Brain-wide and cell-specific transcriptomic insights into MRI-derived cortical morphology in macaque monkeys.
Integrative analyses of transcriptomic and neuroimaging data have generated a wealth of information about biological pathways underlying regional variability in imaging-derived brain phenotypes in humans, but rarely in nonhuman primates due to the lack of a comprehensive anatomically-defined atlas of brain transcriptomics. Here we generate complementary bulk RNA-sequencing dataset of 819 samples from 110 brain regions and single-nucleus RNA-sequencing dataset, and neuroimaging data from 162 cynomolgus macaques, to examine the link between brain-wide gene expression and regional variation in morphometry. We not only observe global/regional expression profiles of macaque brain comparable to human but unravel a dorsolateral-ventromedial gradient of gene assemblies within the primate frontal lobe. Furthermore, we identify a set of 971 protein-coding and 34 non-coding genes consistently associated with cortical thickness, specially enriched for neurons and oligodendrocytes. These data provide a unique resource to investigate nonhuman primate models of human diseases and probe cross-species evolutionary mechanisms.


MORPHOLOGY AND BEHAVIOR OF CRABS AND GASTROPODS FROM LAKE TANGANYIKA, AFRICA: IMPLICATIONS FOR LACUSTRINE PREDATOR-PREY COEVOLUTION.
The shells of most lacustrine gastropods are typically small, weakly calcified, and modestly ornamented to unornamented. Similarly, most lacustrine crabs are usually small detritivores with weak chelae. A number of invertebrate taxa in Lake Tanganyika, however, deviate from these generalities. This study explores a predator-prey coevolution model as an explanation for the large, heavily calcified, and ornate gastropods and the robust, durophagous crabs of Lake Tanganyika. The endemic thiarid and viviparid gastropods from Lake Tanganyika have significantly thicker shells and higher frequencies of terminal apertural lip thickening than closely related cosmopolitan taxa from outside the lake. Tanganyikan gastropods also display considerably higher incidence of shell repair, following nonlethal shell damage, than cosmopolitan taxa of the same families. There is a strong positive correlation between gastropod apertural lip thickness and shell repair frequency among all the gastropod species analyzed. The endemic Tanganyikan potamonautid crab Platytelphusa armata (a molluscivore) possesses larger, more robust crushing chelae than other African potamonautid or potamonid crabs. In contrast with the cosmopolitan African crabs, the Tanganyikan crabs display molariform, rather than serrate dentition on their crushing chelipeds. In shell-crushing experiments, the Tanganyikan gastropod shells were an order of magnitude stronger than typical lacustrine gastropod shells, many well within the range of tropical marine gastropod shell strengths. Predation experiments with the endemic gastropods Spekia, Neothauma, Lavigeria spp., Paramelania spp. and the crab Platytelphusa armata showed that increased size, apertural lip thickness or shell sculpture reduced the successful predation rate of P. armata. Crabs with large chelae have a greater ratio of successful: unsuccessful attacks than crabs with small chelae. Among cases of successful predation, crabs with large chelae employed predation methods that required less time and energy (such as crushing the shell in the cheliped) than the methods employed by crabs with small chelae (such as peeling the shell from the aperture or the spire). The morphological, shell-crushing, and aquarium experiment data, considered in concert, provide strong support for the idea that the endemic gastropods and crabs of Lake Tanganyika have coevolved over the past 7 million years.


Survival in Idiopathic Pulmonary Fibrosis: Perspectives from Pulmonary Arterial Hypertension.
Maher has received grants, consulting fees, and speaker fees from GlaxoSmithKline and UCB and grants from Novartis. He has also received consulting fees and speaker fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, Lanthio, InterMune International AG (a wholly owned Roche subsidiary since 2014), F. Hoffmann-La Roche, Sanofi-Aventis, and Takeda. Maher is supported by a National Institute for Health Research Clinician Scientist Fellowship (NIHR Ref: CS:-2013-13-017). Dejonckheere is an employee of F. Hoffmann-La Roche. Nathan has received consulting fees from Roche-Genentech and Boehringer Ingelheim. He is also on the speakers bureau for Roche-Genentech and Boehringer Ingelheim and has received research funding from both companies. All authors contributed equally to study concept and design, data collection and analysis, and manuscript preparation.


Managing an Older Adult with Cancer: Considerations for Radiation Oncologists.
Older adults with cancer present a unique set of management complexities for oncologists and radiation oncologists. Prognosis and resilience to cancer treatments are notably dependent on the presence or risk of "geriatric syndromes," in addition to cancer stage and histology. Recognition, proper evaluation, and management of these conditions in conjunction with management of the cancer itself are critical and can be accomplished by utilization of various geriatric assessment tools. Here we review principles of the geriatric assessment, common geriatric syndromes, and application of these concepts to multidisciplinary oncologic treatment. Older patients may experience toxicities related to treatments that impact treatment effectiveness, quality of life, treatment-related mortality, and treatment compliance. Treatment-related burdens from radiotherapy are increasingly important considerations and include procedural demands, travel, costs, and temporary or permanent loss of functional independence. An overall approach to delivering radiotherapy to an older cancer patient requires a comprehensive assessment of both physical and nonphysical factors that may impact treatment outcome. Patient and family-centered communication is also an important part of developing a shared understanding of illness and reasonable expectations of treatment.


Maintenance interventions for overweight or obesity in children: a systematic review and meta-analysis.
Childhood obesity is associated with significant health consequences. Although several intervention programmes for children result in weight loss or stabilization in the short-term, preventing relapse after treatment remains an important challenge. This systematic review summarizes the evidence about maintenance interventions after treatment in childhood obesity. Studies were identified by searching PubMed, Embase, Cochrane Library, Scopus, Web of Science, PsycINFO, CINAHL and SocINDEX. The primary outcome measure for this review was body mass index standard deviation score (BMI-Z-score). Data were pooled using quality effect models. Eleven studies (1,532 participants, age 2-18 years) were included, covering a wide range of maintenance approaches. Included studies varied widely in methodological quality. Pooled analysis showed that the BMI-Z-score of maintenance intervention participants remained stable, whereas control participants experienced a slight increase. No differences were observed regarding intensity and duration of therapy. A slight preference for 'face-to-face' versus 'on distance' interventions was shown. In summary, this review shows that, although there is limited quality data to recommend one maintenance intervention over another, continued treatment does have a stabilizing effect on BMI-Z-score. Considering the magnitude of the problem of childhood obesity, this is an important finding that highlights the need for further research on weight loss maintenance.


Effect of contaminating red blood cells on OKT3-mediated polyclonal activation of peripheral blood mononuclear cells.
Erythrocytes are typically present as impurities in the majority of peripheral blood mononuclear cell (PBMC) preparations. This study was undertaken to investigate the effects of contaminating red blood cells (RBC) on the ability of OKT3 to activate CD4(+) and CD8(+) T cells. Surprisingly, the levels of gamma interferon, tumor necrosis factor alpha, and interleukin-1 beta (IL-1 beta) produced by PBMC upon stimulation by OKT3 were increased (P < 0.05) in a dose-dependent manner when increasing amounts of autologous RBC (RBC-to-PBMC ratios of 2:1, 10:1, and 50:1) were spiked into PBMC preparations. The OKT3-driven induction of the IL-2 receptor (CD25) and the proliferation of T lymphocytes in response to phorbol myristate acetate were not affected by the addition of RBC.


Mechanism of neuronal injury in cerebral venous thrombosis.
The impact of CVT on the brain is wide spectrum, ranging from completely normal parenchyma to brain oedema and/or haemorrhage. Multiple factors relate to neuronal injury in CVT including; dural sinus pressure, increased venous flow velocities, collateralization of venous channels, rate of occlusion, development of cytotoxic and vasogenic oedema, recanalization and accelerated myelination. It is suggested that recanalization of occluded vein, as well as, the presence or absence and the efficiency of intracranial venous collaterals, may have an impact on the extent of brain tissue damage and hence the prognosis of acute CVT.


Crystallographic characterization of the radixin FERM domain bound to the cytoplasmic tail of adhesion molecule CD44.
CD44 is an important adhesion molecule that specifically binds hyaluronic acid and regulates cell-cell and cell-matrix interactions. Increasing evidence has indicated that CD44 is assembled in a regulated manner into the membrane-cytoskeletal junction, a process that is mediated by ERM (ezrin/radixin/moesin) proteins. Crystals of a complex between the radixin FERM domain and the C-terminal cytoplasmic region of CD44 have been obtained. The crystal of the radixin FERM domain bound to the CD44 cytoplasmic tail peptide belongs to space group P2(1)2(1)2(1), with unit-cell parameters a = 62.70, b = 66.18, c = 86.22 A, and contain one complex in the crystallographic asymmetric unit. An intensity data set was collected to a resolution of 2.1 A.


Actin(g) on mitochondria - a role for cofilin1 in neuronal cell death pathways.
Actin dynamics, the coordinated assembly and disassembly of actin filaments (F-actin), are essential for fundamental cellular processes, including cell shaping and motility, cell division or organelle transport. Recent studies highlighted a novel role for actin dynamics in the regulation of mitochondrial morphology and function, for example, through mitochondrial recruitment of dynamin-related protein 1 (Drp1), a key factor in the mitochondrial fission machinery. Mitochondria are dynamic organelles, and permanent fission and fusion is essential to maintain their function in energy metabolism, calcium homeostasis and regulation of reactive oxygen species (ROS). Here, we summarize recent insights into the emerging role of cofilin1, a key regulator of actin dynamics, for mitochondrial shape and function under physiological conditions and during cellular stress, respectively. This is of peculiar importance in neurons, which are particularly prone to changes in actin regulation and mitochondrial integrity and function. In neurons, cofilin1 may contribute to degenerative processes through formation of cofilin-actin rods, and through enhanced mitochondrial fission, mitochondrial membrane permeabilization, and the release of cytochrome c. Overall, mitochondrial impairment induced by dysfunction of actin-regulating proteins such as cofilin1 emerge as important mechanisms of neuronal death with relevance to acute brain injury and neurodegenerative diseases, such as Parkinson's or Alzheimer's disease.


