Mechanism of anaemia in rheumatoid arthritis: demonstration of raised interleukin 1 beta concentrations in anaemic patients and of interleukin 1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukaemia (HEL) cells in vitro.
The pathogenesis of the anaemia associated with rheumatoid disease is unclear. It has previously been shown that the degree of the anaemia correlates with the severity of the inflammatory disease and that serum from patients with arthritis inhibits erythropoiesis. This study was designed to examine whether interleukin 1 could be a mediator of the anaemia in rheumatoid arthritis. Radioimmunoassay of interleukin 1 beta in serum showed that patients with rheumatoid arthritis and associated anaemia had significantly higher interleukin 1 beta concentrations than patients with rheumatoid arthritis without anaemia. Pure recombinant human interleukin 1 alpha and interleukin 1 beta, in concentration ranges similar to those found in the arthritic patients, markedly suppressed the colony formation of the erythroid, but not the granulocyte-macrophage progenitor cells in cultures of normal bone marrow. Natural human interleukin 1 and recombinant interleukin 1 beta, but not interleukin 1 alpha, suppressed in a dose dependent manner the proliferation of the human erythroleukaemia cell line (HEL) in cultures, suggesting that the interleukin 1 effect is a direct one. The results show that interleukin 1 is a humoral inhibitor of erythropoiesis and suggests that interleukin 1 is involved in the development of anaemia in association with rheumatoid arthritis.


Non-offspring nursing by a nulliparous pregnant female just before first parturition in free-ranging Japanese macaques.
A nulliparous pregnant Japanese macaque, Macaca fuscata, suckled her 1-year-old sister 44 days before her own parturition. Other Japanese macaque yearlings did not hold the nipples of this nulliparous female in their mouths. Although this non-offspring nursing before first parturition did not improve the rate of milk secretion, the nulliparous female may have improved her indirect fitness and her suckling behavior.


Antigenic structure of hepatitis B surface antigen: identification of the "d" subtype determinant by chemical modification and use of monoclonal antibodies.
Hepatitis B surface antigens (HBsAg) of both the adw and ayw subtypes were reductively methylated with formaldehyde in the presence of sodium cyanoborohydride. The effect on antigenicity was determined by radioimmunoassay with monoclonal antibodies specific for seven different antigenic determinants. The reaction was shown to eliminate specifically the "d" antigenic activity of HBsAg/adw and to have no effect on HBsAg/ayw. Moreover, the reaction had only a slight affect on HBsAg/adw at one of the "a" antigenic determinants. The sites of modification were determined and the extent of modification of each site was compared to the loss of "d" antigenic activity. These studies demonstrated that the loss of "d" activity was due to the modification of lysine 122 in HBsAg/adw, and that although the amino terminus and lysine residues 141 and 160 of both HBsAg/adw and HBsAg/ayw are reactive, their modification does not alter any measurable antigenic activity.


American Society of Clinical Oncology 41st annual meeting.
For many years the annual meeting of the American Society of Clinical Oncology (ASCO) has been the premier meeting in clinical oncology, and one that is closely scrutinised by Wall Street and international investors because of the economic significance of cancer therapies to the pharmaceutical and biotechnology industries. The area of biologicals and targeted therapies exploded in the late 1990s after the blockbuster results with the monoclonal antibody rituximab in the treatment of lymphoma. Although historically a somewhat conservative organisation that is still closely tied to classical cytotoxic chemotherapy, ASCO has been able to integrate various areas of biological therapy into its scope of clinical activity. Although ASCO still has 'American' in its title, it is really the 'International' Society of Clinical Oncology, as reflected by the attendance at this year's meeting by approximately 30,000, with approximately two-thirds attending from outside the US. There were 9708 abstracts published in conjunction with the meeting, 86 of which are referenced in this review. There were 10 papers chosen for plenary presentations and many other key papers were presented at other oral abstract sessions and poster discussion session that were organised by tumour type. In addition to key papers submitted by specific tumour type, for this year's meeting there were 103 abstracts published in the session entitled 'Developmental Therapeutics: Immunotherapy', and 218 in the session entitled Developmental Therapeutics: Molecular Targets', for a total of 321 biological therapy abstracts compared with only 125 abstracts for the session entitled 'Developmental Therapeutics: Cytotoxic Therapy'. This meeting review is organised by biotherapy modality rather than tumour type.


Experimental Klebsiella septicemia in mice: treatment with specific antibodies from the rabbit alone and in combination with gentamicin.
Using a model of an experimental Klebsiella pneumoniae septicemia in mice, we examined the therapeutic effect of passively administered specific antibacterial antibodies from rabbits. Both specific IgM and IgG antibody proved to be therapeutically effective. However, the effect of IgG was markedly superior to that of IgM with regard both to the degree of protection and the time interval allowing efficient therapy after infection. The effect of IgG was due to a marked enhancement of in vivo phagocytosis, as demonstrated by monitoring bacterial numbers in the liver, spleen, lungs and kidneys. In mice immunocompromised with cyclophosphamide, treatment with IgG still exerted protection against low challenge inocula. When higher inocula were used, treatment with IgG ceased to influence the final mortality rates but delayed the course of the disease for several days by transient reduction of bacterial numbers in the parenchymal organs. In both normal and immunocompromised mice, concomitant treatment with gentamicin resulted in a marked synergistic enhancement of survival.


Twins Switched at Birth: Frequency, Life Histories, Twin Relationships, and Critical Issues/Twin Research Reviews: Classroom Placement; Mirror Syndrome; Unusual Twinning; Parenting Stress/Human Interest: Triplet Film; Educational Achievement; Prison Release; Co-Twin Impersonation; Facial Recognition Technology.
Twins switched at birth are a rare subtype of twins who grow up apart. The frequency with which this event occurs, as well as selected life history events, twin relationships, and critical issues generated by the nine recorded cases are reviewed. This is followed by summaries of recent studies addressing classroom placement for twins, mirror syndrome in mothers, unusual twin types, and parenting stress. The article concludes with a review of human interest items from the general media, namely a triplet film, educational achievement, prison release, co-twin impersonation, and facial recognition technology.


