosed in 8 IG patients and 1 CG patient (1.7 vs. 0.2%, respectively, P = 0.018). After 2 years of follow-up, 11 IG patients and 6 CG patients had newly diagnosed AF (2.5 vs. 1.3%, respectively, P = 0.132). Time to first diagnosis of AF was shorter in IG patients [median (inter-quartile range): 7 (192) days vs. 227 (188.5) days in CG, P = 0.029]. The simple screening proposed could be useful for the early detection of AF in primary care.


The effect of the air blast sprayer speed on the chemical distribution in vineyard.
A study was conducted to determine the spray deposition patterns for air blast sprayers used to apply chemicals to the canopy of Semillon grapevine in vineyard. The application carried out in 12 bars and three sprayer speed (2.1-4.9-7.7 km h(-1)). The spray deposition was measured on the point in the different distances (1.5-3-6-9 m). Tartrazine were applied as tracer material. Maximum spray deposit was obtained 66.1 mg cm(-2) at sprayer speed of 2.1 km h(-1) and minimum deposit was obtained 37.1 mg cm(-2) at sprayer speed of 7.7 km h(-1). The results showed that the sprayer speeds had significant effect on spray deposit distribution and increasing of the sprayer speed increased drift.


Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington's disease.
Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD(+)/Rhes(-/-) mice showed significantly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.


Analysis of the role of the two flagella of Bradyrhizobium japonicum in competition for nodulation of soybean.
Bradyrhizobium japonicum has two types of flagella. One has thin filaments consisting of the 33-kDa flagellins FliCI and FliCII (FliCI-II) and the other has thick filaments consisting of the 65-kDa flagellins FliC1, FliC2, FliC3, and FliC4 (FliC1-4). To investigate the roles of each flagellum in competition for nodulation, we obtained mutants deleted in fliCI-II and/or fliC1-4 in the genomic backgrounds of two derivatives from the reference strain USDA 110: the streptomycin-resistant derivative LP 3004 and its more motile derivative LP 3008. All mutations diminished swimming motility. When each mutant was co-inoculated with the parental strain on soybean plants cultivated in vermiculite either at field capacity or flooded, their competitiveness differed according to the flagellin altered. ΔfliCI-II mutants were more competitive, occupying 64-80% of the nodules, while ΔfliC1-4 mutants occupied 45-49% of the nodules. Occupation by the nonmotile double mutant decreased from 55% to 11% as the water content of the vermiculite increased from 85% to 95% field capacity to flooding. These results indicate that the influence of motility on competitiveness depended on the water status of the rooting substrate.


Integrating oxalate desensitizers with total-etch two-step adhesive.
Compromised bonding of total-etch adhesives to dentin treated with oxalate desensitizers results from the interference of a surface layer of acid-resistant crystals of calcium oxalate. We hypothesize that effective tubular occlusion and dentin bonding may be simultaneously achieved by depleting dentin surfaces of calcium with acids before desensitizer application. Dentin specimens treated with 4 oxalate desensitizers before or after being acid-etched were bonded with a two-step adhesive. Microtensile bond strengths ( micro TBS) were significantly lower, compared with the control, when oxalates were used before the specimens were acid-etched; in contrast, when oxalates were used after acid-etching. micro TBS were similar to nonoxalate-treated controls. Dentin surfaces and tubular orifices were covered with a surface layer of crystals when desensitizers were applied to fractured dentin and smear-layer-covered dentin before specimens were acid-etched. However, when the dentin was acid-etched prior to the application of oxalate desensitizers, the crystals were largely limited to the subsurface of dentinal tubules, where they did not interfere with subsequent resin bonding.


Children use salience to solve coordination problems.
Humans are routinely required to coordinate with others. When communication is not possible, adults often achieve this by using salient cues in the environment (e.g. going to the Eiffel Tower, as an obvious meeting point). To explore the development of this capacity, we presented dyads of 3-, 5-, and 8-year-olds (N = 144) with a coordination problem: Two balls had to be inserted into the same of four boxes to obtain a reward. Identical pictures were attached to three boxes whereas a unique--and thus salient--picture was attached to the fourth. Children either received one ball each, and so had to choose the same box (experimental condition), or they received both balls and could get the reward independently (control condition). In all cases, children could neither communicate nor see each other's choices. Children were significantly more likely to choose the salient option in the experimental condition than in the control condition. However, only the two older age groups chose the salient box above chance levels. This study is the first to show that children from at least age 5 can solve coordination problems by converging on a salient solution.


[Esophageal aspergillosis in a patient with acute myelogenous leukemia and febrile neutropenia].
Aspergillosis usually compromises the respiratory system, but can also affect others. We report a 46 yo female with acute myeloid leukemia, developed febrile neutropenia and dysphagia. Endoscopy revealed esophageal cytomegalovirus-like ulcers, but biopsies showed Aspergillus spp. It's important to consider aspergillosis in the differential diagnosis of esophageal lesions in high-risk patients.


