Rhabdomyomatous hamartomata of the pharyngeal region with bilateral microtia and aural atresia: a new association?
Bilateral microtia with aural atresia is rare. Rhabdomyomatous hamartomata containing salivary tissue, situated bilaterally and symmetrically simulating the palatine (faucial) tonsils, has apparently not been reported. We present the combination of these findings in two unrelated patients. In the first case, the patient was exposed prenatally to 13-cis-retinoic acid (isotretinoin) and has typical features of this exposure, including bilateral microtia with aural atresia and bilateral 7th nerve palsies. Due to symptoms of obstructive sleep apnea, patient 1 had a "tonsillectomy" and adenoidectomy. Histopathologic studies demonstrated rhabdomyomatous hamartomata containing salivary and striated muscle tissue in place of the palatine tonsils. In the second case, the patient had been prenatally exposed to alcohol, cocaine, and marijuana. He has been noted to have developmental delay and behavioral issues in addition to bilateral microtia with aural atresia. "Tonsillectomy" and adenoidectomy were performed to alleviate chronic upper respiratory infections and snoring. Again, histopathologic studies of the tissue submitted as "tonsil" demonstrated rhabdomyomatous hamartomata containing salivary and muscle tissue. Although an extended banded karyotype and subtelomere panel were normal, a genetic etiology for the second patient's features cannot be excluded. We hypothesize that the findings of bilateral microtia with aural atresia and rhabdomyomatous hamartomata containing salivary and muscle tissue in the area of the palatine tonsils may represent a newly recognized association, which may have a teratogenic and/or genetic etiology.


[HANSEN'S DISEASE IN ISRAEL].
Hansen's disease (HD) is an anthropophylic, infectious, chronic disease, caused by Mycobacterium leprae. The systemic disease, affecting both males and females at any age, involves mainly the skin and the peripheral nerves located in the limbs close to the skin. Traditionally the treatment of HD patients was entrusted to dermatologists. Current drug therapy given at an early stage can prevent many of the complications, and enables patients to go on with life. In 95% of the population there is an innate immunity, which following exposure, enables the development of an effective immune response preventing the development of overt clinical disease. So far, there is neither an effective vaccination nor a simple test which can predict susceptibility to the infection. A long history of ignorance and stigmatization may add a social dimension to the physical ailment and suffering of HD patients. Despite the elimination campaign declared by the WHO in the early 1990s, the disease continues to exist. New patients are diagnosed each year, though in lower numbers and HD patients can be found all over the world. The relatively low prevalence of HD in non-endemic countries and the misconception that it has been eradicated long ago, make the awareness to the disease extremely poor. HD is usually not included in the differential diagnosis even when clear symptoms are present. This results in a very late diagnosis of new HD patients, thus missing the window of opportunity for early treatment which could prevent complications and disability. The purpose of this update is to raise awareness to the existence of HD in Israel and its diagnosis, to present updated epidemiological data for Israel and a glimpse at the global situation.


Prebiotic materials from on and off the early Earth.
One of the greatest puzzles of all time is how did life arise? It has been universally presumed that life arose in a soup rich in carbon compounds, but from where did these organic molecules come? In this article, I will review proposed terrestrial sources of prebiotic organic molecules, such as Miller-Urey synthesis (including how they would depend on the oxidation state of the atmosphere) and hydrothermal vents and also input from space. While the former is perhaps better known and more commonly taught in school, we now know that comet and asteroid dust deliver tons of organics to the Earth every day, therefore this flux of reduced carbon from space probably also played a role in making the Earth habitable. We will compare and contrast the types and abundances of organics from on and off the Earth given standard assumptions. Perhaps each process provided specific compounds (amino acids, sugars, amphiphiles) that were directly related to the origin or early evolution of life. In any case, whether planetary, nebular or interstellar, we will consider how one might attempt to distinguish between abiotic organic molecules from actual signs of life as part of a robotic search for life in the Solar System.


Inequity aversion is observed in common marmosets but not in marmoset models of autism induced by prenatal exposure to valproic acid.
Humans and various nonhuman primates respond negatively to inequity not in their favor (i.e., inequity aversion), when inequity between two individuals is introduced. Common marmosets, a highly prosocial species, further discriminated between human actors who reciprocated in social exchanges, and those who did not. Conversely, marmoset models of autism, induced via prenatal exposure to valproic acid (VPA marmosets), did not discriminate. Interestingly, previous studies of inequity aversion in marmosets have produced negative results, or were limited to males. Recent studies suggest that inequity aversion is highly influenced by the tasks employed. Here we show inequity aversion in both male and female marmosets using a novel task which required a relatively long duration of response. Marmosets were required to hold a spoon for 2 s to receive a reward. Marmosets successfully performed the task when they observed an unfamiliar conspecific partner obtaining the same reward (equity test). However, when they witnessed the partner receiving a more attractive reward for equal effort (inequity test), unexposed marmosets, which were not exposed to either valproic acid or saline during the fetal period refused to respond. This inequity aversion was not observed in unexposed marmosets when the partner was absent. In contrast, marmosets with fetal exposure to valproic acid (VPA marmosets) successfully executed the task irrespective of their partners' reward conditions. As prenatal exposure to valproic acid is a well-known procedure to induce autism spectrum disorder (ASD)-like behaviors in rodents, we propose that VPA marmosets failed to show inequity aversion due to weak social motivation or interest towards others.


Estimation of aerosol mass scattering efficiencies under high mass loading: case study for the megacity of Shanghai, China.
Aerosol mass scattering efficiency (MSE), used for the scattering coefficient apportionment of aerosol species, is often studied under the condition of low aerosol mass loading in developed countries. Severe pollution episodes with high particle concentration frequently happened in eastern urban China in recent years. Based on synchronous measurement of aerosol physical, chemical, and optical properties at the megacity of Shanghai for two months during autumn 2012, we studied MSE characteristics at high aerosol mass loading. Their relationships with mass concentrations and size distributions were examined. It was found that MSE values from the original US IMPROVE algorithm could not represent the actual aerosol characteristics in eastern China. It results in an underestimation of the measured ambient scattering coefficient by 36%. MSE values in Shanghai were estimated to be 3.5 ± 0.55 m(2)/g for ammonia sulfate, 4.3 ± 0.63 m(2)/g for ammonia nitrate, and 4.5 ± 0.73 m(2)/g for organic matter, respectively. MSEs for three components increased rapidly with increasing mass concentration in low aerosol mass loading, then kept at a stable level after a threshold mass concentration of 12–24 μg/m(3). During severe pollution episodes, particle growth from an initial peak diameter of 200–300 nm to a peak diameter of 500–600 nm accounts for the rapid increase in MSEs at high aerosol mass loading, that is, particle diameter becomes closer to the wavelength of visible lights. This study provides insights of aerosol scattering properties at high aerosol concentrations and implies the necessity of MSE localization for extinction apportionment, especially for the polluted regions.


ERCC1: impact in multimodality treatment of upper gastrointestinal cancer.
Platinum-based drugs and radiation are key elements of multimodality treatment in a wide variety of solid tumors and especially tumors of the upper gastrointestinal tract. Cytotoxicity is directly related to their ability to cause DNA damage. This event consecutively triggers the nucleotide excision repair (NER) complex. The NER capacity has a major impact on chemo and radiation sensitivity, emergence of resistance and patient outcome. Excision repair cross-complementing group 1 (ERCC1) is a key molecule in NER. This review provides an overview of the NER complex with a focus on ERCC1. Recent literature has been analyzed and provides information regarding the potential role of ERCC1 as a prognostic factor in multimodality treatment of upper gastrointestinal cancer and cancer risk. To date, the role of ERCC1 as a predictive marker for individual multimodality treatment is far from being firmly established for routine use. However, with reliable methods, established cut-off values and validation in large, prospective, randomized trials, ERCC1 may possibly prove to play an important role as a tumor marker in individualized treatment for upper gastrointestinal cancer.


Use of bone grafts for the enhancement of a GTR-based root coverage procedure: a pilot case study.
The use of guided tissue regeneration (GTR) procedures for the treatment of gingival recession has shown encouraging results and is gaining clinical acceptance. However, attaining space maintenance beneath the membrane remains a problem for clinicians. Hence, the purpose of this pilot case study was to evaluate the effect of adjunctive demineralized freeze-dried bone allograft (DFDBA) placement during collagen membrane GTR-based root coverage procedures. Five patients with Miller Class I or II defects were treated with a combination of DFDBA and collagen membrane. Clinical parameters monitored include recession depth, probing attachment level, probing depth, width of keratinized gingiva, and recession width. Measurements were taken at baseline and 6 months. A statistically significant reduction in recession depth (3.1 +/- 0.7 mm) was observed at 6 months, representing 93.4% total attainable root coverage. A significant reduction of recession width (3.5 +/- 1.2 mm) after 6 months was also noted. Clinically, a statistically significant mean gain of 3.3 +/- 0.6 mm in clinical attachment and 0.8 +/- 0.9 mm in keratinized gingiva were obtained at 6 months. No statistically significant difference was found in probing depth between baseline and 6 months postoperative. Plaque and gingival indices remained low and showed no statistically significant change throughout the study period. Results from this pilot case study indicate that use of DFDBA during collagen membrane GTR-based root coverage could be beneficial.