E-cigarette or vaping product use associated lung injury (EVALI) in the time of COVID-19: A clinical dilemma.
To report on the clinical, laboratory, and radiological findings of adolescents who presented during the SARS-CoV-2 surge with symptoms of Coronavirus disease 2019 (COVID-19), did not test positive for the infection, and were diagnosed with E-cigarette and vaping product use associated lung injury (EVALI). A retrospective review of 12 cases of EVALI admitted to the Bristol Meyers Squibb Children's Hospital between February 2020 and June 2020 was conducted. The ages of the patients ranged from 14 to 19 years. There were six males and six females. Three patients had a past history of anxiety, depression, or other psychiatric/mental health disorder, 9 had prolonged coagulation profile (prothrombin time, partial thromboplastin time, and/or International Normalized Ratio), and 11 had elevated inflammatory markers. Eight needed respiratory support. All 12 were negative for SARS-CoV-2 PCR. Four were tested for IgG antibodies and were negative. As these cases were admitted to rule out COVID infection, initial treatment included hydroxychloroquine. Steroids were started only after SARS-CoV-2 PCR was shown to be negative. Urine tetrahydrocannabinol was positive in all cases. Chest X-ray and computed tomography findings showed ground glass opacities. Clinical and radiological features are similar in both EVALI and SARS-CoV-2 infection. Inflammatory markers are elevated in both conditions. A detailed social and substance use history in patients presenting with "typical" COVID pneumonia like illness is important. EVALI should be ruled in early to start the appropriate treatment. Given the ongoing pandemic, pediatricians and other health-care providers need to be aware of other conditions that can masquerade as SARS-CoV-2.


Evaluation of cytotoxic function and apoptosis in interleukin (IL)-12/IL-15-treated umbilical cord or adult peripheral blood natural killer cells by a propidium-iodide based flow cytometry.
Both deficient natural killer (NK) cell effector function and increased propensity to apoptosis of neonatal NK cells contribute to the increased susceptibility to infection in the neonates. Interleukin (IL)-12 and IL-15 are two immunoregulatory cytokines known to enhance cytolytic function of neonatal NK cells. The present study aims to simultaneously investigate the effect of IL-12/IL-15 on K562 cytotoxicity as well as NK cells apoptosis of enriched umbilical cord blood (CB) and adult peripheral blood (APB) NK cells, using flow cytometric cytotoxicity assays. The results indicated that (i) prior to cytotoxicity assays, CB NK cells underwent greater degree of spontaneous apoptosis than did APB NK cells; (ii) both IL-12 and IL-15 inhibited the spontaneous apoptosis of CB NK cells, while IL-15 promoted the apoptosis in APB NK cells; (iii) the deficient K562 cytotoxicity of CB NK cells could be enhanced to levels comparable with that of APB NK cells by IL-15; (iv) IL-15 increased the percentages of apoptosis in NK-K562 conjugates in a dose-dependent manner in both CB and APB with a greater effect seen with APB NK cells; (v) target-induced apoptosis was observed with APB NK cells which were further enhanced with IL-15. However, CB NK cells, unstimulated or IL-15-activated, were resistant to K562-induced apoptosis. Thus, the multi-parameter flow cytometry analysis not only demonstrates better for the deficient CB NK function but also provides greater details for cytotoxic mechanisms of NK cells.


Distribution of 22:6n-3 newly synthesized from 18:3n-3 into glycerolipid classes from tissues of rainbow trout (Oncorhynchus mykiss).
The distribution of D5-22:6n-3 following ingestion of a pulse of D5-18:3n-3 was measured quantitatively by GC-negative chemical ionization MS in lipid classes from liver, cecal mucosa, and brain from rainbow trout to further our understanding of the processes determining accretion and turnover of 22:6n-3 in fish. The accretion of D5-22:6n-3 was expressed in two ways, as percent enrichment and as ng D5-22:6n-3/microg 22:6n-3/ mg D5-18:3n-3 eaten. In cecal mucosa at 2 d post-dose, PC was the most enriched lipid class followed by PE and then TAG. Enrichment fell in all lipid classes in cecal mucosa from 2 to 7 d post-dose of D5-18:3n-3. In liver, PC was also the most enriched lipid class at 2 d, but in this tissue all lipid classes were more enriched in D5-22:6n-3 by 7 d. When expressed in terms of the 22:6n-3 content of the different lipid classes, TAG became relatively less important in cecal mucosa and more important in liver. Over a time course of 3 to 35 d, the percent enrichment of D5-22:6n-3 in liver peaked at 7 d in PC, PE, PS, and PI and fell rapidly in TAG from 3 d. PC from liver was the most enriched lipid class at 3 and 7 d, and thereafter PE was the most enriched lipid class. However, TAG had the highest specific activity at all times except 7 d. In brain, the enrichment of D5-22:6n-3 was very low in all lipid classes at 3 d and increased progressively to 35 d with PC and PE similarly enriched. TAG from brain had the highest specific activity at all times. This study is the first to present quantitative information on rates of accretion and depletion of newly synthesized 22:6n-3 into the main lipid classes of fish tissues.


Dual-targeting lanthanide-ICG-MOF nanoplatform for cancer Theranostics: NIR II luminescence imaging guided sentinel lymph nodes surgical navigation.
Sentinel lymph node imaging is important for breast tumor staging and prediction of postoperative metastasis. However, clinical sentinel lymph node imaging has limitations such as low specificity, low contrast, and short retention time. The combination of bio-conjugates chemistry and luminescence technology may achieve the specific targeting effect. In this research, we designed a dual-targeting composite nanoprobe (∼50 nm) using a metal-organic framework (MOF) as carrier, loaded with lanthanide and ICG, and combined with hyaluronic acid and folic acid to detect metastatic lymph nodes. The coupled hyaluronic acid and folic acid can target to the tumor cells and dentritic cells with a dual-targeting effect. The FA-HA/ZIF-8@ICG nanoprobes can accumulate rapidly in sentinel lymph node with a stronger luminescence intensity (1.6 times) than that of normal popliteal lymph nodes in vivo, thus distinguish metastatic sentinel lymph node from normal effectively. Furthermore, due to the MOF carrier, the integrated lanthanide and near-infrared dye by transferring the absorbed excitation energy from ICG to Nd3+ can enhance the signal-to-background ratio of NIR II imaging and have long retention time in vivo imaging. Finally, the FA-HA/ICG@Ln@ZIF-8 nanoplatform increased the penetration depth and contrast of imaging, prolonged the retention time, and achieved the sentinel lymph nodes surgical resection. This study has important implications for lymph node imaging and surgical navigation.


Navigating difficult conversations: the role of self-monitoring and reflection-in-action.
Clinicians draw upon experiential knowledge to manoeuvre difficult conversations, using tacit knowledge that is difficult to explicitly teach. Instead, learners are taught to communicate through role-play and checklists, both of which are approaches that may fail during moments of clinical complexity. We know that difficult conversations may provoke anxiety in learners, but we know little about how they learn to navigate them. Without a deeper understanding, we may fail to equip learners with the skills to manoeuvre these conversations in practice. Using constructivist grounded theory, we applied the sensitising concepts of self-monitoring and reflection-in-action both to explore the process in which trainees engage to navigate difficult conversations and to expand understanding about these theories. We situated our research in the neonatal intensive care unit (NICU), in which difficult conversations are ubiquitous. Fifteen resident and fellow trainees drew rich pictures about difficult conversations, and shared their drawings and experiences during semi-structured interviews. Interview transcripts were analysed using constant comparative analysis. Participants described how they responded when checklist approaches became ineffective during moments of unexpected uncertainty and complexity. For participants, these indeterminate zones of practice triggered a process of seeing families differently and then pausing to understand problems that arose with the checklist-based approach. Throughout this process, learners actively observed others' communication approaches, negotiated their roles within difficult conversations, and abandoned the checklist to engage differently with families. Our findings suggest links between the theories of self-monitoring and reflection-in-action, and describe the engagement of both processes in the context of NICU conversations. Self-monitoring may lead to the realisation of an indeterminate zone of practice, after which trainees may respond through reflection-in-action. We recognise that training programmes may need to teach a checklist-based approach as a starting point. We suggest that trainees also be given purposeful opportunities and support to depart from checklists in order to compassionately and flexibly navigate difficult conversations with families.


