Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas.
Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1-21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.


Branched germline cysts and female-specific cyst fragmentation facilitate oocyte determination in mice.
During mouse gametogenesis, germ cells derived from the same progenitor are connected via intercellular bridges forming germline cysts, within which asymmetrical or symmetrical cell fate occurs in female and male germ cells, respectively. Here, we have identified branched cyst structures in mice, and investigated their formation and function in oocyte determination. In fetal female cysts, 16.8% of the germ cells are connected by three or four bridges, namely branching germ cells. These germ cells are preferentially protected from cell death and cyst fragmentation and accumulate cytoplasm and organelles from sister germ cells to become primary oocytes. Changes in cyst structure and differential cell volumes among cyst germ cells suggest that cytoplasmic transport in germline cysts is conducted in a directional manner, in which cellular content is first transported locally between peripheral germ cells and further enriched in branching germ cells, a process causing selective germ cell loss in cysts. Cyst fragmentation occurs extensively in female cysts, but not in male cysts. Male cysts in fetal and adult testes have branched cyst structures, without differential cell fates between germ cells. During fetal cyst formation, E-cadherin (E-cad) junctions between germ cells position intercellular bridges to form branched cysts. Disrupted junction formation in E-cad-depleted cysts led to an altered ratio in branched cysts. Germ cell-specific E-cad knockout resulted in reductions in primary oocyte number and oocyte size. These findings shed light on how oocyte fate is determined within mouse germline cysts.


Molecular parameters indicating adaptation to mechanical stress in fibrous connective tissue.
The present study pursues the hypothesis that local compressive force and the occurrence of cartilage-specific transformation processes within the extracellular matrix of tendons and ligaments are directly correlated. We compare the pattern of certain marker molecules typical of (fibro)cartilage in select examples. Investigations are carried out of the extensor tendons of toes and fingers, the transverse ligament of the atlas, the transverse ligament of the acetabulum, and of the tendon of the superior oblique muscle and its trochlea. The marker molecules are detected with standardized immunohistochemical methods. The results show that certain molecules only occur under conditions of (relatively high) compressive stress, others being the result of tensile stress. The molecular spectrum of the molecules of the ECM allows qualifying conclusions as to the mechanical situation of a given part of the tissue. A quantifying statement about the intensity of compressive stress is not possible to make thus far, but the extension of the restructuring areas corresponds to the area of compressive stress. Depending on the intensity and duration of the local compressive strain, the molecules involved may be ordered chronologically according to their occurrence in the ECM. The glycosaminoglycans react at lower stress levels than the proteoglycans, which in turn react earlier than the collagens, especially with regard to the vanishing of type I collagen and the first occurrence of type II collagen. Of the glycosaminoglycans, dermatan sulfate and keratan sulfate occur first. These are detectable in virtually all cases. They are followed by chondroitin 4 sulfate. The last glycosaminoglycan, which occurs in already significantly fibrocartilaginous tissue, is chondroitin 6 sulfate. Under chronologically intensifying compressive stress in the increasingly fibrocartilaginous tissues, the proteoglycans versican and, to a lesser extent, tenascin--characteristic markers of fibrous tissue--can still be detected. However, their spatial expansion steadily decreases until they finally vanish. Contrastingly, aggrecan and link protein expression becomes increasingly prominent in such tissues. The spatial expansion of the adaptation zones in tendons and ligaments roughly corresponds with the zones subjected to compressive force; tensile stress alone does not result in a production of fibrocartilage. The questions asked at the beginning may thus be answered as follows: The molecular composition of the various fibrous connective tissues, such as tendons and ligaments, can be directly correlated with the respective tissue's mechanical function. As an expression of this regular interrelation, a ranking of certain ECM molecules may be set up that corresponds to the type, intensity, and duration of the mechanical stress. Grounded on this, it seems possible to prognosticate the occurrence of certain components in the ECM depending on the nature of the mechanical stress. The occurrence of certain molecules within the fibrocartilaginous tissue is of clinical importance in connection with various forms of rheumatoid arthritis and perhaps other diseases with an autoimmune-related etiology. Since a considerable part of the inflammatory destructions involved may at least indirectly result from autoimmune processes directed against the cartilage-type components of the ECM, every fibrocartilage constitutes a potential target to a certain degree. This applies particularly to those fibrocartilages whose ECM has a molecular composition closely resembling that of hyaline articular cartilage. Therefore, knowledge of the regional molecular composition allows a prediction of sites where clinical symptoms may occur in the course of rheumatoid arthritis.


Architecture and consequent physiological properties of the semitendinosus muscle in domestic goats.
Morphological and physiological analyses confirm that the semitendinosus muscle of goats contains two separate compartments in series, each with distinct innervation. These compartments of the muscle are in turn composed of short fibers (approximately four fibers in series in the proximal compartment and seven to eight fibers in the distal compartment) which overlap each other for more than 30% of their length, with much of the overlapping portions consisting of slender tails that terminate at one-tenth of the midfiber diameter. Groups of fibers are associated into relatively narrow bands that run end-to-end in each compartment. The data suggest that the maximum length of muscle fibers may be limited; even the fibers of parallel-fibered muscles may not scale with the dimension of the animal.


Effect of apical root resection, orthodontic extrusion, and surgical crown lengthening on load capability.
This study aims to investigate the load-to-fracture of procedures changing crown-to-root ratio (RCRR) aimed to restore severely damaged upper central incisors to avoid tooth extraction compared to implant placement. There is no evidence on load capability after apical root resection (AR), orthodontic extrusion (OE), and surgical crown lengthening (SCL) in respect to RCRR, respectively. Human maxillary central incisors were endodontically treated, decoronated, and divided into 4 groups (n = 48). The following specimen preparation was performed: (I) adhesive core-and-post build-up (control), (II) as (I) and 2 mm apical root resection (AR), (III) before adhesive core-and-post build-up teeth were shortened 2 mm coronally (OE) (IV) as (I), but specimens were embedded 4 mm instead of 2 mm below the CEJ (SCL), group (V) implant-borne restoration with individual all-ceramic abutments (n = 12; ∅4.1/l = 12 mm) (IBR). All specimens received all-ceramic crowns, thermo-mechanical (TML), and subsequent linear loading (LL) until failure. RCRR were calculated and log-rank, Kruskal-Wallis, Mann-Whitney U, ANOVA, and chi-square tests applied (p = 0.05). Fracture loads after subsequent LL differed significantly (p = 0.001) between groups, while implants showed the highest values. Fmax median (min/max) were as follows: (I) 252 (204/542), (II) 293 (243/443), (III) 253 (183/371), (IV) 195 (140/274), and (V) 446 (370/539). Pair-wise comparison showed significant differences (p = 0.001) between group I/IV and group V, I, and IV (p = 0.045), II and IV (p = 0.001), and III compared to IV (p = 0.033), respectively. RCRR below 1 significantly increased load capability compared to RCRR = 1. OE appears to preferably ensure biomechanical stability of teeth that are endodontically treated and receive core-and-post and crown placement compared to SCL. AR has no adverse biomechanical impact. RCRR < 1 is biomechanically beneficial. For endodontically treated and restored teeth, orthodontic extrusion should be preferred compared to surgical crown lengthening prior single-crown restoration. As orthodontic extrusion, apical root resection has no adverse effect on load capability. Single-crown implant-borne restorations are most load capable.


Application of a two-stage temperature control strategy for enhanced glutathione production in the batch fermentation by Candida utilis.
In batch culture for glutathione production with Candida utilis, a higher temperature (30 degrees C) was required to hasten cell growth while a lower temperature (26 degrees C) was needed to increase the production of glutathione. A two-stage temperature control strategy was used to enhance both the yield and the productivity of glutathione. As a result, glutathione production was increased by 5% and 23% of that at 26 degrees C and 30 degrees C, respectively, and the intracellular glutathione content reached 2.5% (w/w).


Short and long-term outcomes after esophagectomy for cancer in elderly patients.
As worldwide life expectancy rises, the number of candidates for surgical treatment of esophageal cancer over 70 years will increase. This study aims to examine outcomes after esophagectomy in elderly patients. This study is a retrospective review of 474 patients undergoing esophagectomy for cancer during 2002 to 2011. A total of 334 (70.5%) patients were less than 70 years old (group A), 124 (26.2%) 70 to 79 years (group B), and 16 (3.4%) 80 years or greater (group C). We analyzed the effect of age on outcome variables including overall and disease specific survival. Major morbidity was observed to occur in 115 (35.6%) patients of group A, 58 (47.9%) of group B, and 10 (62.5%) of group C (p = 0.010). Mortality, both 30-day and 90-day was observed in 2 (0.6%) and 7 (2.2%) of group A, 4 (3.2%) and 7 (6.1%) of group B, and 1 (6.3%) and 2 (14.3%) of group C, respectively (p = 0.032 and p = 0.013). Anastomotic leak was observed in 16 (4.8%) patients of group A, 6 (4.8%) of group B, and 0 (0%) of group C (p = 0.685). Anastomotic stricture (defined by the need for ≥ 2 dilations) was observed in 76 (22.8%) of group A, 13 (10.5%) of group B, and 1 (6.3%) of group C (p = 0.005). Five-year overall and disease specific survival was 64.8% and 72.4% for group A, 41.7% and 53.4% for group B, 49.2% and 49.2% for group C patients (p = 0.0006), respectively. Esophagectomy should be carefully considered in patients 70 to 79 years old and can be justified with low mortality. Outcomes in octogenarians are worse suggesting esophagectomy be considered on a case by case basis. Stricture rate is inversely associated to age.


Progress and pitfalls: bipolar molecular linkage studies.
This paper reviews the history of molecular genetic linkage studies of bipolar disorder. The topic is introduced with a brief discussion of various genetic concepts, including linkage, lod scores and non-parametric statistics. It is emphasized that criteria for declaring linkage must include independent confirmation by a second group of investigators. Given that the inherited susceptibility for bipolar disorder is most likely explained by multiple genes of small effect, simulations indicate that universal confirmation of valid linkages cannot be expected. With this background, several valid linkages of BP disorder to genomic regions are reviewed. These valid linkages include 18p11, 18q22, 21q21, Xq26 and 4pter. The issue of anticipation and expanding triplet repeats is discussed. Finally, there is a brief section on recommendations for future genetic linkage studies of bipolar disorder.