Endometrial cancer and microsatellite instability status.
Microsatellite instability (MSI) is an important factor in the development of various cancers as an identifier of a defective DNA mismatch repair system. The objective of our study was to define the association between microsatellite instability status and traditional clinicopathologic characteristics of endometrioid type adenocarcinoma. MSI status of endometrial cancer was examined by employing the Promega MSI Analysis System. This system uses 5 mononucleotide markers to identify MSI in tumour and normal tissue DNA (BAT-25, BAT-26, NR-21, NR-24, and MONO-27), and 2 pentanucleotide markers (Penta C and Penta D) for specimen identification. In this study, we investigated MSI status in 109 endometrial carcinomas. One hundred (92%) of 109 endometrial cancers showed endometrioid type histology and only 9 (8%) non-endometrioid type. MSI-high was found in 17% (17/100) of endometrioid type adenocarcinomas, in 0% (0/9) of non-endometrioid carcinomas. Selected clinicopathologic parameters for endometrioid type adenocarcinomas were compared to the MSI status which was separated into two groups - MSI-high and MSI stable. The results showed that MSI-high status was related to clinicopathologic parameters such as deep myometrial invasion and higher histologic grade in endometrioid type adenocarcinomas.


Correlation between Xerostomia index, Clinical Oral Dryness Scale, and ESSPRI with different hyposalivation tests.
Xerostomia is a subjective measure of dry mouth, while hyposalivation is an objective measure of reduced saliva flow rate. In this study, we aim to assess the association between commonly used xerostomia scoring systems, with different hyposalivation measures among Sjogren Syndrome (SS) patients. In a cohort of SS patients, we assessed xerostomia using Xerostomia index, clinical oral dryness scale (CODS), and the European League Against Rheumatism SS Patient-Reported Index (ESSPRI), and we assessed hyposalivation using unstimulated whole saliva flow (UWS), stimulated whole saliva flow (SWS), and stimulated parotid flow (SPF). We analyzed the association between xerostomia and hyposalivation using association tests in SPSS. We included a total of 49 patients in this study, of which 34 (68%) had primary SS, and 15 (32%) had secondary. CODS was significantly correlated with SWS (P=0.048), with a negative correlation coefficient of 0.216, and with SPF (P=0.009), with a negative correlation coefficient of 0.291. The dryness domain of ESSPRI was significantly correlated with UWS (P=0.031) with a negative correlation coefficient of 0.233. CODS is the scoring system with the highest correlation with hyposalivation, particularly SWS and SPF, followed by ESSPRI dry domain, which is correlated with UWS. Xerostomia index is not correlated with hyposalivation.


Nrf2-Mediated Antioxidant Defense and Peroxiredoxin 6 Are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid.
Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative trait locus mapping, and correlation analyses in rat BXH/HXB recombinant inbred strains, as well as response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs. Comprehensive analysis of WAT samples identified ∼160 regioisomers, documenting the complexity of this lipid class. The linkage analysis highlighted several members of the nuclear factor, erythroid 2 like 2 (Nrf2)-mediated antioxidant defense system (Prdx6, Mgst1, Mgst3), lipid-handling proteins (Cd36, Scd6, Acnat1, Acnat2, Baat), and the family of flavin containing monooxygenases (Fmo) as the positional candidate genes. Transgenic expression of Nrf2 and deletion of Prdx6 genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.


[The endocrine function of skeletal muscle].
Skeletal muscle has long been considered as an effector organ under the control of neural and humoral regulation. Recent studies indicated that skeletal muscle is not only an effector organ but also an endocrine organ. It is reported that the skeletal muscle can express, synthesis and secrete a lot of active factors, such as regulatory peptide, cytokine, growth factor and so on. The active factors play important roles not only in the growth, metabolism and motor function of skeletal muscle per se by paracrine/autocrine pathway but also in the function of peripheral tissues and organs by endocrine pathway. It is worthwhile to pay close attention to the significant effects of the skeletal muscle active factors on locomotor disease and some systemic diseases. This paper reviews the active factors secreted by skeletal muscles and their physiological and pathophysiological significance.


Chronic Intermittent Hypobaric Hypoxia (4600 M) Attenuates Pulmonary Vasodilation Induced by Acetylcholine or Sodium Nitroprusside.
Moraga, Fernando A., Giselle Miranda, Vasthi López, Carmen Vallejos, and Daniel Silva. Chronic intermittent hypobaric hypoxia (4600 M) attenuates pulmonary vasodilation induced by acetylcholine or sodium nitroprusside. High Alt Med Biol. 19:149-155, 2018. Previous studies performed in rats exposed to chronic intermittent hypobaric hypoxia (CIHH), at a simulated altitude of 4600 m, showed reduced nitric oxide (NO) production, increased arginase activity, and increased oxidative stress. However, studies on vascular function are scarce. Our aim was to measure plasma nitrate and nitrite (NOx) concentration and study pulmonary vascular function in rats exposed to CIHH in the presence of potassium chloride (KCl), acetylcholine (Ach), and sodium nitroprusside (SNP). Thirty male Wistar rats were divided into two groups: A control group (normoxia (N), n = 10) and a CIHH group (2N × 2H × 30 days, n = 20). CIHH exposure was performed in a hypobaric chamber at 428 Torr (4600 m). Noninvasive systolic blood pressure (SBP), heart rate, and body weight (BW) were measured. Blood samples were obtained to measure NOx levels and hematocrit (Hct). CIHH animals that gained BW and presented a Hct <20% and maintained SBP were classified as tolerant, and animals that lost >30% of their BW, increased Hct and SBP >20% were classified as intolerant. Animals were sacrificed and small pulmonary arteries (SPA) were obtained to perform concentration-response curves to KCl, Ach, and SNP. Intolerant rats (30%) had decreased NOx levels. SPA had a larger vasocontraction response to KCl and a lower dilation response to SNP in the SPA compared to tolerant and control animals. In addition, SPA had a lower dilatation response to Ach compared with the control. Together, these results show that CIHH alters endothelium-dependent vasodilation.


Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development.
Cleavage of heparan sulphate proteoglycans (HSPGs) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Heparanase, degrading heparan sulphate (HS) at specific intrachain sites, is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase enzyme is preferentially expressed in human tumours and its overexpression in low-metastatic tumour cells confers a highly invasive phenotype in experimental animals. Heparanase also releases angiogenic factors and accessory fragments of HS from the tumour microenvironment and induces an angiogenic response in vivo. Heparanase may thus facilitate tumour cell invasion, vascularization and survival in a given microenvironment, all critical events in cancer progression. These observations, the anticancerous effect of heparanase-inhibiting molecules, and the unexpected identification of a single predominant functional heparanase suggest that the enzyme is a promising target for drug development.


Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C-7 or C-15 and Disubstitutions at C-7 and C-25.
The taccalonolides are a unique class of microtubule stabilizers isolated from Tacca spp. that have efficacy against drug-resistant tumors. Our previous studies have demonstrated that a C-15 acetoxy taccalonolide, AF, has superior in vivo antitumor efficacy compared to AJ, which bears a C-15 hydroxy group. With the goal of further improving the in vivo efficacy of this class of compounds, we semisynthesized and tested the biological activities of 28 new taccalonolides with monosubstitutions at C-7 or C-15 or disubstitutions at C-7 and C-25, covering a comprehensive range of substituents from formic acid to anthraquinone-2-carbonyl chloride. The resulting taccalonolide analogues with diverse C-7/C-15/C-25 modifications exhibited IC50 values from 2.4 nM to >20 μM, allowing for extensive in vitro structure-activity evaluations. This semisynthetic strategy was unable to provide a taccalonolide with improved therapeutic window due to hydrolysis of substituents at C-7 or C-15 regardless of size or steric bulk. However, two of the most potent new taccalonolides, bearing isovalerate modifications at C-7 or C-15, demonstrated potent and highly persistent antitumor activity in a drug-resistant xenograft model when administered intratumorally. This study demonstrates that targeted delivery of the taccalonolides to the tumor could be an effective, long-lasting approach to treat drug-resistant tumors.


A Bir1-Sli15 complex connects centromeres to microtubules and is required to sense kinetochore tension.
Proper connections between centromeres and spindle microtubules are of critical importance in ensuring accurate segregation of the genome during cell division. Using an in vitro approach based on the sequence-specific budding yeast centromere, we identified a complex of the chromosomal passenger proteins Bir1 and Sli15 (Survivin and INCENP) that links centromeres to microtubules. This linkage does not require Ipl1/Aurora B kinase, whose targeting and activation are controlled by Bir1 and Sli15. Ipl1 is the tension-dependent regulator of centromere-microtubule interactions that ensures chromosome biorientation on the spindle. Elimination of the linkage between centromeres and microtubules mediated by Bir1-Sli15 phenocopies mutations that selectively cripple Ipl1 kinase activation. These findings lead us to propose that the Bir1-Sli15-mediated linkage, which bridges centromeres and microtubules and includes the Aurora kinase-activating domain of INCENP family proteins, is the tension sensor that relays the mechanical state of centromere-microtubule attachments into local control of Ipl1 kinase activity.


Clinics in diagnostic imaging (86). Ruptured bronchogenic cyst.
An eight-year-old boy presented with a sudden onset of chest pain. He had been diagnosed to have a left spontaneous pneumothorax. Chest radiographs and computed tomography of the chest showed a thin-walled cyst in the left lower lobe. Thoracotomy and a segmentectomy of the apical segment of the lower lobe was performed, confirming the diagnosis of a ruptured bronchogenic cyst. Imaging findings of various pulmonary cystic lesions in children are discussed.


Remote terahertz wireless power transfer with self-resonating spoof plasmonic structures.
In this paper, we use a pair of self-resonating subwavelength spoof plasmonic structures to achieve remote non-radiative terahertz wireless power transfer, while nearly without affecting the electromagnetic environment of free space around the structure. The resonating frequency and quality factor of the magnetic dipole mode supported by the spoof plasmonic structures can be freely tuned by tailoring the geometric structure. By putting the weak source and detector into the self-resonating structures, we can find that the effective non-radiative terahertz power transferring distance can reach several hundred times the radius of the structures. Finally, we also demonstrate the efficient wireless power transfer capability for the multi-target receiving system. These results may provide a novel approach to the design of non-radiative terahertz wireless power transfer and communications.


