Effects of hyperoxia on mitochondrial multienzyme complex III and V in premature newborn rat lung.
To investigate the effects of hyperoxia on mitochondrial multienzyme complex III (cytochrome, Cytb) and V (ATPase6, 8) in premature newborn rat lung, the 1-day-old preterm SD rats were randomly assigned to hyperoxia group and air group. The rats in hyperoxia group were continuously exposed to 85% oxygen and those in air group to room air. After 1, 4, 7, 10, 14 day(s) of exposure, these rats were killed, total lung RNA was extracted and Cytb, ATPase6, 8 mRNA were detected by reverse transcription polymerase chain reaction (RT-PCR). Western blotting was used to detect the expression of Cytb protein in lung tissue. The results showed that compared with air group, Cytb mRNA expression was significantly increased (P>0.05) after 1, 4 day(s) of exposure. The general tendency decreased after 7 days, and its expression became weak but difference in mRNA expression between the two groups was not significant (P>0.05). ATPase6 mRNA expression was significantly increased 1 day after the exposure (P<0.05) and did not show any significant change 4, 7, 10 days after the exposure (P>0.05). At the 14th day, ATPase6 mRNA expression was significantly increased (P<0.05). ATPase8 mRNA expression did not show any significant change 1, 4, 10 day(s) after the exposure (P>0.05). At the 7th and 14th day, ATPase8 mRNA expression was significantly increased (P<0.05). Western blotting showed that Cytb protein expression was increased 1,4 day(s) after the exposure, but the difference between the two groups was not significant (P>0.05). The general tendency was decreased after 7 days, and its expression became weak but difference was not significant 7, 10 days after the exposure (P>0.05). At day 14 its expression became significantly weak (P<0.05). We are led to conclude that exposure to high concentrations of oxygen can significantly change the expression of Cytb and ATPase6, 8, which results in uncoupling of oxidative phosphorylation in mitochondrial respiration chain, and plays an important role in the mechanism of hyperoxia-induced lung injury.


Physical activity promotion for patients transitioning to dialysis using the "Exercise is Medicine" framework: a multi-center randomized pragmatic trial (EIM-CKD trial) protocol.
Patients on dialysis are physically inactive, with most reporting activity levels below the fifth percentile of healthy age-matched groups. Several small studies have reported efficacy of diverse exercise interventions among persons with CKD and those on dialysis. However, no single intervention has been widely adopted in real-world practice, despite a clear need in this vulnerable population with high rates of mortality, frailty, and skilled nursing hospitalizations. We describe a pragmatic clinical trial for an exercise intervention among patients transitioning to dialysis. We will use an existing framework - Exercise is Medicine (EIM) - developed by the American College of Sports Medicine. After undertaking formative qualitative research to tailor the EIM framework to the advanced CKD population (eGFR < 30 ml/min/1.73m2), we will randomize 96 patients from two regions-Atlanta and Bay Area-in two intervention arms with incremental levels of clinical-community integration: physical activity assessment during Nephrology clinical visit, brief counseling at pre-dialysis education, and physical activity wearable (group 1) versus group 1 intervention components plus a referral to a free, EIM practitioner-led group exercise program over 16 weeks (group 2; 8 week core intervention; 8-week follow up). We will assess efficacy by comparing between group differences in minutes/week of objectively measured moderate intensity physical activity. To evaluate implementation, we will use questionnaires for assessing barriers to referral, participation and retention along the path of the intervention. Further we will have a plan for dissemination of the intervention by partnering with relevant stakeholders. The overall goal is to inform the development of a practical, cost-conscious intervention "package" that addresses barriers and challenges to physical activity commonly faced by patients with advanced CKD and can be disseminated amongst interested practices. ClinicalTrials.gov identifier (Dated:10/17/2017): NCT03311763 .


Identification and characterization of a novel Cut family cDNA that encodes human copper transporter protein CutC.
Copper is an essential heavy metal trace element that plays important roles in cell physiology. The Cut family was associated with the copper homeostasis and involved in several important metabolisms, such as uptake, storage, delivery, and efflux of copper. In this study, a novel Cut family cDNA was isolated from the human fetal brain library, which encodes a 273 amino acid protein with a molecular mass of about 29.3 kDa and a calculated pI of 8.17. It was named hCutC (human copper transporter protein CutC). The ORF of hCutC gene was cloned into pQE30 vector and expressed in Escherichia coli M15. The secreted hCutC protein was purified to a homogenicity of 95% by using the Ni-NTA affinity chromatography. RT-PCR analysis showed that the hCutC gene expressed extensively in human tissues. Subcellular location analysis of hCutC-EGFP fusion protein revealed that hCutC was distributed to cytoplasm of COS-7 cells, and both cytoplasm and nucleus of AD293 cells. The results suggest that hCutC may be one shuttle protein and play important roles in intracellular copper trafficking.


Historical background.
Surgery, radiation therapy, chemotherapy, steroid therapy and radiosurgery have been the mainstream of management of brain metastasis and the trend has been continuously changed along with the advancement of cancer management, development of new technology and changing in perception of quality of life. A glance at the historical perspective on brain metastasis management clearly shows two major shifts which have been made in last two decades. One is the changes of leading treatment modalities from whole-brain radiation therapy to multimodal management focusing on radiosurgery, and the other is changes of the attitude of the treatment from palliative purpose to disease control. The epoch-making change in the understanding of brain metastasis is that brain metastasis is no longer a death sentence as considered in the past.


What's in it for me? A mixed-methods study on teachers' value creation in an inter-institutional community on open educational resources in higher education.
The affordances of Open Educational Resources (OER) have resulted in various initiatives around the world, but most of them cease to exist once the initial project funding stops. Communities might be a means to create sustainable practices, yet, such communities can only function if their members perceive these communities as valuable. We applied the value creation framework of Wenger, Trayner, and De Laat to examine the value teachers ascribe to their engagement with an inter-institutional community on OER. In this community, 15 universities of applied sciences collaborated on sharing knowledge and resources across their institutional barriers. We collected data through user statistics, an online questionnaire, and semi-structured interviews. Major value creation occurred from teachers' personal needs, with dominant immediate and potential values. Findings on applied and realized values denote that it became easier for teachers to connect with peers, and to initiate collaboration projects across institutes. The framework we used is helpful to inform actions to further promote value creation in communities on OER. Recommendations relating to communities' aspirations, its relations with the wider organization, and adoption of OER are formulated to inform sustainable practices of inter-institutional communities.


Effects of pentoxifylline administration on urinary N-acetyl-beta-glucosaminidase excretion in type 2 diabetic patients: a short-term, prospective, randomized study.
Tubulointerstitial injury is a major feature of diabetic nephropathy and an important predictor of renal dysfunction. In 45 patients with type 2 diabetes mellitus (DM), we prospectively analyzed urinary excretion of N-acetyl-beta-glucosaminidase (NAG), a marker of tubular renal damage; the potential relationship with urinary protein excretion; and effects of pentoxifylline (PTF) administration. Forty-five patients with type 2 DM initially were compared with 15 healthy controls matched for age and sex. After randomization, PTF (1,200 mg/d) was administered for 4 months to 30 patients and results were compared with data from a control group (n = 15). Proteinuria and urinary NAG excretion were significantly greater in patients with DM with respect to healthy controls. Before PTF administration, baseline parameters were similar in both groups of patients with DM. At the end of the study, urinary protein excretion and NAG-creatinine ratios decreased in the active group from 920 +/- 522 mg/d and 14.3 +/- 16.9 U/g to 803 +/- 523 mg/d (P < 0.001) and 10.5 +/- 9.3 U/g (P < 0.05), respectively. Conversely, proteinuria and urinary NAG excretion did not change in the control group. Regression analysis showed that urinary NAG excretion was significantly associated with duration of DM (r = 0.61; P < 0.001) and proteinuria (r = 0.51; P < 0.001). Urinary NAG excretion is elevated in patients with type 2 DM compared with healthy individuals and increases as nephropathy progresses. PTF administration is effective in reducing proteinuria and urinary NAG excretion in these patients. These findings suggest that PTF may have beneficial effects on tubulointerstitial damage in diabetic kidney disease.


Disseminated anetoderma in a patient with nodal Epstein-Barr virus-associated classical Hodgkin lymphoma: Anetodermic form of a concurrent discordant cutaneous marginal zone lymphoma.
Patients with a lymphoma have an increased risk of developing a second lymphoproliferative disorder. The association of nodal Hodgkin lymphoma and primary cutaneous marginal zone lymphoma (MALT type) is exceptional, and only very few cases have been documented. Anetoderma represents a circumscribed loss or rarefication of elastic fibers. Different underlying processes may result in anetoderma, including cutaneous marginal zone lymphoma. We report a 50-year-old male patient with Epstein-Barr virus (EBV)-associated nodal Hodgkin lymphoma who presented with disseminated anetodermic skin lesions. Biopsies of the skin lesions revealed a B-cell infiltrate containing monoclonal plasma cells but without detection of EBV. The skin lesions represent an anetodermic form of primary cutaneous marginal zone lymphoma. It is the first case report of an association of anetodermic cutaneous marginal zone lymphoma and a synchronous EBV-associated nodal Hodgkin lymphoma.


Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors.
Atypical teratoid rhabdoid tumors (AT-RT) are pediatric tumors of the central nervous system with limited treatment options and poor survival rate. We investigated whether enhancing chemotherapy toxicity by depleting intracellular glutathione (GSH; a key molecule in cisplatin resistance) with high dose acetaminophen (AAP), may improve therapeutic efficacy in AT-RT in vitro. BT16 (cisplatin-resistant) and BT12 (cisplatin-sensitive) AT-RT cell lines were treated with combinations of AAP, cisplatin, and the anti-oxidant N-acetylcysteine (NAC). Cell viability, GSH and peroxide concentrations, mitochondrial damage, and apoptosis were evaluated in vitro. AAP enhanced cisplatin cytotoxicity in cisplatin-resistant BT16 cells but not cisplatin-sensitive BT12 cells. Baseline GSH levels were elevated in BT16 cells compared to BT12 cells, and AAP decreased GSH to a greater magnitude in BT16 cells than BT12 cells. Unlike BT12 cells, BT16 cells did not have elevated peroxide levels upon treatment with cisplatin alone, but did have elevated levels when treated with AAP + cisplatin. Both cell lines had markedly increased mitochondrial injury when treated with AAP + cisplatin relative to either drug treatment alone. The enhanced toxic effects were partially reversed with concurrent administration of NAC. Our results suggest that AAP could be used as a chemo-enhancement agent to potentiate cisplatin chemotherapeutic efficacy particularly in cisplatin-resistant AT-RT tumors with high GSH levels in clinical settings.


