Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies.
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and survival in mammalian cells. mTOR pathways are frequently dysregulated in various malignancies, providing targets for new anticancer drugs and therapeutic strategies. Here, we summarize the clinical experience of trials using the first generation of mTOR inhibitors, the rapalogs, and highlight the development of the next generation of catalytic inhibitors of the pathway. mTOR inhibitors have shown major clinical activity in the treatment of renal cell carcinoma and two rapalogs have been approved for treatment of this malignancy. Recently, clinically significant trials with these agents were conducted in mantle cell lymphoma, pancreatic neuroendocrine tumors and astrocytomas. There are also promising results emerging in sarcomas, breast cancer and lung carcinoma. Multiple agents targeting mTOR, belonging to the new class of catalytic inhibitors with activity against both mTORC1 and mTORC2, are currently in various stages of preclinical and clinical development. The rapalogs are the first mTOR inhibitors to show promising, yet modest, antitumor effects. To fully exploit the potential of targeting this pathway, it will be important to better understand the mechanisms of action and precise targets of the various inhibitors. Moreover, definition of biomarkers of susceptibility and identification of predictors and/or correlates to drug resistance will substantially advance this area.


High performance zeolite LTA pervaporation membranes on ceramic hollow fibers by dipcoating-wiping seed deposition.
We demonstrate for the first time that by one single hydrothermal synthesis a zeolite LTA membrane with a high flux of 9.0 kg/m(2) h and high water/ethanol separation factor of 10,000 could be formed on a ceramic hollow fiber that is known for its ability to form a compact module. The flux is the highest reported in the literatures. A novel seeding method, dipcoating-wiping, is key to obtaining zeolite membranes with high separation performance because it reproducibly produces a uniform and trace seed layer on the support. This new seeding method is expected to have serious implications for making defect-free zeolite films and membranes for many applications. The membranes reported here have the potential to solve the key problems that have prevented zeolite membranes from widespread use for biofuel production.


Understanding the response of dendritic cells to activation by streptococcal preparation OK-432.
The streptococcal preparation OK-432 induces maturation of T cells and dendritic cells (DCs). However, the mechanisms by which OK-432 induces DC maturation are not well understood. The effects of OK-432 and TNF-alpha on peripheral blood mononuclear cells (PBMCs) were compared. Antibody-based approaches were used to detect proteins characteristic of antigen-presenting cells and cytokines. Cytotoxicity was evaluated by measuring the release of LDH after incubation of effector and target cells. The TLR-4 levels were measured by real-time quantitative PCR. Changes in cell surface marker levels were detected in both treatment groups but OK-432 had a greater effect on induction of Th-1-type cytokines. Furthermore, TLR-4 mRNA was up-regulated in cells from two out of five patients in response to OK-432, but not in response to TNF-alpha. OK-432 has a more profound effect on human DCs than TNF-alpha and may act through multiple signaling pathways.


Characteristics of human adipose mesenchymal stem cells isolated from healthy and cancer affected people and their interactions with human breast cancer cell line MCF-7 in vitro.
Adipose tissue is an attractive source of mesenchymal stem/stromal cells (MSCs) with potential applications in reconstructive plastic surgery and regenerative medicine. The aim of this study was to characterise human adipose tissue MSCs (ASCs) derived from healthy individuals and cancer patients and to compare their interactions with tumour cells. ASCs were isolated from adipose tissue of healthy donors, breast cancer-adjacent adipose tissue of breast cancer patients and tumour-adjacent adipose tissue of non-breast cancer patients. Their proliferation, differentiation, immunophenotype and gene expression were assessed and effects on the proliferation of human breast cancer cell line MCF-7 compared. ASCs from all sources exhibited similar morphology, proliferative and differentiation potential, showing the characteristic pattern of mesenchymal surface markers expression (CD90, CD105, CD44H, CD73) and the lack of HLA-DR and hematopoietic markers (CD11a, CD33, CD45, Glycophorin-CD235a), but uneven expression of CD34. ASCs also shared a common positive gene expression of HLA-DR, HLA-A, IL-6, TGF-β and HIF-1, but were negative for HLA-G, while the expression levels of Cox-2 and IDO-1 varied. All ASCs significantly stimulated the proliferation of MCF-7 tumour cells in direct mixed co-cultures and transwell system, although their conditioned media displayed antiproliferative activity. Data obtained showed that ASCs with similar characteristics are easily isolated from various donors and sites of origin, although ASCs could both suppress and favour tumour cells growth, emphasising the importance of cellular context within the microenvironment and pointing to the significance of safety studies to exclude any potential clinical risk of their application in regenerative medicine.


Meta-analysis approaches to combine multiple gene set enrichment studies.
In the field of gene set enrichment analysis (GSEA), meta-analysis has been used to integrate information from multiple studies to present a reliable summarization of the expanding volume of individual biomedical research, as well as improve the power of detecting essential gene sets involved in complex human diseases. However, existing methods, Meta-Analysis for Pathway Enrichment (MAPE), may be subject to power loss because of (1) using gross summary statistics for combining end results from component studies and (2) using enrichment scores whose distributions depend on the set sizes. In this paper, we adapt meta-analysis approaches recently developed for genome-wide association studies, which are based on fixed effect and random effects (RE) models, to integrate multiple GSEA studies. We further develop a mixed strategy via adaptive testing for choosing RE versus FE models to achieve greater statistical efficiency as well as flexibility. In addition, a size-adjusted enrichment score based on a one-sided Kolmogorov-Smirnov statistic is proposed to formally account for varying set sizes when testing multiple gene sets. Our methods tend to have much better performance than the MAPE methods and can be applied to both discrete and continuous phenotypes. Specifically, the performance of the adaptive testing method seems to be the most stable in general situations.


Advocating for pregnant women in prison: the role of the correctional nurse.
On any given day, approximately 6%-10% of women who are incarcerated in prisons and jails in the United States are pregnant. Although incarcerated pregnant women have been identified as a high-risk group because of compromised physical and emotional health when they enter these settings, their specific healthcare needs are frequently unmet or partially met during their imprisonment. Stressors imposed by prison life and separation from their newborn at birth often exacerbate existing mental health issues including posttraumatic stress disorder, depression, anxiety, and insomnia. Nurses in correctional settings play a strategic role in improving the health care of this population by promoting teamwork, incorporating standards of care, and advocating for changes in policies. Collaboration with the warden, physician or nurse practitioner, correctional officers, and social workers can lead to positive changes in health outcomes. Given the national emphasis on gender responsive treatment in prisons and jails, a window of opportunity exists to be a voice for these women and make significant changes in health care for this largely underserved [corrected] population.


α-Chymotrypsin-catalyzed reaction confined in block-copolymer vesicles.
Herein the reactivity of the enzyme α-chymotrypsin in the confinement of polystyrene-block-poly(acrylic acid) (PS-b-PAA) vesicles was investigated. Enzyme and substrate molecules were encapsulated in PS-b-PAA vesicles with internal diameters ranging from 26 nm to 165 nm during the formation of the vesicles. While the loading efficiencies of enzyme and substrate molecules were practically identical for vesicles of identical size, they were found to increase with decreasing vesicle size. The kinetics of the α-chymotrypsin catalyzed hydrolysis of N-succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin (AMC) was evaluated following the increase of the absorption of the product 7-amino-4-methylcoumarin by UV/Vis spectroscopy. The values of the catalytic turnover number obtained for reactions inside vesicles with different sizes showed an increase of up to fourteen times compared to the bulk value with decreasing vesicle volume, while the values of the Michaelis-Menten constant decreased, respectively. This increase in reactivity of α-chymotrypsin is attributed to the effect of vesicle-wall interactions in the finite encapsulated space, where the reagents could diffuse, leading to enhanced collision frequencies.


On-pump beating heart mitral valve repair in patients with patent bypass grafts and severe ischemic cardiomyopathy.
Re-operative mitral valve surgery in patients with poor ventricular function can be challenging especially in the presence of patent bypass grafts. We report the case of 11 patients with severe ischemic cardiomyopathy who underwent reoperative mitral valve repair through a limited right thoracotomy approach, on a non-fibrillating beating heart. All patients had their valves successfully repaired with no operative mortality and minimal morbidity. The technical aspects of the procedure are discussed, and the pertinent literature reviewed.


Total Synthesis of Limaol.
A nonthermodynamic array of four skipped methylene substituents on the hydrophobic tail renders limaol, a C40-polyketide of marine origin, unique in structural terms. This conspicuous segment was assembled by a two-directional approach and finally coupled to the polyether domain by an allyl/alkenyl Stille reaction under neutral conditions. The core region itself was prepared via a 3,3'-dibromo-BINOL-catalyzed asymmetric propargylation, a gold-catalyzed spirocyclization, and introduction of the southern sector via substrate-controlled allylation as the key steps.


Inositol-containing lipids in suspension-cultured plant cells: an isotopic study.
Polar lipids were extracted from suspension-cultured tomato (Lycopersicon esculentum Mill.) cells and analyzed by thin layer chromatography. Four major inositol-containing compounds were found, and incorporation of [(32)P]orthosphosphate, [2-(3)H]glycerol, and myo-[2-(3)H]inositol was studied. Results showed that phosphatidylinositol-monophosphate is the phospholipid in these cells displaying the most rapid incorporation of [(32)P]orthophosphate. We suggest that the tracer is incorporated primarily into the phosphomonoester group. Two inositol-containing lipids showed chromatographic behavior similar to phosphatidylinositol-4,5-bisphosphate when using standard thin layer chromatography techniques. The labeling pattern of these compounds, however, reveals that it is unlikely that either of these is identical to phosphatidylinositol-4,5-bisphosphate. Should phosphatidylinositol-bisphosphate be present in suspension cultured plant cells, our data indicate chemical abundancies substantially lower than previously reported.