Diffusion-weighted magnetic resonance imaging in dura mater graft-associated Creutzfeldt-Jakob disease.
To elucidate the extension patterns of the hyperintense areas on diffusion-weighted magnetic resonance imaging (DW-MRI) in patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD). We collected the DW-MRI of dCJD cases identified by the CJD Surveillance Committee in Japan, between April 1999 and February 2018. The dCJD cases were classified into non-plaque and plaque-types. The relationship among the abnormal signals, the pathological classification, and the sites of grafting were analyzed. We collected DW-MRI of 11 patients with dCJD, all of whom were methionine homozygous at codon 129 of the prion protein gene. The age at onset was 41 (26-76) [median (range)] years, the age at dural grafting was 19 (10-53) years, and the incubation period was 22 (16-29) years. Eight dCJD cases were classified as non-plaque-type and three cases were plaque-type. Five of the non-plaque-type cases and all the plaque-type cases were pathologically confirmed. Brain DW-MRI was performed 3 (1-22) months after the onset. Most of the non-plaque-type cases showed brighter hyperintensity in the cerebral cortex and basal ganglia on the side of dural grafting. Subsequent DW-MRI showed widespread hyperintense lesions in the brain. Regarding the plaque-type cases, initial scans showed hyperintensity in the basal ganglia and the thalamus in one patient. Another patient's lesion was confined to the basal ganglia. The third patient showed no abnormalities seven months post-onset; however, serial images showed a hyperintensity confined to the thalamus. Non-plaque and plaque-types demonstrated different patterns of propagation of distinct prion strains.


Adolescent fluoxetine history impairs spatial memory in adult male, but not female, C57BL/6 mice.
Epidemiological reports indicate that mood-related disorders are common in the adolescent population. The prevalence of juvenile major depressive disorder has resulted in a parallel increase in the prescription rates of fluoxetine (FLX) within this age group. Although such treatment can last for years, little is known about the enduring consequences of adolescent antidepressant exposure on memory-related performance. We exposed separate groups of adolescent (postnatal day [PD] 35) male and female C57BL/6 mice to FLX (20 mg/kg) for 15 consecutive days (PD35-49). Three weeks after FLX exposure (PD70), we assessed learning and memory performance on a single-day training object novelty recognition test, or a spatial memory task on the Morris water maze (MWM). We found that FLX pretreatment did not influence performance on either the object novelty recognition task or the MWM, 24 h after training. Conversely, 48 h post spatial-training on the MWM, FLX pretreated male mice spent significantly less time on the quadrant of the missing platform during a standard probe trial. No differences in MWM performance were observed in the adult female mice pretreated with FLX. A limitation of this study is that normal adolescent mice (i.e., non-stressed) were evaluated for memory-related behavior three weeks after antidepressant exposure. Thus, it is possible that FLX pre-exposure in combination with animal models for the study of depression may yield different results. Together, these results demonstrate enduring spatial memory-related deficiencies after pre-exposure to FLX during adolescence in male, but not female, C57BL/6 mice.


Mild Innate Immune Activation Overrides Efficient Nanoparticle-Mediated RNA Delivery.
Clinical mRNA delivery remains challenging, in large part because how physiology alters delivery in vivo remains underexplored. For example, mRNA delivered by lipid nanoparticles (LNPs) is being considered to treat inflammation, but whether inflammation itself changes delivery remains understudied. Relationships between immunity, endocytosis, and mRNA translation lead to hypothesize that toll-like receptor 4 (TLR4) activation reduced LNP-mediated mRNA delivery. Therefore, LNP uptake, endosomal escape, and mRNA translation with and without TLR4 activation are quantified. In vivo DNA barcoding is used to discover a novel LNP that delivers mRNA to Kupffer cells at clinical doses; unlike most LNPs, this LNP does not preferentially target hepatocytes. TLR4 activation blocks mRNA translation in all tested cell types, without reducing LNP uptake; inhibiting TLR4 or its downstream effector protein kinase R improved delivery. The discrepant effects of TLR4 on i) LNP uptake and ii) translation suggests TLR4 activation can "override" LNP targeting, even after mRNA is delivered into target cells. Given near-future clinical trials using mRNA to modulate inflammation, this highlights the need to understand inflammatory signaling in on- and off-target cells. More generally, this suggests an LNP which delivers mRNA to one inflammatory disease may not deliver mRNA to another.


Practice styles and preferences of ASCRS members--1986 survey.
A survey of the practice styles and preferences of 1986 ASCRS members was taken in the summer of 1986. A total of 4,042 surveys were mailed in June of 1986 and 1,184 were returned--a return rate of 29%. The responses were analyzed using D Base III. Response rate was 5% greater than for the 1985 survey. There was no financial incentive for return of the survey other than return postage paid for by the author. Three main profile areas were analyzed: age of the ophthalmologist, volume of cataract surgery per month, and geographic location. Areas of interest were surgery locations, surgical techniques, Nd:YAG laser application, intraocular lens design preferences, radial keratotomy, and advertising in ophthalmology. The influence of age of the ophthalmologist, cataract surgery volume, and geographic location were cross-analyzed for each question. The results were compared to the results of comparable questions in the 1985 survey. This report looks at each question and looks for variances from the national average, as well as for trends from the 1985 survey.


Deconvolution method for two-dimensional spatial-response mapping of lithographic infrared antennas.
The spatial impulse response of antenna-coupled infrared detectors with dimensions comparable with the wavelength is obtained from a two-dimensional scan of a tightly focused CO(2)-laser beam. The method uses an experimental setup with submicrometer resolution and an iterative deconvolution algorithm. The measured spatial response is compared with numerically computed near-field distributions of a dipole antenna, with good agreement.