Cell to cell relationships in the seminiferous epithelium in the mouse embryo.
Germ cells and Sertoli cells in embryonic mouse testes (day 14 to 20 of gestation) were examined by sectioning and freeze-fracture. Intercellular cytoplasmic bridges between the germ cells are observed in day 14 and older embryos. Membrane specializations with dense fuzzy material similar to the so-called "desmosome-like structures" are found between Sertoli cells and germ cells. A cell contact area with dense opposed membranes is also found between adjacent germ cells. Asymmetrical dense fuzzy lining of both Sertoli and germ cell membranes is noted. Pinocytotic pits or caveolae are frequently found in the Sertoli cell membrane. Between adjacent Sertoli cells, gap junctions of various sizes and focal meshworks of the occluding junctions are found. Most of the occluding junctional particles are located in the center of the grooves in the E face, and are similar to those in postnatal and adult Sertoli cell junctions. In addition, on both fractured faces there are ridges and grooves devoid of particles which are continuous with occluding junctions with particles, suggesting an initial stage in the formation of occluding junctions of the Sertoli cells. Particles gathered at the site of desmosome-like structures are present on the P face of the Sertoli cell.


[Erectile dysfunction as the first sign of systemic vascular diseases and of organovascular arterial ischemic diseases. Guidelines and Challenge of the Angiology section of Slovak Medical Chamber (AS SMC, 2015)].
Erectile dysfunction is a highly prevalent and progressive condition affecting the quality of life of man and his sexual partner. Evidence is accumulating in favour of erectile dysfunction as a sign of a genitovascular disease (GVD) in the majority of patients. Erectile dysfunction may be considered as the clinical manifestation of a organovascular disease affecting penis (male genitovascular disease - MGVD) as well as angina pectoris is the typical manifestation of a vascular disease affecting coronary arteries of a heart (cardiovascular disease - CVD). Several studies confirm the assumption that erectile dysfunction symptoms were found to come prior to cardiovascular disease symptoms in 60-95 % of CVD patients with mean interval of 2-3 years and likewise of all organovascular diseases (OVD). Four potent selective PDE5Is have been approved by the EMA for the treatment of erectile dysfunction. Physicians should systematically look for erectile dysfunction in any male with vascular risk factors.


Variation in the use of postoperative radiotherapy among high-risk patients following radical prostatectomy.
We used data from the Michigan Urological Surgery Improvement Collaborative (MUSIC) to investigate the use of adjuvant and salvage radiotherapy (ART, SRT) among patients with high-risk pathology following radical prostatectomy (RP). For patients with pT3a disease or higher and/or positive surgical margins, we examined post-RP radiotherapy administration across MUSIC practices. We excluded patients with <6 months follow-up, and those that failed to achieve a postoperative PSA nadir ⩽0.1. ART was defined as radiation administered within 1 year post RP, with all post-nadir PSA levels <0.1 ng ml(-1). Radiation administered >1 year post RP and/or after a post-nadir PSA ⩾0.1 ng ml(-1) was defined as SRT. We used claims data to externally validate radiation administration. Among 2337 patients undergoing RP, 668 (28.6%) were at high risk of recurrence. Of these, 52 (7.8%) received ART and 56 (8.4%) underwent SRT. Patients receiving ART were younger (P=0.027), more likely to have a greater surgical Gleason sum (P=0.009), higher pathologic stage (P<0.001) and received treatment at the smallest and largest size practices (P=0.011). Utilization of both ART and SRT varied widely across MUSIC practices (P<0.001 and P=0.046, respectively), but practice-level rates of ART and SRT administration were positively correlated (P=0.003) with lower ART practices also utilizing SRT less frequently. Of the 88 patients not receiving ART and experiencing a PSA recurrence ⩾0.2 ng ml(-1), 38 (43.2%) progressed to a PSA ⩾0.5 ng ml(-1) and 20 (22.7%) to a PSA ⩾1.0 ng ml(-1) without receiving prior SRT. There was excellent concordance between registry and claims data κ=0.98 (95% CI: 0.94-1.0). Utilization of ART and SRT is infrequent and variable across urology practices in Michigan. Although early SRT is an alternative to ART, it is not consistently utilized in the setting of post-RP biochemical recurrence. Quality improvement initiatives focused on current postoperative radiotherapy administration guidelines may yield significant gains for this high-risk population.


Reifying racism in medicineMasters of Health: Racial Science and Slavery in U.S. Medical Schools Christopher D. E. Willoughby University of North Carolina Press, 2022. 282 pp.
False beliefs about racial differences have a long history in physician training programs.


A square-planar Ni(II) complex with an asymmetric coordination of a novel polynucleative 2,6-diacetylpyridine bis{[2-(hydroxyimino)propanoyl]hydrazone} ligand.
The title compound, (2,6-diacetylpyridine bis{[2-(hydroxyimino)propanoyl]hydrazone}(2-))nickel(II) dimethyl sulfoxide solvate monohydrate, [Ni(C(15)H(17)N(7)O(4))] x C(2)H(6)OS x H(2)O, represents the first example of square-planar N(4) coordination via N atoms with four different functions, namely amide, azomethine, hydroxyimino and pyridine. The coordination polyhedron of the central Ni atom has a slightly distorted square-planar geometry. The 2,6-diacetylpyridine bis{[2-(hydroxyimino)propanoyl]hydrazone} ligand forms one six- and two five-membered chelate rings, and a pseudo-chelate ring through an intramolecular hydrogen bond with an amide group as donor and a deprotonated hydroxyimino group as acceptor, resulting in a pseudomacrocyclic arrangement.


Short review of plutonium applications for the sediment transport studies.
The transport of sediments in surface waters is a natural process involving the relocation of the sediments themselves and the nutrients, pollutants and radionuclides associated with them. Plutonium isotopes have proven to be a useful tool for studying this process over several decades. In this article, we review the characteristics of the behaviour of plutonium in the water column and the main directions of its use to study the transport of sediments at different scales. The characteristic isotopic fingerprints of the sources and their known input functions, as well as the good reactivity of the particles, favour the widespread use of plutonium for the study of the chronology of sediments and deposits and for studies of the fate and migration pathways of sediments at different scales. While other radionuclides are losing relevance due to the short half-life the 239Pu and 240Pu will remain useable for a long time.


The mental health impact of terrorism in Israel: a repeat cross-sectional study of Arabs and Jews.
Since September 2000 Israeli society has been subjected to numerous deadly terror attacks. Few studies have studied the comparative mental health vulnerability of minorities and majorities to continuous terror attacks. Two telephone surveys (N = 512 and 501) on two distinct representative samples of the Israeli population after 19 months and after 44 months of terror. The Arab minority and Jewish majority were compared on measures of exposure to terrorism, posttraumatic stress symptomatology, feeling depressed, coping, sense of safety, future orientation, and previous traumatic experiences. After 19 months of terrorist attacks Arab Israelis and Jewish Israelis reacted roughly similarly to the situation, however after 44 months of terror, posttraumatic symptom disorder in the Arab population increased three-fold, posttraumatic symptomatology doubled and resiliency almost disappeared. We suggest that certain conditions inherent to political conflict situations may potentially put minorities at risk and may only be observable as terrorism-related stressors become chronic.


Limited intestinal inflammation despite diarrhea, fecal viral RNA and SARS-CoV-2-specific IgA in patients with acute COVID-19.
We sought to characterize the role of the gastrointestinal immune system in the pathogenesis of the inflammatory response associated with COVID-19. We measured cytokines, inflammatory markers, viral RNA, microbiome composition and antibody responses in stool from a cohort of 44 hospitalized COVID-19 patients. SARS-CoV-2 RNA was detected in stool of 41% of patients and more frequently in patients with diarrhea. Patients who survived had lower fecal viral RNA than those who died. Strains isolated from stool and nasopharynx of an individual were the same. Compared to uninfected controls, COVID-19 patients had higher fecal levels of IL-8 and lower levels of fecal IL-10. Stool IL-23 was higher in patients with more severe COVID-19 disease, and we found evidence of intestinal virus-specific IgA responses associated with more severe disease. We provide evidence for an ongoing humeral immune response to SARS-CoV-2 in the gastrointestinal tract, but little evidence of overt inflammation.


Structural identification of the beta-hydroxy fatty acid-based diester preen gland waxes of shorebirds.
The intact C33-C52 diester wax esters of the preen gland of the shorebirds Limosa lapponica, Pluvialis squatarola, and Pluvialis fulva were determined, using synthesized standards, to comprise predominantly C12-C16 beta-hydroxy fatty acids esterified with a C8-C18 fatty acid at the beta-hydroxy position and with predominantly C12-C20 fatty alcohols esterified at the carboxyl group.


Chemotherapy in colorectal carcinoma.
The use of chemotherapy in patients with colorectal carcinoma has changed considerably in recent years. New drugs, drug combinations, and innovative methods of administration are now available for the palliative treatment of patients with metastatic disease. Based on the results of recent clinical trials, adjuvant chemotherapy appears to prolong survival for certain patients who have undergone surgical resection of colorectal cancer. This review article includes a summary of pertinent medical literature and ongoing clinical trials, and provides treatment recommendations.


SCAN: a method of community collaboration.
Recent research has highlighted the complexity of the battered child syndrome. Clinical experience suggests that treatment of troubled families is a long-term process, draining financial resources of agencies and emotional resources of professionals. The need to provide support and case consultation to professionals working in the area of child abuse and neglect evolved in the establishment, in 1968, of the Suspected Child Abuse and Neglect (SCAN) Program at Children's Hospital, Pittsburgh, Pennsylvania. This program provides an effective method of intervention through identification, consultation, referral and follow-up of at-risk families. Weekly meetings offer multi-disciplinary case coordination, treatment recommendations, and a channel of communication for representatives of community agencies. This paper traces the history and present status of the SCAN Program, as well as the role of SCAN as a force for change of community attitudes.


Darbepoetin alfa: its use in anemia associated with chronic kidney disease.
Darbepoetin alfa (Aranesp), Nespo) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses. Darbepoetin alfa is generally well tolerated, and clinical trials of 20-52 weeks' duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks' duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.