Red cell hypoplasia and monoclonal gammopathy in a patient with lymphoproliferative disorder.
A 69-year-old male was observed to have red cell hypoplasia. Two years later monoclonal gammopathy IgG-I, K, Gma+ and InV (1-) was documented in this patient. Persistent lymphocytosis, abnormal response to phytohemagglutinin, and at autopsy multiple lymphoid nodules occurring in the bone marrow, suggestive of lymphoproliferative disorder, were observed. A review of the literature indicates that this clinical presentation is rare. The possibility that red cell aplasia may be associated with lymphoproliferative disorder in some instances must be considered inasmuch as this may have an important bearing in the management of such patients.


Effect of Cry3Bb1-expressing transgenic corn on plant-to-plant movement by western corn rootworm larvae (Coleoptera: Chrysomelidae).
Dispersal of larvae of the western corn rootworm, Diabrotica virgifera virgifera LeConte, in specific combinations of transgenic corn expressing the Cry3Bb1 protein and nontransgenic, isoline corn was evaluated in a 2-yr field study. In total, 1,500 viable western corn rootworm eggs were infested in each subplot. Each year, plant damage and larval recovery were evaluated among four pedigree combinations (straight transgenic; straight nontransgenic corn; nontransgenic corn with a transgenic central, infested plant; and transgenic corn with a nontransgenic central, infested plant) on six sample dates between egg hatch and pupation. For each subplot, the infested plant, three successive plants down the row (P1, P2, and P3), the closest plant in the adjacent row of the plot, and a control plant were sampled. The number of western corn rootworm larvae recovered from transgenic rootworm-resistant plants adjacent to infested nontransgenic plants was low and not statistically significant in either 2001 or 2002. In 2001, significantly fewer larvae were recovered from transgenic rootworm-resistant plants than from nontransgenic plants when both were adjacent to infested, nontransgenic plants. In 2002, significantly more neonate western corn rootworm larvae were recovered from nontransgenic plants adjacent to infested, transgenic rootworm-resistant plants than nontransgenic plants adjacent to infested, nontransgenic plants on the second sample date. Together, these data imply that both neonate and later instar western corn rootworm larvae prefer nontransgenic roots to transgenic rootworm-resistant roots when a choice is possible. However, when damage to the infested, nontransgenic plant was high, western corn rootworm larvae apparently moved to neighboring transgenic rootworm-resistant plants and caused statistically significant, although only marginally economic, damage on the last sample date in 2001. Implications of these data toward resistance management plan are discussed.


Neural Correlates of Response Inhibition and Conflict Control on Facial Expressions.
Response inhibition and conflict control on affective information can be regarded as two important emotion regulation and cognitive control processes. The emotional Go/Nogo flanker paradigm was adopted and participant's event-related potentials (ERPs) were analyzed to investigate how response inhibition and conflict control interplayed. The behavioral findings revealed that participants showed higher accuracy to identify happy faces in congruent condition relative to that in incongruent condition. The electrophysiological results manifested that response inhibition and conflict control interplayed during the detection/conflict monitoring stage, and Nogo-N2 was more negative in the incongruent trials than the congruent trials. With regard to the inhibitory control/conflict resolution stage, Nogo responses induced greater frontal P3 and parietal P3 responses than Go responses did. The difference waveforms of N2 and parietal P3 showed that response inhibition and conflict control had distinct processes, and the multiple responses requiring both conflict control and response inhibition processes induced stronger monitoring and resolution processes than conflict control. The current study manifested that response inhibition and conflict control on emotional information required separable neural mechanisms during emotion regulation processes.


Limonoids of the phragmalin type from Swietenia macrophylla and their chemotaxonomic significance.
Species of Swietenia elaborate limonoid chemistry along only one route, which leads to the mexicanolide type in most species and the phragmalin type in S. mahogani. A hexane extract from leaves of S. macrophylla afforded six new phragmalins with a 8,9,30-ortho-ester unit, namely, 6-O-acetylswietephragmin E (1), 3beta-O-destigloyl-3beta-O-benzoyl-6-O-acetylswietephragmin E (2), 12alpha-acetoxyswietephragmin C (3), 3beta-O-destigloyl-3beta-O-benzoyl-12alpha-acetoxyswietephragmin C (4), 12alpha-acetoxyswietephragmin D (5), and 3beta-O-destigloyl-3beta-O-benzoyl-12alpha-acetoxyswietephragmin D (6). This appears to be the first record of phragamalins from S. macrophylla, and this study shows the potential of tricyclic [3.3.1(2,10).1(1,4)]-decane limonoids as taxonomically useful chemical markers in the Meliaceae.


Human Immunoglobulin Heavy Gamma Chain Polymorphisms: Molecular Confirmation Of Proteomic Assessment.
Immunoglobulin G (IgG) proteins are known for the huge diversity of the variable domains of their heavy and light chains, aimed at protecting each individual against foreign antigens. The IgG also harbor specific polymorphism concentrated in the CH2 and CH3-CHS constant regions located on the Fc fragment of their heavy chains. But this individual particularity relies only on a few amino acids among which some could make accurate sequence determination a challenge for mass spectrometry-based techniques.The purpose of the study was to bring a molecular validation of proteomic results by the sequencing of encoding DNA fragments. It was performed using ten individual samples (DNA and sera) selected on the basis of their Gm (gamma marker) allotype polymorphism in order to cover the main immunoglobulin heavy gamma (IGHG) gene diversity. Gm allotypes, reflecting part of this diversity, were determined by a serological method. On its side, the IGH locus comprises four functional IGHG genes totalizing 34 alleles and encoding the four IgG subclasses. The genomic study focused on the nucleotide polymorphism of the CH2 and CH3-CHS exons and of the intron. Despite strong sequence identity, four pairs of specific gene amplification primers could be designed. Additional primers were identified to perform the subsequent sequencing. The nucleotide sequences obtained were first assigned to a specific IGHG gene, and then IGHG alleles were deduced using a home-made decision tree reading of the nucleotide sequences. IGHG amino acid (AA) alleles were determined by mass spectrometry. Identical results were found at 95% between alleles identified by proteomics and those deduced from genomics. These results validate the proteomic approach which could be used for diagnostic purposes, namely for a mother-and-child differential IGHG detection in a context of suspicion of congenital infection.


Do women with complex alcohol and other drug use histories want women-only residential treatment?
Women-only addiction services tend to be provided on a poorly evidenced assumption that women want single-sex treatment. We draw upon women's expectations and experiences of women-only residential rehabilitation to stimulate debate on this issue. Semi-structured interviews were undertaken with 19 women aged 25-44 years [currently in treatment (n = 9), successfully completed treatment (n = 5), left treatment prematurely (n = 5)]. All had histories of physical or sexual abuse, and relapses linked to relationships with men. Interviews were audio-recorded, transcribed verbatim, coded and analysed inductively following Iterative Categorization. Women reported routinely that they had been concerned, anxious or scared about entering women-only treatment. They attributed these feelings to previous poor relationships with women, being more accustomed to male company and negative experiences of other women-only residential settings. Few women said that they had wanted women-only treatment, although many became more positive after entering the women-only service. Once in treatment, women often explained that they felt safe, supported, relaxed, understood and able to open up and develop relationships with other female residents. However, they also described tensions, conflicts, mistrust and social distancing that undermined their treatment experiences. Women who have complex histories of alcohol and other drug use do not necessarily want or perceive benefit in women-only residential treatment.


[Systemic treatment of liver and biliary tumors].
Hepatocellular carcinoma (HCC) is generally difficult to treat. This is primarily due to the reduced liver function of most patients and the low sensitivity of liver cancer cells to chemotherapy. This has been demonstrated in many clinical trials. Molecular therapies might represent an improvement in the systemic treatment of patients with HCC. In addition to anti-angiogenic drugs, compounds which interfere with specific signal transduction cascades have shown promising results in smaller trials. There are only limited numbers of studies about the systemic treatment options for biliary cancers. To date, the best response rates have been achieved with combination chemotherapies containing platinum analogues and gemcitabine. In the absence of larger clinical phase III trials, no standard chemotherapy for biliary cancers exists today.


[Research progress of the anti-proliferation effect of emodin on VSMCs].
Emodin has such pharmacological effects as ant-inflammatory, anti-tumor, immunoregulation. Meanwhile, emodin could be used for inhibiting the proliferation of vascular smooth muscle cells (VSMC). Many foreign studies demonstrated that emodin had an effect on inhibiting proliferation of VSMCs and cell migration and promoting cell apoptosis, and probed into molecular mechanisms in all aspects. Besides, clinical translational researches and application explorations were also carried out. This article summarizes the research progress of the anti-proliferation effect of emodin on VSMCs.


Concurrent large spindle cell and ordinary lipomas.
The number of reported coexistences of ordinary lipoma and spindle cell lipoma is very limited in the literature. We present a patient with neighboring large spindle cell lipoma and ordinary lipoma in the posterior neck. Clinical, radiologic, and histologic findings of the case are presented with distinguished figures. Complete surgical removal confirmed the diagnoses. These lipomatous tumors may develop coincidentally and magnetic resonance imaging is overtly adequate in identifying their nature.