Parameterization of magnetic vector potentials and fields for efficient multislice calculations of elastic electron scattering.
The multislice method, which simulates the propagation of the incident electron wavefunction through a crystal, is a well established method for analysing the multiple scattering effects that an electron beam may undergo. The inclusion of magnetic effects into this method proves crucial towards simulating enhanced magnetic interaction of vortex beams with magnetic materials, calculating magnetic Bragg spots or searching for magnon signatures, to name a few examples. Inclusion of magnetism poses novel challenges to the efficiency of the multislice method for larger systems, especially regarding the consistent computation of magnetic vector potentials A and magnetic fields B over large supercells. This work presents a tabulation of parameterized magnetic (PM) values for the first three rows of transition metal elements computed from atomic density functional theory (DFT) calculations, allowing for the efficient computation of approximate A and B across large crystals using only structural and magnetic moment size and direction information. Ferromagnetic b.c.c. (body-centred cubic) Fe and tetragonal FePt are chosen to showcase the performance of PM values versus directly obtaining A and B from the unit-cell spin density by DFT. The magnetic fields of b.c.c. Fe are well described by the PM approach while for FePt the PM approach is less accurate due to deformations in the spin density. Calculations of the magnetic signal, namely the change due to A and B of the intensity of diffraction patterns, show that the PM approach for both b.c.c. Fe and FePt is able to describe the effects of magnetism in these systems to a good degree of accuracy.


Understanding the selection of catalytic pathway on graphene-supported nitrogen coordinated Ru-atom by ab initio molecular dynamics simulation.
In the paper, the ORR/OER on graphene-supported nitrogen coordinated Ru-atom (Ru-N-C) is simulated. We discuss nitrogen coordination influences electronic properties, adsorption energies, and catalytic activity in a single-atom Ru active site. The over potentials on Ru-N-C are 1.12 eV/1.00 eV for ORR/OER. We calculate Gibbs-free energy (ΔG) for every reaction step in ORR/OER process. In order to gain a deeper understanding of the catalytic process on the surface of single atom catalysts, the ab initio molecular dynamics (AIMD) simulations show that Ru-N-C has a structural stability at 300 K and that ORR/OER on Ru-N-C can occur along a typical four-electron process of reaction. AIMD simulations of catalytic processes provide detailed information about atom interactions. In this paper, we use density functional theory (DFT) with PBE functional to study the electronic properties and adsorption properties of graphene-supported nitrogen coordinated Ru-atom (Ru-N-C) Gibbs-free energy and Gibbs-free energy for very reaction step. The structural optimization and all the calculations are carried out by Dmol3 package, adopting the PNT basis set and DFT semicore pseudopotential. Ab initio molecular dynamics simulations (AIMD) were run for 10 ps. The canonical (NVT) ensemble, massive GGM thermostat, and a temperature of 300 K are taken into account. The functional of B3LYP and the DNP basis set are chosen for AIMD.


Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications.
Here we report 41 novel mutations in the TCIRG1 gene that is responsible for the disease in more than 50% of ARO patients. The characterisation of mutations in this gene might be useful in the process of drug design for osteoporosis treatment. Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder due to reduced bone resorption by osteoclasts. In this process, a crucial role is played by the proton pump V-ATPase. Biallelic mutations in the TCIRG1 gene, encoding for the a3 subunit of this pump, are responsible for more than one half of ARO patients. Patients with a clinical diagnosis of ARO have been collected for 7 years and mutation analysis of the TCIRG1 gene was performed using direct DNA sequencing of PCR-amplified exons according to both a standard protocol and a modified one. We report here 41 novel mutations identified in 67 unpublished patients, all with biallelic mutations. In particular, we describe two novel large genomic deletions and two splice site mutations in the 5' UTR of the TCIRG1 gene, in patients previously classified as mono-allelic. Our data highlights the importance of two large genomic deletions and mutations in the 5' UTR with respect to patient management and, more critically, to prenatal diagnosis. With the present work, we strongly contribute to the molecular dissection of TCIRG1-deficient ARO and identify several protein residues which are fundamental for proton pump function and could thus be the target of future drugs designed to inhibit osteoclast resorptive activity.


Intra-articular fibroma-like perivascular epithelioid tumor (PEComa) mimicking tenosynovial giant cell tumor, diffuse type.
Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms composed of perivascular epithelioid cells that are immunoreactive for both melanocytic and myogenic markers. Recently, a fibroma-like PEComa associated with tuberous sclerosis complex (TSC) has been identified. We describe the first intra-articular case of a fibroma-like PEComa in a 44-year-old man who presented with a hypointense intra-articular knee mass, which was mistaken for tenosynovial giant cell tumor, diffuse type. This case report demonstrates that fibroma-like PEComa should be included in the extended differential diagnosis of intra-articular soft tissue masses. In addition, given their strong association with TSC mutations, a diagnosis of fibroma-like PEComa should trigger an evaluation for TSC.


Cross-ancestry genome-wide association meta-analyses of hippocampal and subfield volumes.
The hippocampus is critical for memory and cognition and neuropsychiatric disorders, and its subfields differ in architecture and function. Genome-wide association studies on hippocampal and subfield volumes are mainly conducted in European populations; however, other ancestral populations are under-represented. Here we conduct cross-ancestry genome-wide association meta-analyses in 65,791 individuals for hippocampal volume and 38,977 for subfield volumes, including 7,009 individuals of East Asian ancestry. We identify 339 variant-trait associations at P < 1.13 × 10-9 for 44 hippocampal traits, including 23 new associations. Common genetic variants have similar effects on hippocampal traits across ancestries, although ancestry-specific associations exist. Cross-ancestry analysis improves the fine-mapping precision and the prediction performance of polygenic scores in under-represented populations. These genetic variants are enriched for Wnt signaling and neuron differentiation and affect cognition, emotion and neuropsychiatric disorders. These findings may provide insight into the genetic architectures of hippocampal and subfield volumes.


The inflammatory response to skeletal muscle injury: illuminating complexities.
Injury of skeletal muscle, and especially mechanically induced damage such as contusion injury, frequently occurs in contact sports, as well as in accidental contact sports, such as hockey and squash. The large variations with regard to injury severity and affected muscle group, as well as non-specificity of reported symptoms, complicate research aimed at finding suitable treatments. Therefore, in order to increase the chances of finding a successful treatment, it is important to understand the underlying mechanisms inherent to this type of skeletal muscle injury and the cellular processes involved in muscle healing following a contusion injury. Arguably the most important of these processes is inflammation since it is a consistent and lasting response. The inflammatory response is dependent on two factors, namely the extent of actual physical damage and the degree of muscle vascularization at the time of injury. However, long-term anti-inflammatory treatment is not necessarily effective in promoting healing, as indicated by various studies on NSAID treatment. Because of the factors named earlier, human studies on the inflammatory response to contusion injury are limited, but several experimental animal models have been designed to study muscle damage and regeneration. The early recovery phase is characterized by the overlapping processes of inflammation and occurrence of secondary damage. Although neutrophil infiltration has been named as a contributor to the latter, no clear evidence exists to support this claim. Macrophages, although forming part of the inflammatory response, have been shown to have a role in recovery, rather than in exacerbating secondary damage. Several probable roles for this cell type in the second phase of recovery, involving resolution processes, have been identified and include the following: (i) phagocytosis to remove cellular debris; (ii) switching from a pro- to anti-inflammatory phenotype in regenerating muscle; (iii) preventing muscle cells from undergoing apoptosis; (iv) releasing factors to promote muscle precursor cell activation and growth; and (v) secretion of cytokines and growth factors to facilitate vascular and muscle fibre repair. These many different roles suggest that a single treatment with one specific target cell population (e.g. neutrophils, macrophages or satellite cells) may not be equally effective in all phases of the post-injury response. To find the optimal targeted, but time-course-dependent, treatments requires substantial further investigations. However, the techniques currently used to induce mechanical injury vary considerably in terms of invasiveness, tools used to induce injury, muscle group selected for injury and contractile status of the muscle, all of which have an influence on the immune and/or cytokine responses. This makes interpretation of the complex responses more difficult. After our review of the literature, we propose that a standardized non-invasive contusion injury is the ideal model for investigations into the immune responses to mechanical skeletal muscle injury. Despite its suitability as a model, the currently available literature with respect to the inflammatory response to injury using contusion models is largely inadequate. Therefore, it may be premature to investigate highly targeted therapies, which may ultimately prove more effective in decreasing athlete recovery time than current therapies that are either not phase-specific, or not administered in a phase-specific fashion.


Photodynamic Therapy in Combination with Chemotherapy, Targeted, and Immunotherapy As a Successful Therapeutic Approach for Advanced Gastric Adenocarcinoma: A Case Report and Literature Review.
Objective: To explore the efficacy of photodynamic therapy combined with chemotherapy, targeted therapy, and immunotherapy in poorly differentiated gastric adenocarcinoma (GAC). Background: Advanced GAC has high malignancy and mortality rate. To date, no study has applied photodynamic treatment (PDT) combined with chemo-, targeted, and immunotherapy to treat this cancer. Patient and methods: Clinical data of a patient diagnosed with poorly differentiated GAC admitted to the department of oncology of the Lanzhou University Second Hospital were retrospectively analyzed. The patient underwent four PDT procedures combined with chemo-, targeted, and immunotherapy. Results: A 72-year-old male patient received combination therapy of PDT. This treatment resolved the cancerous tissues and levels of tumor markers. There was no recurrence and metastasis during a 7-month follow-up. Conclusions: Combination therapy of PDT can effectively treat tumors and may be a method suitable for elderly patients with advanced GAC.