Interventions to prevent in-hospital falls in older people with cognitive impairment for further research: A mixed studies review.
While advances in falls prevention in the adult population have occurred, the care requirements for older patients with cognitive impairment at risk of falling are less established. To identify interventions to prevent in-hospital falls in older patients with cognitive impairment for further research and describe the strategies used to implement those interventions. A seven-stage mixed studies review was used. Seven electronic databases were searched. The SPIDER framework guided the review question and selection of search terms. The Mixed Methods Assessment Tool was used to appraise the quality of research studies, and the Quality Improvement Minimum Quality Data Set was used to appraise the quality of quality improvement projects. A convergent qualitative synthesis was used to analyse the extracted data. The adapted PRISMA guideline informed the procedures. Ten projects (five quality improvements and five researches) were included. Five themes emerged from the synthesis: engaging with families in falls prevention, assessing falls risk to identify interventions, extending nursing observation through technology, conducting a medication review and initiating nonpharmacological delirium prevention interventions. Implementation was not well described and commonly focused on capital investment to initiate a falls prevention programme and education to introduce staff to the new techniques for practice. Emerging research and quality improvement studies demonstrate that effective falls prevention with this vulnerable population is possible but requires further investigation before widespread practice recommendations can be made. Further research and quality improvement in this area should consider adoption of an implementation framework to address sustainability. Reducing falls in older people with cognitive impairment requires nurses to work more closely with pharmacists, occupational therapists and social workers to develop strategies that work and are sustainable.


Positive selection on a high-sensitivity allele of the human bitter-taste receptor TAS2R16.
During periods of human expansion into new environments, recognition of bitter natural toxins through taste may have conferred an important selective advantage. The G protein-coupled receptor encoded by TAS2R16 mediates response to salicin, amygdalin, and many bitter beta-glucopyranosides. beta-glucopyranosides are ubiquitous in nature, with many having a highly toxic cyanogenic activity. We examined evidence for natural selection on the human receptor TAS2R16 by sequencing the entire coding region, as well as part of the 5' and 3' UTRs, in 997 individuals from 60 human populations. We detected signatures of positive selection, indicated by an excess of evolutionarily derived alleles at the nonsynonymous site K172N and two linked sites and significant values of Fay and Wu's H statistics in 19 populations. The estimated age range for the common ancestor of the derived N172 variant is 78,700-791,000 years, placing it in the Middle Pleistocene and before the expansion of early humans out of Africa. Using calcium imaging in cells expressing different receptor variants, we showed that N172 is associated with an increased sensitivity to salicin, arbutin, and five different cyanogenic glycosides. We have detected a clear signal of positive selection at the bitter-taste receptor gene TAS2R16. We speculate that the increased sensitivity that is shown toward harmful cyanogenic glycosides and conferred by the N172 allele may have driven the signal of selection at an early stage of human evolution.


31P NMR study of intracellular pH during the calcium paradox.
Reperfusion of an isolated mammalian heart with a calcium-containing solution after a brief calcium-free perfusion results in irreversible cell damage: the calcium paradox. It has been suggested that acidification of the cytosol, as a result of hydrolysis of ATP and accumulation of calcium by mitochondria, is an important factor in the development of the calcium paradox. Phosphorus nuclear magnetic resonance (31P NMR) spectroscopy was used to investigate the course of intracellular pH during the calcium paradox in isolated rabbit heart at 37 degrees C. Intracellular pH was measured from the chemical shift of the intracellular inorganic phosphate (Pi) peak. During control perfusion and the subsequent calcium-free period intracellular pH amounted to 7.1. After induction of the calcium paradox by readmitting calcium to the perfusion fluid, intracellular pH amounted to 7.0. It is concluded that acidification of the cytosol does not play a causal role in the development of the calcium paradox.


Involvement of MAP kinase in the mediation of GH action on ovarian granulosa cells.
Growth hormone (GH), prostaglandins F (PGF) and prostaglandins E (PGE) are important regulators of ovarian function. Therefore, interrelationships between GH and these substances and their intracellular mechanisms might be of physiological significance in the ovary. The aims of this study on cultured porcine ovarian granulosa cells were to determine the effect of GH on the secretion of oxytocin (OT), PGF and PGE and whether MAP kinase could be involved in the mediation of GH action. Experiments were carried out with cultured porcine granulosa cells to investigate the effects of exogenous pGH (1-100 ng/ml) on the expression of MAP kinase (ERK-1, -2) and of PGH (1-100 ng/ml) and the MAP kinase blocker PD 98059 (1 microg/ml) on the secretion of PGF, PGE and OT. The cellular content of ERK-1 and -2 was analyzed by Western immunoblotting and immunocytochemistry, whilst PGF, PGE and OT accumulation in the medium was measured by RIA. Addition of GH to culture medium significantly altered the pattern of ovarian ERK MAP kinase on SDS-PA gels: the 44 and 42 kDa bands were reduced and additional 50 and 48 kDa bands appeared. Moreover, there was an increase in the percentage of cells containing ERK MAP kinase. GH stimulated the secretion of PGF (at a concentration of 1 ng GH per ml medium) and OT (100 ng GH per ml), but not PGE. The MAP kinase blocker alone did not affect PGF, PGE and OT secretion but did prevent the stimulatory effects of GH on PGF and induced stimulatory action of GH (10 ng/ml) on PGE. GH-stimulated OT secretion was unaffected. These observations confirm the role of GH in regulating porcine ovarian PGF, PGE and OT secretion and the presence of ERK MAP kinase in porcine granulosa cells. Furthermore, our studies demonstrate that MAP kinase-dependent intracellular mechanisms are dependent on GH, and that these mechanisms are involved in the mediation of GH action on ovarian PGF and PGE but not OT secretion.


VP26, a herpes simplex virus type 1 capsid protein, increases DNA methylation in COASY promoter region.
It has been reported that some specific changes in DNA methylation can be due to aging or infection by tumor-related viruses but the effect of herpes simplex virus type 1 (HSV-1) in this regard is unknown. HSV-1 is a well-known virus that causes cold sores. After the primary infection, the virus switches to latent infection and remains in the body for the whole life. As the location of DNA methylation, we focused on the promoter region of the COASY gene, which codes for coenzyme A synthase, because methylation in this region is reportedly associated with Alzheimer's disease (AD). During HSV-1 lytic infection, compared to non-infected cells, COASY DNA methylation decreased but when HSV-1 replication was inhibited by acyclovir, an anti-herpes agent, COASY DNA methylation increased. In addition, for expression of immediate early protein only, there was no significant change in COASY DNA methylation, while for expression of the capsid protein VP26, a late protein known to bind with DNA methyltransferase DNMT3A, in the nucleus only, COASY DNA methylation significantly increased compared to the control, without changes in DNMT3A mRNA. Our results suggested that DNA methylation occurred not due to transcriptional changes in DNMT3A but through translational regulation. In this research, we showed that host COASY DNA methylation is altered by HSV-1 infection, in particular by HSV-1 VP26. It is a potential cause of various diseases, and this is particularly relevant for AD.


Salmonellae from dogs in Vom, Northern Nigeria.
Examination by culture of single faecal samples from 120 domestic dogs in the Vom area of Nigeria showed 22 (18 per cent) of the animals to be excreting Salmonella organisms. One of the dogs yielded two and another three different serotypes. The total number of Salmonella serotypes isolated in the survey was 21. Dogs may be important in Nigeria as agents for the transmission of salmonellosis to man and domestic livestock.


Native-like intermediate on the folding pathway of Escherichia coli succinyl-CoA synthetase.
The transition between the native and denatured states of the tetrameric succinyl-CoA synthetase from Escherichia coli has been investigated by circular dichroism, fluorescence spectroscopy, cross-linking by glutaraldehyde and activity measurements. At pH 7.4 and 25 degrees C, both denaturation of succinyl-CoA synthetase by guanidine hydrochloride and refolding of the denatured enzyme have been characterized as reversible reactions. In the presence of its substrate ATP, the denatured enzyme could be successfully reconstituted into the active enzyme with a yield of 71-100%. Kinetically, reacquisition of secondary structure by the denatured enzyme was rapid and occurred within 1 min after refolding was initiated. On the other hand, its reactivation was a slow process which continued up to 25 min before 90% of the native activity could be restored. Both secondary and quaternary structures of the enzyme, reconstituted in the absence of ATP, were indistinguishable from those of the native enzyme but the renatured protein was catalytically inactive. This observation indicates the presence of catalytically inactive tetramer as an intermediate in the reconstitution process. The reconstituted protein could be reactivated by ATP even 10 min after the reacquisition of the native secondary structure by the refolding protein. However, reactivation of the protein by ATP 60 min after the regain of secondary structure was significantly less, suggesting that rapid refolding and reassociation of the monomers into a native-like tetramer and reactivation of the tetramer are sequential events; the latter involving slow and small conformational rearrangements in the refolded enzyme that are likely to be associated with phosphorylation.


Metastases to the uterine cervix from a gastric carcinoma presenting with obstructive renal failure: a case report.
Metastases to the uterine cervix are infrequent(1-3). Except for cases of endometrial primary carcinoma, the most common origin of neoplastic dissemination to the uterine cervix is the ovary, followed by the breast(1,2). Primary gastrointestinal tumors are rare, and in most of these cases cervical metastases are associated with adnexal bilateral masses (Krukenberg's tumors)(1).


Celecoxib Oral Solution and the Benefits of Self-Microemulsifying Drug Delivery Systems (SMEDDS) Technology: A Narrative Review.
The oral route of drug delivery is the most widespread and preferred route of administration, but it has several limitations, including variable pharmacokinetics (PK), reduced dissolution and absorption, and gastrointestinal irritation. Further, many compounds have low aqueous solubility, which also limits intestinal absorption. For this narrative review, we conducted a literature search of PubMed until August 2022, focusing on emulsions, microemulsions, nanoemulsions, and self-emulsifying drug delivery systems. The self-microemulsifying drug delivery system (SMEDDS) overcomes these limitations of hydrophobic compounds to enhance their bioavailability. A SMEDDS formulation is a clear, thermodynamically stable, oil-in-water emulsion of lipid, solubilized drug, and two surfactants, which spontaneously forms droplets < 100 nm in diameter. These components help deliver presolubilized drugs to the gastrointestinal tract, while protecting them from degradation in gastric acid or first-pass hepatic metabolism. SMEDDS formulations have improved oral drug delivery in the treatment of cancer (paclitaxel), viral infections (ritonavir), and migraine headache (ibuprofen and celecoxib oral solution). The American Headache Society recently updated their consensus statement for the acute treatment of migraine and included a selective cyclo-oxygenase-2 selective inhibitor formulated in SMEDDS, celecoxib oral solution. This SMEDDS formulation showed pronounced improvement in bioavailability compared with celecoxib capsules, allowing for a low dose of celecoxib in the oral solution to provide safe and effective acute migraine treatment. Here, we will focus on SMEDDS formulations, what differentiates them from other analogous emulsions as vehicles for poorly soluble drugs, and their clinical application in the acute treatment of migraine. Oral drugs reformulated in SMEDDS have shown accelerated times to peak plasma drug concentrations and increased maximum plasma concentrations, compared with capsules, tablets, or suspensions. SMEDDS technology increases both drug absorption and bioavailability of lipophilic drugs, compared with other formulations. Clinically, this allows the use of lower doses with improved PK profiles without compromising efficacy, as shown with celecoxib oral solution for the acute treatment of migraine.