Large-scale plant protein subcellular location prediction.
Current plant genome sequencing projects have called for development of novel and powerful high throughput tools for timely annotating the subcellular location of uncharacterized plant proteins. In view of this, an ensemble classifier, Plant-PLoc, formed by fusing many basic individual classifiers, has been developed for large-scale subcellular location prediction for plant proteins. Each of the basic classifiers was engineered by the K-Nearest Neighbor (KNN) rule. Plant-PLoc discriminates plant proteins among the following 11 subcellular locations: (1) cell wall, (2) chloroplast, (3) cytoplasm, (4) endoplasmic reticulum, (5) extracell, (6) mitochondrion, (7) nucleus, (8) peroxisome, (9) plasma membrane, (10) plastid, and (11) vacuole. As a demonstration, predictions were performed on a stringent benchmark dataset in which none of the proteins included has > or =25% sequence identity to any other in a same subcellular location to avoid the homology bias. The overall success rate thus obtained was 32-51% higher than the rates obtained by the previous methods on the same benchmark dataset. The essence of Plant-PLoc in enhancing the prediction quality and its significance in biological applications are discussed. Plant-PLoc is accessible to public as a free web-server at: (http://126.96.36.199/bioinf/plant). Furthermore, for public convenience, results predicted by Plant-PLoc have been provided in a downloadable file at the same website for all plant protein entries in the Swiss-Prot database that do not have subcellular location annotations, or are annotated as being uncertain. The large-scale results will be updated twice a year to include new entries of plant proteins and reflect the continuous development of Plant-PLoc.


Population-based birth weight reference percentiles for Chinese twins.
Birth weight percentiles by gestational age are important for assessing prenatal growth and predicting postnatal outcomes of newborns. Several countries have developed nation-specific birth weight references for twins, but China still lacks such references. Birth weight data for twins born between October 2006 and September 2015 were abstracted from the China National Population-based Birth Defects Surveillance System. A total of 54,786 live twin births aged ≥28 weeks of gestation without birth defects were included in the analysis. The LMS method was adopted to generate gestational age-specific birth weight percentiles and curves for male and female twins separately. Significant differences were observed between the current reference and other references developed for Chinese or non-Chinese twins. The neonatal mortality rate in this cohort was 12.3‰, and much higher rates at very early gestation weeks were identified in small-for-gestational-age twins grouped by the newly developed reference cutoffs. The established birth weight centiles represent the first birth weight norm for contemporary Chinese twins and can be a useful tool to assess growth of twins in clinical and research settings. Key Messages There have been no population-based birth weight percentiles for Chinese twins prior to this study. The established birth weight centiles for female and male twins are markedly lower than those for Chinese singletons. Twin-specific curves should be used for determining inappropriate for gestational age in twins rather than using existing singleton reference. The birth weight percentiles for twins differed significantly from those for non-Chinese twins. In addition to ethnic influences, the observed differences could be ascribed to variations in prenatal care, fetal or maternal nutrition status or other environmental factors. Neonatal mortality rates varied considerably among twins grouped by the newly developed reference percentiles. Small-for-gestational-age twins had much higher mortality than did appropriate-for-gestational-age twins, highlighting the need to reduce postnatal mortality by improving perinatal health care for twins.


Methods of assessing gingival and periodontal disease: a review.
There has been an effort by the dental profession working in the field of gingival and periodontal disease to find a method of recording the extent and degree of pathological change in tissues leading from gingivitis to periodontitis and to measure reversible as well as irreversible changes. It is obvious that some form of index is required and it should have the following well-defined criteria: (1) Simplicity, (2) Accuracy, (3) Quantitativeness, (4) Reproducibility, (5) Speed, (6) Objectivity, and (7) Amenability to statistical analysis. Indices, as well as determining the prevalence of disease in the group under investigation at a given period in time, must also provide information on incidence of disease, i.e. at different periods of time. Indices must also give data that make it possible to verify the nature, severity and aetiology of the disease process and to evaluate therapeutic measures. Indices yield information about the success or failure of control and prevention of disease, affecting the gingivae and the periodontal tissues. A review of methods of assessing and recording gingival and periodontal disease is presented starting from the early investigations of the century. It is shown that subsequently many variations evolved, often with the same inherent difficulties of interpretation or application. Usually the initial stages of inflammation of the gingivae are more difficult to recognize than established disease. Present methods of recording as objectively and as quickly as possible the gingival state in population groups are discussed with emphasis upon the necessity for providing effective preventive measures based upon assessment of schoolchildren.


Heating and Compression Bandage Treatment Is Effective for Chronic Lymphedema with Dermatolymphangioadenitis-A Case-Controlled Study.
To investigate the therapeutic effect of far infrared rays and compression bandaging in the treatment of chronic lymphedema with dermatolymphangioadenitis (DLA). Between 2005 and 2013, 106 patients with chronic lymphedema with DLA treated at the Shanghai Ninth People's Hospital were retrospectively reviewed. These patients were divided into an infrared and a bandaging group (80 patients, group 1) and bandaging only group (26 patients, group 2). Outcome measures include DLA frequency, patients' subjective feedback with regards to their symptoms, and the relationship between continuous elastic compression bandaging and relapse of DLA. The frequency of DLA in group 1 and group 2 were significantly reduced after treatment (p = 0.000 and 0.004, respectively). Seventy five percent (60) of patients in group 1 and 19% (5) of patients in group 2 suffered no further episodes of DLA during the follow-up period. In group 1, over 90% of patients reported a subjective improvement in their symptoms and the relapse rate was shown to be lower using elastic compression bandaging when higher pressures were applied. Heating with compression bandaging can be an effective treatment strategy to reduce DLA and improve the quality of life for those patients with chronic lymphedema associated with DLA.


[Expression and clinical significance of CD1a+ dendritic cells in glottic squamous cell carcinoma].
Dendritic cells (DCs) are the most important antigen-presenting cells. CD1a, a marker of immature DCs, plays a role in tumorigenesis. This study was designed to explore the correlation of CD1a(+) DCs to pathologic degree, T stage, local recurrence, and prognosis of glottic squamous cell carcinoma. Clinical and follow-up data of 111 patients with glottic squamous cell carcinoma were analyzed retrospectively. The expression of CD1a(+) DCs in the 111 specimens of glottic squamous cell carcinoma and 17 specimens of non-tumor tissue was detected by immunohistochemistry. Correlations of CD1a(+) DCs to pathologic degree, T stage, local recurrence, and prognosis of glottic squamous cell carcinoma were analyzed. Positive rates of CD1a(+) DCs were 59.46% in glottic squamous cell carcinoma tissues, and 0 in non-tumor tissues; it was significantly higher in well-differentiated group than in moderately-and poorly-differentiated group [71.43% (55/77) vs. 28.57% (11/34), P<0.05], higher in T1-T2 group than in T3-T4 group [67.16% (45/67) vs. 47.73% (21/44), P<0.05], and higher in non-recurrence group than in local recurrence group [65.06% (54/83) vs. 42.86% (12/28), P<0.05]. The lower pathologic degree and higher T stage of glottic squamous cell carcinoma, the lower expression of CD1a(+) DCs. The positive rate of CD1a(+) DCs is low in recurrent glottic tumor. High expression of CD1a(+) DCs may indicate better prognosis of glottic squamous cell carcinoma.


Disclosure to sexual partner and condom use among HIV positive clients attending ART clinic at a tertiary health facility in South West Nigeria.
Condom use and disclosure of HIV status increase the safety of sexual activity. Its extent will determine the need for appropriate interventions. The objective of this study was to identify determinants of condom use and disclosure to sexual partners among individuals receiving Antiretroviral Therapy at a tertiary health facility in South West Nigeria. A cross-sectional study of 578 clients enrolled in the ART program of Federal Medical Centre Owo, Ondo State Nigeria, was conducted. The mean age of respondents was 38.6+9.6 years, more than half (66.6%) were females and 7% were currently married. Three-quarter were sexually active out of which 324(75.9%) used condom consistently and correctly and 323(75.6%) disclosed their status to their sexual partner. Use of condom was by 81% of those with tertiary education (p=0.002), and 84.5% of singles utilized condom (p<0.001). Determinant of condom use were, male (OR: 2; CI: 1.1- 3.3; p=0.013), secondary and tertiary education (OR: 3.69; CI: 1.48 - 9.19; p=0.005) and (OR: 4.79; CI: 1.84 - 12.44; p=0.001) respectively. Determinant of disclosure was being married (OR: 11.8; CI- 5.5-25.7; p<0.001). No significant association exist between disclosure and condom use. Most of the people living with HIV accessing ART were sexually active. A good proportion of them used condom consistently and correctly. Disclosure did not have significant effect on condom use. More health education intervention to increase disclosure rate and safe sexual behaviour among HIV positive clients is needed.


Outpatient cholecystectomy simulated in an inpatient population.
This prospective clinical trial evaluates the feasibility and safety of elective cholecystectomy in a simulated outpatient protocol in 40 patients. Results were compared with a 19-patient control group managed by conventional postoperative methods. Oral liquids were begun in the recovery room, intravenous fluids were discontinued 4 hours after surgery, and enteral analgesics and antiemetics were provided on the ward. Protocol patients were randomized in a double-blind fashion to receive metoclopramide or placebo after surgery to assess its influence on the early tolerance of oral intake. In the protocol group, nausea without emesis occurred in nine patients (23%); 11 others (28%) had nausea with emesis. This was not significantly different from the control group. Metoclopramide-treated patients did not demonstrate a lower incidence of nausea or emesis but did tolerate oral liquids earlier after surgery than the placebo group (P less than 0.05). After release from recovery, eight protocol patients (20%) requested parenteral narcotics for relief of pain. Postoperative urinary catheterization was required in nine protocol patients (23%) and five control patients (26%). No major complications occurred. Outpatient cholecystectomy is both feasible and safe. Metoclopramide may allow earlier tolerance of enteral liquids postoperatively.