A newly improved method of primary cell culture: Tissue block with continuous adhesion subculture in skin fibroblast.
Fibroblasts (FBs) have been widely used as a typical in vitro cell model for investigating the biological processes and cell pathophysiological mechanisms. However, FBs are prone to senescence in cell culture process after several passages. Thus, a new approach to cell culture is quite required to enhance the viability of cells. To explore a novel method of cell culture based on skin FBs. Dermal tissue blocks were obtained from BALB/c neonatal mice and randomly divided into experimental group and control group. The experimental group received the newly improved culture method, namely, continuous adherence subculture of tissue block (CASTB) method; while the traditional subculture method was applied in the control group. Cells at 1st, 5th and 10th passages were collected and identified by using histological/immunohistochemical and western blot analysis. Cellular viability, proliferation, senescence and apoptosis were analyzed through application of cell growth curve, CCK-8 assay, Ki67 assay, PCNA protein analysis, β-galactosidase staining, flow cytometry and western blot analysis. Cells under two culture patterns exhibited spindle/irregular shape and vimentin positive expression. With the increase of passage times, the cellular growth rate in the control group gradually decreased, but no alterations emerged from the experimental group. CASTB method remarkably promoted cell growth and proliferation. Moreover, a greatly lower apoptosis and senescence tendency appeared in the experimental group than the control group with passages increasing. The method of CASTB is superior to traditional subculture, offering a large number of primary FBs with higher efficiency and success rate and being worth of further popularization and application.


Spiked environmental matrix for use as a reference material for gamma-ray spectrometry: Production and homogeneity test.
The application of a spiking method for reference material production and its utilisation for a food matrix is presented. The raw rice powder was tested by means of γ-ray spectrometry and spiked with a (137)Cs solution. The spiked material was mixed and tested for homogeneity. The future use of the rice powder reference material after the entire characterisation cycle will be for γ-ray spectrometry method validation.


Fallot's tetralogy. Its occurrence with absent pulmonary valve and sinus of Valsalva aneurysm in an adult.
A patient with a right aortic sinus of Valsalva aneurysm, Fallot's tetralogy, and pulmonic valve absence survived into adulthood without surgical intervention.


Herpes simplex virus persistence in mouse neuroblastoma (C 1300) cell cultures: role of interferon.
The Mp strain of herpes simplex virus type 1 (HSV1) induced a persistent infection in the mouse C 1300 neuronal cell line (clone N 115). C 1300 cultures infected at an MOI of 0.01 or 0.001 survived the initial infection and continued to produce infectious virus and viral antigens for 185 days and 31 days, respectively. Viral antigens were not detected in cultures no longer producing infectious virus; these "cured" cultures had comparable susceptibility to reinfection with HSV as previously uninfected C 1300 cells. While significant amounts of interferon were produced by C 1300 cells when challenged with Newcastle Disease Virus (NDV) or when treated with poly I:C, HSV-induced interferon could not be detected in either the acutely or persistently infected cell lines. The persistent state was not significantly altered by the addition of 1,000 units/ml of murine interferon alpha plus beta (MuIFN alpha + beta), nor was it affected by the addition of antibody to MuIFN. It appears that IFN does not play an important role in the establishment and/or maintenance of viral persistence in this neuronal system.


Pertussis toxin-catalyzed ADP-ribosylation of a G protein in mouse oocytes, eggs, and preimplantation embryos: developmental changes and possible functional roles.
G proteins, which in many somatic cells serve as mediators of signal transduction, were identified in preimplantation mouse embryos by their capacity to undergo pertussis toxin-catalyzed ADP-ribosylation. Two pertussis toxin (PT) substrates with Mr = 38,000 and 39,000 (alpha 38 and alpha 39) are present in approximately equal amounts. Relative to the amount in freshly isolated germinal vesicle (GV)-intact oocytes, the amount of PT-catalyzed ADP-ribosylation of alpha 38-39 falls during oocyte maturation, rises between the one- and two-cell stages, falls by the eight-cell and morula stages, and increases again by the blastocyst stage. The decrease in PT-catalyzed ADP-ribosylation of alpha 38-39 that occurs during oocyte maturation, however, does not require germinal vesicle breakdown (GVBD), since inhibiting GVBD with 3-isobutyl-1-methyl xanthine (IBMX) does not prevent the decrease in the extent of PT-catalyzed ADP-ribosylation. A biologically active phorbol diester (12-O-tetradecanoyl phorbol 13-acetate, TPA), but not an inactive one (4 alpha-phorbol 12,13-didecanoate, 4 alpha-PDD), totally inhibits the increase in PT-catalyzed ADP-ribosylation of alpha 38-39 that occurs between the one- and two-cell stage; TPA inhibits cleavage, but not transcriptional activation, which occurs in the two-cell embryo (Poueymirou and Schultz, 1987. Dev. Biol. 121, 489-498). In contrast, cytochalasin D, genistein, or aphidicolin, each of which inhibits cleavage of one-cell embryos, or alpha-amanitin or H8, each of which inhibits transcriptional activation but not cleavage of one-cell embryos, have little or much smaller inhibitory effects on the increase in PT-catalyzed ADP-ribosylation of alpha 38-39. Results of immunoblotting experiments using an antibody that is highly specific for alpha il-3 reveal the presence of a cross-reactive species of Mr = 38,000 (alpha 38) in the GV-intact oocyte, metaphase II-arrested egg, and one-, two-cell embryos. Relative to these stages, a reduced amount of this species is present in the eight-cell, morula, and blastocyst stages. Treatment of oocytes with PT results in a small but significant acceleration in the rate of GVBD, but has no effect on the extent of polar body emission. Treatment of one-cell embryos with PT has no effect on the extent of cleavage, onset of transcriptional activation at the two-cell stage, or development of two-cell embryos to the hatching blastocyst stage.


Feasibility and acceptability of safety screening among patients receiving addiction treatment.
Premature mortality associated with opioid-related overdose and suicide is a significant public health problem in the United States. Approximately 20-30% of individuals with opioid use disorder (OUD) have a history of both suicide attempt and unintentional opioid overdose. The objective of this study is to evaluate the feasibility of a standardized screen for suicide and overdose among patients receiving addiction treatment. We conducted a cross-sectional study using a convenience sample of patients (n = 113) recruited from two inpatient treatment programs. We used a modified version of the Patient Safety Screener (mPSS) to screen for suicidal ideation, suicide attempt, and overdose. Study staff administered the screen in-person during treatment, and we linked results to administrative clinical data. Subjects (n = 108) and members of their clinical care team (n = 20) completed a screening acceptability survey. We recorded a positive mPSS if a patient reported suicidal ideation in the past two weeks, a suicide attempt, and/or an overdose in the past six months. Fifty-eight percent of subjects had a positive mPSS screen, and 30.3% reported suicidal ideation, suicide attempt, and overdose. Subjects and clinical staff reported that it was acceptable to screen for suicide attempt(s) and overdose(s). About a third of the clinical staff reported concerns about administration time (n = 7) and impact on workflow (n = 6). Both suicide and overdose are important patient safety factors that should be incorporated into addiction treatment and discharge planning. This study's findings support simultaneously screening for suicide and overdose in OUD inpatient treatment settings. Future research needs to determine whether screening improves provision of services and reduces self-injurious behavior.