The genome of Mycobacterium africanum West African 2 reveals a lineage-specific locus and genome erosion common to the M. tuberculosis complex.
M. africanum West African 2 constitutes an ancient lineage of the M. tuberculosis complex that commonly causes human tuberculosis in West Africa and has an attenuated phenotype relative to M. tuberculosis. In search of candidate genes underlying these differences, the genome of M. africanum West African 2 was sequenced using classical capillary sequencing techniques. Our findings reveal a unique sequence, RD900, that was independently lost during the evolution of two important lineages within the complex: the "modern" M. tuberculosis group and the lineage leading to M. bovis. Closely related to M. bovis and other animal strains within the M. tuberculosis complex, M. africanum West African 2 shares an abundance of pseudogenes with M. bovis but also with M. africanum West African clade 1. Comparison with other strains of the M. tuberculosis complex revealed pseudogenes events in all the known lineages pointing toward ongoing genome erosion likely due to increased genetic drift and relaxed selection linked to serial transmission-bottlenecks and an intracellular lifestyle. The genomic differences identified between M. africanum West African 2 and the other strains of the Mycobacterium tuberculosis complex may explain its attenuated phenotype, and pave the way for targeted experiments to elucidate the phenotypic characteristic of M. africanum. Moreover, availability of the whole genome data allows for verification of conservation of targets used for the next generation of diagnostics and vaccines, in order to ensure similar efficacy in West Africa.


Misclassification of subjects with insulin resistance and associated cardiovascular risk factors by homeostasis model assessment index. Utility of a postprandial method based on oral glucose tolerance test.
Different methods are available for assessing insulin sensitivity in the fasting state. However, insulin resistance (IR) is initially a postprandial disturbance; and usually, when basal (fasting) disturbance appears, the process has been in progress for some time. Our aim was to investigate if a postprandial measurement, performing an oral glucose tolerance test (OGTT), is more sensitive than fasting values. We wished to identify early IR states in healthy, nonobese individuals and ascertain if this situation was associated with other cardiovascular risk factors. A total of 90 nonobese, nondiabetic, and nonsmoker individuals were studied. They were divided into 3 groups according to IR state--group 1: non-IR--homeostasis model assessment of IR (HOMA(IR)) and insulin sensitivity index of Matsuda-De Fronzo (ISI-Mat) were normal (HOMA(IR) <3.2 and ISI-Mat >4.0); group 2: with IR post-OGTT (ISI-Mat ≤4.0 and HOMA(IR) <3.2); and group 3: subjects with IR in basal conditions (HOMA(IR) ≥3.2). An intravenous glucose tolerance test to compare both indices was also performed. In 14.4% of subjects, the fasting HOMA(IR) values failed to identify IR (false-negative results). The ISI-Mat values were better correlated than HOMA(IR) (r = 0.875, P = .0001 and r = -0.631, P = .0001, respectively) with insulin sensitivity index obtained with intravenous glucose tolerance test. Subjects with IR had higher prevalence of a cluster of cardiovascular risk factors than non-IR subjects. These data show that that a significant percentage of subjects were misclassified with HOMA(IR). Early identification of IR by OGTT was associated with other cardiovascular risk factors. The OGTT is a simple method that could be applied to accurately identify IR subjects in the general population.


[Perineal hernia: an undescribed complication following operative repair of vault vaginal prolaps].
The presented case reports the treatment of a 80-year-old V gravida IV para suffering from a large perineal hernia and rectocele after vaginal hysterectomy and subsequently performed threefold colpocleisis due to recurrent vault vaginal prolaps.[nl]Since perioperative morbidity and mortality of geriatric patients differ not significantly from thoses of younger women age should not be used as an argument to withhold elderly organ preserving operative strategies with low recurrence rates.


Construction of a Streptomyces lydicus A01 transformant with a chit42 gene from Trichoderma harzianum P1 and evaluation of its biocontrol activity against Botrytis cinerea.
Streptomyces lydicus A01 and Trichoderma harzianum P1 are potential biocontrol agents of fungal diseases in plants. S. lydicus A01 produces natamycin to bind the ergosterol of the fungal cell membrane and inhibits the growth of Botrytis cinerea. T. harzianum P1, on the other hand, features high chitinase activity and decomposes the chitin in the cell wall of B. cinerea. To obtain the synergistic biocontrol effects of chitinase and natamycin on Botrytis cinerea, this study transformed the chit42 gene from T. harzianum P1 to S. lydicus A01. The conjugal transformant (CT) of S. lydicus A01 with the chit42 gene was detected using polymerase chain reaction (PCR). Associated chitinase activity and natamycin production were examined using the 3, 5-dinitrosalicylic acid (DNS) method and ultraviolet spectrophotometry, respectively. The S. lydicus A01-chit42 CT showed substantially higher chitinase activity and natamycin production than its wild type strain (WT). Consequently, the biocontrol effects of S. lydicus A01-chit42 CT on B. cinerea, including inhibition to spore germination and mycelial growth, were highly improved compared with those of the WT. Our research indicates that the biocontrol effect of Streptomyces can be highly improved by transforming the exogenous resistance gene, i.e. chit42 from Trichoderma, which not only enhances the production of antibiotics, but also provides a supplementary function by degrading the cell walls of the pathogens.


Oxymatrine attenuates cognitive deficits through SIRT1-mediated autophagy in ischemic stroke.
To investigate if oxymatrine could ameliorate hippocampus ischemia/reperfusion (I/R) injury induced in rats and explore the possible mechanism. Rats were randomly divided into four groups: sham group, I/R group, I/R + OMT-treated group, I/R + Vehicle-treated group. Oxymatrine or vehicle solution was intraperitoneally injected OMT (150 mg/kg) 60 min before renal ischemia respectively. Water maze was measured; cell apoptosis was assessed by doing TUNEL assay and detecting the expression of P53, Bax, and Cleaved-Caspase-3; autophagy were assessed by measuring the expression of LC3 and P62. The expression of SIRT1 was also detected. Oxymatrine treatment alleviated histological injury in I/R rats, inhibiting apoptosis, promoting autophagy and accompanied by upregulated expression of SIRT1 proteins. Oxymatrine may attenuate hippocampus ischemia/reperfusion injury through upregulation SIRT1, further influencing the processes of apoptosis and autophagy.


Hypocrellin derivative with improvements of red absorption and active oxygen species generation.
A novel diamino-substituted hypocrellin derived from hypocrellin B (HB) was synthesized by a mild method. The red absorption of the resulting product was significantly enhanced relative to the parent hypocrellins and any other hypocrellin derivatives, and the active oxygen species generating abilities were enhanced distinctly, which will remarkably improve its photodynamic therapy effectiveness.


Endoscopy-assisted latissimus dorsi muscle flap harvesting technique for immediate breast reconstruction.
The purpose of this study is to investigate the usefulness of endoscopy-assisted latissimus dorsi muscle flap (LDMF) harvesting in immediate breast reconstruction following partial mastectomy. From November 2016 to December 2019, sixteen female breast cancer patients who underwent immediate breast reconstruction following partial mastectomy underwent LDMF harvesting with endoscopic assistance. This surgical technique was carried out with only one subaxillary skin incision without leaving a scar on the back. Patients' demographic characteristics, histopathologic factors, operative data, postoperative complications, and oncologic safety were collected through electronic chart review. In sixteen patients, LDMFs were harvested successfully using an endoscopy-assisted technique without conversion to an open technique. The mean age of the patients was 48.0±8.0 years, and the mean body mass index was 24.4±3.9kg/m2. The most common histologic subtype was invasive ductal carcinoma, with a mean tumor size of 3.2±2.3cm. In terms of LDMF harvesting time, it took 168.4±44.0minutes. The most common postoperative complication, donor site seroma (75%), was managed non-surgically during the outpatient visit. In terms of cosmetic aspects, we've seen a high level of patient satisfaction, especially with scarring. Endoscopy-assisted LDMF harvesting technique is safe and useful for breast reconstruction after partial mastectomy. Compared to the conventional open technique, this method does not leave a long scar on the donor site. As a result, it leads to better cosmetic outcomes and improves patient satisfaction.


Possible apoptotic mechanism in epidermal cell acantholysis induced by pemphigus vulgaris autoimmunoglobulins.
Through a still unclear mechanism, pemphigus vulgaris autoantibodies (PV-IgG) induce intra-epidermal acantholytic lesions responsible for severe to fatal skin wounding. We present evidence that PV lesions contain apoptotic keratinocytes, and that cell death is induced in the lesional tissue apparently before cell separation. These data suggest that apoptosis could be the cause of the acantholytic phenomenon. We show that PV-IgG and an antibody against Fas receptor (anti-FasR) induce lesions in vitro in a similar way, causing: (1) secretion of soluble FasL; (2) elevated cellular amounts of FasR, FasL (soluble and membranal), Bax and p53 proteins; (3) reduction in levels of cellular Bcl-2; (4) enrichment in caspase 8, and activation of caspases 1 and 3; (5) co-aggregation of FasL and FasR with caspase 8 in membranal death-inducing signaling complex (DISC). Hence, the Fas-mediated death signaling pathway seems to be involved in lesion formation. Moreover, we have shown that in skin organ cultures and in keratinocyte cultures, PV-IgG can induce caspase activation and DNA fragmentation, and caspase inhibitors can prevent the formation of PV-IgG-induced epidermal lesions. Altogether, these results suggest that PV-IgG-induced acantholysis may proceed through the death-signaling pathway. They highlight new perspectives on mechanisms of tissue damage in autoimmune diseases.


Thrombocytosis is associated with complications after microvascular surgery: An NSQIP data analysis.
Complications after microvascular surgery, such as partial flap loss, and arterial/venous compromise cannot only increase morbidity for the patient but also tax the healthcare system. Thrombocytosis, both essential and reactive, can predispose patients to thrombosis and hemorrhage and thus should intuitively have an effect on the outcome of microvascular free tissue transfers. We sought to evaluate the effect of preoperative thrombocytosis on outcomes after microvascular free flap surgery. A retrospective review of the 2013-2016 American Collges of Surgeons, National Surgical Quality Improvement Program (ACS NSQIP) database identified 4,299 patients who had microsurgical flaps. Of these 3,744 had preoperative platelet levels recorded. Fifty-four patients had preoperative thrombocytosis, defined as a platelet count >450 K/CUMM, while 3,690 did not. The groups were compared; demographics, comorbidities, and smoking status were recorded. We then examined outcomes between groups including average operative time, length of hospital stay, need for transfusion, deep vein thrombosis (DVT) postoperatively, and need for reoperation. When comparing the two cohorts, there was no statistical difference in comorbidities. We found a significant difference between the thrombocytosis and control cohort in need for transfusion (29.6 vs. 12.8%, p = .0002), average days till discharge (8.36 vs. 5.75, p = .009), and need for reoperation (27.8 vs. 13.8%, p = .003). There was no difference in DVT occurrence (0 vs. 0.1%, p = .46) or average operation time (535 m vs. 482 min, p = .088). Patients with thrombocytosis undergoing microvascular free flaps are at increased risk for complications, including the need for a blood transfusion, prolonged hospital stays, and reoperation.