HLA markers in a community-based rheumatoid arthritis series.
We wanted to investigate whether rheumatoid arthritis (RA) patients, defined by the American College of Rheumatology (ACR) 1987 criteria and selected from one community by the help of the official Finnish data registers, share the common HLA susceptibility genes. The HLA frequencies of 88 RA patients representing 85% of the prevalent cases of RA in the community were compared with those of 188 healthy controls. Fifty-four per cent of the index cases with RA had DR4 compared with 30% of the healthy controls (P <0.001). The 'RA susceptibility sequence' was found in 75% of the DRB1 genes in the index cases, but it did not correlate with the severity of the disease. The frequency of DR3 was not increased in RA patients but it was associated with features of severe disease, that is, with a high erythrocyte sedimentation rate (P<0.05), extra-articular disease (P<0.01) and prostheses in large joints (P<0.05). According to our results community-based RA patients satisfying the new ACR criteria show the common DR4 association. DR3 was the only HLA allele which showed some disease-modifying effect correlating with the severity of RA.


Metabolite changes in early relapsing-remitting multiple sclerosis. A two year follow-up study.
Previous in vivo proton magnetic resonance spectroscopic imaging ((1)H-MRSI) studies have found reduced levels of N-acetyl-aspartate (NAA) in multiple sclerosis (MS) lesions, the surrounding normal-appearing white matter (NAWM) and cortical grey matter (CGM), suggesting neuronal and axonal dysfunction and loss. Other metabolites, such as myoinositol (Ins), creatine (Cr), choline (Cho), and glutamate plus glutamine (Glx), can also be quantified by (1)H-MRSI, and studies have indicated that concentrations of these metabolites may also be altered in MS. Relatively little is known about the time course of such metabolite changes. This preliminary study aimed to characterise changes in total NAA (tNAA, the sum of NAA and N-acetyl-aspartyl-glutamate), Cr, Cho, Ins and Glx concentrations in NAWM and in CGM, and their relationship with clinical outcome, in subjects with clinically early relapsing-remitting MS (RRMS). Twenty RRMS subjects and 10 healthy control subjects underwent (1)H-MRSI examinations yearly for two years. Using the LCModel, tNAA, Cr, Cho, Ins and Glx concentrations were estimated both in NAWM and CGM. At baseline, the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group (-7%, p = 0.003), as well as in the CGM (-8.7%, p = 0.009). NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in the MS subjects, or relatively between MS and healthy control subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible. Compared with other MR imaging measures, serial (1)H-MRSI may be relatively less sensitive to progressive pathological tissue changes in early RRMS.


Intestinal obstruction due to idiopathic mesenteric phlebosclerosis colitis: A case report.
Idiopathic mesenteric phlebosclerosis colitis (IMP) is a rare condition that impairs colonic venous blood return owing to mesenteric venous sclerosis and fibrosis. At present, many studies have suggested that long-term intake of Chinese herbal medicines is associated with its pathogenesis. IMP has no characteristic clinical manifestations, and most patients with IMP present with acute intestinal obstruction. As a rare disease, the etiology, pathogenesis, pathophysiology, and treatment of IMP are being explored and studied. A 60-year-old Chinese male patient with IMP was admitted to our hospital for acute intestinal obstruction, received subtotal colectomy and ileostomy after 10 days of ineffective conservative treatment, and was discharged after postoperative supportive treatment for 1 month. There are many causes of intestinal obstruction, and we report a relatively rare one. After failure of conservative treatment, it is necessary to surgically resect part of the diseased bowel.


Human Yersinia enterocolitica infection in the eastern Cape. A report on 18 cases and a review of yersiniosis in the RSA.
Yersinia enterocolitica infections with a wide spectrum of clinical presentations have been reported in South Africa. An additional 18 cases were encountered in the eastern Cape region during the period May 1982 - December 1984. Y. enterocolitica isolates comprised 1% of 1,634 faecal examinations performed by the Microbiology Department of the South African Institute for Medical Research in Port Elizabeth during this period, compared with isolation rates of 5.1% for shigellae, 3.7% for salmonellae and 1.3% for Campylobacter jejuni. The majority of Y. enterocolitica infections were in children who presented with diarrhoea and only 2 systemic cases were documented. Although more cases were seen in summer there was no distinct seasonal incidence and this may be attributed to the even climatic conditions prevailing in the region.


Prolonged evaluation of patients with corticosteroid-dependent asthma stage of allergic bronchopulmonary aspergillosis.
Eight cases with stage IV allergic bronchopulmonary aspergillosis (ABPA) (corticosteroid-dependent asthma stage) were observed for a total of 82 patient years with individual patients observed for 7 to 19 years (mean 10.2) years. One case is the first case of ABPA diagnosed in the United States in 1967. A second case has been observed through four stages of ABPA. None of these eight cases has demonstrated pulmonary deterioration by clinical, chest roentgenogram, or pulmonary function analysis. After diagnosis, the maintenance dose of prednisone in seven of eight cases was a low to moderate dose alternate-day prednisone. These results suggest that continuous observation and management of episodes of pulmonary consolidation or asthma exacerbations may prevent the progression of ABPA to stage V (fibrotic end stage). The total IgE may remain elevated in these patients, and therapy should not attempt to reduce total serum IgE to normal levels. After prolonged therapy with prednisone for asthma and control of ABPA, the IgE and IgG antibody indices against Aspergillus fumigatus may remain elevated or may be below the levels that are of diagnostic value.


Contribution of protons to post-ischemic Na(+) and Ca(2+) overload and left ventricular mechanical dysfunction.
The intracellular accumulation of Na(+) and Ca(2+) plays a key role in ischemia-induced myocardial injury that may be manifest as left ventricular (LV) mechanical dysfunction, dysrhythmias, or infarction. This review considers the potential contributions of protons (H(+)) produced during ischemia as well as reperfusion to intracellular Na(+) and Ca(2+) homeostasis. ATP hydrolysis produces H(+) and the resulting intracellular acidosis directly impairs LV contractility. However, it is the accumulation of intracellular H(+) and the activation of Na(+)-dependent pH regulatory mechanisms, including the Na(+)-H(+) exchanger (NHE-1) and the Na(+)-HCO(3) (-) cotransporter, which contribute to Na(+) accumulation. Intracellular Na(+) accumulation, coupled with the NHE-1, then causes Ca(2+) overload and further LV mechanical dysfunction. As glycolysis uncoupled from glucose oxidation is an important determinant of the rate of H(+) production, factors that affect glucose metabolism, including degree of ischemia, myocardial workload, and competition from other energy substrates, are expected to influence Na(+) and Ca(2+) accumulation, and hence the recovery of post-ischemic LV mechanical function. Whereas an increase in the uncoupling of glycolysis from glucose oxidation accelerates H(+) production and worsens the recovery of LV mechanical function, inhibition of H(+) production improves recovery of post-ischemic LV mechanical function. Thus, alteration of glucose metabolism, either by inhibition of an excessive rate of glycolysis or by stimulation of glucose oxidation, is an attractive drug target to reduce H(+) production and limit Na(+) and Ca(2+) accumulation and thereby prevent post-ischemic LV dysfunction.


[Nodular fasciitis arose in the pelvis : a case report].
A 58-year-old woman presented to our emergency room with cystitis-like symptoms and macroscopic hematuria. Her symptoms were improved by the administration of an antibiotic, but transabdominal ultrasonography revealed a mass in her pelvis. The pelvic magnetic resonance imaging (MRI) depicted a solid tumor in the retropubic space. The patient requested hasty surgical excision of the tumor, rather than the conservative treatment after the diagnosis by cytology and biopsy. The postoperative histopathological examination revealed nodular fasciitis. She has been followed up for 8 months without any evidence of local recurrence. Nodular fasciitis is a mesenchymal lesion of proliferated fibroblast and commonly occurs in the subcutaneous tissue of the extremities. Frequently, it resembles a sarcoma, but it is said to be a benign disorder. In the urological domain, 14 intravesical cases have been reported. To our knowledge, this is the first case of the nodular fasciitis arising in the pelvis. We report this case and discuss the literature.


Photopic action of thyrotropin-releasing hormone in the cat retina.
The effects of iontophoretically applied thyrotropin-releasing hormone (TRH) on cat retinal brisk-sustained(X) and brisk-transient(Y) ganglion cells were studied in the intact eye in vivo. Under photopic illumination we found a differential action of TRH on ON- and OFF-centre cells: the maintained activity and light response were suppressed in ON-centre cells and enhanced in OFF-centre cells. This was true for both brisk-sustained(X) and brisk-transient(Y) cells. In contrast, TRH did not influence the ganglion cell discharge under scotopic stimulus conditions. These results indicate that TRH acts on neurons presynaptic to ganglion cells and these neurons are only active under photopic conditions. We suggest that a possible functional role of this specific action of TRH is in light adaptation.


Actin and Nuclear Envelope Components Influence Ectopic Recombination in the Absence of Swr1.
The accuracy of most DNA processes depends on chromatin integrity and dynamics. Our analyses in the yeast Saccharomyces cerevisiae show that an absence of Swr1 (the catalytic and scaffold subunit of the chromatin-remodeling complex SWR) leads to the formation of long-duration Rad52, but not RPA, foci and to an increase in intramolecular recombination. These phenotypes are further increased by MMS, zeocin, and ionizing radiation, but not by double-strand breaks, HU, or transcription/replication collisions, suggesting that they are associated with specific DNA lesions. Importantly, these phenotypes can be specifically suppressed by mutations in: (1) chromatin-anchorage internal nuclear membrane components (mps3∆75-150 and src1∆); (2) actin and actin regulators (act1-157, act1-159, crn1∆, and cdc42-6); or (3) the SWR subunit Swc5 and the SWR substrate Htz1 However, they are not suppressed by global disruption of actin filaments or by the absence of Csm4 (a component of the external nuclear membrane that forms a bridging complex with Mps3, thus connecting the actin cytoskeleton with chromatin). Moreover, swr1∆-induced Rad52 foci and intramolecular recombination are not associated with tethering recombinogenic DNA lesions to the nuclear periphery. In conclusion, the absence of Swr1 impairs efficient recombinational repair of specific DNA lesions by mechanisms that are influenced by SWR subunits, including actin, and nuclear envelope components. We suggest that these recombinational phenotypes might be associated with a pathological effect on homologous recombination of actin-containing complexes.


Pacing the ARRA changes. Tackling the ARRA rules and regulations as they come.
Through the winter and spring healthcare waited for the next round of ARRA-related regulations. Now they are here, and organizations are tagged with implementing compliant programs. How do you get started when it seems that everything needs doing at once?