L-arginine in combination with sildenafil potentiates the attenuation of hypoxic pulmonary hypertension in rats.
Chronic hypoxia induces an increased production of nitric oxide (NO) in pulmonary prealveolar arterioles. Bioavailability of the NO in the pulmonary vessels correlates with concentration of L-arginine as well as activity of phosphodiesterase-5 enzyme (PDE-5). We tested a hypothesis whether a combination of L-arginine and PDE-5 inhibitor sildenafil has an additive effect in reduction of the hypoxic pulmonary hypertension (HPH) in rats. Animals were exposed to chronic normobaric hypoxia for 3 weeks. In the AH group, rats were administered L-arginine during chronic hypoxic exposure. In the SH group, rats were administered sildenafil during chronic hypoxic exposure. In the SAH group, rats were treated by the combination of L-arginine as well as sildenafil during exposure to chronic hypoxia. Mean PAP, structural remodeling of peripheral pulmonary arterioles (%DL) and RV/LV+S ratio was significantly decreased in the SAH group compared to hypoxic controls even decreased compared to the AH and the SH groups in first two measured parameters. Plasmatic concentration of cGMP and NOx were significantly lower in the SAH group compared to hypoxic controls. We demonstrate that NO synthase substrate L-arginine and phosphodiesterase-5 inhibitor sildenafil administered in combination are more potent in attenuation of the HPH compared to a treatment by substances given alone.


Antihypertensive Potential of Coenzyme Q10 via Free Radical Scavenging and Enhanced Akt-nNOS Signaling in the Nucleus Tractus Solitarii in Rats.
In the Natural Medicines database, coenzyme Q10 (CoQ10) is classified as possibly effective for the treatment of hypertension. Patients with hypertension frequently have a significant deficiency of the antioxidant CoQ10. Furthermore, reactive oxygen species are overproduced in the nucleus tractus solitarii (NTS) during the cardiovascular regulation of hypertension in vivo. However, the molecular mechanisms by which CoQ10 modulates cardiovascular functions in the NTS are unclear. In this study, the effects of CoQ10 on superoxide generation, downstream NO signaling in the NTS, and blood pressure were evaluated in rats with fructose-induced hypertension. Treatment with oral CoQ10 for 4 weeks abolished nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activation, decreased p38 phosphorylation, and increased superoxide dismutase 2 production in the NTS of fructose-fed rats. The serum levels of uric acid decrease in response to CoQ10 treatment in fructose-fed rats. Oral CoQ10 reduced blood pressure by inducing Akt and nNOS phosphorylation in NTS of fructose-induced hypertensive rats. Oral CoQ10 decreases blood pressure by negatively regulating fructose-induced NADPH oxidase levels, abolishing ROS generation, reducing p38 phosphorylation, and enhancing the Akt-nNOS pathway in the NTS. These results support the beneficial effects of CoQ10 in oxidative stressassociated hypertension.


Double vitrification and warming does not compromise the chance of live birth after single unbiopsied blastocyst transfer.
Does double vitrification and thawing of an embryo compromise the chance of live birth after a single blastocyst transfer? The live birth rate (LBR) obtained after double vitrification was comparable to that obtained after single vitrification. Double vitrification-warming (DVW) is commonly practiced to accommodate surplus viable embryos suitable for transfer, to allow retesting of inconclusively diagnosed blastocysts in preimplantation genetic testing (PGT), and to circumvent limitations associated with national policies on embryo culture in certain countries. Despite its popularity, the evidence concerning the impact of DVW practice on ART outcomes is limited and lacking credibility. This is the first thorough investigation of clinical pregnancy and LBR following DVW in the case where the first round of vitrification occurred at the zygote stage and the second round occurred at the blastocyst stage in the absence of biopsy. This is a retrospective observational analysis of n = 407 single blastocyst transfers whereby embryos created by IVF/ICSI were vitrified-warmed once (single vitrification-warming (SVW) n = 310) or twice (DVW, n = 97) between January 2017 and December 2021. In the SVW group, blastocysts were vitrified on Day 5/6 and warmed on the day of embryo transfer (ET). In the DVW group, two pronuclear (2PN) zygotes were first vitrified-warmed and then re-vitrified on Day 5/6 and warmed on the day of ET. Exclusion criteria were ETs from PGT and vitrified-warmed oocyte cycles. All of the ETs were single blastocyst transfers performed at the University Hospital Zurich in Switzerland following natural or artificial endometrial preparation. The biochemical pregnancy rate, clinical pregnancy rate (CPR), and LBR were all comparable between the DVW and SVW groups. The CPR for DVW was 44.3% and for SVW it was 42.3% (P = 0.719). The LBR for DVW was 30.9% and for SVW it was 28.7% (P = 0.675). The miscarriage rate was additionally similar between the groups: 27.9% for DVW and 32.1% for SVW groups (P = 0.765). The study is limited by its retrospective nature. Caution should be taken concerning interpretation of these findings in cases where DVW occurs at different stages of embryo development. The result of the present study on DVW procedure provides a framework for counselling couples on their chance of clinical pregnancy per warming cycle. It additionally provides confidence and reassurance to laboratory professionals in certain countries where national policies limit embryo culture strategies making DVW inevitable. This work was supported by the University Research Priority Program 'Human Reproduction Reloaded' of the University of Zurich. The authors have no conflict of interest related to this study to declare. N/A.


Serum concentrations of markers of type I collagen metabolism in women taking monophasic oral contraceptives.
To investigate serum concentrations of the carboxy-terminal propeptide of type I procollagen (PICP) and cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), reflecting the rate of synthesis and degradation of the parent collagen respectively, in women using monophasic oral contraceptives. PICP and ICTP were estimated in 60 women taking 20 micrograms of ethinyl estradiol (EE) + 150 micrograms of desogestrel (DSG) or 30 micrograms of EE + 150 micrograms DSG over six months. Mean PICP concentration decreased in women receiving 20 micrograms of EE + 150 infinity g of DSG after three cycles of administration. However, after six months this value returned to a level comparable to the initial one. In women taking 30 micrograms of EE + 150 micrograms of DSG the mean concentrations of PICP did not change significantly throughout the period studied. None of the oral contraceptives noticeably influenced the concentrations of ICTP. Investigated oral contraceptives do not significantly affect the metabolism of type I collagen, however a transient decrease in its biosynthesis may be expected during the use of formulations containing 20 micrograms of EE.


[Treatment of Jessner-Kanof disease with thalidomide].
Five patients present a Jessner-Kanof's lymphocytic infiltration of the skin with 6-year duration for 4 of them. The skin lesions are numerous on the face and the back and characteristic of this disease. Histologic examination shows a lymphocytic infiltrate in the dermis without any modification of epidermis. Direct immunofluorescent study is negative in all cases. In 3 cases, response to chloroquine had been inconsistent or negative. The 5 cases have a excellent result with 100 mg/day of Thalidomide. In 4 cases the skin lesions reappear when treatment is stopped. With a continuous treatment of 25-50 mg/day for more than 2 years, 3 of 5 patients have normal skin. Thalidomide appears to be the best treatment of Jessner-Kanof's disease.


Oils' Impact on Comprehensive Fatty Acid Analysis and Their Metabolites in Rats.
Fatty acids, especially polyunsaturated, and their metabolites (eicosanoids) play many pivotal roles in human body, influencing various physiological and pathological processes. The aim of the study was to evaluate the effect of supplementation with edible oils diverse in terms of fatty acid composition on fatty acid contents, activities of converting their enzymes, and on lipoxygenase metabolites of arachidonic and linoleic acids (eicosanoids) in rat serum. Female Sprague-Dawley rats divided into seven groups were used in the study. Animals from six groups were fed one of oils daily (carotino oil, made up by combining of red palm oil and canola oil, linseed oil, olive oil, rice oil, sesame oil, or sunflower oil). One group received a standard diet only. Fatty acids were determined using gas chromatography with flame ionization detection. Eicosanoids-hydroxyeicosatetraenoic (HETE) and hydroxyoctadecadienoic acids (HODE) were extracted using a solid-phase extraction method and analyzed with HPLC. Vegetable oils given daily to rats caused significant changes in serum fatty acid profile and eicosanoid concentrations. Significant differences were also found in desaturases' activity, with the linseed and olive oil supplemented groups characterized by the highest D6D and D5D activity. These findings may play a significant role in various pathological states.


First total synthesis of hinckdentine A.
We have accomplished the first total synthesis of (+/-)-hinckdentine A (1). The key steps are m-CPBA oxidation of 2-arylindole followed by acid-mediated Mannich-type C-C bond formation of 2-hydroxyindolin-3-one, seven-membered ring closure, and regioselective tribromination.


Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis.
Cytotoxic radiotherapy unfavorably induces tumor cells to generate various proangiogenic substances, promoting post-irradiation angiogenesis (PIA), which is one of major causes of radiotherapy failure. Though several studies have reported some mechanisms behind PIA, they have not yet described the beginning proangiogenic motivator buried in the irradiated microenvironment. In this work, we revealed that dying tumor cells induced by irradiation prompted PIA via a caspase 3 dependent mechanism. Proteolytic inactivation of caspase 3 in dying tumor cells by transducing a dominant-negative version weakened proangiogenic effects in vitro and in vivo. In addition, inhibition of caspase 3 activity suppressed tumor angiogenesis and tumorigenesis in xenograft mouse model. Importantly, we identified vascular endothelial growth factor (VEGF)-A as a downstream proangiogenic factor regulated by caspase 3 possibly through Akt signaling. Collectively, these findings indicated that besides acting as a key executioner in apoptosis, caspase 3 in dying tumor cells may play a central role in driving proangiogenic response after irradiation. Thus, radiotherapy in combination with caspase 3 inhibitors may be a novel promising therapeutic strategy to reduce tumor recurrence due to restrained PIA.


[Investigation and optimization on ability of enzymatic hydrolysis of Mori Cortex residue].
Residue of Mori Cortex was studied to optimize its enzymatic hydrolysis process, and explore its potential as a carbon source for biochemistry and biofuel production. The cellulose content of diluted acid pretreated (DAP) and non-pretreated from Mori Cortex were measured in this study, and the results showed that the cellulose content of DAP and non-pretreated from Mori Cortex were 52.5% and 47%, respectively. This higher cellulose content indicated that residue of Mori Cortex had the potential to act as a carbon source for biochemistry and biofuel production. Enzymatic hydrolysis of pretreated and non-pretreated from Mori Cortex was conducted under different enzyme loading amount. 40 FPU·(g DW)⁻¹ enzyme loading was determined as the optimal amount by comparing the yield of sugar and the rate of enzymolysis. Under this condition, the concentrations of glucose, xylose, arabinose sugar were 23.82, 4.84, 3.6 g·L⁻¹, and the corresponding enzymatic hydrolysis rate was 45.33% which was 2.3 times higher than that of non-pretreated from Morus alba residues. Fed-batch enzymatic hydrolysis was conducted finally to get higher sugar yield, and the final glucose concentration reached up to 38 g·L⁻¹ with the enzymatic hydrolysis rate of 36.19%. The results indicated that Mori Cortex residue had higher cellulose and hemicellulose contents, so it had the potential to become a carbon source to produce the bio-chemicals and biofuels. Through enzymatic hydrolysis, it can be converted into microbial available monosaccharides; and through fermentation, it can be converted into high value-added chemicals, biofuels, etc., to solve the problem of residue pollution, and achieve the sustainable development and greening of Chinese pharmaceutical production process.