Construction of exchange-correlation functionals through interpolation between the non-interacting and the strong-correlation limit.
Drawing on the adiabatic connection of density functional theory, exchange-correlation functionals of Kohn-Sham density functional theory are constructed which interpolate between the extreme limits of the electron-electron interaction strength. The first limit is the non-interacting one, where there is only exchange. The second limit is the strong correlated one, characterized as the minimum of the electron-electron repulsion energy. The exchange-correlation energy in the strong-correlation limit is approximated through a model for the exchange-correlation hole that is referred to as nonlocal-radius model [L. O. Wagner and P. Gori-Giorgi, Phys. Rev. A 90, 052512 (2014)]. Using the non-interacting and strong-correlated extremes, various interpolation schemes are presented that yield new approximations to the adiabatic connection and thus to the exchange-correlation energy. Some of them rely on empiricism while others do not. Several of the proposed approximations yield the exact exchange-correlation energy for one-electron systems where local and semi-local approximations often fail badly. Other proposed approximations generalize existing global hybrids by using a fraction of the exchange-correlation energy in the strong-correlation limit to replace an equal fraction of the semi-local approximation to the exchange-correlation energy in the strong-correlation limit. The performance of the proposed approximations is evaluated for molecular atomization energies, total atomic energies, and ionization potentials.


Impulsivity Relates to Relative Preservation of Mesolimbic Connectivity in Patients with Parkinson Disease.
The relationship between Parkinson Disease (PD) pathology, dopamine replacement therapy (DRT), and impulse control disorder (ICD) development is still incompletely understood. Given the sensorimotor-lateral substantia nigra (SN) selective degeneration associated with PD, we posit that a relative sparing of the limbic-medial SN in the context of DRT drives impulsive, reward-seeking behavior in PD patients with recent history of severe impulsivity. Impulsive and control participants were selected from a consecutive list of PD patients receiving pre-operative deep brain stimulation (DBS) planning scans including 3T structural MRI and 64 direction diffusion tensor imaging (DTI). Using previously identified substantia nigra (SN) subsegment network connectivity profiles to develop classification targets, split-hemisphere target-based SN segmentation with probabilistic tractography was performed. The relative subsegment volumes and strength of connectivity between the SN and the limbic, associative, and motor network targets were compared. Our results show that there is greater probability of connectivity between the SN and limbic network targets relative to motor and associative network targets in PD patients with recent history of severe impulsivity as compared to PD patients without impulsivity (P = 0.0075). We did not observe relative volumetric subsegment differences across groups. Firstly, our results suggest that fine-grained, atlas-derived classification targets may be used in PD to parcellate and classify functionally distinct subsegments of the SN, with the apparent preservation of previously reported topographical limbic-medial SN, associative-ventral SN, and sensorimotor-lateral SN orientation. We suggest that relative, as opposed to absolute, degeneration amongst SN-associated dopaminergic networks relates to the impulsivity phenotype in PD.


Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemotherapy moves toward the clinic.
In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G2, and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.


Structures and optical properties of two phases of SrMgF4.
SrMgF4 has an extremely large bandgap Eg of 12.50 eV as obtained from reflection dispersion. The symmetry of this crystal is monoclinic P21 at room temperature and transforms to the orthorhombic Cmc21 phase near 478 K as the temperature increases. The acentric character of the low-temperature (LT) phase is confirmed by pyroelectric luminescence at T < 440 K. The fundamental absorption edge of the LT phase is located at 122 nm (10.15 eV). A considerable difference between the absorption edge and bandgap Eg is due to the strong exciton absorption. The first-principles electronic structure, refractive indices, nonlinear susceptibility and polarizability were calculated for both LT and high-temperature (HT) phases. Band-to-band transitions are direct for the LT phase but indirect for HT. In spite of relatively low birefringence (∼0.017) and nonlinear susceptibility (∼0.044 pm V(-1), an order lower than that in KDP), SrMgF4 crystals are considered promising for nonlinear optics thanks to their transparency far in the vacuum ultraviolet spectral region.


A taxonomic revision of the Old World genus Dichoteleas Kieffer (Hymenoptera, Scelionidae).
The genus Dichoteleas Kieffer (Scelionidae: Scelioninae) is known only from the Old World: Kenya, Tanzania, Malawi, South Africa, Madagascar, southern India, the island of New Guinea, and eastern Australia. After revision, 10 species are recognized. Four species were previously recognized and are redescribed: D.ambositrae Risbec (Madagascar), D.indicus Saraswat (India: Kerala), D.rugosus Kieffer (Australia: Queensland), and D.subcoeruleus Dodd (Australia: Queensland). Six species are described as new: D.fulgidussp. nov. (Indonesia: Papua Barat), D.fuscussp. nov. (Papua New Guinea, Australia: Queensland), D.hamatussp. nov. (Kenya, Tanzania, Malawi, South Africa)., D.rubyaesp. nov. (Madagascar), D.striatussp. nov. (Madagascar), and D.umbrasp. nov. (Tanzania). Dichoteleaspappi Szabó is treated as a junior synonym of D.rugosus. An identification key to species of the genus is provided.


Sensitivity and specificity of 99mTc-HMPAO SPECT cerebral perfusion measurements during the first 48 hours for the localization of cerebral infarction.
There is no routinely used method for imaging the location of the extent and severity of cerebral tissue perfusion changes during the first hours of ischemic stroke, the period during which therapeutic intervention is most likely to be successful. Cerebral perfusion measurements with single-photon emission CT (SPECT) may potentially provide this information rapidly and noninvasively. In this study, the sensitivity and specificity of 99mTc-hexamethylpropyleneamine oxime (HMPAO) SPECT cerebral perfusion measurements during the first 48 hours of cerebral ischemia for the localization of cerebral infarction were determined. One hundred and four patients with acute ischemic stroke underwent 99mTc-HMPAO SPECT and CT scanning during the first 48 hours. In each patient, the location of the SPECT perfusion abnormality was compared with the location of infarction on a second brain CT acquired at a mean of 8 days after stroke. During the first 48 hours of ischemic stroke, the sensitivity of 99mTc-HMPAO SPECT in locating the site of infarction was 79% (110/139), and the specificity was 95% (362/381). SPECT was more sensitive in the localization of the vascular territory of cortical infarction (sensitivity, 93%) than pure subcortical infarcts (sensitivity, 47%). During the first 48 hours, SPECT was significantly more sensitive than brain CT (sensitivity of brain CT during the first 48 hours, 35%; P < .001, Mann-Whitney U test). HMPAO SPECT measurement provides a widely available and practical technique of locating cerebral ischemia acutely and demonstrates high sensitivity and specificity within the first 48 hours for the localization of the vascular territory of cerebral infarction. It is most sensitive for cortical ischemia but is limited by its resolution in the subcortex, particularly of white matter perfusion changes.


Increased Activation of the TRESK K+ Mediates Vago-Vagal Reflex Malfunction in Diabetic Rats.
Patients with diabetes have defects in the vagal afferent pathway that result in abnormal gastrointestinal function. We investigated whether selective increased activation of the 2-pore domain potassium channel TRESK (2-pore-domain weak inward-rectifying potassium channel-related spinal cord potassium channel) contributes to nodose ganglia (NG) malfunction, disrupting gastrointestinal function in diabetic rats. We conducted whole-cell current-clamp and single-unit recordings in NG neurons from diabetes-prone BioBreeding/Worcester rats and streptozotocin-induced diabetic (STZ-D) rats and compared them with control rats. NG neurons in rats or cultured NG neurons were exposed to pharmacologic antagonists and/or transfected with short hairpin or small interfering RNAs that reduced expression of TRESK. We then made electrophysiologic recordings and studied gastrointestinal functions. We observed reduced input resistance, hyperpolarized membrane potential, and increased current threshold to elicit action potentiation in NG neurons of STZ-D rats compared with controls. NG neuron excitability was similarly altered in diabetes-prone rats. In vivo single-unit NG neuronal discharges in response to 30 and 60 pmol cholecystokinin octapeptide were significantly lower in STZ-D rats compared with controls. Reducing expression of the TRESK K+ channel restored NG excitability in vitro and in vivo, as well as cholecystokinin 8-stimulated secretion of pancreatic enzymes and secretin-induced gastrointestinal motility, which are mediated by vago-vagal reflexes. These abnormalities resulted from increased intracellular Ca2+ in the NG, activating calcineurin, which, in turn, bound to an nuclear factor of activated T cell-like docking site on the TRESK protein, resulting in neuronal membrane hyperpolarization. In 2 rate models of diabetes, we found that activation of the TRESK K+ channel reduced NG excitability and disrupted gastrointestinal functions.


The impact of geriatric nutritional risk index on surgical outcomes after esophagectomy in patients with esophageal cancer.
Geriatric Nutritional Index (GNRI) was shown to be closely associated with nutrition-related complications and mortality in elderly hospitalized patients. Impact of GNRI on postoperative outcomes in surgically treated esophageal squamous cell carcinoma (ESCC) patients has not been evaluated extensively. A total of 240 patients with ESCC who underwent radical esophagectomy with two- or three-field lymphadenectomy between April 2000 and April 2012 were included in this retrospective study. GNRI formula was as follows: 1.489 × albumin (g/dl) + 41.7 × current weight/ideal weight. Patients were categorized as GNRI-low (GNRI < 92) or GNRI-high (GNRI ≥ 92) according to the receiver operating characteristics (ROC) curves generated for multiple logistic regression analysis using 5-year overall survival as the end point. The impact of GNRI status on short- and long-term outcomes of curative surgery for ESCC was examined. There were 44 (18.3%) and 196 (82.7%) patients in the GNRI-low and GNRI-high groups, respectively. Among the investigated demographic factors, the rate of nodal metastasis and pathological stage were significantly higher in the GNRI-low group than in the GNRI-high group (p < 0.01 and p < 0.01, respectively). Univariate analysis of postoperative complications revealed that the rate of lung complications was significantly higher in the GNRI-low group than in the GNRI-high group (p = 0.024), while GNRI was not an independent risk factor for the development of lung complications by multivariate analysis (Odds Ratio: 1.746; p = 0.126). 5-year overall survival (OS) was significantly lower in the GNRI-low group than in the GNRI-high group (p < 0.01). Moreover, GNRI was an independent prognostic factor for OS [Hazard ratio: 1.687; 95% confidence interval (CI): 1.038-2.742; p = 0.035], but not for cancer-specific survival. Analysis with stratification by tumor stage revealed that both OS and Cancer-Specific Survival (CSS) were worse in patients with low GNRI than those with high GNRI only among those with stage III ESCC (34.4% vs. 52.1%, p = 0.049 and 36.1% vs. 57.2%, p = 0.041, respectively). In the stage III ESCC, primary tumor size tends to be greater in the GNRI-low group than in the GNRI-high group (5.69 vs. 4.75 cm, p = 0.085) and the incidence of preoperative dysphagia was significantly higher in the GNRI-low group than in the GNRI-high group (74% vs. 45.9%, p = 0.032). GNRI was closely associated with long-term survival after curative surgery in patients with stage III ESCC. Intensive follow-up after surgery should be performed for ESCC patients with low GNRI.