Redistribution of melanosomal complexes within keratinocytes following UV-A irradiation: a possible mechanism for cutaneous darkening in man.
In contrast to other ultraviolet (UV) wavelengths, UV-A can induce long-term or "true" pigmentation rapidly with little or no latency. The response cannot be clearly separated from immediate pigment darkening and is too rapid in onset to be explained by neomelanogenesis. In order to investigate possible mechanisms for this phenomenon, UV-irradiated skin was examined microscopically and ultrastructurally 18 h postirradiation. Specimens from skin sites tanned by exposure to melanogenic doses of UV-A showed a paradoxical reduction in the degree of basal melanization by light microscopy compared to unirradiated skin. Ultrastructurally, there was migration and dispersion of packaged melanosomes within keratinocytes from their normal, aggregated location around the nucleus towards the periphery of the cell. These changes were not observed in specimens exposed to melanogenic doses of UV-B. We propose that UV-A wavelengths can selectively cause redistribution of melanin-laden organelles within human keratinocytes in vivo and that this phenomenon accounts for the visually observed hyperpigmentation that develops soon after single exposures to these wavelengths. Dispersion of melanosomal complexes may be another mechanism by which UV-radiation (UVR) can induce tanning in human skin.


Process and kinetics of azo dye decolourization in bioelectrochemical systems: effect of several key factors.
This study explored the influence of several key factors on the process and kinetics of azo dye decolourization in bioelectrochemical systems (BESs), including cathode potential, dissolved oxygen (DO) concentration of catholyte and biofilm formed on the cathode. The results show that azo dye methyl orange (MO) decolourization in the BES could be well described with the pseudo first-order kinetics. The MO decolourization efficiency increased from 0 to 94.90 ± 0.01% and correspondingly the reaction rate constant increased from 0 to 0.503 ± 0.001 h(-1) with the decrease in cathodic electrode potential from -0.2 to -0.8 V vs Ag/AgCl. On the contrary, DO concentration of the catholyte had a negative impact on MO decolourization in the BES. When DO concentration increased from zero to 5.80 mg L(-1), the MO decolourization efficiency decreased from 87.19 ± 4.73% to 27.77 ± 0.06% and correspondingly the reaction rate constant reduced from 0.207 ± 0.042 to 0.033 ± 0.007 h(-1). Additionally, the results suggest that the biofilm formed on the cathode could led to an adverse rather than a positive effect on azo dye decolourization in the BES in terms of efficiency and kinetics.


Evaluating orelabrutinib as a novel treatment option for relapsed/refractory chronic lymphocytic leukemia in China.
The covalent Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been approved in the USA for B cell malignancies for almost ten years and has improved the survival of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Orelabrutinib is a novel, highly selective covalent BTK inhibitor with proven efficacy and acceptable safety profile. In 2020, it was approved for the treatment of relapsed/refractory (R/R) CLL/SLL in China. In this review, we summarized the current clinical trials exploring orelabrutinib monotherapy or orelabrutinib-based combination regimens in CLL/SLL, especially R/R CLL/SLL. Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of orelabrutinib are also discussed. Orelabrutinib selectively inhibits BTK via covalent binding and exhibits linear pharmacokinetics. BTK is the only kinase targeted by orelabrutinib, and a few off-target toxicities of orelabrutinib have been reported. The phase I/II trial demonstrated the efficacy and safety of orelabrutinib in patients with R/R CLL/SLL; however, further clinical trials are needed to compare orelabrutinib with ibrutinib in patients with R/R CLL/SLL and to evaluate its efficacy and safety in patients with treatment-naive CLL/SLL.


Factors Associated with Fluctuations in Central Subfield Thickness in Patients with Diabetic Macular Edema Using Diabetic Retinopathy Clinical Research Protocols T and V.
To identify baseline ocular and systemic factors associated with central subfield thickness (CST) fluctuations in patients with diabetic macular edema (DME) using data from Diabetic Retinopathy Clinical Research Protocols T and V. Post hoc analysis of clinical trial databases. Patients in Protocols T and V. The standard deviation (SD) of all recorded CSTs for each patient during each Protocol's study period was calculated. The CST SD (corresponding to CST fluctuations) for each patient was analyzed against baseline ocular and systemic factors using linear regression analyses. Each Protocol was analyzed separately. Factors associated with CST fluctuations. A total of 1197 eyes of 1197 subjects were included. In Protocol T (559 eyes, mean CST SD was 56.4 ± 35.1 microns), using multivariate linear regression analysis, baseline urine albumin/creatine ratio (for every 1000 mg/g, CST point estimate 3.50, 95% confidence interval [CI] 0.58 to 6.43, P = 0.0190), and baseline CST (for every 10 microns, 0.87, 95% CI 0.58 to 1.16, P < 0.0001) were positively associated with CST fluctuations. Baseline visual acuity (for every 10 ETDRS letters, -9.52, 95% CI -11.89 to -7.15, P < 0.0001) was negatively associated with CST fluctuations. In Protocol V (638 eyes, mean CST SD 36.6 ± 28.4 microns), gender (female, 2.18, 95% CI 0.30 to 4.06, P = 0.0227), baseline CST (for every 10 microns, 2.51, 95% CI 2.21 to 2.82, P < 0.0001), systolic blood pressure (for every 1 mm of mercury, 0.11, 95% CI 0.01 to 0.21, P = 0.0261), and observation with deferred anti-VEGF injections (5.04, 95% CI 2.51 to 7.58, P < 0.0001) were positively associated with CST fluctuations. Type 2 diabetes (-7.37, 95% CI -13.64 to -1.11, P = 0.0209) and prompt anti-VEGF injections (-6.51, 95% CI -9.07 to -3.96, P < 0.0001) were negatively associated with CST fluctuations. Worse visual acuity at baseline, baseline renal disease, hypertension, female gender, type 1 diabetes, and delayed anti-VEGF treatment may be associated with increased CST fluctuations in patients with DME. Addressing these parameters may limit CST fluctuations and help identify patients requiring more frequent monitoring or treatment.


Characterizing sentence intonation in a right hemisphere-damaged population.
Current production studies present a mixed view of right hemisphere-damaged (RHD) patients' ability to produce normal sentence intonation. The present study characterized the sentence intonation of RHD patients, focusing on a greater number of acoustic parameters than past works, and relying on more naturally elicited speech samples through use of a story completion task. Eight RHD speakers and seven nonneurological control subjects produced declarative and imperative sentences as well as yes-no and wh-questions. Slope of F0 change, linearity of pitch contour, and variance of F0 points were calculated for each utterance as a whole, as well as for the preterminal and the terminal contour separately. RHD contours were less linear and flatter in F0 decline than normal controls for the declarative sentences. The patients' yes-no questions also differed from normal productions, displaying smaller F0 dispersion around a mean F0. Preterminal range values were more restricted for patients' utterances of yes-no questions, while terminal properties between groups differed for three of the four sentence types examined. The present results suggest some disturbance in the patients' ability to manipulate fundamental frequency across sentential domains. These data are discussed in terms of current theories of a general dysprosody in RHD patients.


Pauli-limit upper critical field of high-temperature superconductor La1.84Sr0.16CuO4.
The upper critical field of a cuprate high-temperature superconductor, La1.84Sr0.16CuO4, was investigated by high-frequency self-resonant contactless electrical conductivity measurements in magnetic fields up to 102 T. An irreversible transition was observed at 85 T (T = 4.2 K), defined as the upper critical field. The temperature-dependent upper critical field was argued on the basis of the Werthamer-Helfand-Hohenberg theory. The Pauli-limiting pair-breaking process with a small contribution of the spin-orbit coupling explained the first-order phase transition exhibiting a hysteresis observed at low temperatures.


Effect of predilatation of the uterine cervix by laminaria tent on activity of the placenta.
Serum concentrations of hCG were determined in blood samples taken 18-20 h and immediately before vacuum aspiration in 45 women in gestational weeks 7-9, admitted for legal abortion. In 35 of the women, a laminaria tent was inserted for cervical dilatation immediately after the first blood sampling. Serum hCG values decreased significantly in the women pretreated with laminaria tent, but were unchanged in the untreated women. This finding may indicate that pretreatment with a laminaria tent induces a partial placental detachment.


MAPK-mediated regulation of growth and essential oil composition in a salt-tolerant peppermint (Mentha piperita L.) under NaCl stress.
Peppermint (Mentha × piperita L.) is an important and commonly used flavoring agent worldwide, and salinity is a major stress that limits plant growth and reduces crop productivity. This work demonstrated the metabolic responses of essential oil production including the yield and component composition, gene expression, enzyme activity, and protein activation in a salt-tolerant peppermint Keyuan-1 with respect to NaCl stress. Our results showed that Keyuan-1 maintained normal growth and kept higher yield and content of essential oils under NaCl stress than wild-type (WT) peppermint.Gas chromatography-mass spectrometry (GC-MS) and qPCR results showed that compared to WT seedlings, a 150-mM NaCl stress exerted no obvious changes in essential oil composition, transcriptional level of enzymes related to essential oil metabolism, and activity of pulegone reductase (Pr) in Keyuan-1 peppermint which preserved the higher amount of menthol and menthone as well as the lower content of menthofuran upon the 150-mM NaCl stress. Furthermore, it was noticed that a mitogen-activated protein kinase (MAPK) protein exhibited a time-dependent activation in the Keyuan-1 peppermint and primarily involved in the modulation of the essential oil metabolism in the transcript and enzyme levels during the 12-day treatment of 150 mM NaCl. In all, our data elucidated the effect of NaCl on metabolic responses of essential oil production, and demonstrated the MAPK-dependent regulation mechanism of essential oil biosynthesis in the salt-tolerant peppermint, providing scientific basis for the economic and ecological utilization of peppermint in saline land.