Infected Dentigerous Cyst of Maxillary Sinus Mimicking Intraoral Abscess in a Pediatric Patient: Management of Misdiagnosis and Inaccurate Treatment.
The article presents the case of a 12-year-old male patient who was suffering from exacerbated (infected) dentigerous cyst of maxillary sinus, associated with impacted canine whose symptoms were deceptively similar to intraoral abscess. The first-aid treatment performed by general dental practitioner consisted of intraoral incision and resulted in oroantral fistula formation. Eventually, the patient's ailments were not resolved, and we had to deal with serious local complications and difficulties. The treatment was performed under general anesthesia in one-day surgery system and included enucleation of the lesion, excision, and closure of oroantral fistula. Dislocated canine was not removed, and its subsequent eruption was observed.


Hydroxyproline quantification for the estimation of collagen in tissue using multiple reaction monitoring mass spectrometry.
Collagens are highly abundant mammalian proteins that contain a high content of hydroxylated amino acids such as hydroxyproline. We have exploited the high hydroxyproline content of collagen and developed a method for hydroxyproline quantification as a measure of collagen content in muscle samples. The novel method utilizes a highly selective and sensitive method of multiple reaction monitoring (MRM) by mass spectrometry. The analytical method is simple, rapid (5min), convenient (no derivatization), precise (<17% RSD), accurate (90-108%), sensitive (4.88nmol/L) and linear (R(2)>0.999) over three orders of magnitude (5-5000nmol/L).


Higher Tumor Burden Status Dictates the Impact of Surgical Margin Status on Overall Survival in Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma.
The present study aimed to examine the prognostic significance of margin status following hepatectomy of intrahepatic cholangiocarcinoma (ICC) relative to overall tumor burden and nodal status. Patients who underwent curative-intent surgery for ICC between 1990 and 2017 were included from a multi-institutional database. The impact of margin status and width on overall survival (OS) was examined relative to TBS and preoperative nodal status. Among 1105 patients with ICC who underwent resection, median tumor burden score (TBS) was 6.1 (IQR 4.2-8.8) and 218 (19.7%) patients had N1 disease. More than one in eight patients had an R1 surgical margin (n = 154, 13.9%). Among patients with low or medium TBS, an increasing margin width was associated with an incrementally improved 5-year OS (R1 31.9% vs. 1-3 mm 38.5% vs. 3-10 mm 48.0% vs. ≥ 10 mm 52.3%). In contrast, among patients with a high TBS, margin width was not associated with better survival (R1 28.9% vs. 1-3 mm 22.8% vs. 3-10 mm 29.6% vs. ≥ 10 mm 13.7%). In addition, surgical margin status did not impact survival with cutoffs of TBS 7 or greater. Furthermore, patients with low or medium TBS and preoperative negative lymph nodes derived a survival benefit from an R0 resection (R1 resection, HR 2.15, 95% CI 1.35-3.44, p = 0.001). In contrast, margin status was not associated with prognosis among patients with a high TBS and preoperative positive/suspicious lymph nodes (R1 resection, HR 1.34, 95% CI 0.58-3.11, p = 0.50). R0 resection and wider margin resection resulted in improved outcomes in patients with low tumor burden; however, the survival benefit of negative margin status disappeared in patients with underlying poor tumor biology.


The importance of self-examination in the earliest diagnosis of multiple primary cutaneous melanomas: a report of 47 cases.
Development of more than one primary melanoma in a patient is a relatively uncommon but well-recognized phenomenon. Its frequency has ranged from 1.2% to 8.2% in several series. This subgroup of patients with multiple primary lesions has not been characterized sufficiently. We report the experience of the Melanoma Unit of University Hospital Spedali Civili of Brescia, Italy. Study subjects were drawn from 1240 patients with histologically confirmed melanoma, including melanoma in situ. From this group, multiple melanomas developed in 47 patients (3.79%). Every one of our patients has been taught to perform self-examination of the skin to detect suspicious pigmented lesions. Of the 47 patients described in this study, 38 had two primary melanomas, 7 had three melanomas and 2 had 5 and 10 melanomas, respectively. Mean age at first diagnosis was 46.2 years. The majority of subsequent melanomas (74.5%) were removed within 5 years of the initial operation. Synchronous lesions were found in 10 patients. In male patients, the lesion appeared most frequently on the trunk; in female patients, melanoma appeared mostly on the lower extremities. The second primary melanomas developed in the same anatomic region from the first in 53.2% of our patients. The proportion of in situ to invasive melanomas was greater for the second melanomas compared with the first melanomas. Regarding invasive melanomas, the mean thickness of the first melanomas was 1.31 mm compared with 0.66 mm for the second ones. Dividing patients into two groups, of more and less than 50, it is highlighted that in older patients synchronous lesions appear more frequently (36.4% vs. 8.0%); the median time interval between sequential melanomas is longer (84 vs. 63.7 months); and the ratio between the primary and secondary melanoma mean thickness is lower (1.21 : 1.08 vs. 1.43 : 0.63 mm). The study confirms that second primary melanoma is usually thinner than the first lesion, and it is more common in the same region of the body as the initial melanoma. The highest risk for a second melanoma is during the first 5 years, but a much longer time interval of 28 years is possible. Continued medical follow-up with complete skin examinations seems prudent, but it is very important to promote self-skin evaluation in patients to detect not only metastases but also subsequent primary melanomas in their earliest phases.


Endothelial cell protection in xenotransplantation: looking after a key player in rejection.
The endothelium, as an organ at the interface between the intra- and extravascular space, actively participates in maintaining an anti-inflammatory and anti-coagulant environment under physiological conditions. Severe humoral as well as cellular rejection responses, which accompany cross-species transplantation of vascularized organs as well as ischemia/reperfusion injury, primarily target the endothelium and disrupt this delicate balance. Activation of pro-inflammatory and pro-coagulant pathways often lead to irreversible injury not only of the endothelial layer but also of the entire graft, with ensuing rejection. This review focuses on strategies targeted at protecting the endothelium from such damaging effects, ranging from genetic manipulation of the donor organ to soluble, as well as membrane-targeted, protective strategies.