[Predict value of soluble ST2 on one-year mortality for hospitalized patients with chronic heart failure].
To explore the predict value of plasma soluble ST2 (sST2) on one-year mortality for hospitalized patients with chronic heart failure (HF). A total of 1 244 consecutive hospitalized patients admitted to Heart Failure Center Fuwai Hospital between March 2009 and July 2012 and with HF as their primary diagnosis were included. Plasma sST2 was measured in all patients and patients were followed up for 1 year, and the primary endpoint was defined as all-cause death. There were 193 deaths during follow up. sST2 concentrations at admission were positively correlated with NT-proBNP, NYHA functional class and heart rate, and negatively correlated with left ventricular ejection fraction, blood sodium, total cholesterol and glomerular filtration rate at admission. sST2 concentrations were significantly higher in non-survivors compared with survivors (P < 0.001). Multivariable Cox regression analyses showed that sST2 independently predicted 1-year mortality (per 1 log unit, hazard ratio 1.87, 95% confidence interval: 1.56 to 2.25, P < 0.001). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.776 which was similar to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (AUC = 0.775). The prognostic value was improved when combining these two biomarkers together (AUC = 0.813). sST2 concentration at admission is correlated with clinical and biochemical indexes and associated with 1-year mortality for hospitalized patients with HF.


Pulling back the covers: technical lessons of a real-world health information exchange.
Several nations and local communities are striving to achieve widespread, secure exchange of clinical data between various health care providers and public health organizations. Most of the literature on health information exchange focuses on the financial, political, and privacy aspects of these initiatives. Perhaps just as important are the technical and organizational factors that have influenced development of data exchange methods and results. One mature network in the Midwestern United States has had success in establishing consistent, secure exchange of clinical data for more than ten years. Presented here are the technical lessons learned and design decisions made from this initiative with the hope that they can be used by others striving to connect disparate clinical information systems for the improvement of health care quality and safety.


Do not forget about HELLP!
A 32-year-old female para 4 gravi 3, who was 21 weeks pregnant, presented to the emergency department (ED) with a 2-day history of abdominal pain, headache, blurred vision and vomiting. On arrival, she was agitated and confused with a blood pressure 162/106 mm Hg, pulse rate 107, respiratory rate 18, temperature 37 degrees Celsius, point of care blood glucose 6.2 and her Glasgow coma scale was 13/15 M6V4E3. Paramedics witnessed seizure-like activity lasting <1 min during transport. A diagnosis of eclampsia complicated by the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets count) was made. She was commenced on magnesium and labetalol intravenously for blood pressure control. Initial blood test results were consistent with the HELLP syndrome. Recognition of the HELLP syndrome with prompt management of blood pressure and clotting abnormalities is essential in the ED setting. An aggressive multidisciplinary approach is a key to optimise the prognosis for mother and fetus.


TGR5 supresses cGAS/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy.
Diabetic retinopathy (DR) is a serious and relatively under-recognized complication of diabetes. Müller glial cells extend throughout the retina and play vital roles in maintaining retinal homeostasis. Previous studies have demonstrated that TGR5, a member of the bile acid-activated GPCR family, could ameliorate DR. However, the role of TGR5 in regulating Müller cell function and the underlying mechanism remains to be ascertained. To address this, high glucose (HG)-treated human Müller cells and streptozotocin-treated Sprague-Dawley rats were used in the study. The IP3R1-GRP75-VDAC1 axis and mitochondrial function were assessed after TGR5 ablation or agonism. Cytosolic mitochondrial DNA (mtDNA)-mediated cGAS-STING activation was performed. The key markers of retinal vascular leakage, apoptosis, and inflammation were examined. We found that mitochondrial Ca2+ overload and mitochondrial dysfunction were alleviated by TGR5 agonist. Mechanically, TGR5 blocked the IP3R1-GRP75-VDAC1 axis mediated Ca2+ efflux from the endoplasmic reticulum into mitochondria under diabetic condition. Mitochondrial Ca2+ overload led to the opening of the mitochondrial permeability transition pore and the release of mitochondrial DNA (mtDNA) into the cytosol. Cytoplasmic mtDNA bound to cGAS and upregulated 2'3' cyclic GMP-AMP. Consequently, STING-mediated inflammatory responses were activated. TGR5 agonist prevented retinal injury, whereas knockdown of TGR5 exacerbated retinal damage in DR rats, which was rescued by the STING inhibitor. Based on the above results, we propose that TGR5 might be a novel therapeutic target for the treatment of DR.


Effects of an Erbium:Yttrium-Aluminum-Garnet Laser and Ultrasonic Scaler on Titanium Dioxide-Coated Titanium Surfaces Contaminated With Subgingival Plaque: An In Vitro Study to Assess Post-Treatment Biocompatibility With Osteogenic Cells.
Effects of conventional ultrasonic scaler versus an erbium:yttrium-aluminum-garnet (Er:YAG) laser on titanium surfaces contaminated with subgingival plaque from patients with peri-implantitis are evaluated in terms of: 1) plaque and biocorroded titanium oxide coating removal; 2) surface change induction; and 3) residual biocompatibility toward osteoblasts. Subgingival plaque-coated titanium disks with a moderately rough surface were fixed with ethanol and treated with an ultrasonic scaler (metal tip) or Er:YAG laser (20.3 or 38.2 J/cm2) in non-contact mode. Fluorescent detection of residual plaque was performed. Disk surface morphology was evaluated by scanning electron microscopy. Viability, attachment, proliferation, and differentiation of Saos-2 osteoblasts on new and treated disks were assayed by propidium iodide/DNA stain assay and confocal microscopic analysis of cytoskeleton, Ki67, expression of osteopontin and alkaline phosphatase, and formation of mineralized nodules. Both methods resulted in effective debridement of treated surfaces, the plaque area being reduced to 11.7% with the ultrasonic scaler and ≤0.03% with the Er:YAG laser (38.2 J/cm2). Ultrasound-treated disks showed marked surface changes, incomplete removal of the titanium dioxide (TiO2) layer, and scanty plaque aggregates, whereas the Er:YAG laser (38.2 J/cm2) completely stripped away the plaque and TiO2 layer, leaving a micropitted surface. Both treatments maintained a good biocompatibility of surfaces to Saos-2 osteoblasts. Air-water cooling kept disk temperature below the critical threshold of 47°C. This study shows that an ultrasonic scaler with metal tip is less efficient than high-energy Er:YAG irradiation to remove the plaque and TiO2 layer on anodized disks, although both procedures appear capable of restoring an adequate osseoconductivity of treated surfaces.


Effects on translation pausing of alterations in protein and RNA components of the ribosome exit tunnel.
Amino acids are polymerized into peptides in the peptidyl transferase center of the ribosome. The nascent peptides then pass through the exit tunnel before they reach the extraribosomal environment. A number of nascent peptides interact with the exit tunnel and stall elongation at specific sites within their peptide chain. Several mutational changes in RNA and protein components of the ribosome have previously been shown to interfere with pausing. These changes are localized in the narrowest region of the tunnel, near a constriction formed by ribosomal proteins L4 and L22. To expand our knowledge about peptide-induced pausing, we performed a comparative study of pausing induced by two peptides, SecM and a short peptide, Crb(CmlA), that requires chloramphenicol as a coinducer of pausing. We analyzed the effects of 15 mutational changes in L4 and L22, as well as the effects of methylating nucleotide A2058 of 23S rRNA, a nucleotide previously implicated in pausing and located close to the L4-L22 constriction. Our results show that methylation of A2058 and most mutational changes in L4 and L22 have differential effects on pausing in response to Crb(CmlA) and SecM. Only one change, a 6-amino-acid insertion after amino acid 72 in L4, affects pausing in both peptides. We conclude that the two peptides interact with different regions of the exit tunnel. Our results suggest that either the two peptides use different mechanisms of pausing or they interact differently but induce similar inhibitory conformational changes in functionally important regions of the ribosome.


Deep-fill hyaluronic acid for the temporary treatment of the naso-jugal groove: a report of 303 consecutive treatments.
To report a 2-year experience of treating the naso-jugal groove with injectable hyaluronic acid gel, using a deep-fill method. This was a consecutive, retrospective, nonrandomized case series of patients presenting with concerns involving dark circles, lower eyelid hollows, or other contour irregularities that make up the naso-jugal groove. One author performed all treatments, consisting of transcutaneous injection of hyaluronic acid gel filler, to address the naso-jugal groove. The filler was placed deep on the anterior lip of the orbital rim and molded to the desired shape. Between December 2003 and December 2005, 164 patients (34 male and 130 female) received hyaluronic acid gel filler in the face. Ninety-eight patients were treated just once and 66 had multiple treatment sessions. The mean dose of filler per session was 1.53 +/- 0.8 ml, with 0.84 +/- 0.38 ml divided between the two lower eyelids. The most common complication was localized swelling, followed by bruising, asymmetry, cellulitis (2 cases), and migraine (1 case). There were no cases of visual loss. Hyaluronic acid gel fillers have had an enormous impact on the practice of cosmetic surgery, and this series demonstrates the usefulness of these fillers for treatment of the lower eyelid and midface. The authors recommend the deep-fill method described as a reliable means of addressing the hollow created by the naso-jugal groove.