Phase distribution and risk assessment of PAHs in ambient air of Hamadan, Iran.
In the present study, both gaseous and particulate (PM with dae <2.5 µm) phases of polycyclic aromatic hydrocarbons (PAHs) were measured in the ambient air of Hamadan city, Iran. For this reason, two low-volume samplers equipped with glass fiber filters were used for sampling of particulate phase (N = 30) and XAD-2 sorbent tubes were applied for sampling gaseous phase of PAHs (N = 30). The sampling was conducted during warm and cold seasons in 2019. The average of cold/warm season ratios for Σ16PAH and PM concentrations were 1.14 and 0.62, respectively. Summed PAHs concentration were determined to be in the range 0.008-59.46 (mean: 11.61) ng/m3 and 0.05-40.83 (mean: 10.22) ng/m3 for the cold and warm seasons, respectively. A negative Pearson correlation coefficient was obtained for wind speed and relative humidity. The average Benzo (a) Pyrene equivalent carcinogenic (BaPeq) levels in the cold season were lower than the maximum permissible risk level of 1 ng/m3 for BaP. The BaP toxicity equivalency (ΣBaPTEQ) and BaP mutagenicity equivalency (ΣBaPMEQ) appeared to be significantly higher in the cold season (averaging 0.35 and 1.65 ng/m3, respectively) than those in warm season. Health risk assessment was performed for children and adults based on BaPeq, inhalation cancer risk. The diagnostic ratios of individual PAHs concentration showed that the significant sources of PAH emissions may be related to light duty vehicles (LDVs) in Hamadan. Although, some other sources such as pyrogenic source and petrol combustion were also suggested.


Variation between strains of the cyanobacterium Microcystis aeruginosa isolated from a Portuguese river.
The aim of this study was to investigate toxicological differences between strains of the cyanobacterium Microcystis aeruginosa isolated from a potable water supply in the north of Portugal over a 2-month period. Twenty-six strains of M. aeruginosa were isolated, grown in pure culture, and tested using a range of techniques including matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), ELISA and a PCR procedure targeting the genes implicated in the production of toxic microcystins. There was considerable variation with respect to the amounts of microcystin produced by each of the strains as measured by ELISA, with values ranging from 0.02 to 0.53% dry weight. The results of the MALDI-TOF MS analysis demonstrated the presence of several chemically distinct forms of microcystin as well as aeruginosins, anabaenopeptins and several other unidentified peptide-like compounds. The growth of individual strains that comprise bloom populations, with unique 'chemotypes' can potentially be an important factor affecting the toxicity of bloom populations. Molecular probes, targeting the genes responsible for microcystin production were shown to be useful for distinguishing between toxic and nontoxic strains and showed good agreement with the results obtained from the other analyses. The results of this study show that the analysis of cyanobacterial bloom populations at the subspecies (strain) level can potentially provide important information regarding the toxin-producing potential of a cyanobacterial bloom and could be used as an 'early warning' for toxic bloom development.


Retained pacemaker leads.
Increasingly, functionless pacemaker leads are being abandoned in place because they cannot be safely removed. One hundred eighty-nine intact or partially removed pacemaker leads were abandoned in situ in 152 patients between Jan. 1, 1965, and Dec. 31, 1985. The leads, sometimes several leads in a single patient, were deemed uninfected at the time of abandonment in 137 patients and contaminated with Staphylococcus epidermidis in 15 patients. All of the contaminated leads have remained clinically uninfected during follow-up. One clean lead became infected early after implantation and the patient died after an open cardiac operation to remove that lead and an adjacent abandoned lead that was adherent to the subclavian vein. No other patient has had a late complication during follow-up to 256 months (mean 47.6). Properly managed abandonment of an uninfected lead can carry a very low complication rate.


Infection with the human immunodeficiency virus in prisoners: meeting the health care challenge.
The magnitude and the scope of health care problems posed by human prison inmates seropositive for the human immunodeficiency virus (HIV) are enormous. Prisoners represent a substantial proportion of HIV-infected individuals in North America. A high proportion of prisoners are intravenous drug users who often have not received appropriate health care or HIV-directed services prior to incarceration. Health care of HIV-seropositive prisoners and follow-up medical care after prison release has often been less than optimal. Among inmates at the prison facility in Rhode Island, 4% of the men and 12% of the women are HIV seropositive. The Brown University medical community, in conjunction with the Rhode Island Department of Health and Corrections, has developed an effective program for the health care of such prisoners, both during incarceration and after release from prison. Academic medical centers are uniquely poised to assume the leading role in meeting this obligation. We believe that this general approach, with region-specific modifications, may be effectively applied in many correctional institutions in North America.


Association of FOXO3A with right ventricular myocardial fibrosis and its detection by speckle-tracking echocardiography in pulmonary hypertension.
Myocardial fibrosis can result in right ventricular (RV) dysfunction, a critical factor in poor clinical outcomes and high mortality rates among patients with pulmonary hypertension (PH). Decreased RV myocardial strain rates have been reported in PH patients. The expression of FOXO3A may play a crucial role in myocardial fibrosis; however, the relationship between myocardial fibrosis, speckle-tracking echocardiography (STE), and the transcription factor FOXO3A remains unclear. This study aimed to explore the relationship between the molecular mechanisms of myocardial fibrosis and noninvasive ultrasound evaluation indices to provide a reliable molecular foundation for the early diagnosis of right heart dysfunction in clinical settings. A progressive right heart failure (RHF) rat model was established through subcutaneous injections of monocrotaline. Rats were divided into baseline, 2-week, 4-week, and 6-week groups based on the disease course. RV structure, function, and myocardial strain were assessed via echocardiography. Myocardial fibrosis severity was determined using PSR staining. The correlation between myocardial strain and RV myocardial fibrosis was analyzed. FOXO3A, collagen I, collagen III, and BNP expressions were tested using western blotting. As the disease progressed, the right ventricle significantly expanded, and the RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV global longitudinal strain (RVLS global), and RV free wall longitudinal strain (RVLS FW) gradually declined. However, the reductions in RVLS global and RVLS FW occurred earlier than that of RVFAC, TAPSE. Significant correlations were observed between RVLS global, RVLS FW, and collagen deposition. FOXO3A expression gradually decreased with disease progression, while BNP, collagen I, and collagen III expressions gradually increased. Decreases in RVLS global and RVLS FW in RHF rats occurred earlier than RVFAC and were associated with RV myocardial fibrosis. Furthermore, FOXO3A may have a protective role in the process of RV myocardial fibrosis.


Subjective Visual Vertical Testing in Patients With Chronic Suppurative Otitis Media.
To analyze the results of the subjective visual vertical test using the "bucket method" in patients with chronic suppurative otitis media (CSOM). Cross-sectional, controlled study. Outpatient otology clinic in a tertiary care hospital. Patients had CSOM, defined as the presence of chronic infection or inflammation of the middle ear cleft, associated with a perforation of the tympanic membrane, frequent or intractable middle ear suppuration, with or without cholesteatoma. Controls were selected using a nonprobability, purposive sampling method. We excluded patients with neurologic or metabolic diseases, cognitive deficits, otosclerosis, vestibular migraine, Ménière's disease, past use of ototoxic medication, or head and neck cancer. The volunteers were subjected to the subjective visual vertical test using the "bucket method." The results obtained in our study and control groups were analyzed using nonparametric tests. Our study comprised 51 patients with CSOM and 50 controls. In the CSOM group, we observed that 72.5% of the patients had vestibular symptoms in the past year, and 70.5% had abnormalities identified in at least 1 vestibular function test. The subjective visual vertical test revealed that patients with CSOM (with and without cholesteatoma) had significantly higher deviations of the true vertical as compared with controls (CSOM, 3.66°; controls, 0.76°; P < .001). Our results revealed that CSOM was associated with high rates of vestibular symptoms, abnormal vestibular function tests, and abnormal subjective vertical visual results.


Characterization of a Mo-Nitrogenase Variant Containing a Citrate-Substituted Cofactor.
Nitrogenase converts N2 to NH3 , and CO to hydrocarbons, at its cofactor site. Herein, we report a biochemical and spectroscopic characterization of a Mo-nitrogenase variant expressed in an Azotobacter vinelandii strain containing a deletion of nifV, the gene encoding the homocitrate synthase. Designated NifDKCit , the catalytic component of this Mo-nitrogenase variant contains a citrate-substituted cofactor analogue. Activity analysis of NifDKCit reveals a shift of CO reduction from H2 evolution toward hydrocarbon formation and an opposite shift of N2 reduction from NH3 formation toward H2 evolution. Consistent with a shift in the Mo K-edge energy of NifDKCit relative to that of its wild-type counterpart, EPR analysis demonstrates a broadening of the line-shape and a decrease in the intensity of the cofactor-originated S=3/2 signal, suggesting a change in the spin properties of the cofactor upon citrate substitution. These observations point to a crucial role of homocitrate in substrate reduction by nitrogenase and the possibility to tune product profiles of nitrogenase reactions via organic ligand substitution.


Does insulin dependent diabetes mellitus have a viral etiology?
Clinical, epidemiological, and experimental observations suggest that common viruses may play an etiologic role in at least some cases of insulin dependent diabetes mellitus. The evidence is summarized and critically assessed in this presentation.


Delayed administration of recombinant human parathyroid hormone improves early biomechanical strength in a rat rotator cuff repair model.
Despite advances in intraoperative techniques, rotator cuff repairs frequently do not heal. Recombinant human parathyroid hormone (rhPTH) has been shown to improve healing at the tendon-to-bone interface in an established acute rat rotator cuff repair model. We hypothesized that administration of rhPTH beginning on postoperative day 7 would result in improved early load to failure after acute rotator cuff repair in an established rat model. Acute rotator cuff repairs were performed in 108 male Sprague-Dawley rats. Fifty-four rats received daily injections of rhPTH beginning on postoperative day 7 until euthanasia or a maximum of 12 weeks postoperatively. The remaining 54 rats received no injections and served as the control group. Animals were euthanized at 2 and 16 weeks postoperatively and evaluated by gross inspection, biomechanical testing, and histologic analysis. At 2 weeks postoperatively, rats treated with rhPTH demonstrated significantly higher load to failure than controls (10.9 vs. 5.2 N; P = .003). No difference in load to failure was found between the 2 groups at 16 weeks postoperatively, although control repairs more frequently failed at the tendon-to-bone interface (45.5% vs. 22.7%; P = .111). Blood vessel density appeared equivalent between the 2 groups at both time points, but increased intracellular and extracellular vascular endothelial growth factor expression was noted in the rhPTH-treated group at 2 weeks. Delayed daily administration of rhPTH resulted in increased early load to failure and equivalent blood vessel density in an acute rotator cuff repair model.