Oxygen uptake-heart rate relationship in élite wheelchair racers.
The American College of Sports Medicine (ACSM) recommends that, as a general rule for health purposes, individuals should exercise at 40%-85% of their maximal oxygen uptakes. Moreover, it has been suggested that 55%-90% of the maximal heart rate may be used as an alternative estimate of these percentage maximal oxygen uptake values. The present study examined the relationship between percentage peak heart rate (% HRpeak) and percentage peak oxygen uptake (% VO2peak) during steady-state incremental intensity wheelchair propulsion of 16 élite, male wheelchair racers (WR). Oxygen uptake was determined during each submaximal exercise stage and heart rate (HR) was continuously monitored. The VO2peak was subsequently determined using a separate protocol. Linear regression equations of % HRpeak versus % VO2peak for each participant included % HRpeak values corresponding to 40%, 60%, 80% and 85% VO2peak. The linear regression equation, derived as the group mean of the slope and intercept terms determined for each individual, was: % peak HR = 0.681 x % peak VO2 + 33.2. The group mean of the individual correlation coefficients for the VO2-HR relationship was 0.99. The values of % HRpeak for each of the % VO2peak values below 85% were significantly greater (P<0.01) than those suggested by the ACSM. This suggests that the ACSM guidelines below 85% VO2peak, based on % HRpeak, may underestimate the relative exercise intensity (i.e. % VO2peak) in the WR population. However, in élite level WR, % HRpeak can be recommended as an alternative estimate of % VO2peak at wheelchair propulsion intensities of 85% VO2peak or more.


Serum C-reactive protein concentrations in cyclosporine-treated renal allograft recipients.
Acute or persistent elevations in serum C-reactive protein (CRP) concentration have been shown to be of value in diagnosing acute rejection episodes in azathioprine (AZA)-treated renal transplant recipients. To assess whether changes in serum CRP level might assist in differentiating nephrotoxicity from acute rejection in cyclosporine (CsA)-treated renal transplant recipients, we measured changes occurring in serum CRP concentrations in 74 CsA patients in response to transplant operation, acute rejection, cyclosporine nephrotoxicity, and serious infection, and compared these values with changes in AZA patients. Serum CRP concentration rose in response to operation in virtually all patients, regardless of immunosuppressive regimen, from mean baselines of 5.9 +/- 2.7 mcg/ml (AZA) and 6.8 +/- 6.5 mcg/ml (CsA) to mean peak levels of 43.8 +/- 33.4 mcg/ml and 65.1 +/- 39.5 mcg/ml, respectively. CRP rose during 76% of acute rejection episodes in AZA patients by a mean of 29.7 +/- 37.4 mcg/ml. In contrast, in 80% of acute rejection episodes of CsA patients, CRP remained undetectable or failed to rise above a stable, minimally elevated baseline. Similarly, there was no elevation in CRP in 9 of 10 episodes of nephrotoxicity. In 14 CSA patients with serious infections (8 pulmonary, 3 intraabdominal, 3 genitourinary), CRP rose by a mean of 67.7 +/- 50.7 mcg/ml. Thus, although CRP rises significantly with operation or serious infection in CsA patients, CRP fails to rise with nephrotoxicity or acute rejection.


Ligand-dependent maintenance of ethanol-inducible cytochrome P-450 in primary rat hepatocyte cell cultures.
Administration of ethanol, dimethylsulphoxide, 2-propanol or imidazole to rats caused 2-7-fold increases in the level of hepatic ethanol-inducible cytochrome P-450 (P-450j), without any concomitant enhancement of corresponding mRNA. All the compounds were able to stabilize P-450j in hepatocyte cultures for at least three days, whereas P-450j mRNA rapidly disappeared from the cultures. A correlation was reached between the concentration of Me2SO, ethanol and 2-propanol necessary to maintain P-450j in the cell cultures and their binding affinities to the enzyme. It is suggested that the ligand-bound form of P-450j in the hepatocytes is protected from degradation.


Hemoglobin Dunn: alpha 6 (A4) aspartic acid replaced by asparagine.
Hemoglobin Dunn, alpha 6 (A4) Asp leads to Asn was found in a 39-year-old black woman and her daughter. The hematological data on the propositus were normal and there were no apparent clinical or pathological findings associated with this abnormal hemoglobin. The structural characterization of this variant is described.


An RF-Ultrasound Relay for Adaptive Wireless Powering Across Tissue Interfaces.
Single modality wireless power transfer has limited depth for mm-sized implants across air / tissue or skull / tissue interfaces because they either suffer from high loss in tissue (RF, Optical) or high reflection at the medium interface (Ultrasound (US)). This paper proposes an RF-US relay chip at the media interface avoiding the reflection at the boundary, and enabling efficient wireless powering to mm-sized deep implants across multiple media. The relay chip rectifies the incoming RF power through an 85.5% efficient RF inductive link (across air) using a multi-output regulating rectifier (MORR) with 81% power conversion efficiency (PCE) at 186 mW load, and transmits ultrasound using adiabatic power amplifiers (PAs) to the implant in order to minimize cascaded power loss. To adapt the US focus to implant movement or placement, beamforming was implemented using 6 channels of US PAs with 2-bit phase control (0, 90, 180, and 270°) and 3 different amplitudes (6-29, 4.5, and 1.8 V) from the MORR. The adiabatic PA contributes a 30-40% increase in efficiency over class-D and beamforming increases the efficiency by 251% at 2.5 cm over fixed focusing. The proof-of-concept powering system for a retinal implant, from an external PA on a pair of glasses to a hydrophone with 1.2 cm (air) + 2.9 cm (agar eyeball phantom in mineral oil) separation distance, had a power delivered to the load (PDL) of 946 μW. The 2.3 × 2 mm2 relay chip was fabricated in a 180 nm high-voltage (HV) BCD process.


Mycobacterium fortuitum infection: evidence of bactericidal defect due to hyperactive antigen-specific suppressor cells. Correction in vitro and in vivo by cholinergic agonist and indomethacin.
Immunologic studies in a patient with long-standing Mycobacterium fortuitum infection revealed normal numbers of T cells, T inducers, T suppressors, B cells, and monocytes, significant in vitro proliferative response to M. fortuitum antigen, and poor bactericidal activity against M. fortuitum but not against Escherhicia coli. M. fortuitum antigen-activated suppressor cells contributed to the bactericidal defect. The activity of these suppressor cells could be eliminated by the in vitro treatment of blood mononuclear cells with a combination of a cholinergic agonist and indomethacin, but not with either alone. Administration of the two drugs to the patient resulted in reversal of the bactericidal defect and dramatic clinical improvement. Systemic atypical (nontuberculous) mycobacterial infection may activate specific suppressor cells that could compromise the host's phagocytic cell function. Modulation of those suppressor cells by a combination of a cholinergic agonist and prostaglandin synthetase inhibitor could reverse this abnormality and may be beneficial to the patient.


Management of high-grade renal injuries in children after blunt abdominal trauma: experience of 40 cases.
We present our experience of management of high-grade renal trauma in a pediatric population, including assessment of the long-term function and morphology of the ipsilateral kidney. From 1997 to 2005, 40 children with high-grade renal injury (III, IV, V) after blunt abdominal trauma were managed. Initial evaluation included vital signs, color of urine, hemoglobin (Hb%), hematocrit, serum creatinine and computed tomography (CT). Follow up included vital signs, urine analysis, Hb%, CT, +/-intravenous pyelogram and renogram. One patient needed superselective embolization due to continuing hemorrhage in spite of conservative treatment. Internal stenting plus percutaneous tube drain was indicated in three cases due to progressive extravasation. Exploration was indicated in four cases, one at presentation due to hemodynamic instability which ended in nephrectomy; the other three were successfully repaired. Conservative treatment was successful in 32 cases (80%). Blood transfusion was indicated in 16 cases (40%). Length of hospital stay was 4-20 days (mean 12.1). At the last follow up (range 1-8 years, mean 3.5), scars were detected in 10 cases, while all showed normal levels of Hb% and creatinine. No patient developed hypertension. Apart from in the nephrectomy case, the ipsilateral kidney showed split function of 40-50%. After exclusion of hemodynamic instability and continuing hemorrhage, conservative treatment is successful in 80% of patients. Internal stenting with or without percutaneous drainage is indicated if there is progressive urinoma. Angioembolization is successful in selected cases.


Ecto-enzyme activity of human erythrocyte adenosine deaminase.
Adenosine deaminase is found primarily in the cytoplasm of many cell types. In the human erythrocyte, about 30 per cent of the total adenosine deaminase activity is membrane associated, and about two-thirds of this is inactivated by treatment of intact erythrocytes with the nonpenetrating reagent diazotized sulfanilic acid, without affecting lactate dehydrogenase, a soluble cytoplasmic enzyme. This indicates that within the cell membranes, the catalytic site of about two-thirds of the adenosine deaminase faces the external medium, i.e., ecto adenosine deaminase. Localization of adenosine deaminase activity at the cell membrane is demonstrated directly by electron microscopy by use of the substrate 6-Chloropurine ribonucleoside, which is dechlorinated by adenosine deaminase to produce Cl-, which is precipitated at its locus of formation by added Ag+, and the precipitated AgCl converted into the electron dense Ag0 upon exposure to light. From the Hydropathic Profile of the amino acid sequence of adenosine deaminase it is evident that there are two hydrophobic domains of sufficient length to span a biological membrane, and it is proposed that these domains could function to anchor the enzyme to the membrane. The importance of adenosine deaminase is indicated by the fatal immuno-deficiency which results from untreated genetic adenosine deaminase deficiency. It may be important to determine whether the amount of ecto adenosine deaminase activity is better suited to assess the clinical status of adenosine deaminase deficient patients that the currently used total cellular enzyme activity.