Influence of lyophilization factors and gelatin concentration on pore structures of atelocollagen/gelatin sponge biomaterial.
This study aimed to investigate influences of lyophilization factors and gelatin concentration on pore structures of ACG sponge. ACG sponges of different freezing temperatures (-30, -80 and -196oC), freezing times (1, 2 and 24 h), gelatin concentrations (0.6%AC+0.15%G, 0.6%AC+0.6%G and 0.6%AC+2.4%G), and with 500 μM fluvastatin were fabricated. Pore structures including porosity and pore size were analyzed by scanning electron microscopy and ImageJ. The cytotoxic effects of ACG sponges were evaluated in vitro. Freezing temperature did not affect porosity while high freezing temperature (-30oC) increased pore size. The high gelatin concentration group (0.6%AC+2.4%G) had decreased porosity and pore size. Freezing time and 500 μM fluvastatin did not affect pore structures. The cytotoxicity and cell proliferation assays revealed that ACG sponges had no cytotoxic effects on human mesenchymal stromal cell growth and proliferation. These results indicate that ACG sponge may be a good biomaterial scaffold for bone regeneration.


Predicting inorganic dimensionality in templated metal oxides.
Amine-templated metal oxides are a class of hybrid organic-inorganic compounds with great structural diversity; by varying the compositions, 0D, 1D, 2D, and 3D inorganic dimensionalities can be achieved. In this work, we created a dataset of 3725 amine-templated metal oxides (including some metalloid oxides), their composition, amine identity, and dimensionality, extracted from the Cambridge Structure Database (CSD), which spans 71 elements, 25 main group building units, and 349 amines. We characterize the diversity of this dataset over reactants and in time. Artificial neural network models trained on this dataset can predict the most and least probable outcome dimensionalities with 71% and 95% accuracies, respectively, using only information about reactant identities, without stoichiometric information. Surprisingly, the amine identity plays only a minor role in most cases, as omitting this information only reduces the accuracy by <2%. The generality of this model is demonstrated on a time held-out test set of 36 amine-templated lanthanide oxalates, vanadium tellurites, vanadium selenites, vanadates, molybdates, and molybdenum sulfates, whose syntheses and structural characterizations are reported here for the first time, and which contain two new element combinations and four amines that are not present in the CSD.


Isolation and partial characterization of a 56,000-dalton phosphoprotein phosphatase from the blood-brain barrier.
A 56,000-dalton protein with inherent phosphoprotein phosphatase activity was isolated from porcine brain capillaries. The enzyme is not activated by divalent metal ions but strongly inhibited by zinc ions. As phosphatase inhibitor 2 readily inhibits the enzymatic activity, the protein can be classified as a type I phosphatase. The protein is stable toward protease treatment. Limited digestion with trypsin does not convert the enzyme into an active form of lower molecular weight. The physical and enzymatical properties of the phosphatase exhibit considerable similarities to those of another 56,000-dalton phosphatase derived from rabbit reticulocytes.


Bullous pemphigoid in two young infants.
Bullous pemphigoid (BP) usually affects the elderly. The disease is uncommon in children and only a few cases have been described in infants < or =4 months of age. We describe two infants, ages 3 and 4 months, with BP. One infant had a recalcitrant course, and responded only to a combination of high-dose oral corticosteroids and dapsone.


Whole-genome sequence of a genotype VIII infectious bronchitis virus isolated from California layer chickens in 2021.
Herein, we report the complete genome for an avian infectious bronchitis virus isolated from cecal tonsils of California layers in 2021. This whole-genome sequence belongings to genotype GVIII, previously classified as a unique variant.


Risk factors and outcomes of bacteremia caused by drug-resistant ESKAPE pathogens in solid-organ transplant recipients.
Although infections due to the six ESKAPE pathogens have recently been identified as a serious emerging problem, information regarding bacteremia caused by these organisms in solid-organ transplant (SOT) recipients is lacking. We sought to determine the frequency, risk factors, and outcomes of bacteremia due to drug-resistant ESKAPE (rESKAPE) organisms in liver, kidney, and heart adult transplant recipients. All episodes of bacteremia prospectively documented in hospitalized SOT recipients from 2007 to 2012 were analyzed. Of 276 episodes of bacteremia, 54 (19.6%) were due to rESKAPE strains (vancomycin-resistant Enterococcus faecium [0], methicillin-resistant Staphylococcus aureus [5], extended-spectrum β-lactamase-producing Klebsiella pneumoniae [10], carbapenem-resistant Acinetobacter baumannii [8], carbapenem- and quinolone-resistant Pseudomonas aeruginosa [26], and derepressed chromosomal β-lactam and extended-spectrum β-lactamase-producing Enterobacter species [5]). Factors independently associated with rESKAPE bacteremia were prior transplantation, septic shock, and prior antibiotic therapy. Patients with rESKAPE bacteremia more often received inappropriate empirical antibiotic therapy than the others (41% vs. 21.6%; P=0.01). Overall case-fatality rate (30 days) was higher in patients with rESKAPE bacteremia (35.2% vs. 14.4%; P=0.001). Bacteremia due to rESKAPE pathogens is frequent in SOT recipients and causes significant morbidity and mortality. rESKAPE organisms should be considered when selecting empirical antibiotic therapy for hospitalized SOT recipients presenting with septic shock, particularly those with prior transplantation and antibiotic use.


Studying additive interaction in a healthcare database: Case study of NSAIDs, cardiovascular profiles, and acute myocardial infarction.
There are clinical trial data on risk of acute myocardial infarction (MI) with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at increased cardiovascular (CV) risk requiring chronic daily treatment. This study investigated whether risks of acute MI with real-world prescription NSAIDs, such as low-dose or intermittent use, vary according to an individual's CV profile. Nested case-control analyses were carried out on an administrative health cohort from Quebec, Canada by randomly selecting 10 controls per case matched on age ± 1 year, sex, and month and year of cohort entry. We measured the additive joint effects on acute MI of current NSAID use and presence of hypertension, coronary heart disease (CHD), history of previous MI, or concomitant use of cardioprotective aspirin. The endpoint was the relative excess risk due to interaction (RERI). To verify the robustness of interaction findings, we performed sensitivity analyses with varying specifications of NSAID exposure-related variables. The cohort consisted of 233 816 elderly individuals, including 21 256 acute MI cases. For hypertension, CHD, and previous MI, we identified additive interactions on MI risk with some but not all NSAIDs, which also depended on the definition of NSAID exposure. Hypertension was sub-additive with naproxen but not with the other NSAIDs. Celecoxib and CHD were sub-additive in the primary analysis only (modelling NSAID dose on index date or up to 7 days before-best-fitting base model) whereas celecoxib and rofecoxib were super-additive with a history of previous MI in the secondary analysis only (modelling NSAID use on index date). For cardioprotective aspirin we found no evidence for an additive interaction with any of the NSAIDs. Alternative specifications of NSAID exposure concurred in finding that concomitant use of cardioprotective aspirin does not attenuate the risks of acute MI with NSAIDs. However we were unable to demonstrate consistent interactions between an individual's cardiovascular comorbidities and NSAID-associated acute MI. Our study highlights challenges of studying additive interactions in a healthcare database and underscores the need for sensitivity analyses.


Age-related differences in the trends of fatal Hodgkin's disease as a consequence of immune experience.
It has been proposed by MacMahon, on the basis of the variations among populations in the age distribution of fatal Hodgkin's disease, that there are two etiological factors, one important in young adults and the other important in middle-aged and elderly people. Correa has extended this by suggesting that those who died of the disease as young adults in developed countries would have succumbed to the disease as children under less favorable circumstances. In England and Wales, the mortality rate from Hodgkin's disease doubled from 1911 to 1970. If there were two etiologies, it seems unlikely that they would remain in step with one another over such a long period, when it was clear that some factor of major etiological importance was changing. Examination of the trends with time of the age-specific rates confirmed the previously reported decline in children and rise in elderly people and revealed a rapid rise in the mortality of young adults of both sexes. These changes were not compatible with any reasonable variations in the diagnosis or classification of Hodgkin's disease. Our data are compatible with the hypotheses that the etiology of the disease in young adults in different from that in elderly people and that the rise in the mortality of young adults is due to a transfer of deaths from the disease in childhood.


Chemical labeling of intracellular proteins via affinity conjugation and strain-promoted cycloadditions in live cells.
A versatile chemical labeling approach was developed, where intracellular proteins were first incorporated with a bioorthogonal group via affinity conjugation, and subsequently labeled via strain-promoted cycloaddition reactions in live cells.