Effect of tirofiban in treating patients with progressive ischemic stroke.
Our aim is to investigate the efficacy and safety of tirofiban in the treatment of patients experiencing progressive ischemic stroke (PIS). A retrospective analysis was performed on the clinical data of 150 patients with ischemic stroke admitted to our hospital from May 2018 to December 2019. All the patients were divided into two groups according to different treatment methods. In Control group, conventional comprehensive treatment and antiplatelet therapy with aspirin + clopidogrel were conducted, while tirofiban was administered in Tirofiban group in addition to the treatments in Control group. Neurological deficits were scored by means of the National Institutes of Health Stroke Scale (NIHSS) at the time of progression and 30 d after treatment, and the modified Rankin Scale (mRS) and Activity of Daily Living (ADL) scale were employed to assess prognosis at 90 d after treatment. Thereafter, the platelet aggregation rate, platelet adhesion rate, plateletcrit (PCT), platelet distribution width (PDW), and platelet inhibition rate were measured before and after treatment. Finally, the patients were followed up, and the occurrence of hemorrhage events during treatment and within 90 d after discharge was recorded. After treatment, all the patients had significantly lower NIHSS and mRS scores and a dramatically higher Barthel index (BI) than those before treatment (p<0.001). At 90 d after treatment, Tirofiban group exhibited significantly higher BI (p<0.001) and lower mRS score than Control group (p=0.011). In addition, at 14 d after treatment, the clinical efficacy was assessed for all the patients. It was found that the overall response rate in Tirofiban group was substantially higher than that in Control group [82.7% (62/75) vs. 64.0% (48/75), p=0.009]. At 7 d after treatment, the PCT and adenosine diphosphate (ADP) platelet inhibition rate in Tirofiban group were markedly higher than those in Control group (p=0.006, p<0.001), and Tirofiban group had remarkably lower measured values of platelet aggregation rate, platelet adhesion rate and PDW than Control group (p=0.007, p=0.021, p<0.001). After treatment, the levels of serum IL-6 and hs-CRP declined notably in the two groups of patients, and the differences in their levels at 2 and 14 d after treatment between the two groups were statistically significant (p<0.05). During treatment and within 90 d after discharge, both groups of patients had no cerebral hemorrhage, gastrointestinal hemorrhage, and severe hemorrhage adverse events requiring blood transfusion, but they experienced subcutaneous ecchymosis, epistaxis, gingival hemorrhage, and hemorrhage around the infarct, which were improved after symptomatic treatment. Moreover, the occurrence rate of hemorrhage in Tirofiban group was higher than that in Control group, showing no statistically significant difference (p>0.05). Tirofiban combined with conventional basic treatment can greatly improve neurological deficits and disease outcomes, alleviate platelet adhesion, and reduce platelet activation without increasing the risk of hemorrhage in PIS patients.


Molecular cloning of the gamma-glutamylcysteine synthetase gene of Saccharomyces cerevisiae.
The 4.4 kb SphI DNA fragment (GSH1) that complements the gamma-glutamylcysteine synthetase-deficient mutation (gsh1) of Saccharomyces cerevisiae YH1 was cloned into vector plasmid YEp24. Gene disruption of the cloned fragment confirmed that this segment was the same gene as gsh1. Mutant strain YH1 with this plasmid not only restored gamma-glutamylcysteine synthetase (GSH-I) activity but the glutathione content and the growth rate. DNA sequence analysis of the SphI fragment showed that the GSH1 structural gene contained 2034 bp and predicted a polypeptide of 678 amino acids. The deduced amino acid sequence had about a 45% homology to that of rat kidney GSH-I, but a very low homology (about 26%) to that of Escherichia coli GSH-I. Northern analysis showed that GSH1 had been transcribed into an approximately 2.7 kb mRNA fragment. Southern analysis showed that GSH1 mapped at chromosome X.


Spatial regulation of gene expression during growth of articular cartilage in juvenile mice.
In juvenile mammals, the epiphyses of long bones grow by chondrogenesis within the articular cartilage. A better understanding of the molecular mechanisms that regulate the growth of articular cartilage may give insight into the antecedents of joint disease, such as osteoarthritis. We used laser capture microdissection to isolate chondrocytes from the superficial, middle, and deep zones of growing tibial articular cartilage in the 1-wk-old mouse and then investigated expression patterns by microarray. To identify molecular markers for each zone of the growing articular cartilage, we found genes showing zone-specific expression and confirmed by real-time PCR and in situ hybridization. Bioinformatic analyses implicated ephrin receptor signaling, Wnt signaling, and bone morphogenetic protein signaling in the spatial regulation of chondrocyte differentiation during growth. Molecular markers were identified for superficial (e.g., Cilp, Prg4), middle (Cxcl14, Tnn), and deep zones (Sfrp5, Frzb). Comparison between juvenile articular and growth plate cartilage revealed that the superficial-to-deep zone transition showed similarity with the hypertrophic-to-resting zone transition. Laser capture microdissection combined with microarray analysis identified novel signaling pathways that are spatially regulated in growing mouse articular cartilage and revealed similarities between the molecular architecture of the growing articular cartilage and that of growth plate cartilage.


Etiological pattern of blepharoptosis among patients presenting in teaching hospital.
The purpose of this study was to find out the etiological pattern of blepharoptosis among patients presenting in BPKLCOS, T.U. Teaching Hospital. This was a hospital based descriptive and cross-sectional study conducted from February 2003 to July 2004. A total of 125 patients with ptosis were evaluated. 78 cases (62.4%) were congenital and 47 cases (37.6 %) were acquired. Congenital simple ptosis and congenital complicated ptosis comprised of 58% and 42% respectively. Among the acquired cause, ptosis due to trauma was the commonest 32%, followed by third cranial nerve palsy 25.5%, myasthenia gravis 17%, aponeurotic 10.7%, chronic progressive external ophthalmoplegia 8.5% etc. Aetiology-wise, myogenic ptosis was the commonest (65.6%) which was followed by neurogenic (16.8%), traumatic (12%) and aponeurotic ptosis (5.6%). Congenital ptosis is more common than acquired ptosis. Myogenic ptosis is the most predominant type of ptosis. Among the congenital ptosis, congenital simple ptosis is more common than congenital complicated ptosis. Among the acquired cases trauma, third cranial nerve palsy and myasthenia gravis are the major attendees.


Gut microbial metabolites associated with HIV infection.
HIV infection has been associated with alterations in gut microbiota and related microbial metabolite production. However, the mechanisms of how these functional microbial metabolites may affect HIV immunopathogenesis and comorbidities, such as cardiovascular disease and other metabolic diseases, remain largely unknown. Here we review the current understanding of gut microbiota and related metabolites in the context of HIV infection. We focus on several bacteria-produced metabolites, including tryptophan catabolites, short-chain fatty acids and trimethylamine-N-oxide (TMAO), and discuss their implications in HIV infection and comorbidities. We also prospect future studies using integrative multiomics approaches to better understand host-microbiota-metabolites interactions in HIV infection, and facilitate integrative medicine utilizing the microbiota in HIV infection.


Different pattern of Galleria mellonella jhbp gene expression in high five and Sf9 cells.
Juvenile hormone binding protein (JHBP) is the key element of the system that transmits hormone signals to target tissues. Recently, we found that the core promoter of the jhbp gene is strongly under the control of the TATA box and the transcription start site. In this report, we have shown that the jhbp promoter contains distal regulatory elements whose functionality clearly depends on the particular cell environment and that the scope of research from one cell line is insufficient to generalize the conclusions of the analysis. Cf1/Usp (where Usp is ultraspiracle protein previously known as Cf1, chorion factor 1) elements suppressed transcription of the reporter gene in the High Five cell line but not in the Sf9 cell line. However, upstream from all three Cf1/Usp elements there is a DNA sequence, containing the Zeste element, which activates jhbp in both systems. We found that juvenile hormone strongly inhibited the activity of the jhbp promoter in the Sf9 cell line, whereas it did not have an effect in the High Five cell line. A second key hormone that controls insect development--20-hydroxyecdysone, was also found to suppress the transcription of jhbp. This is the first report describing how these two hormones affect jhbp gene expression in different cell lines.


[Production and identification of anti-paraoxon monoclonal antibodies].
Paraoxon (E600) was conjugated to bovine serum albumin(BSA) or tachypleus tridentatus hemocyanin (TTH) by diazotization. Two hybridoma cell lines secreting monoclonal antibodies(McAb) against paraoxon have been established by fusing mouse myeloma cells and splenocytes from Balb/c mice immunized with E600-BSA. The chromosomes of the hybridoma cell 2B10 were analyzed. The immunoglobulin of the McAb was classified. The affinity and specificity of this antibody were determined. The hybridoma cells have fairly reserved the antibody-producing capacity after continuously growing or stored in liquid nitrogen for 10 weeks.


The use of amniotic fluid viscosity measurements to establish fetal lung maturity.
A Haake viscosimeter was used to determine the viscosity of amniotic fluid and this value correlated with fetal lung maturity. The results were evaluated along the weeks of pregnancy and compared to those obtained using Gluck's method (lecithin/sphingomyelin ratio (L/S). Using 91 separate amniotic fluid samples, free of meconium and blood contamination, we found that the new method was quick and easy to perform. Thirty-one neonates were delivered within 48 h of the amniotic fluid sampling and the percentage of correct prediction of respiratory distress syndrome (RDS) was 71% with a mature L/S ratio and 83% with viscosity less than 1.17 cP. In cases with an immature L/S ratio (value below 2) the correct prediction of RDS was 64%; with the fluorescence polarization (FP) technique it was 91%. We conclude that the amniotic fluid FP value is a reliable index of fetal lung maturity and risk for developing RDS and has also specific technical and diagnostic advantages over the L/S ratio.


Oral Anticoagulants Initiation in Patients with Atrial Fibrillation: Real-World Data from a Population-Based Cohort.
Objective: Little is known about initial prescription of currently used oral anticoagulants (OAC), and correlated characteristics in real-world practice. We aimed to assess patterns of initiation of Vitamin K antagonists (VKA) and non-VKA oral anticoagulants (NOAC) in naive patients with non-valvular atrial fibrillation and the factors associated with starting treatment with NOAC. Methods: Population-based retrospective cohort study of all patients with NVAF who had a first prescription of OAC from November 2011 to February 2014 in the Valencia region, Spain (n = 21,881). Temporal trends of OAC initiation are described for the whole population and by type of OAC and therapeutic agent. Factors associated with starting treatment with NOAC (vs. VKA) were identified using logistic multivariate regression models. Results: Among the patients initiating OAC, 25% started with NOAC 2 years after market release. Regarding temporal trends, prescription of NOAC doubled during the study period. VKA prescription also increased (by around 13%), resulting in a 30% rise in total treatment initiation with OAC during 2011-2014. NOAC initiation (vs. VKA) was associated with a lower baseline risk of thromboembolism and higher income. Conclusions: In this Spanish population-based cohort, initiation of OAC therapy saw a rapid increase, mainly but not exclusively, due to a two-fold rise in the use of NOAC. Initiation with NOAC was associated with a lower baseline risk of thromboembolism and higher income, which opposes the indications of NOAC use and reflects disparities in care. Inadequate prescription patterns might threaten the effectiveness and safety of these therapies, thus monitoring OAC prescription is necessary and should be setting-specific.