Surface enhanced Raman scattering, electronic spectrum, natural bond orbital, and Mulliken charge distribution in the normal modes of diethyldithiocarbamate copper (II) complex, [Cu(DDTC)2].
Surface-enhanced Raman scattering (SERS) was used to study the interactions of the normal modes of the diethyldithiocarbamate copper (II) complex, [Cu(DDTC)2] on nano-structured mixture silver-gold surfaces and on silver surfaces. The electronic spectrum of this complex was measured and the charge transfer bands were assigned through the TD-PBE1PBE procedure. Natural bond orbital (NBO) were also carried out to study the Cu(II) hybridation leading to the square planar geometry of the framework of the [Cu(DDTC)2] complex, and to study which are the donor NBO and the acceptor NBO in meaningful charge transfer through the Second Order Perturbation Theory Analysis of the Fox Matrix in NBO basis. To see the electronic dispersion, the Mulliken electronic charges (MAC) were calculated for each normal mode and correlated with the SERS effect. Full assignment of the SERS spectra was also supported by carefully analysis of the distorted geometries generated by the normal modes.


Simplified mathematical description of longitudinal recovery in multiple-echo sequences.
The intensity of multiple echoes separated by a time 2 tau has been modeled using the closed form of a finite geometric series. This eliminates long exponential series, introduces the number of echoes as an independent parameter, and corrects for the net T1 relaxation during the echo train. Other sequences having echo trains can be modeled similarly.


Aptamer-Based Proteomics Identifies Mortality-Associated Serum Biomarkers in Dialysis-Dependent AKI Patients.
Currently, no effective therapies exist to reduce the high mortality associated with dialysis-dependent acute kidney injury (AKI-D). Serum biomarkers may be useful in understanding the pathophysiological processes involved with AKI and the severity of injury, and point to novel therapeutic targets. Study day 1 serum samples from 100 patients and day 8 samples from 107 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the slow off-rate modified aptamers scan proteomic platform to profile 1305 proteins in each sample. Patients in each cohort were classified into tertiles based on baseline biomarker measurements. Cox regression analyses were performed to examine the relationships between serum levels of each biomarker and mortality. Changes in the serum levels of 54 proteins, 33 of which increased and 21 of which decreased, were detected when comparing samples of patients who died in the first 8 days versus patients who survived >8 days. Among the 33 proteins that increased, higher serum levels of fibroblast growth factor-23 (FGF23), tissue plasminogen activator (tPA), neutrophil collagenase (matrix metalloproteinase-8), and soluble urokinase plasminogen activator receptor, when stratified by tertiles, were associated with higher mortality. The association with mortality persisted for each of these proteins after adjusting for other potential risk factors, including age, sex, cardiovascular sequential organ failure assessment score, congestive heart failure, and presence of diabetes. Upper tertile levels of FGF23, tPA, and interleukin-6 on day 8 were associated with increased mortality; however, FGF23 barely lost significance after multivariable adjustment. Our results underscore an emerging proteomics tool capable of identifying low-abundance serum proteins important not only in the pathogenesis of AKI-D, but which is also helpful in discriminating AKI-D patients with high mortality.


Antibacterial sesquiterpenoids from Solanum lyratum.
Investigation into the chemical diversity of Solanum lyratum led to the discovery of one new sesquiterpenoid, solyraterpenoid A (1), and two known compounds (2 and 3). The structure incorporating absolute configuration of 1 was determined via spectroscopic data, mainly including HRESIMS and NMR, and single-crystal X-ray diffraction analysis. Compound 1 showed significant antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae with MIC values of 8, 8, and 4 μg/mL, respectively.


A mathematical model for the hemoglobin response to iron intake, based on iron absorption measurements from habitually consumed Indian meals.
The prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) is high in India and appear unchanging over decades. To understand the persistence of these disorders, it is critical to measure iron (Fe) absorption from cereal-based Indian meals, its modulation by ID and the time-course of the response of hemoglobin (Hb) to Fe intake. SUBJESTS/METHODS: Fe absorption from rice-based meals was measured by the erythrocyte incorporation of the stable isotope label at 14 days in IDA (N=15) and Fe replete (IR) women (N=15). Hb level was used as surrogate for Fe status, and a response curve for Fe absorption versus the Hb level for a rice-based meal was constructed from measured data. This relationship was used as input for a mathematical model that examined the Hb response to different Fe intakes in normal and anemic women. The mean fractional Fe absorption from a rice-based meal in IR and IDA women was 2.7% and 8.3%, respectively. The model predicted that Fe intakes between 20 and 55 mg/day in low-bioavailability diets would result in stable, non-anemic levels of Hb in women over a 1-year period. This mathematical model suggests that with a Fe intake of 20-30 mg/day and a dietary bioavailability of 3-5%, Hb concentration would hover around 12 g/dl with a variability of 0.5 g/dl in pre-menopausal adult women.


Three-dimensional molecular-field analyses of octopaminergic agonists for the cockroach neuronal octopamine receptor.
The quantitative structure-activity relationship of a set of 40 octopaminergic agonists against receptor 2 in cockroach nervous tissue, was analyzed using molecular-field analysis (MFA). MFA on the study set of those compounds evaluated effectively the energy between a probe and a molecular model at a series of points defined by a rectangular grid. Contour surfaces for the molecular fields were presented and the results provided useful information in the characterization and differentiation of octopaminergic receptor.


External validation of postoperative nausea and vomiting risk scores in patients with liver cancer: A single-centre prospective cohort study.
This study aimed to test the external validity of postoperative nausea and vomiting (PONV) risk assessment tools in patients undergoing hepatectomy, and to guide healthcare professionals' assessment of postoperative patients. The identification of PONV risk is particularly important in the context of prevention. However, the predictive performance of the current PONV risk scores has not been confirmed in patients with liver cancer, and its applicability is still unknown. These uncertainties pose difficulties in performing routine risk assessment of PONV for patients with liver cancer in a clinical practice setting. Patients diagnosed with liver cancer and undergoing hepatectomy were prospectively consecutively recruited. All enrolled patients received PONV assessments and PONV risk assessments via the Apfel risk score and the Koivuranta risk score. Receiver operating characteristic curves (ROC curves) and calibration curves were used to assess the external validity. This study was reported according to the TRIPOD Checklist. Among 214 PONV-assessed patients, 114 patients (53.3%) developed PONV. For the Apfel simplified risk score, the ROC area was 0.612 (95% confidence interval [CI]: 0.543-0.678) in the validation dataset, which demonstrated imperfect discrimination; the calibration curve showed poor calibration with a slope of 0.49. For the Koivuranta score, the ROC area was 0.628 (CI: 0.559-0.693) in the validation dataset, which showed limited discrimination; the calibration curve indicated an unsatisfactory calibration with a slope of 0.71. The Apfel risk score and the Koivuranta risk score were not well validated in our study and disease-specific risk factors should be taken into account when updating or developing PONV risk stratification instruments.


Plasmablastic posttransplant lymphoma: cytogenetic aberrations and lack of Epstein-Barr virus association linked with poor outcome in the prospective German Posttransplant Lymphoproliferative Disorder Registry.
Plasmablastic posttransplant lymphoma is a rare subtype of monomorphic B-cell posttransplant lymphoproliferative disorder (PTLD). There is little published clinical data to guide treatment. The German prospective PTLD registry D2006-2012 records baseline features, treatment, and outcome of rare PTLD subtypes in adults after solid organ transplantation. Treatment is at the discretion of the local physician. Clinical data on the patients in the registry is collected before, during, and at least 4 weeks, 6 months, 12 and 24 months after treatment. Eight cases of plasmablastic posttransplant lymphoma were reported to the registry until 2011. The majority occurred as late PTLD in male heart transplant recipients. Extranodal manifestations were common in stage I and in stage IV disease. Histological Epstein-Barr virus (EBV) association was confirmed in five of eight cases. MYC/IGH rearrangement was present in two of six patients examined. Although five of eight patients died from early disease progression, we observed that long-term survival can be achieved in localized (2/3) and in disseminated disease (1/5) by immunosuppression reduction (IR) followed by immediate systemic chemotherapy. However, all patients with cytogenetic aberrations and patients with non-EBV-associated PTLD were refractory to IR and to chemotherapy. Chemotherapy parallel to IR was associated with a high rate of infectious complications. In this series, IR and local therapy were not sufficient to treat plasmablastic posttransplant lymphoma even in localized disease whereas IR and systemic chemotherapy (CHOP-21) could achieve lasting complete remissions. Cytogenetic aberrations and lack of EBV association were linked with poor outcome.


Simultaneous onset of mitral regurgitation requiring surgery due to primary chordal rupture in middle-aged identical twins.
Primary chordal rupture is a leading cause of severe mitral regurgitation requiring surgery. It has previously been documented that there is a high probability of the occurrence of primary chordal rupture in patients with histological evidence of myxysomatous changes in the mitral valve. The precise etiology of primary chordal rupture and/or myxysomatous changes remains obscure and the relative contribution of genetic factors is debated. We report a pair of middle-aged identical twins requiring surgery for mitral regurgitation due to primary chordal rupture, and discuss the etiology of primary chordal rupture and/or myxysomatous changes.


Characteristics of cationic Red X-GRL biosorption by anaerobic activated sludge.
Anaerobic activated sludge (AAS) was employed for the adsorption of cationic Red X-GRL (X-GRL) from aqueous solutions. The X-GRL uptakes decreased with increases in temperature and salinity, while it was improved with increase in pH. The adsorption of X-GRL by AAS had a better agreement with a fractal-like Langmuir isotherm than a typical Langmuir isotherm. The adsorption rate coefficients at different time had a power-law relationship with time. The surface dimension was positively related to the X-GRL uptakes. The X-GRL uptake by the EPS accounted for only ≈ 19% of the total adsorption. The X-GRL adsorption was therefore largely attributed to the active groups on the cell wall. FTIR analysis showed that -CH(2) and -NH(2) groups were not responsible for the adsorption, which indicated chemical adsorption was negligible.