Dual-core mass-balance approach for evaluating mercury and 210Pb atmospheric fallout and focusing to lakes.
Determining atmospheric deposition rates of mercury and other contaminants using lake sediment cores requires a quantitative understanding of sediment focusing. Here we present a novel approach that solves mass-balance equations fortwo cores algebraicallyto estimate contaminant contributions to sediment from direct atmospheric fallout and from watershed and in-lake focusing. The model is applied to excess 210Pb and Hg in coresfrom Hobbs Lake, a high-altitude lake in Wyoming. Model results for excess 210Pb are consistent with estimates of fallout and focusing factors computed using excess 210Pb burdens in lake cores and soil cores from the watershed and model results for Hg fallout are consistent with fallout estimated using the soil-core-based 210Pb focusing factors. The lake cores indicate small increases in mercury deposition beginning in the late 1800s and large increases after 1940, with the maximum at the tops of the cores of 16-20 microg/m2 x year. These results suggest that global Hg emissions and possibly regional emissions in the western United States are affecting the north-central Rocky Mountains. Hg fallout estimates are generally consistent with fallout reported from an ice core from the nearby Upper Fremont Glacier, but with several notable differences. The model might not work for lakes with complex geometries and multiple sediment inputs, but for lakes with simple geometries, like Hobbs, it can provide a quantitative approach for evaluating sediment focusing and estimating contaminant fallout.


Orthodontic intervention in the early mixed dentition: a prospective, controlled study on the effects of the eruption guidance appliance.
A prospective, controlled cohort study was started in 1998 to investigate the effects of orthodontic treatment in the early mixed dentition with the eruption guidance appliance. Occlusal changes were recorded in 167 treated children and 104 controls after they had reached the middle mixed-dentition stage. Treatment began when the first deciduous incisor was exfoliated (T1) and ended when all permanent incisors and first molars were fully erupted (T2). The children's mean ages were 5.1 years (SD 0.5) at T1 and 8.4 years (SD 0.5) at T2. From T1 to T2, overjet in the treatment group decreased from 3.1 to 1.9 mm and overbite from 3.2 to 2.1 mm. In the control group, overjet increased from 2.9 to 4.1 mm and overbite from 3.3 to 4.1 mm. At T2, the differences between the groups were highly significant (P <.001). At T1, 18% of the children in the treatment group and 22% of the controls had tooth-to-tooth contact between the maxillary and mandibular incisors. All others had an open bite, or the mandibular incisors were in contact with the palatal gingiva. At T2, tooth-to-tooth contact was observed in 99% of the treated children and 24% of the controls (P <.001). Almost half of children in both groups showed incisor crowding at T1. Good alignment of the incisors was observed in 98% of the treated children at T2, whereas maxillary crowding was found in 32% and mandibular crowding in 47% of the controls (P <.001). At T1, 41% of the children in the treatment group and 53% of the controls had a Class I relationship; the rest had either a unilateral or a bilateral Class II relationship. At T2, a Class I relationship was found in 90% of the treated children and 48% of the controls (P <.001). At least 1 occlusal deviation, including overjet > or =5 mm, overbite > or =5 mm, open bite, gingival contact of the mandibular incisors, crowding, or Class II relationship, was observed in 13% of the treated children, but the deviations were mild, and no child was considered to need treatment. In the control group, 88% of the children showed at least 1 occlusal deviation (P <.001). Treatment in the early mixed dentition with the eruption guidance appliance is an effective method to restore normal occlusion and eliminate the need for further orthodontic treatment. Only a few spontaneous corrective changes can be expected without active intervention.


High resolution measurement of translucent plastic wall thicknesses by computerized tomography and neural networks.
Today there is a great deal of interest in the field of plastics design. Several methods can be employed to create plastic products such as injection molding, compression and transfer molding, and blow molding. This paper is concerned with blow molding which is a procedure employed to create hollow plastic containers such as those used to contain liquids and solids in the wholesale and retail markets. An important aspect of blow molding is the measurement of the wall thickness of semi-liquid plastic before the molding procedure has been initiated. Minimization of waste is rapidly becoming a critical consideration within the plastics community due to the cost of raw polymers. Unfortunately, it is also an extremely difficult task to measure the thickness considering the high temperatures and elasticity of the polymers in question. This paper presents initial research on a non-invasive approach for wall thickness measurements of semi-liquid plastics through the utilization of computerized tomography and neural networks. The work described here is based on simulations and on modeling data obtained through experimental means. This technique can be extended to other fields of research as well, such as those related to the development of glass and ceramic products.


Pulsed stimulated Brillouin microscopy enables high-sensitivity mechanical imaging of live and fragile biological specimens.
Brillouin microscopy is an emerging optical elastography technique capable of assessing mechanical properties of biological samples in a three-dimensional, all-optical and noncontact fashion. The typically weak Brillouin scattering signal can be substantially enhanced via a stimulated Brillouin scattering (SBS) process; however, current implementations require high pump powers, which prohibit applications to photosensitive or live imaging of biological samples. Here we present a pulsed SBS scheme that takes advantage of the nonlinearity of the pump-probe interaction. In particular, we show that the required pump laser power can be decreased ~20-fold without affecting the signal levels or spectral precision. We demonstrate the low phototoxicity and high specificity of our pulsed SBS approach by imaging, with subcellular detail, sensitive single cells, zebrafish larvae, mouse embryos and adult Caenorhabditis elegans. Furthermore, our method permits observing the mechanics of organoids and C. elegans embryos over time, opening up further possibilities for the field of mechanobiology.