Joint regulation of cell size and cell number in the wing blade of Drosophila melanogaster.
We used Drosophila melanogaster to test for compensatory control of cell area and cell number in the regulation of total wing area. In two random bred wild-type base stocks collected from different geographic locations we found a negative association between the area and the number of cells in the wing blade. Three replicate lines were selected for increased or decreased wing area, with cell area maintained at the same level as in the three controls. After eight generations of selection, despite a large and highly significant difference in wing area between the large, control and small selection lines, cell area did not differ significantly between them. Rather, the difference in wing area between selection regimes was attributable to differences in cell number. Over the course of selection, the initially significant negative correlation between cell area and cell number in the wing increased, providing evidence for compensatory regulation of cell area and cell number. As a result of the increasingly negative association between the two traits, the variance in wing area declined as selection proceeded. It will be important to discover the mechanisms underlying the compensatory regulation of cell area and cell number.


An ATPase activity associated with the rotavirus phosphoprotein NSP5.
Interactions between NSP5 and NSP2 drive the formation of viroplasms, sites of genome replication and packaging in rotavirus-infected cells. The serine-threonine-rich NSP5 transitions between hypo- and hyper-phosphorylated isomers during the replication cycle. In this study, we determined that purified recombinant NSP5 has a Mg2+-dependent ATP-specific triphosphatase activity that generates free ADP and Pi (Vmax of 19.33 fmol of product/min/pmol of enzyme). The ATPase activity was correlated with low levels of NSP5 phosphorylation, suggestive of a possible link between ATP hydrolysis and an NSP5 autokinase activity. Mutagenesis showed that the critical residue (Ser67) needed for NSP5 hyperphosphorylation by cellular casein kinase-like enzymes has no role in the ATPase or autokinase activities of NSP5. Through its NDP kinase activity, the NSP2 octamer may support NSP5 phosphorylation by creating a constant source of ATP molecules for the autokinase activity of NSP5 and for cellular kinases associated with NSP5.


The Community Resiliency Model, an interoceptive awareness tool to support population mental wellness.
The objective of this article is to describe the Community Resiliency Model (CRM)®, a sensory-focused, self-care modality for mental well-being in diverse communities, and CRM's emerging evidence base and neurobiological underpinnings as a task-sharing intervention. Frieden's Health Impact Pyramid (HIP) is used as a lens for mental healthcare interventions and their public health impact, with CRM examples. CRM, a sensory awareness model for self-care and mental well-being in acute and chronic stress states, is supported by neurobiological theory and a growing evidence base. CRM can address mental wellness needs at multiple levels of the HIP and matches the task-sharing concept to increase access to mental health resources globally. CRM has the potential for making a significant population mental health impact as an easily disseminated, mental health, self-care modality; it may be taught by trained professionals, lay persons, and community members. CRM carries task-sharing to a new level: scalable and sustainable, those who learn CRM can share the wellness skills informally with persons in their social networks. CRM may alleviate mental distress and reduce stigma, as well as serve a preventive function for populations facing environmental, political, and social threats.


Enantioselective Iridium-Catalyzed Allylic Cyclizations.
A method for the enantioselective synthesis of carbo- and heterocyclic ring systems enabled through the combination of Lewis acid activation and iridium-catalyzed allylic substitution is described. The reaction proceeds with branched, allylic alcohols and carbon nucleophiles as well as heteronucleophiles to give a diverse set of ring systems in good yields and with high enantioselectivities. The utility of the method is highlighted by the asymmetric syntheses of erythrococcamides A and B.


A critical appraisal of registry-based objective performance goals in peripheral arterial disease.
The multidisciplinary Superficial Femoral Artery-Popliteal EvidencE Development (SPEED) Study Group, under the auspices of the Registry Assessment of Peripheral Interventional Devices (RAPID) partnership, recently published objective performance goals for peripheral vascular interventions in the femoropopliteal arteries. Retrospective outcomes from the Vascular Quality Initiative provided the sole study data source. Strengths and weaknesses of this landmark effort are examined. Critical concerns include the substantial risks of ascertainment bias, flawed end point selection, sparse and variable capture of midterm follow-up data, and lack of expected discrimination between treatment modalities. The current Vascular Quality Initiative registry data thus appear insufficiently robust for the generation of objective performance goals and practice benchmarks; suggestions for redesign are provided. The impact of the statutory framework of the US Food and Drug Administration on device approval pathways and the maturation of an evidence-based approach to peripheral vascular intervention is explored.


The importance of supercooled stability for food during supercooling preservation: a review of mechanisms, influencing factors, and control methods.
Supercooling can preserve food in its original fresh state below its ice point temperature without freezing. However, the supercooled state is unstable in thermodynamics, state breakdown can occur at any moment, resulting in irregular and larger ice crystals formation, leading to food tissue damage, and loss of quality and nutrients. While the effectiveness of supercooling preservation has been verified in the lab and pilot scale tests, the stability of the supercooled state of food remains an open question, posing a limitation for larger industrial-scale application of supercooling preservation. Based on this background, this review presents the instability mechanisms of supercooling preservation and summarizes the factors such as food properties (e.g., material size, food components, specific surface area, and surface roughness) and preservation circumstances (e.g., cooling rate, temperature variation, and mechanical disturbance) that influence the stability of the supercooled state of food. The review also discusses novel techniques for enhancing the supercooling capacity and their limitations (e.g., precise temperature control and magnetic field). Further studies are necessary to comprehensively evaluate the effects of influence factors and supercooling technologies on supercooling, realizing the true sense of 'no-crystal' food products under subzero temperature preservation conditions in commercial applications.


Safety and efficacy of inhaled interferon-β1a (SNG001) in adults with mild-to-moderate COVID-19: a randomized, controlled, phase II trial.
With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need. Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.govNCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021. The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm. In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia. The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


The claudin-like megatrachea is essential in septate junctions for the epithelial barrier function in Drosophila.
Vertebrate claudin proteins are integral components of tight junctions, which function as paracellular diffusion barriers in epithelia. We identified Megatrachea (Mega), a Drosophila transmembrane protein homologous to claudins, and show that it acts in septate junctions, the corresponding structure of invertebrates. Our analysis revealed that Mega has transepithelial barrier function similar to the claudins. Also, Mega is necessary for normal tracheal cell morphogenesis but not for apicobasal polarity or epithelial integrity. In addition, we present evidence that Mega is essential for localization of the septate junction protein complex Coracle/Neurexin. The results indicate that claudin-like proteins are functionally conserved between vertebrates and Drosophila.


A Review of Cardiac Surgical Procedures and Their Outcomes for Paediatric Rheumatic Heart Disease in Western Australia.
Surgical intervention is an important treatment modality for advanced rheumatic heart disease (RHD). This study aimed to describe patient characteristics and outcomes from cardiac surgery for RHD in patients referred to the only tertiary paediatric hospital in Western Australia. An analysis of patient characteristics and cardiac surgery outcomes in patients with RHD was undertaken, using data from clinical cardiac databases, medical notes, and correspondence from rural outreach clinics. 29 patients (59% female, 97% Aboriginal, Māori or Pacific Islander) underwent 41 valve interventions over 34 cardiac surgeries for RHD between 2000-2018. Median age at first surgery was 12.2 (range 4-16) years. Severe mitral regurgitation (MR) was the most common indication for primary surgery (62%), followed by mixed mitral regurgitation/aortic regurgitation (21%) and severe aortic regurgitation (17%). Mitral valve repair was the most common valve intervention (56%). Two patients had mitral valve replacement (MVR) at first operation, two patients had MVR at second operation and two had MVR at third operation. There was no early mortality. One patient required early (<30 days) reoperation for aortic valve repair failure. Two patients had late reoperations at 3.3 and 6.1 months after the first procedure for MR. Four (14%) patients experienced documented ARF recurrences. Late mortality occurred in 3 (10%) patients, all due to cardiac causes. On last follow-up echocardiogram 5 patients (17%) had moderate MR and none had severe MR. This is the first study to describe characteristics and outcomes in WA paediatric patients having surgery for RHD. Outcomes are comparable to similar studies, with favourable long-term survival.


Ferredoxin molecular thin film with intrinsic switching mechanism for biomemory application.
A biomemory device consisting of cysteine modified ferredoxin molecules which possess a memory effect via a charge transfer mechanism was developed. For achieving an efficient bioelectronic device, cysteine modified ferredoxin was developed by embodying cysteine residues in ferredoxin by site--directed mutagenesis method to directly coordinate with the gold (Au) surface without use of any additional linkers. The thin film formation of ferredoxin molecules on Au electrode is confirmed by surface plasmon resonance (SPR) spectroscopy and scanning tunneling microscope (STM). Cyclic voltammetry (CV) and open circuit potential amperometry (OCPA) methods were used to verify the memory switching characteristics of the fabricated device. The charge transfer between ferredoxin protein molecules and Au electrode enables a bi-stable electrical conductivity allowing the system to be used as a digital memory device. Data storage is achieved by applying redox voltages which are within the range of -500 mV. These results suggest that the proposed device has a function of memory and can be used for the construction of a nano-scale bioelectronic device.