Chronic myeloid leukemia: why does it evolve from chronic phase to blast transformation?
Clinically chronic myeloid leukemia is a biphasic or triphasic disease that is usually diagnosed in the initial 'chronic', 'indolent' or 'stable' phase and then spontaneously evolves after some years into an advanced phase. This advanced phase can sometimes be subdivided into an earlier accelerated phase and a later blast phase or blast transformation--in about one-half of patients the chronic phase transforms unpredictably and abruptly to a blast phase, while in the other half of patients, the disease evolves somewhat more gradually, through an accelerated phase, which may last for months or years, before a blast phase ensues; this may have myeloblastic or lymphoblastic features. Although much is now known about the molecular biology of the disease, the molecular basis of disease progression is still obscure. The popular thinking has been that one or more probably a sequence of additional genetic events occurs in the BCR-ABL positive clone. When the critical combination of additional events is achieved, clinically definable transformation occurs. Here we review what is known of the mechanisms underlying the evolution of chronic myeloid leukemia from a chronic phase to a blast transformation.


Synthesis of cyclic hexameric porphyrin arrays. Anchors for surface immobilization and columnar self-assembly.
To investigate new architectures for the self-assembly of multiporphyrin arrays, a one-flask synthesis of a shape-persistent cyclic hexameric array of porphyrins was exploited to prepare six derivatives bearing diverse pendant groups. The new arrays contain 6-12 carboxylic acid groups, 12 amidino groups, 6 thiol groups, or 6 thiol groups and 6 carboxylic acid groups in protected form (S-acetylthio, TMS-ethyl, TMS-ethoxycarbonyl). The arrays contain alternating Zn and free base (Fb) porphyrins or all Zn porphyrins. The one-flask synthesis entails a template-directed, Pd-mediated coupling of a p/p'-substituted diethynyl Zn porphyrin and a m/m'-substituted diiodo Fb porphyrin. The porphyrin building blocks (trans-A(2)B(2), trans-AB(2)C) contain the protected pendant groups at nonlinking meso positions. A self-assembled monolayer (SAM) of a Zn(3)Fb(3) cyclic hexamer containing one thiol group on each porphyrin was prepared on a gold electrode and the surface-immobilized architecture was examined electrochemically. Together, the work reported herein provides cyclic hexameric porphyrin arrays for studies of self-assembly in solution or on surfaces.


Optimization of extraction and quantification of Flavonoids from Averrhoa bilimbi fruits using RP-HPLC and its correlation between total flavonoids content against antimicrobial activity.
The present study was conducted to evaluate Averrhoa bilimbi fruits flavonoids extraction and quantification analysis through RP-HPLC and its comparison study on total flavonoids concentration versus antimicrobial activity analysis based on minimum inhibitory concentrations. Optimization of extraction was carried out using three different methods; among all methods the ultrasonic conventional assistant extraction (UCAE) showed an excellent recovery of flavonoids with solid phase elution. UCAE was performed with ethanol using different solvents ratio, the total flavonoid content was quantified through spectrophotometrically (850 ± 25 mg/kg) and flavonoids (myricetin and luteolin) were quantified by RP-HPLC. Optimized yield of myricetin and luteolin were presented in A. bilimbi fruits 336 ± 15 and 231 ± 18 mg/kg, respectively. Antimicrobial activity examined against E. coli, S. aureus and B. subtilis species using spectroscopically. The extracted sample with known quantity of total flavonoids content (10-200 µg/mL) used against E. coli, S. aureus and B. subtilis, MIC results shows 55.6 ± 6, 31 ± 3 and 28 ± 2 µg/mL respectively. Higher flavonoid content plays major role on antioxidant activities, which were evaluated and compared with commercial antioxidant butylated hydroxytoluene (BHT) employing superoxide anion scavenging activity and total reducing power IC50 value results shows 100 and 175 µg/mL, respectively. The maximum yield of flavonoid content results shows method suitability of flavonoids extraction and quantification.


C-peptide as a therapeutic tool in diabetic nephropathy.
Insulin is synthesised as a pro-hormone with an interconnecting C-peptide, cleaved during post-translational modification. This review discusses growing evidence which indicates that C-peptide is biologically active, benefiting microvascular complications associated with diabetes. To explore the renoprotective role of C-peptide in diabetic nephropathy (DN), we reviewed the literature using PubMed for English language articles that contained key words related to C-peptide, kidney and DN. Numerous studies have demonstrated that C-peptide ameliorates a number of the structural and functional renal disturbances associated with uncontrolled hyperglycaemia in human and animal models of type 1 diabetes mellitus that lead to the development and progression of nephropathy, including abrogation of glomerular hyperfiltration, reduced microalbuminuria, decreased mesangial expansion and increased endothelial nitric oxide synthase levels. The in vitro exposure of kidney proximal tubular cells to physiological concentrations of C-peptide activates extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, protein kinase C, elevates intracellular calcium, and stimulates transcription factors NF-kappaB and peroxisome proliferator-activated receptor-gamma. Burgeoning studies suggest that C-peptide is more than merely a link between the A and B chains of the proinsulin molecule and represents a future therapeutic tool in reducing complications of DN.


Further evidence for preoperative chemoradiotherapy and transanal endoscopic surgery (TEM) in T2-3s,N0,M0 rectal cancer.
Preoperative chemoradiotherapy and local excision via transanal endoscopic surgery (TEM) in T2-3s,N0,M0 rectal cancer achieve promising results in selected patients. We describe our long-term follow-up experience with this combination, and evaluate complete clinical and pathological responses, local recurrence and overall survival. The prospective observational follow-up study carried out since 2007. Out of 476 consecutive patients treated with TEM, we selected those with adenocarcinoma of low or moderate grade of differentiation, clinical stages T2-superficial T3,N0,M0, who refused radical surgery. Preoperative chemoradiotherapy comprised 5-fluorouracil or capecitabine combined with radiotherapy at a dose of 50.4 Gy. TEM was performed after 8 weeks. Complications were recorded and long-term follow-up was conducted. Fifteen patients undergoing preoperative chemoradiotherapy and TEM (median age 76 years, 95 % CI 70.3-80.4, and median follow-up 38 months, 95 % CI 20-44) were studied. No local recurrence was observed, and only one patient (6.7 %) presented systemic relapse. The overall survival was 76 %. Complete clinical response was achieved in seven patients (46.7 %) and complete pathological response in four (26.7 %). With regard to toxicity associated with neoadjuvant treatment, four patients (26.7 %) developed grade 3 adverse effects; no grade 4 or 5 adverse effects were observed. There was no postoperative mortality. The results of our study, with a response rate of 26.7 % and without local relapse, support the treatment of T2-3s,N0,M0 of rectal cancer with preoperative chemoradiotherapy and local excision (TEM).


Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4+CD25+FoxP3+ regulatory T cells and CD8+ memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4-CD8- double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z=-2·50, p=0·012), neutrophil counts (Z=-1·92, p=0·054), and haemoglobin (Z=-2·83, p=0·005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z=2·06, p=0·0400). These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus. Pfizer, the National Institutes of Health, and the Central New York Community Foundation.


[Interprofessional teamwork in health care].
Providing health care requires the integrative co-operation of physicians, nurses and other professionals in the health care sector. The success of such interprofessional teamwork does not only rely on the team members' task knowledge, but also on their teamwork-related knowledge, their skills and attitudes. In this paper a theoretical framework for team effectiveness is developed and used to identify factors improving team success. Within this context interprofessional team composition is perceived as a characteristic of team diversity, which needs to be perceived as a chance for better patient care in order to be used effectively.


Long-term results of postoperative and definitive (chemo)radiotherapy in sinonasal carcinoma. Adult Comorbidity Evaluation 27 score as a predictor of survival.
The objective was to evaluate the efficacy and toxicity of curative radiotherapy in patients with sinonasal carcinoma and to identify prognostic factors influencing treatment outcomes. The authors conducted a retrospective study of 61 consecutive patients treated with postoperative or definitive radiotherapy from 2002 to 2018 (median age 59 years, current/former smokers 71%, maxillary sinus 67%, nasal cavity 26%). The majority of patients were diagnosed with locally advanced disease (85% clinical stage ≥ III). Regional cervical metastases were initially diagnosed in 23% of patients. The most common histology was squamous cell carcinoma (61%). Radiation therapy was preceded by radical surgery in 64% of patients. 29 patients received chemotherapy (48%). The median follow-up was 53 months. The median total dose of radiotherapy achieved was 70 Gy. The 5- and 10-year locoregional control, distant control, overall survival, and disease-free survival were 74% and 64%, 90% and 90%, 51% and 35%, and 38% and 25%, respectively. Severe acute toxicity occurred in 36%, severe late toxicity in 23% of patients. Severe unilateral visual impairment occurred in 6 patients, temporal lobe necrosis in 1 patient, and osteoradionecrosis requiring surgery in 2 patients. The results of the study demonstrated the high effectiveness of curative treatment in patients with sinonasal carcinoma with long-term locoregional and distant control. The multivariate analysis indicated that N-staging, age, comorbidity score [as assessed by Adult Comorbidity Evaluation 27 (ACE-27)] and initial response to treatment were the strongest prognostic factors.


[Prevention programs of risk factors for falls].
Approximately 17% of Japanese older people fall for a year. The femoral neck fractures with falls caused by various functional problems make them depress remarkably activities of daily living and quality of life. In risk factors for falls in old people, muscle weakness, balance and gait disorders particularly increases to falls. The major results from recent systematic reviews have indicated that interventions of exercise, multifactorial, environmental modification and gradual withdrawal of psychotropic medication in community-dwelling elderly people were effective for preventing falls. Regarding the older people in hospitals and sanatoriums, it appeared that comprehensive multifactorial interventions and vitamin D supplementation could be effective in falls rather than exercises intervention only. However, the short period of the exercise intervention may affect ineffectiveness in preventing falls.