Clinical implementation of circulating tumour DNA testing for EGFR T790M for detection of treatment resistance in non-small cell lung cancer.
Epidermal growth factor receptor (EGFR) T790M mutations can be detected in the circulating tumour DNA from plasma of patients with non-small cell lung cancer (NSCLC) to triage patients for osimertinib eligibility and monitor patients longitudinally for development of T790M-mediated resistance. Using droplet digital PCR (ddPCR), we examined the EGFR T790M status of 343 sequential patients with NSCLC and correlated mutational status with demographic and clinical features. Where available, serial T790M blood test results were assessed to identify clinical triggers and timing of repeat testing. Of the 343 patients with liquid biopsy test results, 24% were T790M positive. No clear clinical correlation with a T790M positive test result was identified in this study, although the number of metastatic sites did correlate significantly with the presence of EGFR sensitising mutations (L858R or exon 19 deletion) in patient plasma, as a measure of tumour DNA shedding. Of the 59 serial blood tests from patients that initially tested negative, 14% were positive on sequential testing, at a time interval up to 6 months after an initially negative blood test. The ddPCR test for EGFR T790M mutations effectively triaged 24% of patients for treatment with osimertinib, avoiding the need for invasive tissue biopsy in these patients. Our findings suggest that initial and repeat ctDNA testing can be used to monitor for acquired EGFR T790M resistance for NSCLC.


Lactobacillus plantarum IS-10506 supplementation reduced SCORAD in children with atopic dermatitis.
Lactobacillus plantarum IS-10506 is a novel probiotic isolated from dadih, an Indonesian traditional fermented buffalo milk. It's in vitro and in vivo probiotic properties have been assessed. Probiotic function has been shown in vivo by the suppression of allergic reactions in BALB/c mice through the action of T-regulatory cells cytokines by balancing Th1 and Th2 immune response. Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease characterised by the imbalance of Th1 and Th2. The aim of the study was to assess the probiotic function of L. plantarum IS-10506 in children with mild and moderate AD. A randomised double-blind placebo-controlled trial comparing microencapsulated L. plantarum IS-10506 (1010 cfu/day) and placebo (skim milk-Avicel) twice daily for 12 weeks was conducted in an outpatient clinic on children with mild and moderate AD. The trial included 22 AD children divided into intervention and control groups of n=12 and n=10 patients, respectively. Scoring Atopic Dermatitis Index (SCORAD) and serum immunoglobulin E (IgE), interleukin (IL)-4, interferon gamma (IFN-γ), forkhead box P3 (Foxp3+)/IL-10, and IL-17 levels were assessed. Demographic and baseline characteristics were not significantly different between the two groups. SCORAD and levels of IL-4, IFN-γ, and IL-17 were significantly lower in the probiotic group than those in the placebo group, while the IgE levels were not significantly changed. The ratio of Foxp3+ to IL-10 was significantly higher in the probiotic group than that in placebo group. Supplementation with the probiotic L. plantarum IS-10506 offered a potential treatment for children with AD. Further long-term studies with a larger sample size are required to confirm the therapeutic efficacy of L. plantarum IS-10506 in AD.


Bilateral upper-limb rehabilitation after stroke using a movement-based game controller.
This study aimed to determine the effectiveness of a bilateral, self-supported, upper-limb rehabilitation intervention using a movement-based game controller for people with chronic stroke. Fourteen participants received a control treatment, followed by a washout period, and then the intervention. The intervention comprised playing computer games with the CyWee Z (CyWee Group Ltd; Taipei, Taiwan), a movement-based game controller similar to the Nintendo Wii remote. The CyWee Z was incorporated into a handlebar, making bilateral exercises possible by allowing the unaffected side to support and assist the affected side. The intervention lasted for 8 to 10 sessions of 45 to 60 minutes over a period of 2.5 weeks. The Fugl-Meyer Assessment upper-limb section (FMA-UL) was used as the primary outcome. The Wolf Motor Function Test and the Disabilities of Arm, Shoulder, and Hand outcome measure were used as secondary outcomes. Postintervention, motor performance as measured by the FMA-UL was significantly improved compared with all preintervention assessments (p < 0.001), whereas no changes were found on both secondary outcomes. It can be concluded from this pilot study that upper-limb motor performance of adults with chronic stroke improves with repetitive, game-assisted, self-supported bilateral exercises.


Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).
Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome. Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing. Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not. Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.


Dietary views and habits of students in health professional vs. non-health professional graduate programs in a single university.
Students enrolled in health professional (HP) programs receive varying amounts of credit hours dedicated to nutritional education, and obesity remains an issue in the United States among healthcare providers. To assess whether HP students differ in nutrition and exercise habits from non-health professional (NHP) students at a single university, and whether any gender-related differences existed in those habits. From September 25, 2018 to October 10, 2019, a 16-question multiple-choice survey was distributed via e-mail or in person to HP and NHP students enrolled at Nova Southeastern University (NSU) in Fort Lauderdale, Florida. Questions targeted participant dietary and exercise habits. Each question had five multiple-choice answer options, each of which was assigned a coded value to compare similarities and differences between the HP and NHP groups. Of 732 responses (569 HP, 163 NHP), results showed no statistically significant difference between enrollment groups (p>0.05) in any response parameter including consumption of sweets, fast food, red meat, caffeine, water, fruit, and vegetables. Comparisons among sexes demonstrated significant differences. Women consumed less red meat, water, and protein, and women participated in less exercise compared to men. Women also consumed more sweets compared to men. Results suggest that NSU students enrolled in HP and NHP programs have similar nutritional concepts and eating habits. This may indicate a need to strengthen nutritional education in dietary health and wellness for HP students.