[MRI findings and pathological features of occult breast cancer].
Objective: To investigate the magnetic resonance imaging (MRI) findings and clinicopathological features of primary lesions in patients with occult breast cancer (OBC). Methods: The imaging reports from the Breast Imaging Reporting and Data System in 2013 were retrospectively analyzed to investigate the morphology and the time signal intensity curve (TIC) of breast lesions in patients with OBC. The clinical and pathological characteristics of these patients were also included. Results: A total of 34 patients were enrolled. Among these patients, 24 patients underwent modified radical mastectomy and 18 of them had primary breast carcinoma in pathological sections. MRI detected 17 cases of primary lesions, including six masse lesions with a diameter of 0.6-1.2 cm (average 0.9 cm), and 11 non-mass lesions with four linear distributions, three segmental distributions, three focal distributions, and one regions distribution. Five patients had TIC typeⅠprimary lesions, ten had TIC type Ⅱ primary lesions, and two had TIC type Ⅲ primary lesions. Among all 34 cases, 23 of them had complete results of immunohistochemistry: 11 estrogen receptor (ER) positive lesions (47.8%), tenprogesterone receptor (PR) positive lesions (43.5%), seven human epidermal growth factor receptor 2 (HER-2) positive lesions (30.4%), and 20high expression(>14%) of Ki-67 (87.0%). The proportion of type luminal A was 4.3%, type luminal B was 43.5%, triple negative breast cancer (TNBC) was 30.4%, and HER-2 over expression accounted for 21.7%. Conclusions: The primary lesions of OBC usually manifested as small mass lesions, or focal, linear or segmental distribution of non-mass lesions. The positive rate of ER and PR was low, but the positive rate of HER-2 and the proliferation index of Ki-67 was high. Type luminal B is the most common molecular subtype.


Effect of increased levels of adiponectin by administration of the adeno vector rAAV2/1-Acrp30 on glucose, lipid metabolism and ultrastructure of the aorta in Goto-Kakizaki rats with arteriosclerosis.
We used recombinant adeno-associated virus vector of adiponectin (AAV2/1-Acrp30) to study the effects of increased levels of adioponectin (by the administration of rAAV2/1-Acrp30) on arteriosclerosis, glucose and lipid metabolism in Goto-Kakizaki (GK) rats with arteriosclerosis. Thirty GK rats with arteriosclerosis were divided into 3 equal groups: control group 1, control group 2 and the rAAV2/1-Acrp30-administered group. Saline, virus vector or rAAV2/1-Acrp30 (10 12 ng/ml) vector genomes administered to the rats in the corresponding group by intramuscular injection to the posterior limb by single administration, respectively. After 8 weeks, fasting blood glucose, 2-hour postprandial blood glucose, glycosylated haemoglobin, serum insulin, serum total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein were measured in each group, and the ultrastructure of the aorta was seen by light and electron microscopy. Compared with control groups 1 and 2, in the rAAV2/1-Acrp30 group, there was a decrease in urine volume, fasting blood glucose, 2-hour postprandial blood glucose, glycosylated haemoglobin, serum total cholesterol, triglycerides and low-density lipoprotein, and an increase in body weight and high-density lipoprotein (p< 0.05), while the level of serum insulin was not changed (p>0.05). Ultrastructure studies of the aorta showed that aortosclerosis in the rAAV2/1-Acrp30-administered group was less, and fewer lipid droplet vacuoles were seen in the vascular endothelial cytoplasm. Also various cell organelles and internal elastic lamina were seen, and there was no formation of lipid droplet and foam cells in the cytoplasm of the media of the smooth muscle. Adiponectin could improve blood glucose and lipid parameters and decrease atherosclerosis in the aorta of GK rats.


Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is an aggressive neoplasm with poor clinical outcome because most patients present at an advanced stage, at which point curative surgical options, such as tumor excision or liver transplantation, are not feasible. Therefore, the majority of HCC patients require systemic therapy. Nonetheless, the currently approved systemic therapies have limited effects, particularly in patients with advanced and resistant disease. Hence, there is a critical need to identify new molecular targets and effective systemic therapies to improve HCC outcome. The liver is a major target of the growth hormone receptor (GHR) signaling, and accumulating evidence suggests that GHR signaling plays an important role in HCC pathogenesis. We tested the hypothesis that GHR could represent a potential therapeutic target in this aggressive neoplasm. We measured GH levels in 767 HCC patients and 200 healthy controls, and then carried out clinicopathological correlation analyses. Moreover, specific inhibition of GHR was performed in vitro using siRNA and pegvisomant (a small peptide that blocks GHR signaling and is currently approved by the FDA to treat acromegaly) and in vivo, also using pegvisomant. GH was significantly elevated in 49.5% of HCC patients, and these patients had a more aggressive disease and poorer clinical outcome (P<0.0001). Blockade of GHR signaling with siRNA or pegvisomant induced substantial inhibitory cellular effects in vitro. In addition, pegvisomant potentiated the effects of sorafenib (P<0.01) and overcame sorafenib resistance (P<0.0001) in vivo. Mechanistically, pegvisomant decreased the phosphorylation of GHR downstream survival proteins including JAK2, STAT3, STAT5, IRS-1, AKT, ERK, and IGF-IR. In two patients with advanced-stage HCC and high GH who developed sorafenib resistance, pegvisomant caused tumor stability. Our data show that GHR signaling represents a novel "druggable" target, and pegvisomant may function as an effective systemic therapy in HCC. Our findings could also lead to testing GHR inhibition in other aggressive cancers.


Blind jealousy? Romantic insecurity increases emotion-induced failures of visual perception.
Does the influence of close relationships pervade so deeply as to impact visual awareness? Results from two experiments involving heterosexual romantic couples suggest that they do. Female partners from each couple performed a rapid detection task where negative emotional distractors typically disrupt visual awareness of subsequent targets; at the same time, their male partners rated attractiveness first of landscapes, then of photos of other women. At the end of both experiments, the degree to which female partners indicated uneasiness about their male partner looking at and rating other women correlated significantly with the degree to which negative emotional distractors had disrupted their target perception during that time. This relationship was robust even when controlling for individual differences in baseline performance. Thus, emotions elicited by social contexts appear to wield power even at the level of perceptual processing.


Deletion of the msdS/AfmsdC gene induces abnormal polarity and septation in Aspergillus fumigatus.
alpha-Mannosidases play an important role in the processing of mannose-containing glycans in eukaryotes. A deficiency in alpha-mannosidase is lethal in humans and cattle. In contrast to mammals, Saccharomyces cerevisiae does not require the endoplasmic reticulum alpha-mannosidase gene for growth. However, little is known of the consequence of loss of function of class I alpha-mannosidases in filamentous fungi. In this study, the msdS/AfmsdC gene was identified to encode 1,2-alpha-mannosidase MsdS in Aspergillus fumigatus. Soluble MsdS expressed in Escherichia coli was characterized as a typical class I alpha-mannosidase. The msdS gene was deleted by replacement of the msdS gene with a pyrG gene. Although the mutant showed a defect in N-glycan processing, as well as a reduction of cell wall components and a reduced ability of conidiation, it appeared that the rate of hyphal growth was not affected. Morphology analysis revealed abnormal polarity and septation at the stages of germination, hyphal growth and conidiation. Although the mechanism by which the N-glycan processing affects polarity and septation is unclear, our results show that msdS is involved in polarity and septation in A. fumigatus.


Assessment of systemic right ventricular function in adult overweight and obese patients with congenitally corrected transposition of the great arteries.
In congenitally corrected transposition of the great arteries the right ventricle (RV) supports systemic circulation, and patients are prone to develop heart failure over time. Chronic volume overload secondary to obesity may contribute to premature dysfunction of the systemic RV. The aim of our study was to assess the systemic RV function in overweight/obese adult patients with congenitally corrected transposition of the great arteries. Transthoracic echocardiographic studies and laboratory testing (N-terminal pro-B-type natriuretic peptide [NT-proBNP] assessment) were performed in patients with congenitally corrected transposition, who were scheduled for a routine examination, and the body mass index was calculated for each patient. We studied 56 adults (31 men; mean age 33.9 years); 22 of whom were overweight (body mass index [BMI] of 25-29.9 kg/m²) or obese (BMI of 30 kg/m² or more), and 34 of whom were normal weight (BMI below 25 kg/m²). Age, gender, heart rate, and blood pressure were similar in both groups. The mean NT-proBNP levels were not significantly different. On echocardiography, the overweight/obese patients had a decreased systemic RV fractional area change (0.38) compared to normal weight patients (0.43); p = 0.02. Moreover, a significant reduction in the global longitudinal strain in the overweight/obese group was observed (-15.3% vs. -18.3%; p = 0.01). Overweight/obesity in adult patients with congenitally corrected transposition of the great arteries is associated with impaired systemic RV function.


Adenosine deaminase in the diagnosis of pleural effusions.
The activity of adenosine deaminase (ADA) was determined in serum and pleural fluid of 90 patients with pleural effusions of various aetiology. Tuberculous pleural effusions, empyemas and rheumatoid pleural effusions demonstrated significantly higher activities of ADA than parapneumonic , nonspecific and malignant pleural effusions and effusions in systemic lupus erythematosus and congestive heart failure. In tuberculosis, empyema and rheumatoid arthritis ADA activity was significantly higher in pleural fluid than in serum, indicating a local synthesis of ADA by cells within the pleural cavity in these diseases.


A protodermal miR394 signal defines a region of stem cell competence in the Arabidopsis shoot meristem.
A long-standing question in plants and animals is how spatial patterns are maintained within stem cell niches despite ongoing cell divisions. Here we address how, during shoot meristem formation in Arabidopsis thaliana, the three apical cell layers acquire stem cell identity. Using a sensitized mutant screen, we identified miR394 as a mobile signal produced by the surface cell layer (the protoderm) that confers stem cell competence to the distal meristem by repressing the F box protein LEAF CURLING RESPONSIVENESS. This repression is required to potentiate signaling from underneath the stem cells by the transcription factor WUSCHEL, maintaining stem cell pluripotency. The interaction of two opposing signaling centers provides a mechanistic framework of how stem cells are localized at the tip of the meristem. Although the constituent cells change, the surface layer provides a stable point of reference in the self-organizing meristem.