A Diagnostic Algorithm to Guide Operative Intervention of Zone 5 Flexor Injuries.
Background: Given the importance of the neurovascular structures in the volar forearm, accurate diagnosis of zone 5 flexor injuries is critical. Purpose: We sought to test the hypothesis that tendinous injury would be more likely in the distal 50% of the forearm and muscle belly injury would be more likely in the proximal 50% of the forearm. Methods: From December 2015 to December 2016, we conducted a prospective clinical study of patients 18 years and older with zone 5 flexor lacerations. We excluded those with concomitant ipsilateral injuries in flexor zones 1 to 4, multiple lacerations in flexor zone 5, prior neurovascular injuries, crush injuries, patients who underwent operative exploration prior to transfer to our facility, and patients who were unable or unwilling to provide consent. Neurovascular and musculotendinous injuries on physical examination were recorded. All patients underwent operative exploration. Physical examination accuracy and the incidence of musculotendinous and neurovascular injury in the distal 50% of the forearm were compared with the proximal 50% of the forearm. Results: The distal 50% of the forearm (group 1, n = 14) had higher probability of tendon injury (64%), whereas lacerations of the proximal 50% of the forearm (group 2, n = 5) did not result in any tendinous injuries. Rather, all patients in group 2 had muscle belly injuries. There was no difference in the rate of neurovascular injury between groups. Physical examination alone was highly accurate in diagnosing nerve injuries (93%-100%) but less accurate in diagnosing arterial injuries (79%-80%) regardless of the location of injury. Conclusions: Due to the lack of tendinous injuries in proximal zone 5 lacerations, along with the accuracy of physical examination in determining the presence of neurovascular injuries, patients with lacerations in the proximal half of the forearm, without evidence of nerve or arterial injury, can likely be observed in lieu of immediate operative exploration.


Single particle technique for one-step homogeneous detection of cancer marker using gold nanoparticle probes.
In this paper, we reported a single particle technique for the one-step homogeneous immunoassay of a cancer marker by resonance light scattering correlation spectroscopy (RLSCS). The setup of RLSCS was similar to fluorescence correlation spectroscopy (FCS), and its principle was based on measuring the resonance light scattering fluctuations in a small volumes (less than 1 fL) due to Brownian motion of single particles. In homogeneous immunoassay, we used a sandwich strategy and conjugated two different antibodies (Ab) with gold nanoparticles (GNPs) respectively. When two different GNPs labeled with antibodies are mixed in a sample containing antigen (Ag) targets, the binding of targets will cause GNPs to form dimers (or oligomers), which leads to the significant increase in the characteristic diffusion time of GNPs in the detection volume. The RLSCS method can sensitively detect the change in the characteristic diffusion time of GNPs before and after immune reactions. We used this technology in homogeneous immunoassays for the liver cancer biomarker alpha-fetoprotein (AFP). The conditions of the immune reaction were investigated systematically. In the optimal conditions, the linear range of this assay is from 1 pM to 1 nM and the detection limit is 1 pM for AFP. This new method was successfully applied for the direct determination of AFP levels in sera from healthy subjects and cancer patients. Our results were in good agreement with ELISA assays.


Ischemic optic neuropathy: are we any further?
Postoperative vision loss (POVL) as related to spinal surgery and the prone position has garnered increasing attention in the US over the last 15 years, resulting in an increase of litigations submitted to the legal system. It might be associated with the development of new surgical techniques involving complex instrumentation of the spine. By 2000, the magnitude of this problem was such that the American Society of Anesthesiologists developed a Postoperative Visual Loss Registry in an effort to better understand and evaluate this devastating operative complication. The cause of ischemic optic neuropathy (ION) as the most complex entity of POVL is still unclear. Retrospective studies show that although it can strike patients of any age, there is an increased incidence in patients less than 18 and more than 65 years of age. Significant risk factors include male sex, anemia, surgery lasting over 6 h, and intraoperative hypotension. Profound anatomical knowledge and new animal studies have helped to define possible mechanisms underlying ION. ION is still poorly understood and risk factors remain speculative. Given that there is no known treatment, increased understanding should help to prevent this postoperative complication.


[Vasculitides of the coronary arteries].
It is generally accepted that myocardial ischemia, and its extreme consequence, acute myocardial infarction, can result from transient or permanent disproportion between myocardial oxygen demand and coronary artery blood supply. Insufficient coronary artery blood supply may have many reasons. The aim of the study is to point to the clinical features of the coronary vasculitides as well as to the diagnostic and therapeutic possibilities. Coronary artery involvement in infectious angiitis, in Takayasu's arteritis, in granulomatous giant cell arteritis, in thromboangiitis obliterans, in polyarteritis nodosa, in Wegener's granulomatosis and in Churg--Strauss syndrome is discussed. The diagnosis of coronary vasculitis must be supposed in every patient with primary or secondary vasculitis in whom chest pain or cardiac failure appear. In young patients with clinical, electrocardiographic or laboratory signs of coronary artery disease, especially in absence of risk factors for atherosclerosis, the diagnosis of coronary vasculitis must be considered in differential diagnosis. (Fig. 4, Tab. 1, Ref. 32.).


[Clinical evaluation of serum basic fetoprotein for prostatic cancer--comparative study with PAP, gamma-Sm and PSA].
The clinical significance of serum basic fetoprotein (BFP) in prostatic cancer was investigated together with serum prostatic acid phosphatase (PAP), gamma-seminoprotein (gamma-Sm) and prostate specific antigen (PA). Investigated in this study were 40 patients with prostatic cancer, ranging in age from 50 to 85 years (mean age: 69.5 years). According to clinical staging, 3 cases (7.5%) had a stage A disease, 10 cases (25.0%) a stage B disease, 7 cases (17.5%) a stage C disease, and 20 cases (50.0%) a stage D disease. The positive rates for serum BFP, PAP, gamma-Sm, and PSA were 60.0, 45.0, 63.6, and 68.4%, respectively, and these rates increased as the stage advanced. The above results suggest that BFP is the most useful marker of the four for monitoring prostatic cancer. In a combination assay of these four markers, 29 (87.9%) of 33 patients with prostatic cancer could be diagnosed by observing an elevated serum level in one of the markers. This suggests that a combination assay of BFP, PAP, gamma-Sm and PSA in patients with prostatic cancer is useful for diagnosis and monitoring of the disease.


Dosimetric comparison of postoperative whole pelvic radiotherapy for endometrial cancer using three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy.
The use of Intensity-modulated radiotherapy (IMRT) and Helical tomotherapy (HT) is increasing in gynecological cancer patients. No published studies have performed a dosimetric evaluation of whole pelvic radiotherapy (WPRT) using HT for postoperative endometrial cancer. The purpose of this study was to perform a direct dosimetric comparison of three-dimensional conformal radiotherapy (3D-CRT), IMRT and HT plans for WPRT in postoperative endometrial cancer patients, and to evaluate the integral dose to organs at risk (OARs) and normal tissue. We selected ten patients with endometrial cancer undergoing postoperative WPRT. Plans for 3D-CRT, IMRT and HT were developed for each patient. All plans were normalized to deliver 50 Gy to 95% of the PTV. The dosimetry and integral dose to OARs and normal tissue were compared. The significance of differences was tested using a paired two-tailed Student t-test. IMRT were superior to 3D-CRT in dose conformity (conformity index: 0.87 vs. 0.61, p = 0.00) and integral dose to OARs and normal tissue, although a greater volume of normal tissue receiving dose below 10 Gy was observed. The results were similar in HT except that the integral dose to normal tissue increased slightly. Compared directly with IMRT, HT showed better dose homogeneity and lower integral dose to rectum and bladder, but the integral dose to pelvic bones and normal tissue slightly increased. In postoperative WPRT of endometrial cancer, IMRT and HT result in better conformity and lower integral dose to OARs compared with 3D-CRT. The integral dose to normal tissue did not increase significantly in IMRT, although a greater volume of normal tissue is irradiated to the dose below 10 Gy. HT further improves the dose homogeneity and integral dose to rectum and bladder, at the expense of a slightly higher integral dose to pelvic bones and normal tissue.


Construction of the [6,5,7,5] Tetracyclic Core of Calyciphylline A Type Alkaloids via a Tandem Semipinacol Rearrangement/Nicholas Reaction.
A novel and efficient approach toward the assembly of the synthetically challenging tetracyclic [6,5,7,5] core structure of calyciphylline A-type alkaloids is developed. The synthetic route features a tandem semipinacol rearrangement/Nicholas reaction that has been devised strategically to construct the spirocyclic A/B ring and the sterically congested vicinal all-carbon quaternary carbon centers in high diastereoselectivity. Late-stage installation of the hydropyrrole ring and the strained 7-membered ring via a double-reductive amination and ring-closing metathesis, respectively, has also been realized.


Preoperative latent medial laxity and correction angle are crucial factors for overcorrection in medial open-wedge high tibial osteotomy.
This study aimed to determine which preoperative factors affect the postoperative change in the joint line convergence angle (JLCA) by preoperatively quantifying soft tissue laxity. Thirty-four patients who underwent medial open-wedge high tibial osteotomy (HTO) with a navigation were analysed. The JLCA change after HTO was calculated using standing long-bone anteroposterior radiographs taken preoperatively and 6 months postoperatively. Latent soft tissue laxity was defined as the amount of soft tissue that can be extended to valgus or varus from the weight-bearing position, and calculated by subtracting the JLCA on weight-bearing standing radiographs from that on stress radiographs. Multiple linear regression was performed to determine the preoperative factors that statistically correlated with the postoperative JLCA change. In multiple linear regression, JLCA change had a statistically significant correlation with latent medial laxity (R = 0.6) and a statistically borderline significant correlation with correction angle (R = 0.2). These imply that the postoperative JLCA change increased by 0.6° per 1° increase in latent medial laxity, and increased by 0.2° per 1° increase in correction angle. Latent medial laxity was the most crucial factor associated with postoperative JLCA changes. The JLCA change could be larger in patients with large latent medial laxity or severe varus deformity requiring a large correction, which could lead to unexpected overcorrection in HTO. Postoperative JLCA change should be considered in preoperative surgical planning. Target point shifting within the hypomochlion point could be a strategy to prevent overcorrection, especially in patients with large latent medial laxity. Level IV.