IFCT-1502 CLINIVO: real-world evidence of long-term survival with nivolumab in a nationwide cohort of patients with advanced non-small-cell lung cancer.
Immunotherapy using inhibitors targeting immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) is currently the standard of care in patients with advanced non-small-cell lung cancer (NSCLC). We carried out a nationwide cohort retrospective study of consecutive patients with advanced, refractory NSCLC who received nivolumab as second to later lines of treatment as part of the expanded access program. Key objectives were to assess the efficacy and safety of nivolumab and the efficacy of first post-nivolumab treatment. Nine hundred and two patients were enrolled: 317 (35%) with squamous cell carcinoma and 585 (65%) with non-squamous cell carcinoma. Median age was 64 years; there were 630 (70%) men, 795 (88%) smokers, 723 (81%) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0/1, 197 (22%) patients with brain metastases, and 212 (27%) with liver metastases. Best response was partial response for 16.2% and stable disease (SD) for 30.5%. Progression-free survival and overall survival (OS) rates at 2, 3, and 5 years were 8% and 25%, 6% and 16%, and 4% and 10%, respectively. At multivariate analysis, ECOG PS ≥2 [hazard ratio (HR) = 2.13, 95% confidence interval (95% CI) 1.78-2.55, P < 0.001], squamous histology (HR = 1.17, 95% CI 1.01-1.36, P = 0.04), and presence of central nervous system metastases (HR = 1.29, 95% CI 1.08-1.54, P = 0.005) were significantly associated with lower OS. Four hundred and ninety-two patients received at least one treatment after discontinuation of nivolumab, consisting of systemic therapies in 450 (91%). Radiation therapy was delivered to 118 (24%) patients. The CLINIVO cohort represents the largest real-world evidence cohort with the use of immune checkpoint inhibitor in advanced, metastatic NSCLC after failure of first-line chemotherapy, with long-term follow-up and analysis of subsequent therapies. Our data confirm the efficacy of nivolumab in a cohort larger than that reported in landmark clinical trials and identify prognostic factors, which reinforces the need for accurate selection of patients for treatment with immune checkpoint inhibitors. Our data indicate that oligoprogression is frequent after nivolumab exposure and provide a unique insight into the long-term survival.


Low density lipoprotein (LDL) receptor-related protein 6 (LRP6) regulates body fat and glucose homeostasis by modulating nutrient sensing pathways and mitochondrial energy expenditure.
Body fat, insulin resistance, and type 2 diabetes are often linked together, but the molecular mechanisms that unify their association are poorly understood. Wnt signaling regulates adipogenesis, and its altered activity has been implicated in the pathogenesis of type 2 diabetes and metabolic syndrome. LRP6(+/-) mice on a high fat diet were protected against diet-induced obesity and hepatic and adipose tissue insulin resistance compared with their wild-type (WT) littermates. Brown adipose tissue insulin sensitivity and reduced adiposity of LRP6(+/-) mice were accounted for by diminished Wnt-dependent mTORC1 activity and enhanced expression of brown adipose tissue PGC1-α and UCP1. LRP6(+/-) mice also exhibited reduced endogenous hepatic glucose output, which was due to diminished FoxO1-dependent expression of the key gluconeogenic enzyme glucose-6-phosphatase (G6pase). In addition, in vivo and in vitro studies showed that loss of LRP6 allele is associated with increased leptin receptor expression, which is a likely cause of hepatic insulin sensitivity in LRP6(+/-) mice. Our study identifies LRP6 as a nutrient-sensitive regulator of body weight and glucose metabolism and as a potential target for pharmacological interventions in obesity and diabetes.


Monomer and Excimer Emission in a Conformational and Stacking-Adaptable Molecular System.
A design strategy that combines molecular conformation, alkyl chain length, and charge-transfer effects has been developed to obtain conformational and stacking-adaptable donor-acceptor-π type molecules for precisely regulating the monomer and excimer emission in a single luminous platform under different environments. These fluorophores can exhibit bright monomer emissions when they are in the dispersed state based on their planar conformation. However, when the luminous molecules with short alkyl side chains are in the crystalline state, their molecular conformation can become distorted, further inducing strong intermolecular interactions and staggered π-π stacking for bright excimer emission. More importantly, their dispersed and aggregated states can be reversibly regulated in a phase-change fatty acid matrix, to achieve temperature-responsive fluorescence for temperature monitoring and advanced information encryption.


LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis.
Leucine-rich repeat kinase 2 (LRRK2) has been associated with a variety of human diseases, including Parkinson's disease and Crohn's disease, whereas LRRK2 deficiency leads to accumulation of abnormal lysosomes in aged animals. However, the cellular roles and mechanisms of LRRK2-mediated lysosomal regulation have remained elusive. Here, we reveal a mechanism of stress-induced lysosomal response by LRRK2 and its target Rab GTPases. Lysosomal overload stress induced the recruitment of endogenous LRRK2 onto lysosomal membranes and activated LRRK2. An upstream adaptor Rab7L1 (Rab29) promoted the lysosomal recruitment of LRRK2. Subsequent family-wide screening of Rab GTPases that may act downstream of LRRK2 translocation revealed that Rab8a and Rab10 were specifically accumulated on overloaded lysosomes dependent on their phosphorylation by LRRK2. Rab7L1-mediated lysosomal targeting of LRRK2 attenuated the stress-induced lysosomal enlargement and promoted lysosomal secretion, whereas Rab8 stabilized by LRRK2 on stressed lysosomes suppressed lysosomal enlargement and Rab10 promoted lysosomal secretion, respectively. These effects were mediated by the recruitment of Rab8/10 effectors EHBP1 and EHBP1L1. LRRK2 deficiency augmented the chloroquine-induced lysosomal vacuolation of renal tubules in vivo. These results implicate the stress-responsive machinery composed of Rab7L1, LRRK2, phosphorylated Rab8/10, and their downstream effectors in the maintenance of lysosomal homeostasis.


Association between demographic and diagnostic factors and employment outcomes for people with psychiatric disabilities: a synthesis of recent research.
Employment outcome for individuals with psychiatric disabilities has been a focus of empirical research over the past decade or so. The purpose of this paper is to review recent literature on the association between demographic and diagnostic factors and employment outcome, and to conduct meta analyses of the results of studies that report the association between these variables. Seventeen studies were included in these meta analyses. Results of the meta analyses tended to corroborate most of the significant findings found in the literature review. The authors review some of the issues for the meta-analyst interested in synthesizing research findings on employment outcome, including the challenges and limitations encountered in the published research currently available.


Odontogenic Cysts.
Odontogenic cysts are epithelial-lined pathologic cavities and surrounded by fibrous connective tissue that originate from odontogenic tissues that occur in tooth-bearing regions of maxilla and mandible. Cystic conditions of the jaw cause bony destruction and may cause resorption or displacement of adjacent teeth. Odontogenic cysts have developmental or inflammatory origins. More cases have been published in the adult age group than the pediatric population. Periapical cyst and dentigerous cysts are frequently reported conditions in dental practice. Histopathologic examination remains the gold standard investigation. Odontogenic cysts are managed with enucleation or marsupialization procedures. Early recognition and referral to oral surgery minimize the extent of jaw bone destruction.


Transdiagnostic and functional predictors of depression severity and trajectory in the Penn state psychiatry clinical assessment and rating evaluation system (PCARES) registry.
Timely, accurate diagnosis and subsequent identification of risk factors for depression that is difficult-to-treat can aid in decreasing the burden of depressive illness and reducing probability of future disability. We aimed to identify sociodemographic, clinical, and functional factors that predict depression severity over one year in a real-world, naturalistic, transdiagnostic clinical sample. A subset sample with moderate depression was examined to determine the magnitude of improvement. The Penn State Psychiatry Clinical Assessment and Rating System (PCARES) Registry houses data from systematically-structured patient-reported outcomes and clinical data from an Electronic Medical Record (EMR) gathered during routine clinical care of patients seeking mental health care at a mid-Atlantic clinic. Self-report symptom and functional measures were obtained, and sociodemographic features and clinical diagnoses were extracted from the EMR from 1,766 patients between 2/6/2016 to 9/30/2019. The Patient Health Questionnaire 9 (PHQ-9) depression scale was obtained at each visit. Using a discrete mixture clustering model, the study population was divided into five longitudinal trajectory groups, termed depression severity groups, based on intra-individual PHQ-9 score trajectories over one year. Multinomial logistic regression models were estimated to evaluate associations between characteristics and the likelihood of depression severity group membership. To determine the magnitude of improvement, predictors of the slope of the PHQ-9 trajectory were examined for patients with moderate depression. The strongest predictors of high depression severity over one year were poor functioning, high transdiagnostic DSM-5 Level 1 crosscutting symptom score, diagnosis of Post-Traumatic Stress Disorder (PTSD), public/self-pay insurance, female gender, and non-White race. Among the subset of patients with moderate depression, strong predictors of improvement were commercial insurance and exposure to trauma; the strongest predictors of worsening were high functional impairment, high transdiagnostic Level 1 symptom score, diagnosis of PTSD, diagnosis of bipolar disorder, and marital status of single or formerly married; depression-specific symptom measures were not predictive. Limitations include inferring education and income status from zip code level-data, the non-random missingness of data, and the use of diagnoses collected from the electronic medical record. Functional impairment, transdiagnostic measures of symptom burden, and insurance status are strong predictors of depression severity and poor outcome.


Mortality in a cohort of diabetic patients. Causes and relative risks.
In a prospective study of mortality in a large group of Scottish diabetic patients, ischaemic heart disease was responsible for 51% of deaths, with the diabetic relative risks of death being 3.8, 2.7 and 2.2 for the age groups 45-64, 65-74, and 75 years and over, respectively. The diabetic relative risks for mortality from all causes were 5.5, 2.3, 1.7, 1.3 for age ranges 15-44, 45-64, 65-74, and 75 and over, respectively. The all cancer mortality rate is not reduced in diabetic individuals.


Multiple minute digitate hyperkeratosis.
We report a case of multiple minute digitate hyperkeratosis. The patient had hundreds of keratotic lesions--some tiny and spiked, others larger, flat papules--localized on the trunk and arms. Histologic sections showed focal areas of compact hyperorthokeratosis with few dermal changes. Ultrastructurally, keratohyalin granules were smaller than normal. The keratin pattern was one of a normal variant. Odland bodies present. Various family members of the patient, in different generations, were affected.