The Impact of Scientific and Technical Training on Improving Routine Collection of Antenatal Care Data for Maternal and Foetal Risk Assessment: A Case Study in the Province of South Kalimantan, Indonesia.
First, to assess the impact of scientific and technical training on midwives' abilities in collecting and recording the results of routine antenatal care examinations. Second, to explore midwives' views with regard to factors affecting their abilities to successfully complete the data documentation tasks. The study was conducted in South Kalimantan, Indonesia (April 2016-October 2017). Nineteen urban and rural midwives were selected. Access to antenatal care information on 4,946 women (retrospective cohort study) and 381 women (prospective cohort study) was granted. A descriptive and exploratory design was used to describe midwives' abilities and challenges pertaining to timely collection and recording of results concerning antenatal care examinations. Scientific and technical training has significantly improved the average amount of recorded antenatal care data (from 17.5% to 62.1%, p-value < 0.0005). Lack of awareness, high workload, and insufficient skills and facilities are the main reasons for the database gaps. The training has equipped midwives with scientific knowledge and technical abilities to allow routine collection of antenatal care data. Provision and adequate use of this information during different stages of pregnancy is crucial as an evidence-based guideline to assess maternal and foetal risk factors to ending preventable mortality.


Consulting children and young people on what makes a good nurse.
Health and education agencies collaborated in a hospital's special school to ask children what made a 'good' nurse. Eleven children aged between 11 and 14 years took part and described the 'good' nurse as having a professional persona and the ability to connect with them, delivering timely and effective care and being respectful of children's dignity. The results are now being used in an undergraduate children's nursing curriculum.


Low autonomic arousal as a risk factor for reoffending: A population-based study.
Low resting heart rate (RHR) and low systolic blood pressure (SBP) are associated with criminal behavior. However, knowledge is lacking about their predictive value for reoffending. We aimed to examine associations of RHR and SBP with reoffending in a large population-based sample. We conducted a cohort study of all convicted male conscripts born in Sweden 1958-1990 (N = 407,533). We obtained data by linking Swedish population-based registers. Predictor variables were RHR and SBP, measured at conscription which was mandatory until 2010 for men at age 18. The outcome variable was reoffending, defined as criminal convictions (any crime, violent crime and non-violent crime), obtained from the National Crime Register. We used survival analyses to test for associations of RHR and SBP with reoffending, adjusting for pertinent covariates such as socioeconomic status, height, weight and physical energy capacity. In fully adjusted Cox regression models, men with lower RHR (≤60 bpm) had higher risk of reoffending (any crime: HR = 1.17, 95% CI: 1.14, 1.19, violent crime: HR = 1.23, 95% CI: 1.17, 1.29, non-violent crime: HR = 1.16, 95% CI: 1.14, 1.19), compared to men with higher RHR (≥ 82 bpm). Men with lower SBP (≤80 mmHg) had higher risk of reoffending (any crime: HR = 1.19, 95% CI: 1.17, 1.21, violent crime: HR = 1.16, 95% CI: 1.12, 1.20, non-violent crime: HR = 1.20, 95% CI: 1.18, 1.22), compared to men with higher SBP (≥138 mmHg). Low autonomic arousal is associated with increased risk of reoffending. RHR and SBP should be investigated further as potential predictors for reoffending as they each may have predictive value in risk assessment protocols.


Incipient criticality in ecological communities.
In ecology, there have been attempts to establish links between the relative species abundance (RSA), the fraction of species in a community with a given abundance, and a power-law form of the species area relationship (SAR), the dependence of species richness on sampling area. However the SAR and other patterns in ecology often do not exhibit power-law behavior over an appreciable range of scales. This raises the question whether a scaling framework can be applied when the system under analysis does not exhibit power-law behavior. Here, we derive a general finite-size scaling framework applicable to such systems that can be used to identify incipient critical behavior and links the scale dependence of the RSA and the SAR. We confirm the generality of our theory by using data from a serpentine grassland plot, which exhibits a power-law SAR, and the Barro Colorado Island plot in Panama, whose SAR shows deviations from power-law behavior at every scale. Our results demonstrate that scaling provides a model-independent framework for analyzing and unifying ecological data and that, despite the absence of power laws, ecosystems are poised in the vicinity of a critical point.


Chronic silent otitis media.
Otitis media occurs along a continuum. For example, otitis media with effusion characterized by fluid pathology can lead to chronic otitis media plus chronic mastoiditis, characterized by the presence of intractable tissue pathology such as cholesteatoma, cholesterol granuloma or granulation tissue. The literature defines chronic otitis media as having a tympanic membrane perforation and otorrhea. Amongst many other sequelae, which can result from the continuum, an important common one is chronic silent otitis media. This overlooked entity which includes pathology beneath an intact tympanic membrane is commonly seen in our human temporal bone laboratory and in patients. The clinical pathological correlates of this important disease are discussed herein.


Relationship between Carotid Computed Tomography Dual-Energy and Brain Leukoaraiosis.
The purpose of this study was to assess if there is a correlation between the carotid computed tomography (CT) Hounsfield unit (HU)-based plaque attenuation values measured using dual-energy CT (DECT) scanner and brain leukoaraiosis (LA). Fifty consecutive patients (34 males, 16 females; mean age, 69 years; age range, 46-84 years) who underwent carotid CT and brain magnetic resonance imaging were included in the study. CT examinations were performed with a DECT scanner, and LA lesion volume quantification was performed using a semiautomated segmentation technique. We found an inverse statistically significant correlation between the HU-based carotid artery plaque attenuation and the LA lesion volume. Because of the presence of calcified plaques, a second model was calculated at low kiloelectron volt levels from 66 to 100 and 100 kV by taking into consideration the fatty and mixed plaques, and this further led to the associations between HU-based attenuation and LA volume in brain and vascular territories. The results of our study suggest that the associations between HU attenuation of the carotid artery plaques (with the exclusion of calcified plaques) and the volume of LA are emphasized at low keV energy levels.


LAMP4yaws: Treponema pallidum, Haemophilus ducreyi loop mediated isothermal amplification - protocol for a cross-sectional, observational, diagnostic accuracy study.
Yaws, caused by the bacterium Treponema pallidum subsp. pertenue, is a neglected tropical disease targeted for eradication by 2030. Improved diagnostics will be essential to meet this goal. Diagnosis of yaws has relied heavily on clinical and serological tools. However, the presence of coendemic cutaneous skin ulcer diseases, such as lesions caused by Haemophilus ducreyi (HD), means these techniques do not provide a reliable diagnosis. Thus, new diagnostic tools are needed. Molecular tools such as PCR are ideal, but often expensive as they require trained technicians and laboratory facilities, which are often not available to national yaws programmes. The LAMP4yaws project is a cross-sectional, observational, diagnostic accuracy study of a combined Treponema pallidum (TP) and HD loop mediated isothermal amplification (TPHD-LAMP) test performed under real world conditions in three endemic countries in West Africa. Individuals with serologically confirmed yaws will be recruited in Cameroon, Côte d'Ivoire and Ghana. Each participant will provide paired swabs, one of which will be sent to the respective national reference laboratory for yaws quantitative PCR and the other will be tested for both TP and HD using the TPHD-LAMP test at local district laboratories. Sensitivity and specificity of the TPHD-LAMP test will be calculated against the reference standard qPCR. We will also assess the acceptability, feasibility and cost-effectiveness of the test. We anticipate that results from this study will support the adoption of the TPHD-LAMP test for use in global yaws eradication efforts. We have received ethical approval from all relevant institutional and national ethical committees. All participants, or their parents or guardians, must provide written informed consent prior to study enrolment. Study results will be published in an open access journal and disseminated with partners and the World Health Organization. NCT04753788.


Curcumin-induced promoter hypermethylation of the mammalian target of rapamycin gene in multiple myeloma cells.
Curcumin, a polyphenol derived from the rhizome of Curcuma, is a potential tumor inhibitor through affecting signaling pathways and epigenetic regulation. The mammalian target of rapamycin (mTOR) gene serves a crucial role in the carcinogenesis of multiple myeloma. The curcumin-induced epigenetic regulation of mTOR, including promoter DNA methylation in multiple myeloma, has not yet been fully elucidated. In the present study, antitumor effects of curcumin were investigated in RPMI-8226 and NCI-H929 cells using an MTT assay and flow cytometry. The expression of mTOR and DNA methyltransferase proteins were determined by western blot analysis, and the methylation status of the mTOR promoter were detected by sequencing following bisulfite conversion. The results of the present study revealed that the half-maximal inhibitory concentration of curcumin was 10 µM in myeloma cells. Following curcumin treatment, the mRNA and protein expression levels of mTOR were decreased by 43.31 and 39.34% in NCI-H929 cells, respectively. The promoter of mTOR, located in chromosome 1 (chromosome position, 11262153-11263153), contains a CpG island that was hypermethylated in myeloma cells following curcumin treatment. The expression levels of DNA methyltransferase (DNMT)3a and DNMT3b were increased in curcumin-treated cells. Collectively, these results indicate that curcumin serves a role in the epigenetic regulation of mTOR expression, and that mTOR downregulation is due to promoter hypermethylation, which may be associated with DNMT3a and DNMT3b upregulation. The results of the present study contribute towards improving the understanding of curcumin treatment in multiple myeloma and provide novel insights into the molecular mechanisms underlying the epigenetic regulation of mTOR.


Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats.
The basolateral amygdala (BLA) is extensively implicated in emotional learning and memory. The current study investigated the contribution of cholinergic afferents to the BLA from the nucleus basalis magnocellularis in influencing aversive learning and memory. Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the nucleus basalis magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 microg) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test. Because lesioned rats did not differ from sham-operated controls in performance on a spatial water maze task or in shock sensitivity, it is not likely that the memory impairments produced by the phthalic acid lesions are due to any general sensory or motor deficits. These findings suggest that the dense cholinergic projection from the nucleus basalis magnocellularis to the BLA is involved in both the acquisition and the consolidation of the aversive inhibitory avoidance task.