Posttraumatic growth moderates the effects of posttraumatic stress symptoms on adjustment and positive affective reactions in digestive system cancer patients.
The study aims were twofold: (1) To investigate the associations of posttraumatic stress symptoms (PTSS) and posttraumatic growth (PTG) with adjustment and affective reactions of digestive system cancer patients and (2) To assess the moderating effects of PTG on the associations of PTSS with adjustment and affective reactions. The sample consisted of 200 respondents 1-4 years following diagnosis and treatment for digestive system cancer. Participants completed questionnaires assessing PTSS, PTG, adjustment, positive affect (PA), and negative affect (NA). The results showed that PTG was positively associated with adjustment and PA, while PTSS was negatively associated with these outcomes and positively associated with NA. Moderation effects of PTG were also observed: The negative associations between PTSS and adjustment or PA were weaker under high levels than under low levels of PTG. It was concluded that PTG is important both as a contributor to better adjustment and PA, as well as a moderator of the detrimental effects of PTSS on adjustment and PA following recovery from cancer. Thus, when developing post-cancer intervention programs, PTG should be viewed as a factor to be encouraged and nurtured for the benefit of cancer patients' adjustment and their long-term well-being.


Effect of HIV-infection and cumulative viral load on age-related decline in grip strength.
Grip strength predicts functional decline and death, and is regarded as a biomarker of biological aging. The primary objective of this manuscript was to assess differences in the rate of decline in grip strength in persons aging with and without HIV. Grip strength was assessed in 1552 (716 HIV+ and 836 HIV-) men aged at least 50 years participating in the Multicenter AIDS Cohort Study between 2007 and 2014. Grip strength decline was modeled longitudinally, adjusting for serostatus, demographics, comorbidities, and conditions. In HIV-specific models, coefficients were included for cumulative viral load and history of AIDS. Grip strength at the age of 50 years averaged 37.9 and 38.2 kg for HIV+ and HIV- men, respectively (P = 0.70). In fully adjusted models, grip strength declined 0.33 kg/year in HIV- men (P < 0.001) and 0.42 kg/year in HIV+ men (P = 0.01). In HIV-stratified models, higher cumulative viral load indicated greater strength decline (-0.884 kg for 3.1-4.0 log10 copies-years/ml and -1.077 kg for ≥4.1 log10 copies-years/ml) relative to men with consistently low viral load (≤3.0 log10 copies-years/ml). Adjusted Cox proportional hazard models revealed a 70% greater risk of clinically weak grip strength in HIV+ men (adjusted hazard ratio 1.70; 95% confidence interval, 1.22-2.40). Grip strength decline is accelerated in HIV-infected men, which may contribute to decreased life expectancy and lower quality of life with aging. Greater cumulative viral load exposure appears to be an important driver of this decline and underscores the importance of early initiation of therapy.


Design, synthesis, and biological evaluation of potent quinoline and pyrroloquinoline ammosamide analogues as inhibitors of quinone reductase 2.
A variety of ammosamide B analogues have been synthesized and evaluated as inhibitors of quinone reductase 2 (QR2). The potencies of the resulting series of QR2 inhibitors range from 4.1 to 25,200 nM. The data provide insight into the structural parameters necessary for QR2 inhibitory activity. The natural product ammosamide B proved to be a potent QR2 inhibitor, and the potencies of the analogues generally decreased as their structures became more distinct from that of ammosamide B. Methylation of the 8-amino group of ammosamide B was an exception, resulting in an increase in quinone reductase 2 inhibitory activity from an IC(50) of 61 nM to IC(50) 4.1 nM.


Risk factors for nonmelanoma skin cancer in Taubaté, São Paulo, Brazil: a case-control study.
To identify factors associated with non-melanoma skin cancer in the city of Taubaté, São Paulo, Brazil. Hospital-based case-control study with individuals residing in Taubaté, treated between January 2005 and December 2006. The subjects were matched 1:1 according to gender and age. Age, gender, phototype, European descent, time of residence, sun exposure, time (in years), number of hours and time of occupational and non-occupational sun exposure, photoprotection, family history and photodamage were independent variables. A hierarchical logistic regression was used at three levels. The model adjustment was performed using the Hosmer-Lemeshow test and its accuracy was verified by ROC curve. The significance level was p < 0.05. There were 132 cases and 132 controls. Phototype with OR = 3.14 (95% CI 1.79-5.49), hours of occupational 1.76 (1.04-2.99) and non-occupational sun exposure 1.80 (0.98-3.29) and family history 2.10 (1.13-3.93) were the variables in the final model. Hosmer-Lemeshow test, p = 0.97. Accuracy 70% (95% CI 63-76). We concluded that fair skin, family history and occupational and non-occupational sun exposure were associated with non-melanoma skin cancer in Taubaté-São Paulo.


Experimental determination of the effect of temperature on refractive index and optical path length of glass.
With the Fizeau interferometer method, the change in optical path length with temperature is measured at six wavelengths for twenty new Corning optical glasses. The sample, a polished block with a few seconds of wedge, is held in a double-walled chamber with temperature control provided over the range -20 degrees C to +80 degrees C by a circulating water-glycol mixture. A Gaertner interferometer viewing apparatus is modified by addition of a monitor head that permits simultaneous photoelectric fringe detecting and viewing. Measurement of thermal expansion with the Plummer-Hagy high precision dilatometer permits the extraction of the temperature coefficient of absolute refractive index from the optical path measurement. The coefficient of refractive index relative to standard air at the temperature of the glass is found by further data reduction using Edlén's equations. The experimental values of the index change as a function of temperature are curve-fitted by a FORTRAN program, and the slopes are computed to give instantaneous values of the coefficients. The average residual for the fit is about 1.0 x 10(-6). The precision of the absolute coefficient values is estimated to be +/-0.05 x 10(-6). Representative data for one glass are presented to illustrate the results available from this work.


[Characterization of daptomycin-resistance in environmental actinomycetes].
Daptomycin-resistance in environmental actinomycetes was studied to provide warning systems for emerging clinical resistance. In total 49 soil and 10 endophytic acitnomycetes were used in this study. The daptomycin resistant strains were identified by measuring daptomycin resistance profile. Subsequently, daptomycin inactivating assay was preformed to distinguish resistance from other nondestructive mechanisms. Then, the strains of interest were determined by morphology and 16S rRNA gene sequence analysis. Finally, PCR analysis was used to detect the daptomycin acylase gene (dpa) encoding daptomycin acylase in those strains. All strains tested in this study were resistant towards daptomycin. Of them 24 soil acitnomycetes and 4 endophytic actinomycetes had the ability to inactivate daptomycin, while the remaining strains used other measures to confer resistance. Sequence analysis demonstrated that strains inactivating daptomycin were Streptomyces, Micromonospora and Norcadia. PCR analysis shows that 17.9% strains contained the dpa. There is very high percentage of resistance in environmental actinomycetes and inactivating daptomycin is one of the main resistant mechanisms.


Thrombin induces GRO alpha/MGSA production in human umbilical vein endothelial cells.
Thrombin, besides being a potent coagulation factor, exerts influence on endothelial and leukocyte functions and may thus be involved in the regulation of inflammatory reactions. The present study investigated whether thrombin stimulates the production of growth-related cytokine/melanoma growth-stimulatory activity (GRO alpha/MGSA) in endothelial cells. Human umbilical vein endothelial cells (HUVEC) stimulated with thrombin were found to product GRO alpha/MGSA in a dose- and time-dependent manner. This action of thrombin was completely suppressed by preincubation with either hirudin or antithrombin-III (AT-III)-heparin. Interestingly, the thrombin receptor-activating peptide SFLLRN mimicked the action of thrombin. In addition, staurosporine, a protein kinase C (PKC) inhibitor, attenuated the production of GRO alpha/MGSA by thrombin, SFLLRN and phorbol 12-myristate 13-acetate (PMA), but left the action of interleukin-1 beta (IL-1 beta) unchanged. These results suggest that catalytic activation of thrombin receptor by thrombin results in GRO alpha/MGSA production, at least in part, via a pathway involving PKC in HUVEC.


Cerebrospinal fluid concentrations of soluble CD27 in HTLV-I associated myelopathy and multiple sclerosis.
Stimulation of T lymphocytes via the T cell receptor strongly enhances CD27 membrane expression and induces the release of a soluble 32 kDa form of CD27 (sCD27). CD27 is a member of the TNF receptor family, a group of molecules that have important roles in lymphocyte differentiation and survival. Raised concentrations of sCD27 have been reported in various immunopathological conditions and there is evidence that this molecule can serve as a marker of T cell activation in vivo. Concentrations of sCD27 in CSF were compared between patients with T cell mediated neurological disease and non-inflammatory controls. Also, the relation of CSF-sCD27 concentrations with clinical disease activity was investigated in patients with multiple sclerosis. Four groups were studied: (1) eight patients with HTLV-1 associated myelopathy/ tropical spastic paraparisis (HAM)/TSP), (2) eight HTLV-I carriers, (3) 41 patients with multiple sclerosis, and (4) 43 patients with other neurological disease (OND). Concentrations of CSF-sCD27 were determined by enzyme linked immunosorbent assay (ELISA). Quantification of CSF-sCD27 differentiates patients with HAM/TSP from HTLV-I carriers (p<0.01) and from patients with OND (p<0.001). Moreover, the multiple sclerosis patient group was different from the OND group (p<0.0001). In patients with multiple sclerosis, CSF-sCD27 concentrations were higher in 24 patients with clinically active disease than in 17 with clinically stable disease. In addition, most of the patients with multiple sclerosis with high sCD27 concentrations showed an increase in EDSS, whereas none of the patients with low sCD27 had an EDSS increase. As a reliable marker of immunological disease activity in inflammatory white matter disease is still not available, it is proposed that quantification of CSF-sCD27 concentrations is a good candidate. Also, it may serve as a tool to stratify neurological diseases in inflammatory and non-inflammatory states.