Quantitative susceptibility mapping in β-Amyloid PET-stratified patients with dementia and healthy controls - A hybrid PET/MRI study.
Post-mortem and in-vivo MRI data suggest an accumulation of iron in the brain of Alzheimer's disease (AD) patients. The majority of studies in clinically diagnosed AD patients found an increase of iron-sensitive MRI signals in the putamen. As the clinical diagnosis shows only a moderate sensitivity, Aβ-PET was used to further stratify patients with the clinical diagnosis of AD. Aim of this exploratory study was to examine whether Aβ-positive (AD) and Aβ-negative (non-AD) patients differ in their regional magnetic susceptibility compared to healthy controls (HCs) and whether regional susceptibility values correlate with mini mental state examination (MMSE) scores or global Aβ-load. We retrospectively analyzed [11C]PiB PET/MRI data of 11 HCs, 16 AD and 10 non-AD patients. We used quantitative susceptibility mapping (QSM) as iron-sensitive MRI signal measured at the 3 T PET/MR scanner. Global cerebral Aβ-load was determined by composite [11C]PiB SUV ratios. Compared to HCs, AD patients showed higher QSM values in putamen (0.049 ± 0.033 vs. 0.002 ± 0.031; p = 0.006), while non-AD patients showed lower QSM values in caudate nucleus (0.003 ± 0.027 vs. 0.051 ± 0.039; p = 0.006). There was a trend towards a significant correlation between putaminal QSM and MMSE values (ρ=-0.340, p = 0.053). In AD patients, global Aβ-load and putaminal QSM values were significantly correlated (ρ=-0.574, p = 0.020). These data indicate that AD and non-AD patients may show different cerebral iron pathologies which might be detectable by QSM MRI, and might be linked to neurodegeneration. Overall, the data encourage further investigations in well-defined patient cohorts to clarify the value of QSM/magnetic susceptibility in the course of neurodegenerative diseases and its potential as diagnostic biomarker.


Reconsider Alzheimer's disease by the 'calpain-cathepsin hypothesis'--a perspective review.
Alzheimer's disease (AD) is characterized by slowly progressive neuronal death, but its molecular cascade remains elusive for over 100 years. Since accumulation of autophagic vacuoles (also called granulo-vacuolar degenerations) represents one of the pathologic hallmarks of degenerating neurons in AD, a causative connection between autophagy failure and neuronal death should be present. The aim of this perspective review is at considering such underlying mechanism of AD that age-dependent oxidative stresses may affect the autophagic-lysosomal system via carbonylation and cleavage of heat-shock protein 70.1 (Hsp70.1). AD brains exhibit gradual but continual ischemic insults that cause perturbed Ca(2+) homeostasis, calpain activation, amyloid β deposition, and oxidative stresses. Membrane lipids such as linoleic and arachidonic acids are vulnerable to the cumulative oxidative stresses, generating a toxic peroxidation product 'hydroxynonenal' that can carbonylate Hsp70.1. Recent data advocate for dual roles of Hsp70.1 as a molecular chaperone for damaged proteins and a guardian of lysosomal integrity. Accordingly, impairments of lysosomal autophagy and stabilization may be driven by the calpain-mediated cleavage of carbonylated Hsp70.1, and this causes lysosomal permeabilization and/or rupture with the resultant release of the cell degradation enzyme, cathepsins (calpain-cathepsin hypothesis). Here, the author discusses three topics; (1) how age-related decrease in lysosomal and autophagic activities has a causal connection to programmed neuronal necrosis in sporadic AD, (2) how genetic factors such as apolipoprotein E and presenilin 1 can facilitate lysosomal destabilization in the sequential molecular events, and (3) whether a single cascade can simultaneously account for implications of all players previously reported. In conclusion, Alzheimer neuronal death conceivably occurs by the similar 'calpain-hydroxynonenal-Hsp70.1-cathepsin cascade' with ischemic neuronal death. Blockade of calpain and/or extra-lysosomal cathepsins as well as scavenging of hydroxynonenal would become effective AD therapeutic approaches.


Oral contraceptive-induced changes in plasma lipids: do they have any clinical relevance?
The plethora of published studies investigating oral contraceptive pill (OC)-induced changes of various plasma lipids and their ratios together with repeated reviews of these studies in the literature, are all based on the assumption that OC-induced favourable or unfavourable lipid profiles decrease or increase a pill-associated cardiovascular risk. Some authorities have been led to recommend choice of pill formulations based on such changes of plasma lipids. In a combined review of relevant cardiovascular and OC epidemiological studies no evidence is found for these assumptions and recommendations. There is no evidence of OC-induced atherosclerotic disease, and pill-induced changes of plasma lipids within normal limits are therefore probably without any clinical relevance. Profound changes towards a so-called favourable plasma lipid profile may, on the contrary, be detrimental in terms of pill-associated cardiovascular events.


Controlling the three dimensional propagation of spin waves in continuous ferromagnetic films with an increasing out of plane undulation.
The role of three-dimensionality in a ferromagnetic medium in ruling the propagation properties of spin-waves (SW) has been one of the main focuses of the research activity in recent years. In this context, we investigate the evolution of the SW dispersion (frequency vs wave vector) induced by a progressive vertical undulation of a ferromagnetic film. The geometric undulation is taken along a single direction and is periodic with constant period, while the amplitude (differential maximum height with respect to the film thickness) is gradually increased from 0 to 60 nm. We study the characteristic modification of the internal effective field and link it to the resulting SW dispersions and spatial profile. These systems display at once features both of a planar film and a discretized medium, and the dispersion curves change not only when SWs propagate along the undulation direction, but also perpendicular to it. We discuss the geometric and magnetic conditions for having either the invariance of the SW group velocity with respect to even major changes in the undulation, or a large group velocity for some edge modes. We address a potential dual-band activity, namely the simultaneous propagation of two independent SW-signals, with separated frequency bands and disjoint oscillation regions.


A process for specifying integration for multi-tier applications in healthcare.
Integration of the heterogeneous application systems in healthcare is needed to support the clinical and administrative work, patient-centric care, regional interoperability and utilisation of both valuable legacy systems and new technologies. The integration activity is complicated, and must be supported by flexible processes and methods. The integration methods should support the evaluation and specification of different integration approaches, standards and technologies on many interoperability levels. We introduce a process for specifying many integration decisions for a given integration situation. The process is part of an integration method, which is validated in PlugIT project in Finland.


Pharmacological characterization of WAY-121,520: a potent anti-inflammatory indomethacin-based inhibitor of 5-lipoxygenase (5-LO)/phospholipase A2 (PLA2).
WAY-121,520 inhibited human synovial fluid PLA2 (HSF-PLA2) (IC50 = 4 microM) using arachidonic acid-labeled E. coli as substrate. Further biochemical characterization of WAY-121,520 demonstrated potent inhibition of 5-lipoxygenase (5-LO) activity in the murine macrophage (LTC4, IC50 = 4 nM) and rat PMN (LTB4, IC50 = 10 nM) and an ability to antagonize LTD4 binding to isolated guinea-pig trachea (pKB = 6.0). In vivo anti-inflammatory activity was noted in murine TPA-induced (ED50 = 91 micrograms/ear) and arachidonic acid-induced (66% inhibition at 400 micrograms/ear) ear edema and in leukotriene-dependent antigen-induced bronchoconstriction in the guinea pig (73% inhibition at 50 mg/kg, p.o.). WAY-121,520 represents a novel series of indomethacin-based inhibitors of PLA2 with anti-inflammatory activity resulting from a combination of biochemical activities (inhibition of 5-LO and PLA2 and LTD4 antagonism). This agent may provide added therapeutic efficacy over more selective inhibitors.


A case of bulbospinal muscular atrophy with large fasciculation manifesting as spinal myoclonus.
This paper reports a patient with bulbospinal muscular atrophy (BSMA) who presented with spinal myoclonus, documented by video and surface electromyography. A 66-year-old man had progressive gait disturbance, dysphagia, and easy fatigability of all extremities over a period of 4 years. Neurologically, muscle atrophy, fasciculation, and weakness were observed in the bulbar and limb muscles. When the knees were kept in mild flexion in the supine position, fasciculation of the thigh adductor muscles was so large that it caused shock-like involuntary movements of the legs, corresponding to spinal myoclonus. A genetic test revealed 41 repeats of CAG in the androgen receptor gene, and the diagnosis of BSMA was made. The present case suggests that extremely large fasciculation can cause spinal myoclonus.


C-H Fluoromethoxylation of Arenes by Photoredox Catalysis.
Redox-active N-(fluoromethoxy)benzotriazoles were made accessible from fluoroacetic acid and hydroxybenzotriazoles via electrodecarboxylative coupling. After alkylation, they become effective monofluoromethoxylation reagents, enabling the photocatalytic C-H functionalization of arenes. Thus, irradiation of 1-(OCH2 F)-3-Me-6-(CF3 )benzotriazolium triflate with blue LED light in the presence of [Ru(bpy)3 (PF6 )2 ] promotes the synthesis of diversely functionalized aryl monofluoromethyl ethers. This method allows the late-stage functionalization of biologically relevant structures without relying on ecologically problematic halofluorocarbons.


Environmental relevant concentration of λ-cyhalothrin and 3-phenoxybenzoic acid caused endocrine-disrupting effects on male lizards (Eremias argus).
In the present study, the endocrine toxicity of LCT and PBA was investigated through exposure to Eremias argus for two weeks under environmental relevant concentration. RNA-sequencing identified 4442 and 4653 differentially expressed genes in lizard liver after LCT and PBA exposure. Four differentially expressed genes (hsd17β, ar, sult, ugt) related with hypothalamic-pituitary-gonadal axis were quantified by qPCR. The expression of genes associated with HPG axis in different tissues differed significantly. In LCT treatment group, ar, cyp17 and hsd3β genes involved in testosterone synthesis and transportation were significantly decreased in lizard testes, and the spermatogensis was inhibited in the testes, which indicated the anti-androgenic activity of LCT. After PBA exposure, the genes related with estradiol synthesis, transportation and metabolism, such as hsd17β, erα, ugt in lizard liver were important biomarkers and the significant decrease of estradiol level was highly correlated with hsd17β, erα, ugt gene expressions. The relative high binding affinity of PBA with ERα further demonstrated the anti-estrogenic activity of PBA. Our results elucidate the different toxic mechanism of LCT and PBA on lizard endocrine system at environmental relevant concentration. Pyrethroids metabolism may cause more seriously toxicity rather than detoxification.