Impact of thoracic epidural analgesia on blood loss in radical retropubic prostatectomy.
Radical retropubic prostatectomy (RRP) is associated with an increased risk of intraoperative blood loss and the necessity of transfusions. This prospective randomised clinical study evaluates the influence of thoracic epidural analgesia (TEA) on blood loss in RRP. 235 patients were randomised: TEA in group 1 (n = 116; general anaesthesia + TEA) comprised continuous administration of 0.25% bupivacaine, while group 2 (n = 119; general anaesthesia alone) received intravenous analgesia with fentanyl (intubation: 2 µg/kg; maintenance: 0.1-0.3 mg). A restrictive infusion regimen (<1,000 ml until specimen removal) was administered in both groups. Blood loss, infusion rates and anaesthesiological parameters were recorded and analysed using regression models and analyses of variance. Haemoglobin difference between the pre- and the first postoperative day (group 1: 3.35 ± 1.16 g/dl; group 2: 3.56 ± 1.42 g/dl; p = 0.19), overall blood loss (group 1: 665 ± 431.5 ml; group 2: 705 ± 881 ml; p = 0.73) and transfusion rates (0.4% intraoperatively; 2.55% postoperatively; p = 1.0) did not show group differences. In regression analysis blood loss was influenced by preoperative haemoglobin levels (p < 0.0001), patients' weight (p = 0.018) and duration of the operation (p = 0.017). This study did not demonstrate a direct impact of TEA on intraoperative blood loss and transfusion rates in RRP. Further randomised clinical trials are needed to evaluate an impact of the different anaesthetic procedures presented alone or in combination on blood loss.


Great Expectations: Induced pluripotent stem cell technologies in neurodevelopmental impairments.
Somatic cells such as skin fibroblasts, umbilical cord blood, peripheral blood, urinary epithelial cells, etc., are transformed into induced pluripotent stem cells (iPSCs) by reprogramming technology, a milestone in the stem-cell research field. IPSCs are similar to embryonic stem cells (ESCs), exhibiting the potential to differentiate into various somatic cells. Still, the former avoid problems of immune rejection and medical ethics in the study of ESCs and clinical trials. Neurodevelopmental disorders are chronic developmental brain dysfunctions that affect cognition, exercise, social adaptability, behavior, etc. Due to various inherited or acquired causes, they seriously affect the physical and psychological health of infants and children. These include generalized stunting / mental disability (GDD/ID), Epilepsy, autism spectrum disease (ASD), and attention deficit hyperactivity disorder (ADHD). Most neurodevelopmental disorders are challenging to cure. Establishing a neurodevelopmental disorder system model is essential for researching and treating neurodevelopmental disorders. At this stage, the scarcity of samples is a bigger problem for studying neurological diseases based on the donor, ethics, etc. Some iPSCs are reprogrammed from somatic cells that carry disease-causing mutations. They differentiate into nerve cells by induction, which has the original characteristics of diseases. Disease-specific iPSCs are used to study the mechanism and pathogenesis of neurodevelopmental disorders. The process provided samples and the impetus for developing drugs and developing treatment plans for neurodevelopmental disorders. Here, this article mainly introduced the development of iPSCs, the currently established iPSCs disease models, and artificial organoids related to neurodevelopmental impairments. This technology will promote our understanding of neurodevelopmental impairments and bring great expectations to children with neurological disorders.


A computational framework for adjusting flow during peripheral extracorporeal membrane oxygenation to reduce differential hypoxia.
Peripheral veno-arterial extra corporeal membrane oxygenation (VA-ECMO) is an established technique for short-to-medium support of patients with severe cardiac failure. However, in patients with concomitant respiratory failure, the residual native circulation will provide deoxygenated blood to the upper body, and may cause differential hypoxemia of the heart and brain. In this paper, we present a general computational framework for the identification of differential hypoxemia risk in VA-ECMO patients. A range of different VA-ECMO patient scenarios for a patient-specific geometry and vascular resistance were simulated using transient computational fluid dynamics simulations, representing a clinically relevant range of values of stroke volume and ECMO flow. For this patient, regardless of ECMO flow rate, left ventricular stroke volumes greater than 28 mL resulted in all aortic arch branch vessels being perfused by poorly-oxygenated systemic blood sourced from the lungs. The brachiocephalic artery perfusion was almost entirely derived from blood from the left ventricle in all scenarios except for those with stroke volumes less than 5 mL. Our model therefore predicted a strong risk of differential hypoxemia in nearly all situations with some residual cardiac function for this combination of patient geometry and vascular resistance. This simulation highlights the potential value of modelling for optimising ECMO design and procedures, and for the practical utility for personalised approaches in the clinical use of ECMO.