The Effect of Crystallinity on Compressive Properties of Al-PTFE.
Al-PTFE (Al-polytetrafluoroethene) is an important kind of Reactive Material (RM), however only limited importance was placed to the effect of crystallinity of PTFE on the mechanical and reactive behavior. This paper investigated the influence of crystallinity on the compression behavior of Al-PTFE at strain rates range from 10-2 to 3 × 10³ s-1. Two kinds of samples were prepared by different sintering procedures to acquire different crystallinity. The samples' crystallinity was characterized by the density method and X-ray diffraction method. The samples were tested using an electro-hydraulic press for quasi-static loading, and split Hopkinson pressure bars (SHPBs) for high strain rates. Low crystalline samples have consistently higher strength and toughness than the high crystalline samples. The phenomenon was explained by an "elastic-plastic network" model combined with the effect of chain entanglement density. A bilinear dependence of true stress on log ε ˙ was observed, and Johnson-Cook models were fitted separately according to the different strain rate sensitivity. Finally, a close connection between fracture and initiation of Al-PTFE was confirmed in quasi-static tests, SHPB tests, and drop weight tests. It was hypothesized that the high temperature at the crack tips of PTFE is an important promoting factor of initiation.


Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers.
New onset diabetes after transplantation is related to treatment with immunosuppressive medications. Clinical studies have shown that risk of new onset diabetes is greater with tacrolimus compared with ciclosporin. The diabetogenicity of ciclosporin and tacrolimus has been attributed to both beta cell dysfunction and impaired insulin sensitivity. This is the first trial to investigate beta cell function and insulin sensitivity using gold standard methodology in healthy human volunteers treated with clinically relevant doses of ciclosporin and tacrolimus. We document that both drugs acutely increase insulin sensitivity, while first phase and pulsatile insulin secretion remain unaffected. This study demonstrates that ciclosporin and tacrolimus have similar acute effects on glucose metabolism in healthy humans. AIM The introduction of calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) cause impairment of survival rates. The relative contribution of each CNI to the pathogenesis and development of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects. Ten healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double-blind, crossover study. During infusion glucose metabolism was investigated using following methods: a hyperinsulinaemic-euglycemic clamp, an intravenous glucose tolerance test (i.v.GTT), glucose-stimulated insulin concentration-time series and indirect calorimetry. Clamp derived insulin sensitivity was increased by 25% during CsA (P < 0.0001) and 13% during Tac administration (P = 0.047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were observed in circulating glucagon, FFA or adiponectin concentrations. Mean blood concentrations of CNIs were 486.9 ± 23.5 µg l(-1) for CsA and 12.8 ± 0.5 µg l(-1) for Tac. Acute effects of i.v. CsA, and to a lesser degree Tac infusions, in healthy volunteers include increased insulin sensitivity, without any effect on first phase or pulsatile insulin secretion.


Arthur J. Riopelle (1920-2012).
Presents an obituary for Arthur (Art) J. Riopelle. After graduating from the University of Wisconsin in 1942, Art joined the U.S. Army. He returned to the university after the war as a graduate student in psychology and earned a doctorate in experimental psychology under the supervision of Dave Grant and Fred Mote. In 1950, Art completed his degree and moved to the Psychology Department of Emory University in Georgia. This was the beginning of an unusual and eventful career. At Emory, Art worked with Harlow W. Ades, but when Ades eventually left, Art established a small colony of monkeys to pursue his own projects. Art moved from Emory to Fort Knox, Kentucky, in 1957 to become director of the Psychology Division of the U.S. Army Medical Laboratories. He continued to be involved with primates, including on a well-publicized project that entailed launching monkeys into space. In 1959, Art left Fort Knox to become the new director of what was then known as the Yerkes Laboratories of Primate Biology. Art played an important part in the history of regional primate research centers, which have benefited the nation in numerous ways. He had many admirable qualities. He was a tolerant, supportive, fair-minded, and principled administrator, a careful and dedicated scientist, and a steadfast friend who loved a good joke.


Predicting Obstructive Sleep Apnea with Periodic Snoring Sound Recorded at Home.
The cost-effectiveness of diagnosing obstructive sleep apnea (OSA) could be improved by using a preliminary screening method among subjects with no suspicion of other sleep disorders. We aimed to evaluate the diagnostic value of periodic snoring sound recorded at home. We included 211 subjects, aged 18-83 (130 men), who were referred to our laboratory for suspicion of OSA, and had a technically successful overnight polygraphy, measured with the Nox T3 Sleep Monitor (Nox Medical, Iceland) with a built-in microphone. We analyzed the percentage of periodic snoring during the home sleep apnea study. Apnea-hypopnea index (AHI) ranged from 0.1 to 116 events/h and the percentage of periodic snoring from 1% to 97%. We found a strong positive correlation (r = 0.727, p < 0.001) between periodic snoring and AHI. The correlation was slightly stronger among female, younger, and obese subjects. The best threshold value of the periodic snoring for predicting an AHI > 15 events/h with as high sensitivity as possible was found to be 15%. There, sensitivity was 93.3%, specificity 35.1%, and negative predictive value 75.0%. According to our results, it is possible to set a periodic snoring threshold (15% or more) for the subject to advance to further sleep studies. Together with medical history and prior to more expensive studies, measuring periodic snoring at home is a simple and useful method for predicting the probability of OSA, in particular among women who are often unaware of their apnea-related snoring.


Audiovestibular Symptoms in Patients With Idiopathic Hypertrophic Pachymeningitis: Systematic Literature Review.
Hypertrophic pachymeningitis is an infrequent inflammatory disease resulting in thickening and fibrosis of the dura mater. In most cases, the cause in unknown and is called idiopathic hypertrophic pachymeningitis (IHP). Audiovestibular symptoms are infrequent and the pathogenesis is still unclear. A systematic literature review of cases with IHP and vestibular symptoms from 2000 to February 2020 was performed. PRISMA Checklist was followed and PubMED database, Web of Science and Cochrane library were searched. We report a case of an adolescent with a diagnosis of vestibular neuritis in the context of IHP attended in our clinic. We reviewed 5 articles related to IHP and vestibular disorders. A total of 7 cases (5 women and 2 men), with ages between 27 and 68 years with IHP were found. They all had audiovestibular symptoms. In contrast to our patient, uni or bilateral neurosensorial hearing loss was reported in all cases. Furthermore, there is no other case report published describing the association between IHP and vestibular neuritis. High dose steroids improved symptoms in 85.7% of the patients. Vestibular symptoms in IHP are uncommon and the pathogenesis is still debatable. Entrapment of nerves in the internal auditory canal and secondary neuronal damage could be suspected as the main cause of hearing and vestibular loss.


[The value of CA125 and LDH assays in assisting diagnosis of epithelial ovarian carcinoma].
40 first-treated cases of epithelial ovarian cancer, 13 cases of cervical cancer, 13 cases of corpus cancer and 50 cases of benign tumor were included in this study from Jan. 1991 through May 1992 to evaluate the significance of the blood CA125, LDH, CR and SA levels in assisting diagnosis of epithelical ovarian cancer. The CA125 levels of the 40 canses of ovarian cancer were higher than those of cervical cancer and corpus cancer (P < 0.05); the SS, PLR and AC of CA125 in ovarian cancer were higher than those of LDH, SA and CR (P < 0.05); the SS of CA125 in ovarian cancer was higher than that of LDH isoenzyme (P < 0.05). The results show that CA125 may be the best tumor marker in assisting ovarian cancer; CA125 is more informative than LDH, CR and SA; when CA125 is used incombination with other tumor markers, SS, SP, NPV and PPV can be greatly raised.


Associations between Brain Reserve Proxies and Clinical Progression in Alzheimer's Disease Dementia.
The purpose of this study was to investigate whether brain and cognitive reserves were associated with the clinical progression of AD dementia. We included participants with AD dementia from the Alzheimer's Disease Neuroimaging Initiative, provided they were followed up at least once, and candidate proxies for cognitive (education for early-life reserve and Adult Reading Test for late-life reserve) or brain reserve (intracranial volume [ICV] for early-life reserve and the composite value of [18F] fluorodeoxyglucose positron emission tomography regions of interest (FDG-ROIs) for late-life reserve) were available. The final analysis included 120 participants. Cox proportional hazards model revealed that FDG-ROIs were the only significant predictor of clinical progression. Subgroup analysis revealed a significant association between FDG-ROIs and clinical progression only in the larger ICV group (HR = 0.388, p = 0.028, 95% CI 0.167-0.902). Our preliminary findings suggest that relatively preserved cerebral glucose metabolism might delay further clinical progression in AD dementia, particularly in the greater ICV group. In addition to ICV, cerebral glucose metabolism could play an important role as a late-life brain reserve in the process of neurodegeneration. Distinguishing between early- and late-life reserves, and considering both proxies simultaneously, would provide a wider range of factors associated with the prognosis of AD dementia.


Systemic lupus erythematosus evolving into systemic vasculitis: a report of five cases.
Five patients with systemic lupus erythematosus are described who developed the disease in their second or third decade. The pattern of their disease then changed markedly and they developed the clinical features of a systemic vasculitis. The possible explanations for this transition of one connective tissue disease to another is discussed.


Effect of caprylic acid and Yucca schidigera extract on production performance, egg quality, blood characteristics, and excreta microflora in laying hens.
1. A total of 240 Hy-line brown laying hens (36-week-old), were used in this 8 week experiment to evaluate the effect of caprylic acid and Yucca schidigera extract (CY) on production performance, egg quality, blood characteristics, and excreta microflora. 2. Layers were divided into 5 dietary treatment groups which consisted of: (1) NC, basal diet; (2) PC, basal diet + 110 mg/kg of tylosin; (3) CY1, basal diet + 30 mg/kg caprylic acid + 30 mg/kg Yucca extract; (4) CY2, basal diet + 60 mg/kg caprylic acid + 60 mg/kg Yucca extract; (5) CY3, basal diet + 120 mg/kg caprylic acid + 120 mg/kg Yucca extract. The Yucca extract contained 12·5% saponins. 3. Egg production was unaffected, whereas egg weights and feed efficiency were linearly improved by the addition of CY. There were no differences in the egg quality parameters throughout the experimental period. Plasma total triglyceride and cholesterol concentration in plasma and egg yolk were decreased as utilisation of CY increased. The Escherichia coli counts were linearly inhibited by the CY treatments when compared with the NC treatment at both the 5 and 8 week stages. No difference was observed on the Lactobacillus population through the whole experimental period. 4. In conclusion, the addition of 120 mg/kg caprylic acid and 120 mg/kg Yucca extract exerted positive effects on egg weight and feed efficiency, decreased the serum and yolk cholesterol concentration and reduced the proliferation of Escherichia coli.