High-energy proton imaging for biomedical applications.
The charged particle community is looking for techniques exploiting proton interactions instead of X-ray absorption for creating images of human tissue. Due to multiple Coulomb scattering inside the measured object it has shown to be highly non-trivial to achieve sufficient spatial resolution. We present imaging of biological tissue with a proton microscope. This device relies on magnetic optics, distinguishing it from most published proton imaging methods. For these methods reducing the data acquisition time to a clinically acceptable level has turned out to be challenging. In a proton microscope, data acquisition and processing are much simpler. This device even allows imaging in real time. The primary medical application will be image guidance in proton radiosurgery. Proton images demonstrating the potential for this application are presented. Tomographic reconstructions are included to raise awareness of the possibility of high-resolution proton tomography using magneto-optics.


Conformational Strain of Macrocyclic Peptides in Ligand-Receptor Complexes Based on Advanced Refinement of Bound-State Conformers.
Macrocyclic peptides are an important modality in drug discovery, but molecular design is limited due to the complexity of their conformational landscape. To better understand conformational propensities, global strain energies were estimated for 156 protein-macrocyclic peptide cocrystal structures. Unexpectedly large strain energies were observed when the bound-state conformations were modeled with positional restraints. Instead, low-energy conformer ensembles were generated using xGen that fit experimental X-ray electron density maps and gave reasonable strain energy estimates. The ensembles featured significant conformational adjustments while still fitting the electron density as well or better than the original coordinates. Strain estimates suggest the interaction energy in protein-ligand complexes can offset a greater amount of strain for macrocyclic peptides than for small molecules and non-peptidic macrocycles. Across all molecular classes, the approximate upper bound on global strain energies had the same relationship with molecular size, and bound-state ensembles from xGen yielded favorable binding energy estimates.


The association between body size, prostate volume and prostate-specific antigen.
Increasing prostate volume contributes to urinary tract symptoms and may obscure prostate cancer detection. We investigated the association between obesity and prostate volume, prostate-specific antigen (PSA) and PSA density among 753 men referred for prostate biopsy. Among men with a negative biopsy, prostate volume significantly increased approximately 25% from the lowest to highest body mass index (BMI), waist or hip circumference or height categories. PSA was 0.7 ng/ml lower with a high waist-to-hip ratio. These associations were less consistent among subjects diagnosed with high-grade prostatic intraepithelial neoplasia or cancer. Our data suggest that obesity and height are independently associated with prostate volume..


Dental professionals' use of personal protective equipment during COVID-19: a cross-sectional study in China.
Appropriate use of personal protective equipment (PPE) could significantly reduce the risk of viral transmission and infection. This study aimed to assess the use of PPE among dentists during the COVID-19 pandemic in China, explore its influencing factors, and provide some practical recommendations. An online cross-sectional survey was conducted among 384 Chinese dentists in September 2022. The questionnaire comprised a series of questions about demographic characteristics, compliance with proper PPE use, personal barriers to use, and exposure risk estimation. Of the 384 respondents, 57.3% had unacceptable compliance with the proper use of PPE during COVID-19. Medical surgical mask is the most common for dental professionals to wear (93.8%), followed by goggles or face shield (63.8%), and isolation gown (53.1%). Unexpectedly, only 63.3% of respondents always change masks with guidelines. The condition for changing goggles/face shields and isolation gowns is even worse (45.6 and 37.0%, respectively). Visual barriers, physical discomfort, complex procedures, and heavy workload were the most common personal barriers to use. According to the results of Chi-square test and correlation analysis, PPE use compliance was associated with age, years of practice, medical institution type, and exposure risk estimation. Chinese dental professionals need to improve their compliance with the proper use of PPE, especially those in the 31-40 age group, with 11-15 experience years and working in private dental clinics. Increasing compliance with PPE may be achieved by addressing personal barriers to use, human resource shortages, and perceptions of exposure risk.


Improved method for detection of glycosidases in bacterial colonies.
An assay has been developed to detect bacterial glycosidases in colonies grown on the surface of agar plates. Advantages of this technique over previously described methods include elimination of the need for replica plating, better visualization of chromagenic reaction products, and a simple permeabilization step to enable better penetration by chromagenic substrates.


Double-Blind Randomized Trial of Pirfenidone in Chinese Idiopathic Pulmonary Fibrosis Patients.
Idiopathic pulmonary fibrosis (IPF) lacks effective treatment. Pirfenidone has been used to treat IPF patients. N-acetylcysteine (NAC) exerts antioxidant and antifibrotic effects on IPF cases.This study is a double-blind, modified placebo-controlled, randomized phase II trial of pirfenidone in Chinese IPF patients. We randomly assigned the enrolled Chinese IPF patients with mild to moderate impairment of pulmonary function to receive either oral pirfenidone (1800 mg per day) and NAC (1800 mg per day) or placebo and NAC (1800 mg per day) for 48 weeks. The primary endpoints were the changes in forced vital capacity (FVC) and walking distance and the lowest SPO2 during the 6-minute walk test (6MWT) at week 48. The key secondary endpoint was the progression-free survival time. This study is registered in ClinicalTrials.gov as number NCT01504334.Eighty-six patients were screened, and 76 cases were enrolled (pirfenidone + NAC: 38; placebo + NAC: 38). The effect of pirfenidone treatment was significant at the 24th week, but this effect did not persist to the 48th week. At the 24th week, the mean decline in both FVC and ΔSPO2 (%) during the 6MWT in the pirfenidone group was lower than that in the control group (-0.08 ± 0.20 L vs -0.22 ± 0.29 L, P = 0.02 and -3.44% ± 4.51% vs -6.29% ± 6.06%, P = 0.03, respectively). However, there was no significant difference between these 2 groups at the 48th week (-0.15 ± 0.25 L vs -0.25 ± 0.28 L, P = 0.11 and -4.25% ± 7.27% vs -5.31% ± 5.49%, P = 0.51, respectively). The pirfenidone treatment group did not achieve the maximal distance difference on the 6MWT at either the 24th or the 48th week. But pirfenidone treatment prolonged the progression-free survival time in the IPF patients (hazard ratio = 1.88, 95% confidence interval: 1.092-3.242, P = 0.02). In the pirfenidone group, the adverse event (AE) rate (52.63%) was higher than that in the control group (26.3%, P = 0.03). Rash was more common in the pirfenidone group (39.5% vs 13.2%, P = 0.02).Compared with placebo combined with high-dose NAC, pirfenidone combined with high-dose NAC prolonged the progression-free survival of Chinese IPF patients with mild to moderate impairment of pulmonary function. (ClinicalTrials.gov number, NCT01504334).


Parameters affecting tumor-specific delivery of anti-CD5 antibody-ricin A chain immunotoxins in vivo.
The tumor localization of various anti-CD5 immunotoxins (ITs) was studied in vivo in BALB/c nude mice bearing human ascitic Ichikawa tumor cells. Plasma and ascitic clearance of IT as well as the number of intact IT molecules taken up per tumor cell was measured with a highly sensitive immunoenzymometric assay. This assay allowed the quantification of as few as 400 molecules per cell, either bound to cell surface antigens or internalized. Tumor cell localization of an i.v.-administered IT composed of a whole IgG linked by a disulfide bond to native ricin A chain (RTA) was extremely small. The highest binding level of this IT to ascitic cells did not exceed 1,600 molecules per cell, whereas up to 25,000 molecules per cell were quantified after i.p. injection. To improve IT localization after i.v. injection, both the size of the monoclonal antibody moiety and glycosylation of the ricin A chain were examined. Two major additive improvements were obtained by (a) Fc removal and (b) partial deglycosylation of RTA. The localization of F(ab')2-deglycosylated RTA IT was 5.5 times greater than that of IgG-RTA IT, resulting from reduced plasma clearance and better extravasation of the conjugate. However, the IT targeting observed in vivo after i.v. administration was unexpectedly lower than the theoretical number of bound IT molecules, calculated from the concentration of soluble IT molecules in the ascitic fluid. This discrepancy was found to be related to a dramatic decrease in the antigen binding capacity of the antibody moiety in ascitic fluid.


Enhanced intelligent water drops algorithm for multi-depot vehicle routing problem.
The intelligent water drop algorithm is a swarm-based metaheuristic algorithm, inspired by the characteristics of water drops in the river and the environmental changes resulting from the action of the flowing river. Since its appearance as an alternative stochastic optimization method, the algorithm has found applications in solving a wide range of combinatorial and functional optimization problems. This paper presents an improved intelligent water drop algorithm for solving multi-depot vehicle routing problems. A simulated annealing algorithm was introduced into the proposed algorithm as a local search metaheuristic to prevent the intelligent water drop algorithm from getting trapped into local minima and also improve its solution quality. In addition, some of the potential problematic issues associated with using simulated annealing that include high computational runtime and exponential calculation of the probability of acceptance criteria, are investigated. The exponential calculation of the probability of acceptance criteria for the simulated annealing based techniques is computationally expensive. Therefore, in order to maximize the performance of the intelligent water drop algorithm using simulated annealing, a better way of calculating the probability of acceptance criteria is considered. The performance of the proposed hybrid algorithm is evaluated by using 33 standard test problems, with the results obtained compared with the solutions offered by four well-known techniques from the subject literature. Experimental results and statistical tests show that the new method possesses outstanding performance in terms of solution quality and runtime consumed. In addition, the proposed algorithm is suitable for solving large-scale problems.