An unusual case of spontaneous Mycobacterium chelonae corneal ulcer in a healthy middle-aged adult.
To report a rare presentation of culture-positive Mycobacterium chelonae corneal ulcer and its management. We report a rare case of a patient with a history of chronic pain and blurriness of vision. Examination revealed a chronic nonhealing paracentral corneal ulcer inferiorly at the 5-7 o'clock meridian with anterior chamber reaction unresponsive to routine antibiotic and antifungal medications with Mantoux test positivity in a middle-aged nondiabetic patient with no prior history of trauma, ocular surgery, and contact lens usage. Ziehl-Neelsen staining of the nonhealing ulcer revealed acid-fast bacilli typical of M. chelonae, with subsequent culture positivity in Löwenstein-Jensen medium. Subsequent treatment with topical fortified amikacin and tobramycin resulted in rapid healing of the corneal ulcer. M. chelonae presenting as a chronic nonhealing corneal ulcer spontaneously occurring in a healthy adult with no predisposing factor draws attention towards the need to have a good index of suspicion by performing a Ziehl-Neelsen stain and culture, and subsequent successful management with topical fortified amikacin and tobramycin.


Physician-assisted death is illegal in most states, so my patient made another choice.
A patient in his nineties and in decline chooses the only legal way in most of the United States to hasten his death: He stops eating and drinking. His doctor wonders whether that is just or compassionate.


Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection.
We and others have previously shown that heat-shock proteins (HSPs) are involved in protecting the brain from a variety of insults including stroke, epilepsy, and other related insults. While the mechanism of this protection has largely been thought to be due to their chaperone functions (i.e., preventing abnormal protein folding or aggregation), recent work has shown that HSPs may also directly interfere with other cell death pathways such as apoptosis and inflammation. Using models of cerebral ischemic and ischemia-like injury, we overexpressed the 70-kDa heat-shock protein (HSP70) using gene transfer or by studying a transgenic mouse model. HSP70 protected neurons and astrocytes from experimental stroke and stroke-like insults. HSP70 transgenic mice also had better neurological scores following experimental stroke compared to their wild-type littermates. Overexpressing HSP70 was associated with less apoptotic cell death and increased expression of the antiapoptotic protein, Bcl-2. Furthermore, HSP70 suppressed microglial/monocyte activation following experimental stroke. HSP70 overexpression also led to the reduction of matrix metalloproteinases. We suggest that HSPs are capable of protecting brain cells from lethal insults through a variety of mechanisms and should be explored as a potential therapy against stroke and other neurodegenerative diseases.


The use of fluorescence microscopy and image analysis for rapid detection of non-producing revertant cells of Synechocystis sp. PCC6803 and Synechococcus sp. PCC7002.
Ethanol production via genetically engineered cyanobacteria is a promising solution for the production of biofuels. Through the introduction of a pyruvate decarboxylase and alcohol dehydrogenase direct ethanol production becomes possible within the cells. However, during cultivation genetic instability can lead to mutations and thus loss of ethanol production. Cells then revert back to the wild type phenotype. A method for a rapid and simple detection of these non-producing revertant cells in an ethanol producing cell population is an important quality control measure in order to predict genetic stability and the longevity of a producing culture. Several comparable cultivation experiments revealed a difference in the pigmentation for non-producing and producing cells: the accessory pigment phycocyanin (PC) is reduced in case of the ethanol producer, resulting in a yellowish appearance of the culture. Microarray and western blot studies of Synechocystis sp. PCC6803 and Synechococcus sp. PCC7002 confirmed this PC reduction on the level of RNA and protein. Based on these findings we developed a method for fluorescence microscopy in order to distinguish producing and non-producing cells with respect to their pigmentation phenotype. By applying a specific filter set the emitted fluorescence of a producer cell with a reduced PC content appeared orange. The emitted fluorescence of a non-producing cell with a wt pigmentation phenotype was detected in red, and dead cells in green. In an automated process multiple images of each sample were taken and analyzed with a plugin for the image analysis software ImageJ to identify dead (green), non-producing (red) and producing (orange) cells. The results of the presented validation experiments revealed a good identification with 98 % red cells in the wt sample and 90 % orange cells in the producer sample. The detected wt pigmentation phenotype (red cells) in the producer sample were either not fully induced yet (in 48 h induced cultures) or already reverted to a non-producing cells (in long-term photobioreactor cultivations), emphasizing the sensitivity and resolution of the method. The fluorescence microscopy method displays a useful technique for a rapid detection of non-producing single cells in an ethanol producing cell population.


Genetics of psoriasis: the potential impact on new therapies.
There is considerable epidemiologic evidence that genes play a key role in the pathogenesis of psoriasis. It is also clear that multiple genes are involved and that the disease is genetically heterogeneous. Important interactions with the environment are also implicated in its development. A number of genetic loci have been identified by genome wide linkage scans and two loci have been replicated: PSORS1 on chromosome 6, within the major histocompatibility complex, and PSORS2 on chromosome 17q. Understanding the genetic basis of psoriasis will represent a major advance in our understanding of the disease and will reveal novel disease-specific biologic pathways. This information will be used to develop more specific diagnostic and prognostic tools and also lead to the development of individualized treatment plans. Benefits of the latter include more effective and safer treatments and potentially major pharmaco-economic gain.


Dietary restriction augments resistance to oxidant-mediated inhibition of mitochondrial transcription.
The exquisite sensitivity of mitochondrial transcription to oxidant stress suggests that chronic, low level oxidative stress may impair mitochondrial gene expression during the aging process. In this study, we assessed the effects of age and of life-prolonging, anti-oxidative dietary restriction (DR) regimens on sensitivity of mitochondrial transcription to oxidant stress. Studies were carried out using liver mitochondria isolated from male Fischer 344 rats of different ages (6, 12, 18, or 24 months) fed ad libitum (AL) or maintained on DR. Transcriptional capacity was assessed in isolated mitochondria challenged with different doses of either hydrophilic or hydrophobic peroxyl radicals generated by AAPH [2,2'-azobis-(2-amidino-propane) hydrochloride] or AMVN [2, 2'-azobis-(2,4,-dimethyl-valeronitrile), respectively]. The most striking effect was that DR increased resistance to AMVN nearly 400% at 6 months and nearly 700% at 24 months, relative to resistance in AL rats. Results also suggest that resistance to both AAPH and AMVN was decreased slightly in older AL rats, but was maintained in the DR rats. These results show that DR augments the defense systems that protect one of the mitochondria's most vulnerable systems. This augmentation is one of the largest magnitude effects of DR yet observed against oxidative challenge.


Aztreonam in the treatment of serious orthopedic infections.
Aztreozam was evaluated in the treatment of a variety of orthopedic infections. Included were 17 patients with osteomyelitis, three with purulent arthropathy with prostheses, and 16 with superficial infections secondary to trauma or surgical procedure. Pathogens were gram-negative bacilli sensitive to aztreonam. Concomitant antibiotics were administered for gram-positive cocci that were present initially or by superinfection. Infecting organisms included Pseudomonas aeruginosa (minimal inhibitory concentration 4 to 16 micrograms/ml), Serratia marcescens, Enterobacter cloacae, Enterobacter sakazakii, Morganella morganii, Citrobacter freundii, Proteus vulgaris, Proteus rettgeri, Acinetobacter calcoaceticus and others (all with minimal inhibitory concentrations less than 1.0 microgram/ml). Dosage of aztreonam was 2 to 8 g per day administered intravenously or intramuscularly for five to 52 days. Clinical and bacteriologic responses were adequate in all instances. Recurrences were observed in two individuals with osteomyelitis and one with purulent arthropathy. Adverse clinical or laboratory observations were infrequent and inconsequential.