Transitional dialysis care units: A new approach to increase home dialysis modality uptake and patient outcomes.
Home hemodialysis (HHD) and peritoneal dialysis (PD) are associated with better clinical outcomes, lower hospitalization rates, and improved quality of life compared with conventional in-center hemodialysis. However, <12% of patients requiring dialysis therapy use HHD or PD in the United States, even though over 90% of nephrologists would choose home-based dialysis modalities for themselves. Inadequate patient education and decision-making support are key barriers to patients choosing home-based therapy. Likewise, there are key challenges for dialysis providers, including development and optimal delivery of education materials, appropriate staffing, and training. The Satellite Healthcare Optimal Transitions (OT) Program was developed to provide education and decision support to patients during the transitional period. OT provides in-depth education in all dialysis modalities at the start of dialysis over a flexible time period (1-4 weeks, adapted for various learning curves) to allow for time to physical stabilization, self-care training, and modality choice based on each patient's individual life motivations, goals, and environments. OT may provide value to patients and providers by providing comprehensive support for dialysis modality selection, resulting in increased patient confidence to execute home dialysis with the potential for improved patient outcomes, and reduced hospitalizations.


The demographics of same-sex marriages in Norway and Sweden.
The present study investigates the demographics of same-sex marriages--that is, registered partnerships-in Norway and Sweden. We give an overview of the demographic characteristics of the spouses of these partnerships, study patterns of their divorce risks, and compare the dynamics of same-sex couples with those of heterosexual marriages. We use longitudinal information from the population registers of the two countries that cover all persons in partnerships. Our demographic analyses include information on characteristics such as age, sex, geographic background, experience of previous opposite-sex marriage, parenthood, and educational attainment of the partners involved. The results show that in many respects, the distributions of married populations on these characteristics differ by the sex composition of the couples. Patterns in divorce risks are rather similar in same-sex and opposite-sex marriages, but divorce-risk levels are considerably higher in same-sex marriages. The divorce riskforfemale partnerships is double that for male partnerships.


Biomineralization on enzymatically cross-linked gelatin hydrogels in the absence of dexamethasone.
A mechanical stimulus and chemical induction by dexamethasone have been important factors in dental pulp stem cell (DPSC) differentiation and biomineralization. We have demonstrated that the enzymatically crosslinked gelatin hydrogels are extremely effective substrates for DPSC differentiation towards odontoblasts. DPSCs were seeded on the crosslinked hard (∼8 kPa) and soft (∼0.15 kPa) gelatin hydrogels for 35 days with and without dexamethasone. Odontogenic differentiation markers such as OCN, ALP and DSPP were upregulated after 35 days of culture on crosslinked hydrogels with and without dexamethasone. SEM and Alizarin red staining of the crosslinked hydrogels showed a biomineralized sheet of hydroxyapatite deposits laid by the DPSCs on the top surface and inside the hydrogel. We found that the DPSC differentiation and biomineralization were independent of the hydrogel stiffness and dexamethasone. We hypothesize that this biomineralization was indeed triggered by the surface chemistry of the crosslinked gelatin hydrogels since we did not observe any biomineralization on the uncrosslinked gelatin or mTG. We also showed that the DPSCs, when removed from hard hydrogel surfaces and re-seeded on a TCPS, retained their odontogenic lineage and showed a permanent mineralization effect. Our results show the potential of enzymatically crosslinked gelatin hydrogels as scaffolds for dentin regeneration.


The use of induced pluripotent stem cells in domestic animals: a narrative review.
Induced pluripotent stem cells (iPSCs) are undifferentiated stem cells characterized by the ability to differentiate into any cell type in the body. iPSCs are a relatively new and rapidly developing technology in many fields of biology, including developmental anatomy and physiology, pathology, and toxicology. These cells have great potential in research as they are self-renewing and pluripotent with minimal ethical concerns. Protocols for their production have been developed for many domestic animal species, which have since been used to further our knowledge in the progression and treatment of diseases. This research is valuable both for veterinary medicine as well as for the prospect of translation to human medicine. Safety, cost, and feasibility are potential barriers for this technology that must be considered before widespread clinical adoption. This review will analyze the literature pertaining to iPSCs derived from various domestic species with a focus on iPSC production and characterization, applications for tissue and disease research, and applications for disease treatment.


103Rh NMR spectroscopy and its application to rhodium chemistry.
Rhodium is used for a number of large processes that rely on homogeneous rhodium-catalyzed reactions, for instance rhodium-catalyzed hydroformylation of alkenes, carbonylation of methanol to acetic acid and hydrodesulfurization of thiophene derivatives (in crude oil). Many laboratory applications in organometallic chemistry and catalysis involve organorhodium chemistry and a wealth of rhodium coordination compounds is known. For these and other areas, 103Rh NMR spectroscopy appears to be a very useful analytical tool. In this review, most of the literature concerning 103Rh NMR spectroscopy published from 1989 up to and including 2003 has been covered. After an introduction to several experimental methods for the detection of the insensitive 103Rh nucleus, a discussion of factors affecting the transition metal chemical shift is given. Computational aspects and calculations of chemical shifts are also briefly addressed. Next, the application of 103Rh NMR in coordination and organometallic chemistry is elaborated in more detail by highlighting recent developments in measurement and interpretation of 103Rh NMR data, in relation to rhodium-assisted reactions and homogeneous catalysis. The dependence of the 103Rh chemical shift on the ligands at rhodium in the first coordination sphere, on the complex geometry, oxidation state, temperature, solvent and concentration is treated. Several classes of compounds and special cases such as chiral rhodium compounds are reviewed. Finally, a section on scalar coupling to rhodium is provided.