Correlation of androgen receptors with histological differentiation in human endometrial carcinomas.
Primary endometrial carcinomas from 35 non-treated patients were investigated by measurement of androgen receptors in the tumor cytosols. Receptor analysis was done with a labelled synthetic androgen, methyltrienolone 3H-R1881 and triamcinolone acetonide, and dextran-coated charcoal absorption. The concentrations of androgen receptors in the endometrial carcinomas were, in decreasing order: highly-differentiated tumors, 15.7 +/- 1.8 (fmol/mg protein, mean +/- SE) (number of cases, 21); moderately differentiated tumors, 4.6 +/- 1.6 (n = 7); poorly differentiated tumors, undetectable in 7 out of 8 cases. Highly-differentiated tumors contained a much greater concentration of receptors than the two less differentiated ones. One highly-differentiated endometrial carcinoma with pyometra virtually lacked the receptor. The moderately differentiated endometrial carcinomas contained very low levels of the receptors. The poorly differentiated tumors virtually lacked the receptors. Metastatic lymph nodes from primary endometrial carcinomas with moderate differentiation had a very low receptor level. From these results, it is concluded that human endometrial carcinomas, particularly with histologically high differentiation, contain a considerable amount of androgen receptor and that the receptor concentrations appear to correlate with the histologic grade of tumor differentiation.


Definition of a novel symbiovar (sv. retamae) within Bradyrhizobium retamae sp. nov., nodulating Retama sphaerocarpa and Retama monosperma.
In this paper we analyze through a polyphasic approach several Bradyrhizobium strains isolated in Spain and Morocco from root nodules of Retama sphaerocarpa and Retama monosperma. All the strains have identical 16S rRNA genes and their closest relative species is Bradyrhizobium lablabi CCBAU 23086(T), with 99.41% identity with respect to the strain Ro19(T). Despite the closeness of the 16S rRNA genes, the housekeeping genes recA, atpD and glnII were divergent in Ro19(T) and B. lablabi CCBAU 23086(T), with identity values of 95.71%, 93.75% and 93.11%, respectively. These differences were congruent with DNA-DNA hybridization analysis that revealed an average of 35% relatedness between the novel species and B. lablabi CCBAU 23086(T). Also, differential phenotypic characteristics of the new species were found with respect to the already described species of Bradyrhizobium. Based on the genotypic and phenotypic data obtained in this study, we propose to classify the group of strains isolated from R. sphaerocarpa and R. monosperma as a novel species named Bradyrhizobium retamae sp. nov. (type strain Ro19(T)=LMG 27393(T)=CECT 8261(T)). The analysis of symbiotic genes revealed that some of these strains constitute a new symbiovar within genus Bradyrhizobium for which we propose the name "retamae", that mainly contains nodulating strains isolated from Retama species in different continents.


Understanding aquaporin transport system, silicon and other metalloids uptake and deposition in bottle gourd (Lagenaria siceraria).
Aquaporins (AQPs) facilitates the transport of small solutes like water, urea, carbon dioxide, boron, and silicon (Si) and plays a critical role in important physiological processes. In this study, genome-wide characterization of AQPs was performed in bottle gourd. A total of 36 AQPs were identified in the bottle gourd, which were subsequently analyzed to understand the pore-morphology, exon-intron structure, subcellular-localization. In addition, available transcriptome data was used to study the tissue-specific expression. Several AQPs showed tissue-specific expression, more notably the LsiTIP3-1 having a high level of expression in flowers and fruits. Based on the in-silico prediction of solute specificity, LsiNIP2-1 was predicted to be a Si transporter. Silicon was quantified in different tissues, including root, young leaves, mature leaves, tendrils, and fruits of bottle gourd plants. More than 1.3% Si (d.w.) was observed in bottle gourd leaves, testified the in-silico predictions. Silicon deposition evaluated with an energy-dispersive X-ray coupled with a scanning electron microscope showed a high Si accumulation in the shaft of leaf trichomes. Similarly, co-localization of Si with arsenic and antimony was observed. Expression profiling performed with real-time quantitative PCR showed differential expression of AQPs in response to Si supplementation. The information provided in the present study will be helpful to better understand the AQP transport mechanism, particularly Si and other metalloids transport and localization in plants.


Long-Term Dietary Fish Meal Substitution with the Black Soldier Fly Larval Meal Modifies the Caecal Microbiota and Microbial Pathway in Laying Hens.
Feeding laying hens with black soldier fly larval (BSFL) meal improves their performance. However, the beneficial mechanism of BSFL meals in improving the performance of laying hens remains unclear. This study investigated the effects of the BSFL diet on liver metabolism, gut physiology, and gut microbiota in laying hens. Eighty-seven Julia hens were randomly assigned to three groups based on their diets and fed maize grain-and soybean meal-based diets mixed with either 3% fish meal (control diet), 1.5% fish and 1.5% BSFL meals, or 3% BSFL meal for 52 weeks. No significant differences were observed in biochemical parameters, hepatic amino acid and saturated fatty acid contents, intestinal mucosal disaccharidase activity, and intestinal morphology between BSFL diet-fed and control diet-fed laying hens. However, the BSFL diet significantly increased the abundance of acetic and propionic acid-producing bacteria, caecal short-chain fatty acids, and modified the caecal microbial pathways that are associated with bile acid metabolism. These findings indicate that consuming a diet containing BSFL meal has minimal effects on plasma and liver nutritional metabolism in laying hens; however, it can alter the gut microbiota associated with short-chain fatty acid production as well as the microbial pathways involved in intestinal fat metabolism. In conclusion, this study provides evidence that BSFL can enhance enterocyte metabolism and gut homeostasis in laying hens.


Evaluation of the Impact of Policymakers' Decisions in the Management Capacity of Protected Areas: Efficiency Evidence from Five Countries.
Protected areas play an important role in biodiversity conservation and tourism. Significant efforts have been made to increase the amount of protected lands. A problem of increasing the amount of public protected areas is that governments and other institutions face difficulties in providing the necessary resources for effective management. Accordingly, managers must be as efficient as possible but the lack of comparative methods makes the evaluation of efficiency difficult. Using Data Envelopment Analysis, a non-stochastic and non-parametric approach, information from 29 protected areas in 5 countries was analyzed to compare management efficiency amongst them. The first result found is the level of management efficiency that each park has in comparison with the others parks. The other important result is a prediction of the changes in the outputs if there is a hypothetical budget change. These results allow the generation of information for decision making.


Reciprocity: Different behavioural strategies, cognitive mechanisms and psychological processes.
Reciprocity is probably one of the most debated theories in evolutionary research. After more than 40 years of research, some scientists conclude that reciprocity is an almost uniquely human trait mainly because it is cognitively demanding. Others, however, conclude that reciprocity is widespread and of great importance to many species. Yet, it is unclear how these species reciprocate, given its apparent cognitive complexity. Therefore, our aim was to unravel the psychological processes underlying reciprocity. By bringing together findings from studies investigating different aspects of reciprocity, we show that reciprocity is a rich concept with different behavioural strategies and cognitive mechanisms that require very different psychological processes. We reviewed evidence from three textbook examples, i.e. the Norway rat, common vampire bat and brown capuchin monkey, and show that the species use different strategies and mechanisms to reciprocate. We continue by examining the psychological processes of reciprocity. We show that the cognitive load varies between different forms of reciprocity. Several factors can lower the memory demands of reciprocity such as distinctiveness of encounters, memory of details and network size. Furthermore, there are different information operation systems in place, which also vary in their cognitive load due to assessing the number of encounters and the quality and quantity of help. We conclude that many species possess the psychological processes to show some form of reciprocity. Hence, reciprocity might be a widespread phenomenon that varies in terms of strategies and mechanisms.


Equilibrium constants and protonation site for N-methylbenzenesulfonamides.
The protonation equilibria of four substituted N-methylbenzenesulfonamides, X-MBS: X = 4-MeO (3a), 4-Me (3b), 4-Cl (3c) and 4-NO(2) (3d), in aqueous sulfuric acid were studied at 25 °C by UV-vis spectroscopy. As expected, the values for the acidity constants are highly dependent on the electron-donor character of the substituent (the pK(BH+) values are -3.5 ± 0.2, -4.2 ± 0.2, -5.2 ± 0.3 and -6.0 ± 0.3 for 3a, 3b, 3c and 3d, respectively). The solvation parameter m* is always higher than 0.5 and points to a decrease in the importance of solvation on the cation stabilization as the electron-donor character of the substituent increases. Hammett plots of the equilibrium constants showed a better correlation with the σ(+) substituent parameter than with σ, which indicates that the initial protonation site is the oxygen atom of the sulfonyl group.


Cytoskeleton abnormalities in axonopathies of unknown aetiology: correlations with morphometry.
To determine if specific axonal cytoskeleton abnormalities could be demonstrated in axonopathies without aetiology, nerve biopsies from five controls and nine cases were analyzed by morphometry and immunocytochemistry with anti-neurofilament (NF, subunits L, M, H) and anti-beta tubulin (TUB) antibodies. Morphometry revealed either large fiber atrophy (decrease in large fiber density with increased density in small fibers), degeneration of large fibers (decrease in large fiber density and in total density of fibers) or of all diameter fibers. NF immunostaining density decreased (by 21-89%) only in cases with fiber loss, in parallel to myelinated fiber density as determined by morphometry. On the contrary, the density of fibers labelled for TUB increased significantly in all except two cases by 52-102% over controls. Nevertheless, in these two cases--with a severe loss of fibers--as well as in other cases, the ratio of the density of fibers labelled for TUB and NFL (TUB/NFL) increased by 48-404%. Thus, the total density of myelinated fibers was always inversely correlated with the TUB/NFL ratio. Similar abnormalities have been described only after axotomy; our cases could thus be compared to <<permanent axotomy>>.


Threshold Ocular Exposure to Near Infrared Radiation for Causing Acute Opacification in the Rabbit Lens.
Surveys and epidemiological studies have reported an increased prevalence of cataracts in the glass and steel industries, which are associated with exposure to intense infrared radiation (IR). Indeed, animal studies have demonstrated that IR exposure can produce acute changes in the crystalline lens that are likely to lead to cataract formation. However, little is known about threshold IR exposure for causing acute cataractous changes, which is important in the prevention of IR-induced cataract, especially as a basis for short-term IR exposure limits. Previously, we exposed rabbit eyes to 808 nm wavelength IR at different irradiances for 6 min to determine the threshold irradiance to cause acute lens opacification. Presently, we similarly determined the threshold irradiance for exposure durations of 3 min, 1 min, 30 s, 10 s and 4 s. The threshold irradiance increased steadily with decreasing exposure duration, from 1.1 W cm-2 at 6 min to 4.1 W·cm-2 at 4 s. These threshold values are consistent with ICNIRP exposure limits to avoid IR-induced cataract formation in the tested range of exposure duration, but suggest that it may be necessary to lower the exposure limits for shorter exposure durations.


Treatment strategies for Type 2 endoleaks after endovascular aneurysm repair.
Endovascular aneurysm repair (EVAR) is recognized as a minimally invasive alternative to open surgical repair of abdominal aortic aneurysms. However, endoleaks complicate nearly 20-25% of EVAR procedures. We discuss the detection and classification of endoleaks. In addition, we describe different strategies for Type 2 endoleak repair.