Heart failure with preserved ejection fraction (HFpEF) pathophysiology study (IDENTIFY-HF): does increased arterial stiffness associate with HFpEF, in addition to ageing and vascular effects of comorbidities? Rationale and design.
There has been a paradigm shift proposing that comorbidities are a major contributor towards the heart failure with preserved ejection fraction (HFpEF) syndrome. Furthermore, HFpEF patients have abnormal macrovascular and microvascular function, which may significantly contribute towards altered ventricular-vascular coupling in these patients. The IDENTIFY-HF study will investigate whether gradually increased arterial stiffness (in addition to ageing) as a result of increasing common comorbidities, such as hypertension and diabetes, is associated with HFpEF. In our observational study, arterial compliance and microvascular function will be assessed in five groups (Groups A to E) of age, sex and body mass index matched subjects (age ≥70 years in all groups):Group A; normal healthy volunteers without major comorbidities such as hypertension and diabetes mellitus (control). Group B; patients with hypertension without diabetes mellitus or heart failure (HF). Group C; patients with hypertension and diabetes mellitus without HF. Group D; patients with HFpEF. Group E; patients with heart failure and reduced ejection fraction (parallel group). Vascular function and arterial compliance will be assessed using pulse wave velocity, as the primary outcome measure. Further outcome measures include cutaneous laser Doppler flowmetry as a measure of endothelial function, transthoracic echocardiography and exercise tolerance measures. Biomarkers include NT-proBNP, high-sensitivity troponin T, as well as serum galectin-3 as a marker of fibrosis. The study was approved by the regional research ethics committee (REC), West Midland and Black Country 17/WM/0039, UK, and permission to conduct the study in the hospital was also obtained from the RDI, UHCW NHS Trust. The results will be published in peer-reviewed journals and presented in local, national and international medical society meetings. NCT03186833.


Integrated in-syringe magnetic sheet solid-phase extraction and dispersive liquid-liquid microextraction for determination of aflatoxins in fresh and moldy breads.
Magnetic three-dimensional graphene-based nanoadsorbents have unique characteristics such as large surface area, good thermal and chemical stability, and high adsorption capacity that make them efficient materials in sorbent-based extraction techniques. In this study, four aflatoxins (AFs) were analyzed in bread samples using magnetic three-dimensional graphene as the adsorbent phase in dispersive micro solid-phase extraction. In-syringe magnetic sheet solid-phase extraction based on magnetic three-dimensional graphene in tandem with dispersive liquid-liquid microextraction was used for the extraction and preconcentration of the target AFs. The effect of significant parameters of the method was investigated and the optimum conditions were determined as follows: adsorbent dosage, 20 mg; desorption/disperser solvent (methanol) volume, 700 μL; desorption solvent flow rate, 0.7 mL min-1 ; pH, neutral; salt (NaCl) concentration, 10% (w/v); extraction solvent (chloroform) volume, 250 μL; and centrifugation rate (and time), 4000 rpm (5 min). The limits of detection and quantification were in the ranges 0.043-0.083 and 0.14-0.28 μg kg-1 , respectively. The extraction method was followed by the HPLC technique with fluorescence detection and applied to the determination of the AFs in four different Iranian fresh and moldy bread samples. The relative recoveries were in the range 84-107% with relative standard deviations of 3.9-8.6%. © 2019 Society of Chemical Industry.


Can we predict the cardiac benefit of deep inspiration breath hold for left breast and regional nodal irradiation?
Deep inspiration breath hold (DIBH) is used to decrease the dose of radiotherapy delivered to the heart. There is a need to define criteria to select patients with the potential to derive a real clinical benefit from DIBH treatment. Our study's main goal was to investigate whether two CT-scan cardiac anatomical parameters, cardiac contact distance in the parasagittal plane (CCDps) and lateral heart-to-chest distance (HCD), were predictive of unmet dosimetric cardiac constraints for left breast and regional nodal irradiation (RNI). This retrospective single-institution dosimetric study included 62 planning CT scans of women with left-sided breast cancer (BC) from 2016 to 2021. Two independent radiation oncologists measured HCD and CCDps twice to assess inter- and intra-observer reproducibility. Dosimetric constraints to be respected were defined, and dosimetric parameters of interest were collected for each patient. Mean heart dose was 7.9Gy. Inter-rater reproducibility between the two readers was considered excellent. The mean heart dose constraint<8Gy was not achieved in 25 patients (40%) and was achieved in 37 patients (60%). There was a significant correlation between mean heart dose and HCD (rs=-0.25, P=0.050) and between mean heart dose and CCDps (rs=0.25, P=0.047). The correlation between HCD and CCDps and unmet cardiac dosimetric constraints was not statistically significant. Our dosimetric analysis did not find that the cardiac anatomical parameters HCD and CCDps were predictive of unmet dosimetric cardiac constraints, nor that they were good predictors for cardiac exposure in left-sided BC radiotherapy comprising RNI.


Improved methods for the isolation of individual and clustered mitotic chromosomes.
We have optimized procedures for the isolation of mitotic chromosomes from tissue culture cells. The first procedure is a rapid method for obtaining individual, structurally intact chromosomes suitable for analysis by electron microscopy. Further purification of these on Percoll gradients results in chromosomes free of cytoplasmic contamination, allowing biochemical characterization of the structural proteins and enzymatic activities intrinsic to mitotic chromosomes. A third procedure permits efficient, large-scale purification of chromosomes clustered together, referred to as a chromosomal cluster. The use of EDTA-containing polyamine buffers minimizes modifications of proteins and DNA during isolation and maintains the integrity of the chromosomal structure. The conditions which lead to the isolation of chromosomal clusters, as opposed to individual chromosomes, have been analyzed. Comparison of the gei patterns of proteins derived from individual chromosomes, as compared to clusters, identifies additional proteins in the latter pattern. These proteins could be involved in maintaining interchromosomal organization or positioning in the metaphase cell.


Altered brain exposure of morphine in experimental meningitis studied with microdialysis.
During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed. Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated. The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis. This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.


Population-based analysis of the epidemiological features of COVID-19 epidemics in Victoria, Australia, January 2020 - March 2021, and their suppression through comprehensive control strategies.
Victoria experienced the greatest burden of COVID-19 in Australia in 2020. This report describes key epidemiological characteristics and corresponding control measures between 17 January 2020 and 26 March 2021. COVID-19 notifications made to the State Government Department of Health were used in this analysis. Epidemiological features are described over 4 phases, including enhancements to testing, contact tracing and public health interventions. Demographic and clinical features of cases are described. Victoria recorded 20,483 cases of COVID-19, of which 1073 (5•2%) were acquired overseas and 19,360 (95%) were locally acquired. The initial epidemic (Phase I) was well-contained through public health interventions and was followed by relaxation of restrictions and low-level community transmission (Phase II). However, an outbreak in a hotel used to quarantine returned travellers led to wide-scale community transmission accounting for a majority (91%) of cases (Phase III). Outbreaks occurred in vulnerable settings including aged care and hospitals, contributing to high hospitalisation (12%) and case fatality rates (3•7%). Aggressive restrictions ultimately led to local elimination, and subsequent outbreaks have been swiftly managed with improved processes (Phase IV). The demographic composition of cases evolved across phases from an older, wealthier population to a less advantaged younger population, with many from culturally and linguistically diverse backgrounds. Over time, adaptations to the public health response have strengthened capacity to respond to new cases and outbreaks in a more effective manner. The Victorian experience underscores the importance of authentic engagement with diverse communities and balancing restrictions with livelihoods.


[Physiology and pathology of tear film in the course of dry eye syndrome].
Due to the grow-up of number of patients suffering from signs of dry-eye syndrome we are obligated to investigate physiology and pathology of tear film. Data obtained from patients with Sjögren Syndrome and other types of lacrimal dysfunction shows that the expectations for break-up in dry-eye treatment strategy are very high. In our review we are presenting contemporary views concerning tear film production and tear deficiency with special look at the treatment possibilities.


Total Knee Arthroplasty with Concomitant Corrective Tibial Osteotomy Using Patient-Specific Instrumentation and Computed Tomography-Based Navigation in Severe Post-High Tibial Osteotomy Valgus Collapse.
We report the case of a 78-year-old woman with lateral knee osteoarthritis and severe valgus knee deformity after high tibial osteotomy. The patient's severe valgus tibial deformity with a valgus angle of 45° was evaluated using a 3-dimensional bone model, and a closing-wedge osteotomy was planned. Combined total knee arthroplasty and closing-wedge tibial osteotomy were performed using patient-specific instrumentation and a computed tomography-based navigation system. A semiconstrained total knee system with a long stem was implanted for fixation of the osteotomy site in the tibia. The patient was able to walk without pain 2 years postoperatively. The Knee Society Score improved from 13 to 73 points, and the functional score improved from 30 to 65 points. This preoperative planning method and the treatment procedure would be beneficial for clinical decision-making and treatment of severe valgus knee deformities.


Phosphonic and arsonic acids as inhibitors of human red cell acid phosphatase and their use in affinity chromatography.
1. In order to obtain an effective ligand for affinity chromatography of the low molecular weight acid phosphatase (orthophosphoric-monoester phosphohydrolase (acid optimum), EC 22.214.171.124) from human red cells nine phosphonic and two arsonic acid substrate analogues were investigated as potential inhibitors. The two forms of acid phosphatase type B (b1 and b2) were isolated and partially purified using conventional methods and the inhibitory action of the substrate analogs investigated. 2. Four of the phosphonic acids were relatively effective competitive inhibitors. It appears that certain structural and electronic requirements have to be fulfilled by the phosphonic acids in order to exhibit significant affinity for the enzyme. A high affinity appears to require the presence of a bulky, hydrophobic moiety which has to be separated from the phosphorus atom by the distance of one atom. 3. p-Aminobenzylphosphonic acid exerted the highest affinity for acid phosphatase with a pH optimum at 6.5. Ki values of 4 . 10(-4) and 6 . 10(-4) M were found for the b1 and b2 forms, respectively. 4. Coupling of p-aminobenzylphosphonic acid to Agarose yielded an effective and specific affinity medium. By means of affinity chromatography using this medium, acid phosphatase was purified 500-fold in a single step.