Breast conservation therapy without axillary dissection. A rational treatment strategy in selected patients.
Patients with early stage breast cancer are being treated with adjuvant systemic therapy with increasing frequency regardless of the pathological status of the axillary lymph nodes. The purpose of this study was to determine the outcome for local regional control in patients treated with radiation therapy to the intact breast and regional lymph nodes without axillary dissection. The patient population for this study consists of 327 patients with clinical stage I or II invasive breast cancer who were treated by lumpectomy alone without axillary dissection followed by radiation therapy to the intact breast and regional lymph nodes. Outcome for local regional control and survival is reported. As of December 1990, with a median follow-up of more than 10 years, the overall 10-year survival rate was 71%. There were a total of eight regional nodal failures resulting in a 5-year actuarial nodal control rate of 97%. Minimal morbidity was associated with this treatment policy. For selected patients undergoing breast preservation therapy, lumpectomy alone without axillary dissection followed by radiation therapy to the intact breast and regional lymph nodes results in a high rate of local regional control. Selected patients in whom the results of the axillary lymph node dissection will not influence decisions regarding systemic therapy are candidates for this approach.


The use of E/A ratio as a predictor of outcome in cirrhotic patients treated with transjugular intrahepatic portosystemic shunt.
The clinical significance of diastolic dysfunction in cirrhosis, a feature of cirrhotic cardiomyopathy, is unclear. The aim of this study was to assess the utility of E/A ratio, an indicator of diastolic dysfunction, to predict ascites clearance and mortality after transjugular intrahepatic portosystemic stent shunt (TIPS) insertion. A total of 101 cirrhotic patients who received TIPS had pre-TIPS assessments of demographics, severity of liver dysfunction (Child-Pugh and Model for End-Stage Liver Disease (MELD) scores), renal function, hemodynamics, and cardiac function (two-dimensional echocardiography). An E/A ratio of < or =1 was used to indicate diastolic dysfunction. Patients were followed-up for a mean period of 24.6+/-2.4 months post TIPS. A total of 41 patients with an E/A ratio of < or =1 (group A), and 60 patients with an E/A ratio of >1 (group B) were studied. Group A had significantly higher MELD scores (14.0+/-1.0 vs. 11.4+/-0.8; P=0.03), because of higher serum creatinine levels (107+/-5 vs. 86+/-6 micromol/l; P<0.01). There was no difference in pre-TIPS systemic hemodynamics, systolic function, or portal pressure between the two groups. After TIPS, more patients in group B had ascites clearance (log rank, P=0.038), and the same patients had a higher probability of survival (log rank, P=0.046). There were three post-TIPS cardiac deaths in group A only. A multivariate analysis showed that an E/A of ratio < or =1 was predictive of slow ascites clearance (hazard ratio=7.3, 95% confidence interval=1.3-40.7, P=0.021) and death after TIPS (hazard ratio=4.7, 95% confidence interval=1.1-20.2, P=0.035). Diastolic dysfunction, indicated by reduced E/A ratio, is prevalent in advanced cirrhosis and is associated with reduced ascites clearance and increased mortality post TIPS, possibly related to worsening of hemodynamic dysfunction in the post-TIPS period.


Internal proton transfer in the external pyridoxal 5'-phosphate Schiff base in dopa decarboxylase.
Combined quantum mechanical and molecular mechanical (QM/MM) simulations of dopa decarboxylase have been carried out to elucidate the factors that contribute to the tautomeric equilibrium of the intramolecular proton transfer in the external PLP-L-dopa Schiff base. The presence of a carboxylate anion on the alpha-carbon of the Schiff base stabilizes the zwitterions and shifts the equilibrium in favor of the oxoenamine tautomer (protonated Schiff base). Moreover, protonation of the PLP pyridine nitrogen further drives the equilibrium toward the oxoenamine direction. On the other hand, solvent effects favor the hydroxyimine configuration, although the equilibrium favors the oxoenamine isomer with a methyl group as the substituent on the imino nitrogen. In dopa decarboxylase, the hydroxyimine form of the PLP(H+)-L-dopa Schiff base is predicted to be the major isomer with a relative free energy of -1.3 kcal/mol over that of the oxoenamine isomer. Both Asp271 and Lys303 stabilize the hydroxyimine configuration through hydrogen-bonding interactions with the pyridine nitrogen of the PLP and the imino nitrogen of the Schiff base, respectively. Interestingly, Thr246 plays a double role in the intramolecular proton transfer process, in which it initially donates a hydrogen bond to the phenolate oxygen in the oxoenamine configuration and then switches to a hydrogen bond acceptor from the phenolic hydroxyl group in the hydroxyimine tautomer.


Galvanic vestibular stimulation.
In order to gain insight into the origin of the eye movements provoked by galvanic vestibular stimulation, experiments were conducted in rabbits. The animals were subjected to a small galvanic stimulation and to a vestibular stimulation (rotation and sinusoidally changing linear accelerations). Application of several stimuli at the same time shows that the effects on the eye movements of each stimulus given separately are summated. Electric stimulation provoked vestibular reflexes; a stronger effect was observed in unilaterally and in bilaterally labyrinthectomized rabbits. This suggests that there is not only an impact of the oculomotor system but of the peripheral vestibular organs too. The conclusion is drawn that electric stimulation of the vestibular system gives information on the functioning of the labyrinths and also about the side where a labyrinthine lesion is located.