2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one, an Inhibitor from Zea mays with Differential Activity against Soft Rotting Erwinia Species.
[2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one] DIMBOA was extracted with ethyl acetate from acidified water homogenates of corn (Zea mays L.) seedlings. Pure DIMBOA or ethyl acetate extracts of corn tissue were added to bacterial growth medium at five concentrations (measured as hydroxamates). DIMBOA and corn extracts were more inhibitory to soft rot bacteria (Erwinia spp.) that are nonpathogenic to corn than to soft rot bacteria that are corn pathogens. The inhibitory activity of DIMBOA was similar to that of the ethyl acetate extracts. Both corn extracts and DIMBOA prolonged the lag phase of bacterial growth without significantly changing log phase growth rates. At various concentrations of the inhibitor, 50 to 100% of the activity of corn extracts inhibitory to different bacterial isolates was attributable to DIMBOA. Extracts of DIMBOA-deficient plants (genotype bxbx) were not inhibitory to Erwinia spp. It was concluded that DIMBOA is the major active component in those corn extracts which are inhibitory to soft rot Erwinia species.


Acoustic vector sensor beamforming reduces masking from underwater industrial noise during passive monitoring.
Masking from industrial noise can hamper the ability to detect marine mammal sounds near industrial operations, whenever conventional (pressure sensor) hydrophones are used for passive acoustic monitoring. Using data collected from an autonomous recorder with directional capabilities (Directional Autonomous Seafloor Acoustic Recorder), deployed 4.1 km from an arctic drilling site in 2012, the authors demonstrate how conventional beamforming on an acoustic vector sensor can be used to suppress noise arriving from a narrow sector of geographic azimuths. Improvements in signal-to-noise ratio of up to 15 dB are demonstrated on bowhead whale calls, which were otherwise undetectable using conventional hydrophones.


SB365, Pulsatilla saponin D, suppresses the growth of gefitinib-resistant NSCLC cells with Met amplification.
Clinical treatment using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib or erlotinib has been applied in patients with non-small cell lung cancers (NSCLCs). Unfortunately, acquired drug resistance emerges in these patients due to the amplification of the Met proto-oncogene, which may be a compensatory mechanism of NSCLCs against EGFR inhibition. To overcome this resistance, identification of new small-molecule natural compounds is crucial for cancer therapeutics. In this regard, SB365, saponin D from the root of Pulsatilla koreana which has been used as a traditional medicine in Korea for several diseases, has attracted wide interest. In the present study, SB365 effectively suppressed the proliferation of gefitinib-resistant HCC827GR NSCLC cells with Met amplification. Notably, our data revealed that SB365 inhibited the phosphorylation of Met and the downstream signaling pathway required for growth and survival in the Met-amplified HCC827GR cells. Moreover, SB365 suppressed the anchorage-independent growth, migration and invasion along with induction of apoptosis in the HCC827GR cells. Therefore, these results suggest that SB365 is good candidate as a natural product for use in the treatment of Met-amplified NSCLCs.


S100B Impairs Oligodendrogenesis and Myelin Repair Following Demyelination Through RAGE Engagement.
Increased expression of S100B and its specific receptor for advanced glycation end products (RAGE) has been described in patients with multiple sclerosis (MS), being associated with an active demyelinating process. We previously showed that a direct neutralization of S100B reduces lysophosphatidylcholine (LPC)-induced demyelination and inflammation using an ex vivo demyelinating model. However, whether S100B actions occur through RAGE and how oligodendrogenesis and remyelination are affected are not clarified. To evaluate the role of the S100B-RAGE axis in the course of a demyelinating insult, organotypic cerebellar slice cultures (OCSC) were demyelinated with LPC in the presence or absence of RAGE antagonist FPS-ZM1. Then, we explored the effects of the S100B-RAGE axis inhibition on glia reactivity and inflammation, myelination and neuronal integrity, and on oligodendrogenesis and remyelination. In the present study, we confirmed that LPC-induced demyelination increased S100B and RAGE expression, while RAGE antagonist FPS-ZM1 markedly reduced their content and altered RAGE cellular localization. Furthermore, FPS-ZM1 prevented LPC-induced microgliosis and astrogliosis, as well as NF-κB activation and pro-inflammatory cytokine gene expression. In addition, RAGE antagonist reduced LPC-induced demyelination having a beneficial effect on axonal and synaptic protein preservation. We have also observed that RAGE engagement is needed for LPC-induced oligodendrocyte (OL) maturation arrest and loss of mature myelinating OL, with these phenomena being prevented by FPS-ZM1. Our data suggest that increased levels of mature OL in the presence of FPS-ZM1 are related to increased expression of microRNAs (miRs) associated with OL differentiation and remyelination, such as miR-23a, miR-219a, and miR-338, which are defective upon LPC incubation. Finally, our electron microscopy data show that inhibition of the S100B-RAGE axis prevents axonal damage and myelin loss, in parallel with enhanced functional remyelination, as observed by the presence of thinner myelin sheaths when compared with Control. Overall, our data implicate the S100B-RAGE axis in the extent of myelin and neuronal damage, as well as in the inflammatory response that follows a demyelinating insult. Thus, prevention of RAGE engagement may represent a novel strategy for promoting not only inflammatory reduction but also neuronal and myelin preservation and/or remyelination, improving recovery in a demyelinating condition as MS.


P-loop flexibility in Na+ channel pores revealed by single- and double-cysteine replacements.
Replacement of individual P-loop residues with cysteines in rat skeletal muscle Na+ channels (SkM1) caused an increased sensitivity to current blockade by Cd2+ thus allowing detection of residues lining the pore. Simultaneous replacement of two residues in distinct P-loops created channels with enhanced and reduced sensitivity to Cd2+ block relative to the individual single mutants, suggesting coordinated Cd2+ binding and cross-linking by the inserted sulfhydryl pairs. Double-mutant channels with reduced sensitivity to Cd2+ block showed enhanced sensitivity after the application of sulfhydryl reducing agents. These results allow identification of residue pairs capable of approaching one another to within less than 3.5 A. We often observed that multiple consecutive adjacent residues in one P-loop could coordinately bind Cd2+ with a single residue in another P-loop. These results suggest that, on the time-scale of Cd2+ binding to mutant Na+ channels, P-loops show a high degree of flexibility.


Household health expenditures in Morocco: implications for health care reform.
The purpose of this study was to investigate the level and distribution of household health care expenditures in Morocco, and to compare the level of health care funds provided by households with the levels provided by the government and international donors. In addition, the reliance of poor and non-poor households on both public and private providers was investigated. The study was based on data collected in the 1995 Demographic and Health Survey, which included a special supplement on health care expenditures. Descriptive statistics are presented on utilization of out-of-pocket expenditures for antenatal and obstetric care, chronic care, and non-chronic care associated with illness and injury, by urban/rural status and by socio-economic status. The results indicate that government health care providers are an important source of modern health care not only for poor households, but for better-off households as well. While individuals who use private health care providers incur substantially higher costs than those who use public providers, an unexpected finding of the study is the degree to which public clients pay for health care services, despite the fact that public care is nominally priced in Morocco. We conclude by discussing the implications of our results on the design and implementation of health care reform policies.


Identification of a Novel Mutation in SASH1 Gene in a Chinese Family With Dyschromatosis Universalis Hereditaria and Genotype-Phenotype Correlation Analysis.
Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by mottled hyperpigmented and hypopigmented macules. SASH1 and ABCB6 have been identified as the causative genes for this disorder. We performed whole exome sequencing on a Chinese family with DUH and genotype-phenotype correlation analysis in DUH and lentiginous phenotype patients. A novel heterozygous missense mutation p.Q518P in SASH1 gene was detected in this family. A majority of patients with SASH1 mutations presented as a distinct clinical phenotype clearly different from that in patients with ABCB6 mutations. Our findings further enrich the reservoir of SASH1 mutations in DUH. The clinical phenotypic difference between SASH1 and ABCB6 variants is suggestive of a close phenotype-genotype link in DUH.


Early humoral defence: Contributing to confining COVID-19 to conducting airways?
Early airway responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are of interest since they could decide whether coronavirus disease-19 (COVID-19) will proceed to life-threatening pulmonary disease stages. Here I discuss endothelial-epithelial co-operative in vivo responses producing first-line, humoral innate defence opportunities in human airways. The pseudostratified epithelium of human nasal and tracheobronchial airways are prime sites of exposure and infection by SARS-CoV-2. Just beneath the epithelium runs a profuse systemic microcirculation. Its post-capillary venules respond conspicuously to mucosal challenges with autacoids, allergens and microbes, and to mere loss of epithelium. By active venular endothelial gap formation, followed by transient yielding of epithelial junctions, non-sieved plasma macromolecules move from the microcirculation to the mucosal surface. Hence, plasma-derived protein cascade systems and antimicrobial peptides would have opportunity to operate jointly on an unperturbed mucosal lining. Similarly, a plasma-derived, dynamic gel protects sites of epithelial sloughing-regeneration. Precision for this indiscriminate humoral molecular response lies in restricted location and well-regulated duration of plasma exudation. Importantly, the endothelial responsiveness of the airway microcirculation differs distinctly from the relatively non-responsive, low-pressure pulmonary microcirculation that non-specifically, almost irreversibly, leaks plasma in life-threatening COVID-19. Observations in humans of infections with rhinovirus, coronavirus 229E, and influenza A and B support a general but individually variable early occurrence of plasma exudation in human infected nasal and tracheobronchial airways. Investigations are warranted to elucidate roles of host- and drug-induced airway plasma exudation in restriction of viral infection and, specifically, whether it contributes to variable disease responses following exposure to SARS-CoV-2.