An experimental and ultrastructural study on the development of the avian choroid plexus.
The choroid plexus consists of the choroidal epithelium, a derivative of the neural tube, and the choroidal stroma, which originates from the embryonic head mesenchyme. This study deals with epithelio-mesenchymal interactions of these two components leading to the formation of the organ. Grafting experiments of the prospective components have been performed using the quail-chicken marker technique. Prospective choroidal epithelium of quail embryos, forced to interact with mesenchyme of the body wall of chicken embryos, gives rise to a choroid plexus showing normal morphogenesis and differentiation. The choroidal epithelium induces the differentiation of organ-typical fenestrated capillaries, which are highly permeable to intravenously injected horseradish peroxidase. The choroidal epithelium of the grafts constitutes a blood-cerebrospinal fluid barrier. On top of the choroidal epithelium, there are epiplexus cells displaying a typical ultrastructure. The experimental results show that these cells do not originate from the transplanted neural epithelium. Prospective choroidal stroma of chicken embryos does not exert a choroid plexus-inducing influence upon a quail embryo's neural epithelium isolated from parts of the brain that normally do not develop a choroid plexus. The experiments show that the choroidal epithelial cells are determined at least three days before the first organ anlage is detectable.


[The guidelines for the diagnosis and monitoring of endocrine diseases(except of diabetes mellitus)].
The 6th draft for the guidelines for the diagnosis of thyroid disease has been published from the working group of Japan Endocrine Society in 2002. However, there are still controversial about guidelines for diagnosis of Graves disease. Serum-based tests for measuring the concentration of the TRAb and TSAb are available. We should use these tests rather than measuring of radioisotope uptake recommended in the 6th draft.


Effects of Dachengqi Decoction () on morphological changes in enteric nerve system of rats with multiple organ dysfunction syndrome.
To observe the morphological changes in enteric nerve system (ENS) of rats with multiple organ dysfunction syndrome (MODS) treated by Dachengqi Decoction (, DCQD). Fifty Wistar rats were randomly assigned to the control group, MODS model group and DCQD treated group. The rats in MODS model group and DCQD treated group were injected Escherichia coli (E. coli) suspension into abdominal cavity under sterile condition. The DCQD treated group was gavaged with DCQD 2 days before the E. coli suspension was injected. Twenty-four hours after injection, the proximal segment of intestine was resected and studied by immunohistofluorescence using vesicular acetylcholine transporter, vasoactive intestinal polypeptide (VIP), substance P (SP) and neuronal nitric oxide synthase (nNOS) antibodies. The whole-mount preparations were observed by laser scanning confocal microscope to detect the changes of quantity and fluorescence integral optical density (IOD) value of intestine enteric nerves. Compared with the control group, the quantity and IOD value of acetylcholine (ACh), VIP, SP and nitric oxide (NO) nerves of intestine in the MODS group were significantly decreased (P<0.01), and the network of enteric nerves was remarkably disrupted. Compared with the MODS group, the quantity and fluorescence IOD value of ACh, VIP, SP and NO nerves in the DCQD group were significantly increased (P<0.01), and the network of enteric nerves was remarkably recovered. DCQD can protect and repair damage in the network of ACh, SP, NO and VIP nerves in rats with MODS, which may be one of mechanisms involved in promoting gastrointestinal motility by DCQD.


Aberrant Nuclear Export of circNCOR1 Underlies SMAD7-Mediated Lymph Node Metastasis of Bladder Cancer.
Circular RNAs (circRNA) containing retained introns are normally sequestered in the nucleus. Dysregulation of cellular homeostasis can drive their nuclear export, which may be involved in cancer metastasis. However, the mechanism underlying circRNA nuclear export and its role in lymph node (LN) metastasis of bladder cancer remain unclear. Here, we identify an intron-retained circRNA, circNCOR1, that is significantly downregulated in LN metastatic bladder cancer and is negatively associated with poor prognosis of patients. Overexpression of circNCOR1 inhibited lymphangiogenesis and LN metastasis of bladder cancer in vitro and in vivo. Nuclear circNCOR1 epigenetically promoted SMAD7 transcription by increasing heterogeneous nuclear ribonucleoprotein L (hnRNPL)-induced H3K9 acetylation in the SMAD7 promoter, leading to inhibition of the TGFβ-SMAD signaling pathway. Nuclear retention of circNCOR1 was regulated by small ubiquitin-like modifier (SUMO)ylation of DDX39B, an essential regulatory factor responsible for circRNA nuclear-cytoplasmic transport. Reduced SUMO2 binding to DDX39B markedly increased circNCOR1 retention in the nucleus to suppress bladder cancer LN metastasis. By contrast, SUMOylated DDX39B activated nuclear export of circNCOR1, impairing the suppressive role of circNCOR1 on TGFβ-SMAD cascade activation and bladder cancer LN metastasis. In patient-derived xenograft (PDX) models, overexpression of circNCOR1 and inhibition of TGFβ signaling significantly repressed tumor growth and LN metastasis. This study highlights SUMOylation-induced nuclear export of circNCOR1 as a key event regulating TGFβ-SMAD signaling and bladder cancer lymphangiogenesis, thus supporting circNCOR1 as a novel therapeutic agent for patients with LN metastatic bladder cancer. This study identifies the novel intron-retained circNCOR1 and elucidates a SUMOylation-mediated DDX39B-circNCOR1-SMAD7 axis that regulates lymph node metastasis of bladder cancer.


Improved MALDI-TOF imaging yields increased protein signals at high molecular mass.
Matrix assisted laser desorption ionization (MALDI) mass spectrum images are created from an array of mass spectra collected over a tissue surface. We have increased the mass range of proteins that can be detected in tissue sections from kidneys, heart, lung and brain of different rodent species by a modification of the sandwich technique, which involves co-crystallizing matrix with analyte. A tissue section is placed upon a drop of sinapinic acid matrix dissolved in 90% ethanol and 0.5% Triton X-100. Once the matrix has dried, a seed layer of sinapinic crystals is added as a dispersion in xylene. Additional layers of sinapinic acid are added as solutions in 90% ethanol followed by 50% acetonitrile. Numerous peaks with signal to noise ratio of four or greater are observed between 25 kDa to 50 kDa. This represents approximately 10 times as many peaks as are detected using traditional matrix spotting and spraying.


Comparison between immunotherapy efficacy in early non-small cell lung cancer and advanced non-small cell lung cancer: a systematic review.
Currently, immunotherapy is widely used in the treatment of various stages of non-small cell lung cancer. According to clinical experience and results of previous studies, immunotherapy as neoadjuvant therapy seems to exhibit better efficacy against early resectable non-small cell lung cancer as compared to advanced lung cancer, which is often defined as unresectable non-small cell lung cancer. However, this observation has not been established in clinical studies. This systematic review aimed to evaluate the efficacy of immunotherapy in early and late lung cancer, wherein objective response rate (ORR) and disease control rate (DCR) were used as evaluation indexes. The present study also evaluated the safety of immunotherapy in early and late lung cancer, wherein the rate of treatment-related adverse reactions (TRAEs) was used as an indicator. Electronica databases, including PubMed, Cochrane Library, Embase, and other databases, were searched to identify relevant studies. Besides this, all the available reviews, abstracts, and meeting reports from the main international lung cancer meetings were searched manually. ORR, DCR, and TRAEs were extracted as the primary outcomes. A total of 52 randomized controlled trials involving 13,660 patients were shortlisted. It was observed that immunotherapy alone significantly improved DCR in early lung cancer in comparison to advanced lung cancer. Importantly, the improvement in ORR was not to the same extent as reported in the case of advanced lung cancer. The combination of immunotherapy with other therapies, especially immunochemotherapy, significantly improved ORR and DCR in early lung cancer. In terms of safety, immunotherapy either alone or in combination with other therapies exhibited a better safety profile in early lung cancer than in advanced lung cancer. Altogether, the benefits of immunotherapy in early lung cancer appeared to be better than those observed in advanced lung cancer, especially with the regard to the regimen of immunotherapy in combination with chemotherapy. In terms of safety, both immunotherapy alone and its combination with chemotherapy were found to be safer in early lung cancer as compared to advanced lung cancer.


Purification of monoclonal antibodies by complex-displacement chromatography on CM-cellulose.
A single high-capacity chromatographic procedure was used to purify a monoclonal antibody from ascites fluid. A new displacement procedure involving a displacer protein complex is described. The scale-up from 1 ml to 450 ml of ascites sample was easily accomplished with this complex-displacement system. A monoclonal antibody recovery of 79% was measured for the largest-scale purification.


Computed Tomography and Magnetic Resonance Imaging in the Differentiation of Osteoporotic Fractures From Neoplastic Metastatic Fractures.
Determining whether a low-intensity vertebral fracture in an older person, particularly one with a history of cancer, is due to osteoporosis (OP) or is the result of a metastasis, is a not infrequent clinical problem that has important prognostic and therapeutic implications. The 2 types of fracture are usually indistinguishable on plain radiographs and require higher order imaging for diagnosis. Magnetic resonance imaging is the modality of choice because of its unique ability to depict the bone marrow, which becomes transiently edematous in an acute OP fracture. Preservation of at least part of the normal marrow signal, the visualization of a fracture line parallel to the end plates, the presence of an intravertebral cleft, lack of pedicle involvement, and no extra-osseous mass all favor a benign OP fracture. Absence of the preceding signs, particularly if there is complete replacement of the normal bone marrow and a convex posterior contour of the vertebral body, favors a fracture of malignant origin. Non-routine magnetic resonance sequences using diffusion-weighted imaging and/or chemical shift imaging may be helpful in difficult cases.


Recent advances in inhibitors of matrix metalloproteinases for cancer therapy.
Since matrix metalloproteinases (MMPs) have been found to be involved in various diseases, their inhibitors (MMPIs) should be useful as multipotential drugs. Several MMPs are thought to be involved with various diseases in different ways. This review focuses on MMPIs for cancer therapy. MMPIs are expected to be potent antitumor agents with a novel mechanism differing from that of ordinary cytotoxic agents. Numerous studies have been conducted to develop MMPIs for practical use in cancer therapy and some are now in clinical or preclinical stages.