Development of robust multifunctional CrNiCo-P/GCN catalyst for oxygen evolution reaction, electrochemical sensing, and photodegradation of roxarsone.
In this study, we designed a CrNiCo-P/GCN composite for use as a high-performance multifunctional catalyst for the oxygen evolution reaction (OER), electrochemical determination, and photodegradation of roxarsone (ROX). CrNiCo-P/GCN demonstrates favorable charge resistance and electrical conductance due to its intrinsic properties. It exhibits an admirable OER overpotential of 290 mV with a lower Tafel plot value of 125 mV dec-1 in alkaline media and compared with the control samples. Furthermore, this composite also demonstrates high performance in electrochemical sensing of ROX over a wide concentration range of 1-413 μM with a lower limit of detection (LOD) of 31 nM in phosphate buffer. Moreover, this composite is a promising electrocatalyst for ROX sensors in practical analysis and also possesses excellent photodegradation of ROX under visible light irradiation.


Patient-reported outcomes with botulinum neurotoxin type A.
Clinical trials establishing the efficacy of botulinum neurotoxin type A historically have included as outcomes investigator assessments and general patient global assessments of treatment. However, these outcomes are of limited value in determining the specific benefits desired by patients who seek facial rejuvenation. To address this issue, several patient-reported outcomes measures have been developed and utilized in clinical trials of botulinum neurotoxin type A (specifically, the BOTOX Cosmetic brand). The outcomes include the Self-Perception of Age (SPA) measure and the Facial Line Outcomes (FLO) questionnaire. On the FLO questionnaire, patients rate the degree to which their facial lines bother them; make them look older than they would like; prevent them from having a smooth facial appearance; and make them look tired, stressed, or angry when that is not how they feel. Several clinical trials have demonstrated significant improvements in these outcomes from baseline and versus placebo for the treatment of multiple upper facial lines as well as for treating the glabella as a single region. These outcomes data help in understanding patient objectives and motivations, establishing a treatment plan, and ensuring patient satisfaction. Clinicians can use the SPA measure for all patients to help show the value of treatment.


A new formulation concept for drugs with poor water solubility for parenteral application.
The parenteral application of active substances with poor solubility in water is often bound to the use of stabilizing excipients or surfactants with serious undesired side effects. A new concept is introduced based on a drug concentrate, comprising the active substance dissolved in parenterally acceptable organic solvents, and an aqueous dilution medium, which are mixed in a special mixing device immediately prior to application and thus generating the applicable formulation directly prior to administration. Due to the requirement of formulation stability for only a few minutes, the amount of stabilizing agents can be reduced significantly. It can be shown that model drugs dissolved in a mixture of polyoxyethylen glycol, ethanol and soya lecithin as stabilizer may be mixed to an aqueous glucose solution resulting in a parenterally acceptable and administerable dispersion which is physically stable for several minutes. First in vivo data show good tolerability and blood plasma levels which are comparable to conventional solutions.


Functional characterization of the mouse [corrected] solute carrier, SLC41A2.
We have recently demonstrated that the human solute carrier, SLC41A1, is a Mg 2+ transporter that is regulated by extracellular magnesium. A BLAST search found a closely related protein encoded by SLC41A2 that may have related functional properties. In order to determine the function of SLC41A2, the corresponding cRNA was expressed in Xenopus laevis oocytes and Mg2+ currents were determined under voltage-clamp conditions. Further, real-time RT-PCR was performed to determine if SLC41A2 expression is regulated by magnesium. When expressed in oocytes, SLC41A2 mediates voltage-dependent and saturable Mg2+ uptake with a Michaelis constant of 0.34+/-0.05 mM. Expressed SLC41A2 transports a range of other divalent cations: Ba2+, Ni2+, Co2+, Fe2+, or Mn2+, but not Ca2+, Zn2+, or Cu2+. Mg2+ transport was inhibited by large concentrations of Ca2+. Real-time reverse transcription polymerase chain reaction of RNA isolated from renal distal tubule epithelial (MDCT) cells cultured in low-magnesium media relative to normal media and in kidney cortex of mice maintained on low-magnesium diets compared to those animals consuming normal diets showed that SLC41A2 transcript, unlike SLC41A1 mRNA, is not responsive to magnesium. These studies suggest that SLC41A2 is a Mg2+ transporter that might be involved in magnesium homeostasis in epithelial cells.


Enhanced activity of mouse peritoneal cells after aclacinomycin administration.
We have investigated the activation of mouse peritoneal macrophages by injection of aclacinomycin (ACM). Macrophages from ACM-treated mice have an increased phagocytic activity as measured by Candida ingestion. The microbicidal activity indirectly evaluated by chemiluminescence and superoxide determination in response to stimulation with zymosan and 4 beta-phorbol-12-myristate-13 alpha-acetate is also greater in the cells from treated mice. Direct measurement of the cytostatic function, and of in vitro and in vivo cytotoxicity shows comparable significant increases against L1210 or P815 target cells. The enhanced antitumoral activity could not be attributed to the residual presence of ACM in the peritoneal cells since no drug was detected by high-performance liquid chromatography and since their freeze-thaw lysates incubated with P815 cells did not modify the growth of tumor cells as measured by [3H]-thymidine incorporation. We also checked that the presence of ACM did not influence the intensity of the chemiluminescence. In all tests performed, only i.p. ACM administration could stimulate the peritoneal cells. Since the doses of ACM inducing an increase in macrophage activity are effective on the survival of tumor-bearing mice, the participation of this mechanism in tumor control might be suggested.


Phasor Representation Approach for Rapid Exploratory Analysis of Large Infrared Spectroscopic Imaging Data Sets.
Infrared (IR) spectroscopic imaging is potentially useful for digital histopathology as it provides spatially resolved molecular absorption spectra, which can subsequently yield useful information by powerful artificial intelligence methods. A typical analysis pipeline in using IR imaging data for chemical pathology often involves iterative processes of segmentation, evaluation, and analysis that necessitate rapid data exploration. Here, we present a fast, reliable, and intuitive method based on a phasor representation of spectra and discuss its unique applicability for IR imaging data. We simulate different features extant in IR spectra and discuss their influence on the phasor waveforms; similarly, we undertake IR image analysis in the transform space to understand spectral similarity and variance. We demonstrate the potential of phasor analysis for biomedical tissue imaging using a variety of samples, using fresh frozen surgical prostate resections and formalin-fixed paraffin-embedded breast cancer tissue microarray samples as model systems that span common histopathology practice. To demonstrate further generalizability of this approach, we apply the method to data from different experimental conditions─including standard (5.5 μm × 5.5 μm pixel size) and high-definition (1.1 μm × 1.1 μm pixel size) Fourier transform IR (FTIR) spectroscopic imaging using transmission and transflection modes. Quantitative segmentation results from our approach are compared to previous studies, showing good agreement and quick visualization. The presented method is rapid, easy to use, and highly capable of deciphering compositional differences, presenting a convenient tool for exploratory analysis of IR imaging data.


Surgery for severe COPD. Lung volume reduction and lung transplantation.
A management strategy for patients with severe emphysema is shown in figure 2 on page 199. Although the reported physiologic improvements after LVRS are significantly less than those seen after lung transplantation, LVRS has the potential to improve functional performance in a larger number of patients because of wider availability. Moreover, it accomplishes these goals without the attendant risks associated with transplantation and immunosuppression. The efficacy of LVRS over standard medical therapy in influencing survival and favorably affecting physiologic variables at rest and during exercise remains to be elucidated in NETT. Lung transplantation should be reserved for those patients deemed unsuitable or too ill for LVRS. It is to be hoped that future developments in organ preservation techniques and immunosuppressive regimens will expand the donor pool and decrease the incidence of posttransplantation bronchiolitis.


What colour are your eyes? Teaching the genetics of eye colour & colour vision. Edridge Green Lecture RCOphth Annual Congress Glasgow May 2019.
Eye colour and colour perception are excellent examples to use when teaching genetics as they encompass not simply the basic Mendelian genetics of dominant, recessive and X-linked disorders, but also many of the new concepts such as non-allelic diseases, polygenic disease, phenocopies, genome-wide association study (GWAS), founder effects, gene-environment interaction, evolutionary drivers for variations, copy number variation, insertions deletions, methylation and gene inactivation. Beyond genetics, colour perception touches on concepts involving optics, physics, physiology and psychology and can capture the imagination of the population, as we saw with social media trend of "#the dress". Television shows such as Game of Thrones focused attention on the eye colour of characters, as well as their Dire-wolves and Dragons. These themes in popular culture can be leveraged as tools to teach and engage everyone in genetics, which is now a key component in all eye diseases. As the explosion of data from genomics, big data and artificial intelligence transforms medicine, ophthalmologists need to be genetically literate. Genetics is relevant, not just for Inherited Retinal Diseases and congenital abnormalities but also for the leading causes of blindness: age-related macular degeneration, glaucoma, myopia, diabetic retinopathy and cataract. Genetics should be part of the armamentarium of every practicing ophthalmologist. We need to ask every patient about their family history. In the near future, patients will attend eye clinics with genetic results showing they are at high risk of certain eye diseases and ophthalmologists will need to know how to screen, follow and treat these patients.


Low Dimensional Representation of Fisher Vectors for Microscopy Image Classification.
Microscopy image classification is important in various biomedical applications, such as cancer subtype identification, and protein localization for high content screening. To achieve automated and effective microscopy image classification, the representative and discriminative capability of image feature descriptors is essential. To this end, in this paper, we propose a new feature representation algorithm to facilitate automated microscopy image classification. In particular, we incorporate Fisher vector (FV) encoding with multiple types of local features that are handcrafted or learned, and we design a separation-guided dimension reduction method to reduce the descriptor dimension while increasing its discriminative capability. Our method is evaluated on four publicly available microscopy image data sets of different imaging types and applications, including the UCSB breast cancer data set, MICCAI 2015 CBTC challenge data set, and IICBU malignant lymphoma, and RNAi data sets. Our experimental results demonstrate the advantage of the proposed low-dimensional FV representation, showing consistent performance improvement over the existing state of the art and the commonly used dimension reduction techniques.


Round spermatids from prepubertal mouse testis can develop into normal offspring.
We investigated fertilization and embryo development after intracytoplasmic injection of round spermatids collected from mice before puberty. The rates of normal fertilization, blastocyst formation, and development into live offspring were examined. The injection of oocytes with round spermatids from mature or prepubertal males resulted in similar rates of normal fertilization and embryo development. The rates of the development to term of two-cell embryos were also similar, regardless of the origin of the round spermatids injected. This finding suggests that round spermatids from the prepubertal testis already have the ability to fertilize normally and to allow normal embryo development.