B-flow evaluation of carotid arterial stenosis: initial experience.
In this prospective pilot trial, B-flow ultrasonographic (US) imaging was compared with color duplex flow US in the evaluation of internal carotid arterial stenosis. Despite almost excellent interobserver variability, none of the investigated B-flow imaging parameters correlated with those of duplex US. In conclusion, the investigated B-flow imaging parameters cannot be used in evaluating internal carotid arterial stenosis.


Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates.
Differential scanning calorimetry and powder X-ray diffraction studies have been carried out with amorphous coprecipitates of indomethacin and poly(vinylpyrrolidone), PVP, to measure the glass transition temperature, Tg, as a function of mixture composition and the nonisothermal and isothermal crystallization of the indomethacin. Values of Tg as a function of mixture composition followed the ideal Gordon-Taylor equation up to about 50% w/w PVP. Inhibition of crystallization occurred at levels as low as 5% PVP and very significant inhibition was observed at and above 20% PVP. Inhibition of crystallization of indomethacin in the absence of PVP required a storage temperature 40-50 degrees C below Tg, whereas comparable inhibition with PVP was observed at storage temperatures 5 degrees C above Tg. This suggests that the inhibition of indomethacin crystallization by PVP may involve mechanisms other than just the general antiplasticizing effect (raising Tg) by PVP.


Sleep characteristics and parameters of bone turnover and strength in the adult population: results from the Study of Health in Pomerania-TREND.
Poor sleep quality or sleep deprivation may be related to decreased bone mineral density. We aimed to assess whether associations of sleep characteristics and bone turnover or strength are present in adults from the general population and whether these are independent of common risk factors such as sex, age, and obesity. A total of 1037 participants from the Study of Health in Pomerania-TREND underwent laboratory-based polysomnography and quantitative ultrasound measurements at the heel. Of these participants, 804 completed standardised questionnaires to assess daytime sleepiness, insomnia, and sleep quality. Serum concentrations of two bone turnover markers, intact amino-terminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal telopeptide of type 1 collagen (CTX) were measured. Cross-sectional associations of polysomnography variables (total sleep time, sleep efficiency, time spent wake after sleep onset, oxygen desaturation index, apnea-hypopnea index, and obstructive sleep apnea [OSA]), as well as sleep questionnaire scores with the bone turnover markers and the ultrasound-based stiffness index were assessed in linear regression models. In adjusted models, higher insomnia scores and lower sleep quality scores were related to a higher bone turnover in women but not in men. However, associations between polysomnography variables or questionnaire scores and the stiffness index were absent. Our study provides limited evidence for relationships between sleep characteristics and bone turnover and strength independent of common risk factors for OSA and osteoporosis. Nevertheless, women reporting poor sleep or insomnia in combination with risk factors for osteoporosis might benefit from an evaluation of bone health.


Application of dynamic time warping algorithm for pattern similarity of gait.
The purpose of this study was to investigate the effectiveness of dynamic time warping (DTW) in gait research. Participants in this study were consist of 10 males and 10 females. Equipment used for collecting the gait data of participants in this study was three-dimensional (3D) motion analysis system consisted of 8 infrared CCD cameras operated with a sampling frequency of 120 frames/sec. DTW program used in this study was made using the MATLAB and the normal operation of the DTW program was verified by comparison of result manually calculated and output by the DTW program. Flexion angle of the knee joint of both feet obtained by 3D motion analysis system was analyzed by the DTW program and symmetry index (SI) equation. Statistical analysis of the values obtained by DTW was performed by one-sample t-test in confidence interval (CI) 99%, 95%, 90%, 85%, and 80% each using the SPSS. The subjects' left and right legs were compared 20 times, and other steps of the same foot were compared 20 times. In this study, DTW showed different results from SI which is generally used to test the similarity of gait. Compared to that of DTW, the threshold figure for similarity evaluation in SI, 10%, is considered too large/high. When the CI threshold figure of 95% was adopted in statistical analysis, DTW demonstrated a lower rate of judging two sequences as similar even in the case of normal gait. This study suggests that DTW can be used for the similarity test of gait research.


Effects of different regimens of iron prophylaxis on maternal iron status and pregnancy outcome: a randomized control trial.
Iron supplementation is associated with side effects and overload risk. We compared different regimens of iron supplementation on maternal hematological status and pregnancy outcome in a cohort of healthy pregnant women. Eighty non-anemic women with a normal singleton pregnancy were recruited at 11-13 weeks and randomized into controls (C; n = 20) and groups supplemented with ferrous iron 30 mg (FI; n = 20), liposomal iron 14 mg (Sideral® Pharmanutra, Pisa PI, Italy) (LI14; n = 20) and liposomal iron 28 mg/daily (LI28; n = 20) up to 6 weeks post-partum. Longitudinal maternal blood samples for iron markers were collected. Data on birth outcome were recorded. The treatment effect was evaluated using a mixed-effect regression model. Both LI28 and LI14 groups showed significantly higher hemoglobin and ferritin concentrations compared with controls. Birth weight showed a trend to increase with supplementation, resulting in higher birth weight in the LI28 group compared with controls (3499 ± 464.1 g and 3092 ± 469.5 g, respectively, p < 0.01). Our data show the effectiveness of 28 mg and 14 mg LI on maternal anemia prevention, as previously reported with FI 40 mg. LI has similar effects of higher doses of ferrous iron on maternal hematological parameters, thus allowing to reduce iron doses and side effects.


Bangladeshis in London: a challenge to welfare.
"Immigrants of Bangladeshi origin living in Britain are a relatively small part of the population from the New Commonwealth. They are, however, highly distinctive, particularly in their degree of residential concentration within parts of inner London. The paper has two aims: first, using 1981 census data, to plot immigrant distribution within a national and London-wide context; second, to explore some of the implications of this concentration for the provision of welfare services, particularly health, within one of the city's most deprived boroughs." (SUMMARY IN FRE AND SPA)


Γ-glutamyltransferase, hepatic enzymes, and risk of incident heart failure in older men.
The relationship between γ-glutamyl transferase (GGT) and heart failure (HF) in older adults is unknown. We have examined the relationship between GGT, other markers of hepatic function (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase), and incident HF in older men. This was a prospective study of 3494 men aged 60 to 79 years with no diagnosed HF or myocardial infarction followed up for a mean period of 9 years, in whom there were 168 incident HF cases. Elevated GGT (top quartile, ≥38 U/L) was associated with significantly increased risk of incident HF in men aged<70 years but not in men aged≥70 years (test for age-GGT interaction, P<0.0001). The increased risk of HF associated with elevated GGT persisted after adjustment for a wide range of established and novel risk factors for HF, including diabetes, stroke, obesity, systolic blood pressure, atrial fibrillation, lung function, inflammation (C-reactive protein), endothelial dysfunction (von Willebrand factor), leptin, and N terminal pro brain natriuretic peptide (adjusted hazard ratio [95% CI], 1.91 [1.07, 3.42]). Other liver function markers showed no significant associations with HF after similar adjustments. Elevated GGT was associated with increased risk of HF in men aged<70 years. Additional studies are now needed to determine the mechanisms responsible.


Preparation, Supramolecular Organization, and On-Surface Reactivity of Enantiopure Subphthalocyanines: From Bulk to 2D-Polymerization.
The development of chiral materials is severely limited by the challenge to achieve enantiopure derivatives with both configurational stability and good optoelectronic properties. Herein we demonstrate that enantiopure subphthalocyanines (SubPcs) fulfill such demanding requirements and bear the prospect of becoming components of chiral technologies. Particularly, we describe the synthesis of enantiopure SubPcs and assess the impact of chirality on aspects as fundamental as the supramolecular organization, the behavior in contact with metallic surfaces, and the on-surface reactivity and polymerization. We find that enantiopure SubPcs remarkably tend to organize in columnar polar assemblies at the solid state and highly ordered chiral superstructures on Au(111) surfaces. At the metal interface, such SubPcs are singled out by scanning tunneling microscopy. DFT calculations suggest that SubPcs undergo a bowl-to-bowl inversion that was shown to be dependent on the axial substituent. Finally, we polymerize by means of on-surface synthesis a highly regular 2D, porous and chiral, π-extended polymer that paves the way to future nanodevice fabrication.


Some statistical analysis issues at the World Fertility Survey.
"The World Fertility Survey carried out cross-sectional probability surveys of fertility in more than 40 developing countries between 1972 and 1984. Statistical issues in regression analysis of the data are reviewed, including treatment of interactions, the selection of regressor variables, and appropriate linear models for rate variables. Similar issues arise in many other applications of regression to observational data."


Electrically-Responsive Reversible Polyketone/MWCNT Network through Diels-Alder Chemistry.
This study examines the preparation of electrically conductive polymer networks based on furan-functionalised polyketone (PK-Fu) doped with multi-walled carbon nanotubes (MWCNTs) and reversibly crosslinked with bis-maleimide (B-Ma) via Diels-Alder (DA) cycloaddition. Notably, the incorporation of 5 wt.% of MWCNTs results in an increased modulus of the material, and makes it thermally and electrically conductive. Analysis by X-ray photoelectron spectroscopy indicates that MWCNTs, due to their diene/dienophile character, covalently interact with the matrix via DA reaction, leading to effective interfacial adhesion between the components. Raman spectroscopy points to a more effective graphitic ordering of MWCNTs after reaction with PK-Fu and B-Ma. After crosslinking the obtained composite via the DA reaction, the softening point (tan(δ) in dynamic mechanical analysis measurements) increases up to 155 °C, as compared to the value of 130 °C for the PK-Fu crosslinked with B-Ma and that of 140 °C for the PK-Fu/B-Ma/MWCNT nanocomposite before resistive heating (responsible for crosslinking). After grinding the composite, compression moulding (150 °C/40 bar) activates the retro-DA process that disrupts the network, allowing it to be reshaped as a thermoplastic. A subsequent process of annealing via resistive heating demonstrates the possibility of reconnecting the decoupled DA linkages, thus providing the PK networks with the same thermal, mechanical, and electrical properties as the crosslinked pristine systems.