Medical Need: Evaluating a Conceptual Critique of Universal Health Coverage.
Some argue that the concept of medical need is inadequate to inform the design of a universal health care system-particularly an institutional (universal, comprehensive) rather than a residual (minimalist, safety net) system. They argue that the concept (a) contradicts the idea of comprehensiveness; (b) leads to unsustainable expenditures; (c) is too indeterminate for policy; and (d) supports only a prioritarian distribution (and therefore a residual system). I argue (a) that 'comprehensive' understood as 'including the full continuum of care' and 'medically necessary' understood as 'prioritized by medical criteria' are not contradictory, and (b) that UHC is a solution to the problem of sustainability, not its cause. Those who criticize 'medical need' for indeterminacy (c) are not transparent about the source (ethical, semantic, political, or other) of their commitment to their standards of determinacy: they promote standards that are higher than is necessary for legitimate policy, ignoring opportunity costs. Furthermore, the indeterminacy of concepts affects all risk-sharing systems and all systems that rely on medical standard of care. I then argue that (d) the concept of need in itself does not imply a minimal sufficientist standard or a prioritarian distribution; neither does the idea of legitimate public policy dictate that public services be minimalist. The policy choice for a system of health care that is comprehensive and offers as good care as can be achieved when delivered on equal terms and conditions for all is a coherent option.


Aging neural progenitor cells have decreased mitochondrial content and lower oxidative metabolism.
Although neurogenesis occurs in discrete areas of the adult mammalian brain, neural progenitor cells (NPCs) produce fewer new neurons with age. To characterize the molecular changes that occur during aging, we performed a proteomic comparison between primary-cultured NPCs from the young adult and aged mouse forebrain. This analysis yielded changes in proteins necessary for cellular metabolism. Mitochondrial quantity and oxygen consumption rates decrease with aging, although mitochondrial DNA in aged NPCs does not have increased mutation rates. In addition, aged cells are resistant to the mitochondrial inhibitor rotenone and proliferate in response to lowered oxygen conditions. These results demonstrate that aging NPCs display an altered metabolic phenotype, characterized by a coordinated shift in protein expression, subcellular structure, and metabolic physiology.


hDAF porcine cardiac xenograft maintains cardiac output after orthotopic transplantation into baboon--a perioperative study.
Only limited data are available on the physiological functional compatibility of cardiac xenografts after orthotopic pig to baboon transplantation (oXHTx). Thus we investigated hemodynamic parameters including cardiac output (CO) before and after oXHTx. Orthotopic xenogeneic heart transplantation from nine hDAF transgeneic piglets to baboons was performed. We used femoral arterial thermodilution for the invasive assessment of CO and stroke volume. Baseline CO of the baboons after induction of anesthesia was 1.36 (1.0-1.9) l/min. 30 to 60 min after termination of the cardiopulmonary bypass, CO of the cardiac xenograft was significantly increased to 1.72 (1.3-2.1) l/min (P < 0.01). The stroke volumes of the baboon heart before transplantation and the cardiac xenograft was comparable [14.9 (11-26) vs. 11.8 (10-23) ml]. Thus the higher CO was achieved by an increase in heart rate after oXHTx [75.0 (69-110) vs. 140.0 (77-180)/min; P < 0.01]. Despite the increased CO, oxygen delivery was reduced [256 (251-354) vs. 227 (172-477) ml/min; P < 0.01] due to the inevitable hemodilution during the cardiopulmonary bypass and the blood loss caused by the surgical procedures. Our results demonstrate that in the early phase after orthotopic transplantation of hDAF pig hearts to baboons, cardiac function of the donor heart is maintained and exceeds baseline CO. However, in the early intraoperative phase this was only possible by using inotropic substances and vasopressors due to the inevitable blood loss and dilution by the priming of the bypass circuit.


Aromatic hydrocarbon data in sediments from Port Valdez, Alaska.
Polycyclic aromatic hydrocarbons (PAH) were measured in sediments from 14 locations in Port Valdez, Alaska in an effort to understand changes associated with the operation of a marine terminal where crude oil delivered by pipeline was transferred to tankers for marine shipment. Samples of surficial sediment were collected annually from 1989 through 2019 at water depths of roughly 30 to 240 m by haps corer of Van Veen grab. PAH concentrations were determined by flame-ionization gas chromatography from 1989 to 2002 and by single ion monitoring gas chromatography-mass spectrometry from 2003 to 2019. Geographic coordinates and environmental variables (water depth, total organic carbon, and sediment grain-size) were also determined. The data are useful for comparisons to trend data elsewhere as well as the investigation of measurement uncertainty in chemical measurements.


The troubled self in women with severe eating disorders (anorexia nervosa and bulimia nervosa). A study using interviews, self-reports, and percept-genetic methods.
Fifteen anorectic (A) and 13 bulimic (B) patients aged 20-49 years, all seriously ill, and 21 controls were studied, using a half-structured interview, the Tennessee Self Concept Scale, the tachistoscopic Identity Test (IT), and two other percept-genetic tests. The differences between A and B were not particularly pronounced, A patients being on the whole more sensitive and self-directed, and B patients more depressive and object-directed. The IT differentiated between patients and controls very powerfully with regard to alexithymia. A type of response in that test, emphasizing the eyes, was seen as a search for guidance. Descriptions of mother were generally negative.


Effect of institutional quality and renewable energy consumption on CO2 emissions-an empirical investigation for developing countries.
This paper investigates the role of institutional quality in moderating the impact of energy consumption on CO2 emission, with other variables such as trade, capital formation, FDI, financial development and population in 39 developing countries for 1995-2017. We use mean group (MG), augmented mean group (AMG), common correlated effects mean group (CCEMG) estimator, dynamic system GMM, panel grouped-mean FMOLS and panel quantile regression for the empirical results. From the different estimation techniques, we find that institutional quality moderates energy consumption and strengthens its effectiveness in abating carbon emissions. The combined influence of institutional quality and sector wise energy consumption on emissions is significant and negative. Our finding also confirms the Environmental Kuznets curve (EKC) hypothesis in the presence of institutional quality. Renewable energy consumption is also found to reduce emissions significantly in the long run. Given the importance of institutional quality and renewable energy in reducing CO2 emission, the policymakers need to improve the quality of institutions and deploy more renewable energy for final consumption to achieve long-term climate goals.


Relationship between the transport from isolated nuclei of two abundant cytoplasmic messengers and the source of a messenger RNA transport factor.
Messenger RNA transport from isolated nuclei requires a 35 X 10(3) dalton cytoplasmic protein(s) which is present in both the cytosol and polyribosome fractions. Recombinant DNA probes containing cDNA inserts were used to quantitate the transport of rat liver-specific albumin and male rat liver-specific alpha 2U-globulin messenger RNA (mRNA) from male rat liver nuclei in response to the mRNA transport factors from homologous and heterologous tissues. No mRNA transport occurs in the absence of the transport factor(s). Both messengers are transported proportionately in response to the factor(s) from male or female rat liver cytosol, or from the polyribosomes (messenger ribonucleoprotein) of male or female rat liver, or brain. The transport factor(s) do not, therefore, appear to differentiate between the coding sequences of two unrelated hepatic messenger RNA's.


A simple guideline to facilitate axial alignment of vascular grafts.
The proper orientation of vascular prostheses is essential for successful performance of vascular reconstructions. To prevent axial rotation of grafts, particularly in long tunnels such as in the axillo-femoral or subsartorial position, vascular prostheses with a simple guideline incorporated within their fibers were employed. The advantages of these grafts are discussed.


Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model.
We developed a preclinical prostate cancer model to study the feasibility of adoptive immunotherapy for residual tumor following neo-adjuvant in situ adenoviral-vector-mediated interleukin 12 (AdIL-12) gene therapy. Splenocytes were obtained from mice with orthotopic 178-2 BMA metastatic mouse prostate cancers treated previously with AdIL-12, or a vector with the IL-12 genes plus the costimulatory gene B7-1 (AdIL-12/B7), or a control gene (Adbetagal). The splenocytes were subsequently injected intravenously into syngeneic mice bearing orthotopic 178-2 BMA tumors generated 3 days previously. Significant orthotopic tumor growth suppression was achieved with splenocytes derived from mice whose tumors had been injected with AdIL-12 compared to splenocytes from control Adbetagal mice (P = 0.0005) and splenocytes from AdIL-12/B7-treated mice significantly suppressed spontaneous lung metastases compared to splenocytes from control mice (P = 0.0356). Adoptive transfer of splenocytes from either AdIL-12 (P = 0.004) or AdIL-12/B7 (P = 0.009)-treated mice significantly prolonged survival relative to controls. Transfer of NK and tumor-specific CTL activities was detected and depletion of CD4+ and CD8+ T cells by in vitro antibody-mediated complement lysis of the splenocytes prior to injection abrogated the effects. Systemic IL-12 administration delivered by intramuscular AdIL-12 injection enhanced the antitumor effects of adoptive splenocyte transfer and boosted the CTL response. Our data provide evidence that this form of adoptive immunotherapy can enhance the effectiveness of neo-adjuvant in situ IL-12 gene therapy in cases of persistent malignancy.


Comparative proteomic profiling in compatible and incompatible interactions between hop roots and Verticillium albo-atrum.
Verticillium wilt, caused by the soil borne fungal pathogen Verticillium albo-atrum, is a serious threat to hop (Humulus lupulus L.) production in several hop-growing regions. A proteomic approach was applied to analyse the response of root tissue in compatible and incompatible interactions between hop and V. albo-atrum at 10, 20 and 30 days after inoculation, using two-dimensional difference gel electrophoresis (2D-DIGE) coupled with de novo sequencing of derivatized peptides. Approximately 1200 reproducible spots were detected on the gels, of which 102 were identified. In the compatible interaction, 252 spots showed infection-specific changes in spot abundance and an accumulation of defence-related proteins, such as chitinase, β-glucanase, thaumatin-like protein, peroxidase and germin-like protein, was observed. However, no significant infection-specific changes were detected in the incompatible interaction. The results indicate that resistance in this pathosystem may be conferred by constitutive rather than induced defence mechanisms. The identification and high abundance of two mannose/glucose-specific lectin isoforms present only in the roots of the resistant cultivar suggests function of lectins in hop resistance against V. albo-atrum.