Ionic liquid-based ultrasound-assisted emulsification microextraction coupled with high performance liquid chromatography for the determination of four fungicides in environmental water samples.
A highly efficient and environmentally friendly sample preparation method termed ionic liquid-based ultrasound-assisted emulsification microextraction (IL-USAEME) combined with high performance liquid chromatography has been developed for the determination of four fungicides (azoxystrobin, diethofencarb, pyrimethanil and kresoxim-methyl) in water samples. In this novel approach, ionic liquid (IL) was used as extraction solvent in place of the organic solvent used in conventional USAEME assay, and there is no need for using organic dispersive solvent which is typically required in the common dispersive liquid-liquid microextraction method. Various parameters that affect the extraction efficiency, such as the kind and volume of IL, ultrasound emulsification time, extraction temperature and salt addition were investigated and optimized. Under the optimum extraction condition, the linearities of calibration curves were in the range from 3 to 5000 ng mL(-1) for target analytes with the correlation coefficient higher than 0.9992. The enrichment factors and the limits of detection were in the range of 88-137 and 0.73-2.2 ng mL(-1), depending on the analytes. The environmental water samples were successfully analyzed using the proposed method, and the relative recoveries at fortified levels of 50 and 100 ng mL(-1) were in the range of 83.9%-116.2%.


A proteomic method for the analysis of changes in protein concentrations in response to systemic perturbations using metabolic incorporation of stable isotopes and mass spectrometry.
While several techniques exist for assessing quantitative differences among proteomes representing different cell states, methods for assessing how these differences are mediated are largely missing. We present a method that allows one to differentiate between cellular processes, such as protein synthesis, degradation and PTMs which affect protein concentrations. An induced systemic perturbation of a cell culture was coupled to a replacement of the growth medium to one highly enriched in the stable isotope 15N. The relative abundance of the 15N- and 14N-enriched forms of proteins, isolated from cell cultures harvested at time points following the onset of the perturbation, were determined by MS. Alterations in protein synthesis and degradation were quantified by comparing proteins isolated from perturbed and unperturbed cultures, respectively. The method was evaluated by subjecting HeLa cells to heat stress. As expected, a number of known heat shock proteins (Hsp) increased in concentration during heat stress. For Hsp27, increased de novo synthesis accounted for the concentration increase, while for Hsp70, decreased degradation accounted for the increase. A protein that was detected only after prolonged heat stress, vimentin, was not primarily synthesized de novo, but appeared rather as a result of PTM.


Side-to-side neurorrhaphy for high-level peripheral nerve injuries.
The results of peripheral nerve repair, especially for high-level peripheral nerve injuries, have been unsatisfactory. The method of side-to-side neurorrhaphy was developed in our laboratory from 1994 to 2002. This method involves suturing the injured nerve to a nearby donor nerve in a side-to-side manner. This study was performed to assess the clinical results of side-to-side neurorrhaphy in patients with high-level peripheral nerve injuries. Twenty-five patients with various types of high-level peripheral nerve injuries who underwent side-to-side neurorrhaphy were studied. The British Medical Research Council (BMRC) scale was used to assess recovery of nerve function. Average follow-up duration was 3.2 years. Before surgery the patients had a nerve function of M0/S0 to M1/S1. After side-to-side neurorrhaphy, 7 patients had a score of M3/S4, 8 patients a score of M3/S3 and 10 patients a score of M2/S3. The total useful recovery rate (BMRC grade ≥3) was 60% for motor function and 100% for sensory function. Side-to-side neurorrhaphy did not result in any significant loss of donor nerve function. There was significant correlation between both the type of injury and the time interval between injury and surgery and motor nerve function. Age, gender and location of the injured nerve did not correlate with sensory or motor nerve function. Side-to-side neurorrhaphy appears to be promising as a feasible method for repair of high-level peripheral nerve injuries.


Development of an inflammation-inducible gene expression system using helper-dependent adenoviral vectors.
Clinical studies have shown that gene therapy is a promising approach for treating such genetic diseases as the eye disease, Leber's congenital amaurosis. Development of gene therapy approaches for treating chronic inflammatory diseases is, however, more challenging because it requires the production of anti-inflammatory molecules at the diseased tissues only when they are needed. We designed such a system by modifying the human interleukin (IL)-6 gene promoter to direct transgene expression and delivered the system into cultured cells as well as mouse lungs using a helper-dependent adenoviral vector. We have demonstrated both in vitro and in vivo that the reporter LacZ or human IL-10 gene can be induced by inflammatory stimuli. The results obtained indicate that the inflammation inducible gene expression system based on the modified human IL-6 gene promoter has the potential to be used for developing gene therapy for treating inflammatory diseases.


Tumor invasion of the upper inferior vena cava: the use of profound hypothermia and circulation arrest as a surgical adjunct.
Two children presented with abdominal tumors invading the upper inferior vena cava. To facilitate removal of the tumors, cardiopulmonary bypass with profound hypothermia and circulation arrest were utilized. This technique simplifies tumor excision and is worthwhile even in children with advanced malignant disease.


Developing an equivalent toxicity area approach to comparing toxicity of urban road deposited sediments.
Urban road stormwater has been seen as an alternative water resource for mitigating water scarcity. Road deposited sediments (RDS) is the primary source of road stormwater pollution since many toxic pollutants are attached to RDS and eventually enter stormwater runoff when rainfall events occur. This could threaten road stormwater reuse safety. This study developed an innovative equivalent toxicity area (ETA) approach to comparing overall toxicity of RDS among different road sites. In the ETA approach, the road surface area was used to represent how toxic the RDS generated from the area was. This ETA approach overcomes the difficulty to compare RDS toxicity among road sites due to variability of sampling volumes, which constrains the effective application of conventional toxicity comparison method of using pollutant amounts (loads/concentrations). Twelve road sites in Shenzhen, China were selected as a case study, where the ETA approach developed was used to compare their RDS toxicity using Chinese Hamster Ovary cells. Additionally, the key factors influencing RDS toxicity were identified by using a forward stepwise regression method. These outcomes provide a useful approach to comparing overall toxicity where various pollutant types with different amounts (loads/concentrations) and toxicity levels are present. Additionally, the results can also contribute to ensuring safety of RDS polluted stormwater reuse.