Correction of severe vertical maxillary excess with anterior open bite and transverse maxillary deficiency.
Patients requiring correction of large anterior open bites have historically been among the most challenging treatments for orthodontists. Adding to that fundamental challenge for the adult patient in this case was vertical maxillary excess, a severe transverse maxillary deficiency as well as an arch length inadequacy, even though the patient had prior orthodontic treatment. The prior orthodontist had included arch expansion and extracted four first bicuspids, which limited current treatment options. Various treatment modalities that have traditionally been used to correct transverse maxillary deficiency and the accompanying arch length inadequacy include extractions, labial and buccal dental tipping, segmental maxillary osteotomies, and rapid maxillary expansion with or without surgical assistance. Transverse maxillary distraction osteogenesis is a modification (ie, using a latency period and specific rate and rhythm of distraction) of the surgically assisted rapid maxillary expansion technique developed 25 years ago. This case demonstrates the relationship of transverse maxillary deficiency as well as vertical maxillary excess to apertognathia. Considerations regarding the use of segmental maxillary osteotomy vs transverse distraction osteogenesis are discussed. This case report illustrates the benefit of a team approach using transverse maxillary distraction osteogenesis, effective orthodontic mechanics, and orthognathic surgery to correct a severe dentofacial deformity.


Positive effect of FSH but not LH on early development of the dominant follicle in mares.
The effects of FSH, LH or both on follicular growth and intrafollicular free insulin-like growth factor (IGF)-1 and oestradiol were investigated in mares after the beginning of deviation (largest follicle >/= 20 mm; Hour 0). A single treatment with a gonadotropin-releasing hormone antagonist (acyline) was given at Hour 3 to suppress the concentrations of FSH and LH. Five groups (n = 5 mares per group) were evaluated in the present study: (1) control; (2) acyline treated; (3) acyline + recombinant equine (re) FSH treated; (4) acyline + reLH treated; and (5) combined acyline + reFSH + reLH treated. Beginning at Hour 3, reFSH and reLH were given at 6-h intervals in eight decreasing or increasing doses, respectively. The reFSH and reLH prevented the acyline-induced decreases in FSH and LH, respectively. Diameters and concentrations of intrafollicular free IGF-1 and oestradiol of the two largest follicles at Hour 48 did not differ significantly between the control and acyline + FSH groups, but were reduced (P < 0.05) similarly in the acyline and acyline + LH groups. The combination of reFSH and reLH was no more effective than reFSH alone. The results demonstrate a role for FSH but not LH in the growth of the largest follicle and intrafollicular concentrations of free IGF-1 and oestradiol during the 48 h after the beginning of deviation in mares.


Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer.
Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5β1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.


Kinect-Assisted Performance-Sensitive Upper Limb Exercise Platform for Post-stroke Survivors.
One's ability to use upper limbs is critical for performing activities of daily living necessary for enjoying quality community life. However, after stroke, such abilities becomes adversely affected and it often deprives one of their capability to perform tasks that need coordinated movement in the upper limbs. To address issues with upper limb dysfunction, patients typically undergo rehabilitative exercises. Given the high patient to doctor ratio particularly in developing countries like India, conventional rehabilitation with patients undergoing exercises under one-on-one therapist's supervision often becomes a challenge. Thus, investigators are exploring technology such as computer-based platforms coupled with cameras that can alleviate the need for the continuous presence of a therapist and can offer a powerful complementary tool in the hands of the clinicians. Such marker-based imaging systems used for rehabilitation can offer real-time processing and high accuracy of data. However, these systems often require dedicated lab space and high set-up time. Often this is very expensive and suffers from portability issues. Investigators have been exploring marker-less imaging techniques e.g., Kinect integrated computer-based graphical user interfaces in stroke-rehabilitation such as tracking one's limb movement during rehabilitation. In our present study, we have developed a Kinect-assisted computer-based system that offered Human Computer Interaction (HCI) tasks of varying challenge levels. Execution of the tasks required one to use reaching and coordination skills of the upper limbs. Also, the system was Performance-sensitive i.e., adaptive to the individualized residual movement ability of one's upper limb quantified in terms of task performance score. We tested for the usability of our system by exposing 15 healthy participants to our system. Subsequently, seven post-stroke patients interacted with our system over a few sessions spread over 2 weeks. Also, we studied patient's mean tonic activity corresponding to the HCI tasks as a possible indicator of one's post-stroke functional recovery suggesting its potential of our system to serve as a rehabilitation platform. Our results indicate the potential of such systems toward the improvement of task performance capability of post-stroke patients with possibilities of upper limb movement rehabilitation.


Cognitive and Emotion Regulation Change Processes in Cognitive Behavioural Therapy for Social Anxiety Disorder.
The objective of the study was to investigate variables, derived from both cognitive and emotion regulation conceptualizations of social anxiety disorder (SAD), as possible change processes in cognitive behaviour therapy (CBT) for SAD. Several proposed change processes were investigated: estimated probability, estimated cost, safety behaviours, acceptance of emotions, cognitive reappraisal and expressive suppression. Participants were 50 patients with SAD, receiving a standard manualized CBT program, conducted in groups or individually. All variables were measured pre-therapy, mid-therapy and post-therapy. Lower level mediation models revealed that while a change in most process measures significantly predicted clinical improvement, only changes in estimated probability and cost and acceptance of emotions showed significant indirect effects of CBT for SAD. The results are in accordance with previous studies supporting the mediating role of changes in cognitive distortions in CBT for SAD. In addition, acceptance of emotions may also be a critical component to clinical improvement in SAD during CBT, although more research is needed on which elements of acceptance are most helpful for individuals with SAD. The study's lack of a control condition limits any conclusion regarding the specificity of the findings to CBT. Change in estimated probability and cost, and acceptance of emotions showed an indirect effect of CBT for SAD. Cognitive distortions appear relevant to target with cognitive restructuring techniques. Finding acceptance to have an indirect effect could be interpreted as support for contemporary CBT approaches that include acceptance-based strategies.


Efficacy of peritubal local anesthetic infiltration in alleviating postoperative pain in percutaneous nephrolithotomy.
Percutaneous nephrolithotomy (PCNL) is a safe and effective endourologic procedure in patients with renal calculi. It is less morbid than open surgery. However, the patient complains of pain around the nephrostomy tube and demands for good postoperative analgesia. Skin infiltration with bupivacaine around the nephrostomy tube is not effective, so we hypothesize that peritubal infiltration of bupivacaine from renal capsule to the skin along the nephrostomy tract may alleviate postoperative pain. A randomized controlled study was designed in 40 American Society of Anesthesiologists (ASA) grade I patients to assess the impact of peritubal bupivacaine infiltration with 23-gauge spinal needle along the nephrostomy tract after PCNL under fluoroscopic guidance. Patients were randomized to receive 20 mL of 0.25% bupivacaine in block group (n = 20) or no infiltration in control group (n = 20) at the conclusion of the procedure. Postoperative pain score and analgesic requirement for the first 24 hours were assessed by visual and dynamic visual analog scales second hourly. Rescue analgesia with injection tramadol Hcl 50-100 mg was given intravenously to a maximum total dose of 400 mg when pain score exceeded 4. Pain scores and analgesic requirement for the first 24 hours postoperatively were significantly lesser in the block group than in the control group of patients at all points of time and were statistically significant (p < 0.005). In this study a significant difference in the pain scores and analgesic requirement was noted in the two groups of patients. Peritubal infiltration of 0.25% bupivacaine solution is efficient in alleviating postoperative pain after PCNL.


Hybrid optimization model for conjunctive use of surface and groundwater resources in water deficit irrigation system.
The increasing demand for food production with limited available water resources poses a threat to agricultural activities. Conventional optimization algorithms increase the processing stage and perform in the space allocated from user. Therefore, the proposed work was used to design better performance results. The conjunctive allocation of water resources maximizes the net benefit of farmers. In this study, the novel hybrid optimization model developed is the first of its kind and was designed to resolve the sharing of water resource conflict among different reaches based on a genetic algorithm (GA), bacterial foraging optimization (BFO) and ant colony optimization (ACO) to maximize the net benefit of the water deficit in Sathanur reservoir command. The GA-based optimization model considered crop-related physical and economic parameters to derive optimal cropping patterns for three different conjunctive use policies and further allocation of surface and groundwater for different crops are enhanced with the BFO. The allocation of surface and groundwater for the head, middle and tail reaches obtained from the BFO is considered as an input to the ACO as a guiding mechanism to attain an optimal cropping pattern. Comparing the average productivity values, policy 3 (3.665 Rs/m3) has better values relating to policy 1 (3.662 Rs/m3) and policy 2 (3.440 Rs/m3). Thus, the developed novel hybrid optimization model (GA-BFO-ACO) is very promising for enhancing farmer's net income and can be replicated in other irrigated regions to overcome chronic water problems. The productivity value of policy 3 was 6.54% greater than that of policy 2, whereas that of policy 1 was 6.45% greater. Overall, the comparison shows that the better performance analysis of various optimization was done successfully.


Enantioselective assay of nimodipine in human plasma using liquid chromatography-tandem mass spectrometry.
Nimodipine is a dihydropyridine calcium channel blocker that exhibits higher selectivity toward cerebral blood vessels compared with other members of the same class. It has been shown to improve outcomes and prevent delayed cerebral ischemia in the setting of aneurysmal subarachnoid hemorrhage, a life-threatening brain bleed. Nimodipine is a chiral compound and it is marketed as a racemic mixture of (+)-R and (-)-S enantiomers. (-)-S-Nimodipine is approximately twice as potent a vasorelaxant as the racemic mixture and is more rapidly eliminated than the (+)-R counterpart following oral dosing. Few analytical procedures have been reported to determine nimodipine enantiomers in biological samples; however, the reported methods were time-consuming, involved multistep extraction procedures and required large sample volumes. Herein, we present an LC-MS/MS method for quantifying nimodipine enantiomers in human plasma using a small sample volume (0.3 ml) and a single liquid-liquid extraction step. The peak area ratios were linear over the tested concentration ranges (1.5-75 ng/ml) with r2 > 0.99. The intraday CV and percentage error were within ±14% while the interday values were within ±13%, making this analytical method feasible for research purposes and pharmacokinetic studies.


[The progress of morphological research on the parabrachial nucleus].
In this paper, the progress of morphological research on the PBN, the cytoarchitecture of the PBN, and the fiber connections between the PBN and the spinal, the brainstem, the forebrain and the other nucleus were summarized. Its function in the relationship between the meridian and the internal organ was also assumed.