Primary aortoesophageal fistula: a rare cause of acute upper gastrointestinal bleeding.
Acute upper gastrointestinal bleeding is a potentially life-threatening emergency, especially in the elderly. This condition accounts for approximately 1% of all emergency room admissions. Among the causes of such bleeding is aortoesophageal fistula, a dreaded but apparently rare condition, first recognized in 1818. The great majority of cases are of primary aortoesophageal fistula, caused by atheromatous aortic aneurysms or, less frequently, by penetrating aortic ulcer. The clinical presentation of aortoesophageal fistula is typically characterized by the so-called Chiari's triad, consisting of thoracic pain followed by herald bleeding, a variable, short symptom-free interval, and fatal exsanguinating hemorrhage. The prognosis is poor, the in-hospital mortality rate being 60%. Conservative treatment does not prolong survival, and the in-hospital mortality rate is 40% for patients submitted to conventional surgical treatment. Here, we report the case of a 93-year-old woman who presented to the emergency room with a history of hematemesis. The patient was first submitted to upper gastrointestinal endoscopy, the findings of which were suggestive of aortoesophageal fistula. The diagnosis was confirmed by multidetector computed tomography of the chest. Surgery was indicated. However, on the way to the operating room, the patient presented with massive bleeding and went into cardiac arrest, which resulted in her death.


Outstanding women scientists who have broadened the knowledge on biological photoreceptors.
Short biographical sketches are given of women born before 1955 who have contributed to our knowledge on the function, structure, and molecular basis of biological photoreceptors, both energy converters and photosensors.


Evolution of the lymphoid system. I. Evidence for lymphocyte heterogeneity in rainbow trout revealed by the organ distribution of mitogenic responses.
Leukocytes from the various lymphoid tissues of rainbow trout (RBT) were tested for their capacity to respond to the lymphocyte mitogens concanavalin A (Con A), lipopolysaccharide (LPS), and purified protein derivative of tuberculin (PPD). Thymocytes responded to Con A but not to LPS or PPD. In contrast, leukocytes from anterior kidney were stimulated with LPS but not with Con A or PPD. Cells from spleen and peripheral blood were stimulated by each mitogen. However, the degree of stimulation at optimally stimulatory concentrations of each mitogen was distinctive. The finding that the patterns of mitogenic responses of cells from each tissue were significantly different suggested that there is lymphoid heterogeneity in the RBT with a unique tissue distribution. The species source of serum utilized as a medium supplement appeared to be capable of markedly affecting mitogenesis. Thus, LPS and PPD stimulation occurred in medium supplemented with rainbow trout serum (RBTS). On the other hand, LPS and PPD stimulation was not observed in medium supplemented with fetal bovine serum (FBS), with the exception of peripheral blood leukocytes which were stimulated by LPS in culture medium supplemented with FBS. Con A stimulated leukocytes from each lymphoid tissue in medium supplemented with RBTS and, with the exception of cells from anterior kidney, also stimulated cells from each tissue in medium supplemented with FBS. The kinetic profiles of the responses of peripheral blood leukocytes to Con A, LPS, and PPD suggested that the extent as well as the time required for maximal stimulation was dependent on the dose of mitogen.


Checkpoint molecules coordinately restrain hyperactivated effector T cells in the tumor microenvironment.
The immune checkpoint blockade (ICB) immunotherapy has prolonged overall survival for cancer patients but the response rates are low. The resistance to ICB is likely due to compensatory upregulation of additional immune inhibitory molecules. In this study, we first systematically examined Tim-3 expression in immune cells in mouse tumors and found that Tim-3 was specifically up-regulated in a large number of Treg, conventional CD4+, CD8+ T cells, dendritic cell 1 (DC1), and macrophage 1 (M1) in the tumor microenvironment (TME). Interestingly, Tim-3+ T cells in the TME were phenotypically effector but not "exhausted" T cells because Tim-3+ PD-1+ CD8+ T cells had a higher number of mitochondria, greater levels of glycolysis, and higher tumor-specific cytolytic activities compared to Tim-3- PD-1- CD8+ T cells. The combination treatment with Tim-3 and PD-1 mAbs resulted in a synergistic antitumor activity but also increased the expression of Lag-3 and GITR in TIL, demonstrating cross-regulation between multiple checkpoint molecules. Furthermore, we found that the antitumor efficacy with triple combination of Tim-3, PD-1, and Lag3 mAbs was much greater than any two antibodies. Mechanistically, we demonstrated that simultaneous targeting of Tim-3, PD-1, and Lag-3 cooperatively increased the levels of granzyme B and tumor-specific cytolytic activities of CD8+ TIL. Our data indicate that multiple checkpoint molecules are coordinately upregulated to inhibit the function of hyperactivated T cells in the TME and requirement for the simultaneous blockade of PD-1, Tim-3 and Lag3 for cancer treatment.


Optimal Designs of Two-Phase Studies.
The two-phase design is a cost-effective sampling strategy to evaluate the effects of covariates on an outcome when certain covariates are too expensive to be measured on all study subjects. Under such a design, the outcome and inexpensive covariates are measured on all subjects in the first phase and the first-phase information is used to select subjects for measurements of expensive covariates in the second phase. Previous research on two-phase studies has focused largely on the inference procedures rather than the design aspects. We investigate the design efficiency of the two-phase study, as measured by the semiparametric efficiency bound for estimating the regression coefficients of expensive covariates. We consider general two-phase studies, where the outcome variable can be continuous, discrete, or censored, and the second-phase sampling can depend on the first-phase data in any manner. We develop optimal or approximately optimal two-phase designs, which can be substantially more efficient than the existing designs. We demonstrate the improvements of the new designs over the existing ones through extensive simulation studies and two large medical studies.


Designing porous bioartificial membranes for clinical use with desired morphological and transport properties by phase inversion control.
Bioartificial membranes of synthetic (poly(ethylene-co-vinyl alcohol) - EVAL, Clarene (R) ) and biological (dextran) polymers with different compositions were prepared through the phase inversion process. Dimethyl sulfoxide (DMSO) solutions of EVAL and dextran were mixed under stirring in the desired proportions and coagulated in water or DMSO (solvent)/water (non-solvent) mixture. Membrane morphologies were shown to be dependent on the synthetic and biological polymer contents and on the coagulation medium composition. Component release during solid membrane formation was evaluated by a UV method and the final composition of the bioartificial membranes established, confirming the successful entrapment of the biological component in the synthetic network. The porosity degree of the bioartificial membranes was also investigated by permeability tests and the effect of morphological characteristics on transport properties was studied. Water flux across the membranes, solute permeability and sieving coefficients were also calculated. The results revealed that the transport properties of these bioartificial membranes, obtained by the phase inversion method, could be controlled by mainly changing the preparation control parameters and the EVAL-dextran ratio.


Screening and identification of neuraminidase inhibitors from Baphicacanthus cusia by a combination of affinity ultrafiltration, HPLC-MS/MS, molecular docking, and fluorescent techniques.
Natural products provide a new opportunity for the discovery of neuraminidase (NA)inhibitors. In this study, an affinity ultrafiltration (AUF) coupled with HPLC-MS/MS method was firstly developed and optimized for screening of NA inhibitors from natural products. The critical factors influencing the interaction of enzyme-ligand (including sample concentration, enzyme concentration, incubation time and temperature, pH of the buffer, and dissociation solvents and time) were investigated and optimized by a one-factor-at-a-time design. The method was then applied to discover NA inhibitory compounds in stems and leaves of Baphicacanthus cusia. As a result, five active alkaloids were screened out and identifiedas 2,4(1H,3H)-quinazolinedione (1), 4(3H)-quinazolinone (2), 2(3H)-benzoxazolone (3), tryptanthrin (4), and indirubin (5) through analysis of their DAD profiles, MS/MS fragments, and comparison with reference substances. These active compounds were further evaluated for their NA inhibitory activity using a fluorescence-based NA inhibition assay. The result from the fluorescent assay revealed that all the five compounds(1-5) showed pronounced NA inhibitory activities with IC50values of 98.98, 64.69, 40.16, 69.44, and 144.73 μM, respectively. Finally, molecular docking of these five alkaloids with NA showed that hydrogen bond and π-cation interactions dominated within the binding sites with binding energies ranging between -5.7 to -7.9 kcal/mol, which was supported by the results of the AUF and the fluorescence-based enzyme assay. The developed AUF method is simple and efficient for screening potential NA inhibitors from stems and leaves of B. cusia.


Vascular endothelial growth factor induces the migration of human airway smooth muscle cells by activating the RhoA/ROCK pathway.
Airway remodeling due to increased airway smooth muscle cell (ASMC) mass, likely due to enhanced proliferation, hypertrophy, and migration, has been proven to be highly correlated with decreased lung function in asthma patients. Vascular endothelial growth factor (VEGF) mediates vascular and extravascular remodeling and inflammation and has been proven to be involved in the progression of asthma. Previous studies have focused on the effects of VEGF on ASMC proliferation, but few researchers have focused on the effects of VEGF on human ASMC migration. The purpose of this study was to explore the effect of VEGF on the migration of ASMCs and its related signaling pathway mechanism to provide evidence for the treatment of airway remodeling. We examined the effects of VEGF induction on ASMC migration and explored the mechanisms involved in ASMC migration. We found by wound healing and Transwell assays that VEGF promoted ASMC migration. Through the Cell Counting Kit-8 (CCK-8) experiment, we found that VEGF had no significant effect on the proliferation of ASMCs, which excluded the involvement of cell proliferation in the process of wound healing. Moreover, a cellular immunofluorescence assay showed that VEGF promoted F-actin reorganization, and Western blotting showed that VEGF improved RhoA activation and myosin phosphatase targeting subunit-1 (MYPT1) and myosin light chain (MLC) phosphorylation in ASMCs. Treatment with the ROCK inhibitor Y27632 significantly attenuated the effects of VEGF on MYPT1/MLC activation and cell migration. In conclusion, the results suggest that the promigratory function of VEGF activates the RhoA/ROCK pathway, induces F-actin reorganization, improves the migration of ASMCs, and provides a better rationale for targeting the RhoA/ROCK pathway for therapeutic approaches in airway remodeling.