Protection of mammalian telomeres.
Telomeres allow cells to distinguish natural chromosome ends from damaged DNA. When telomere function is disrupted, a potentially lethal DNA damage response can ensue, DNA repair activities threaten the integrity of chromosome ends, and extensive genome instability can arise. It is not clear exactly how the structure of telomere ends differs from sites of DNA damage and how telomeres protect chromosome ends from DNA repair activities. What are the defining structural features of telomeres and through which mechanisms do they ensure chromosome end protection? What is the molecular basis of the telomeric cap and how does it act to sequester the chromosome end? Here I discuss data gathered in the last few years, suggesting that the protection of human chromosome ends primarily depends on the telomeric protein TRF2 and that telomere capping involves the formation of a higher order structure, the telomeric loop or t-loop.


Parental Mental Health, Fathers' Involvement and Bedtime Resistance in Infants.
Around the age of 6 months, difficulties in settling to sleep and frequent night awakenings are generally occurring in 20 to 30% of infants. According to the transactional model parental factors can play a significant role in influencing infant sleep development. The purpose of the current study was to explore the combined effect of infants' factors (temperament and sleep onset problems), and parental factors (parental mental health in terms of post-partum affective disorders, consistent bedtime routines and fathers' involvement at bedtime), on infant bedtime difficulties (e.g. fussing, crying or protesting), including both maternal and paternal perspectives. Sixty Italian intact two-parent families of infants (34 boys and 26 girls) ageing from 8 to 12 months (M = 10.73, SD = 2.54) were enrolled in the study. The parents filled out self-report questionnaires to measure the aforementioned variables. To investigate which infant and parental factors predicted infants' bedtime difficulties, two multiple linear regressions (MR), one for fathers and one for mothers, and relative weight analyses (RWA) were conducted. With regard to infants' bedtime difficulties reported by fathers (R2 = .35) they were explained by infant involvement in constant bedtime routines (β = -.35, p = .030) and paternal involvement at bedtime (β = -.45, p = .007). Instead infants' bedtime difficulties reported by mothers (R2 = .32) were explained by minutes the child taken to fall asleep (β = .24, p = .04), infant involvement in constant bedtime routines (β = -.31, p = .01) and bedtime paternal involvement (β = -.27, p = .05). The main results of this study emphasized the protective role of consistent bedtime routines and bedtime paternal involvement in reducing infants' bedtime difficulties perceived both from mothers and fathers. Future research could help to raise awareness and improve understanding of the familial influences on children's sleep, providing recommendations for educating families, school professionals, healthcare providers, and the general public on risk and protective factors that could play a meaningful role in infants and children's developing sleep patterns.


Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation.
Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10-80 microM) of apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14ARF-mediated downregulation of MDM2 protein, inhibition of NF-kappaB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose- and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-alpha, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from apigenin-induced apoptosis. In vivo, apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways.


Smooth muscle pathology and erectile dysfunction.
Penile erection is a vascular phenomenon that results from smooth muscle relaxation, arterial dilation and venous restriction. The atherosclerosis of the penis that occurs with aging causes a decrease in penile oxygen tension. A reduction of smooth muscle cells has been demonstrated in relation with this change in oxygen tension. Changes in the ratio of penile collagen have also been observed and could explain the decrease in penile elasticity and compliance. Chronic ischemia is, therefore, associated with fibrosis but also with nitric oxide (NO)-cyclic guanosine monophosphate. The sensitivity of the alpha-adrenoceptors on the smooth muscle cells increases with aging. All those modifications can explain the prevalence of erectile dysfunction with aging. Low oxygen tension in prostanoid production may also play a role in the mechanism of ischemia-induced cavernosal fibrosis; however, intracavernous injections of prostaglandin E(1) do not seem to modify the intracavernous structures by reducing muscular atrophy. The effects of androgen on libido and sexual behavior are well established, but their role in the human erectile mechanism remains unclear. Several studies performed on animals have demonstrated impacts directly on both the physiological function and the trabecular structure of the corpora cavernosa in rats, dogs and rabbits. However, in humans, no study seems to demonstrate a role of testosterone on muscular atrophy or penile neurologic control. Testosterone treatment alters the human behavior but not penile physiologic processes. Further studies are necessary to explain the real role of testosterone not only on the peripheral mechanism of erection but also on the central control.


Functionless retained pacing leads in the cardiovascular system. A complication of pacemaker treatment.
Twenty one patients with retained endocardial pacemaker leads were followed during a total observation period of 1097 months to assess the incidence of complications. Two patients developed thrombosis and occlusion of the superior vena cava, which was relieved by the development of a collateral venous circulation. In one patient the broken tip of the lead migrated to a pulmonary artery but did not cause overt complications. The remaining patients were free of symptoms. One patient died for reasons unconnected with pacemaker treatment. The good toleration of retained pacemaker leads by most patients indicates that major surgical procedures to remove the lead should be reserved for patients with life threatening complications, such as persistent infection or dangerous migration of the lead or both.


Eyeblink conditioning deficits in the old cat.
Acquisition of a conditioned eyeblink reflex was studied in aged cats 10-23 years old and young cats one to three years old. All ten young cats became conditioned within 1,000 trials, after a mean of 270 trials, with a stimulus protocol including a 1500 msec 4 kHz tone CS+ followed by a shock unconditioned stimulus, and click CS-. Nine of 15 aged cats failed to become conditioned with 1,000 trials. Six old cats became conditioned after a mean of 522 trials. Four aged cats tested with a simpler protocol involving a 400 msec CS+ and no click CS- became conditioned with less than 500 trials. All retained the conditioned response when clicks were added to the 400 msec CS+. Three aged animals which failed to become conditioned with the 1500 msec CS+ and clicks were trained with an 800 msec CS+ without clicks. Only one became conditioned within 500 trials. Thus duration of the tone CS+ was critically important for acquisition of a conditioned eyeblink response by aged cats.


Bioelectrochemical biosensor for water toxicity detection: generation of dual signals for electrochemical assay confirmation.
Toxicity assessment of water is of great important to the safety of human health and to social security because of more and more toxic compounds that are spilled into the aquatic environment. Therefore, the development of fast and reliable toxicity assessment methods is of great interest and attracts much attention. In this study, by using the electrochemical activity of Shewanella oneidensis MR-1 cells as the toxicity indicator, 3,5-dichlorophenol (DCP) as the model toxic compound, a new biosensor for water toxicity assessment was developed. Strikingly, the presence of DCP in the water significantly inhibited the maximum current output of the S. oneidensis MR-1 in a three-electrode system and also retarded the current evolution by the cells. Under the optimized conditions, the maximum current output of the biosensor was proportional to the concentration of DCP up to 30 mg/L. The half maximal inhibitory concentration of DCP determined by this biosensor is about 14.5 mg/L. Furthermore, simultaneous monitoring of the retarded time (Δt) for current generation allowed the identification of another biosensor signal in response to DCP which could be employed to verify the electrochemical result by dual confirmation. Thus, the present study has provided a reliable and promising approach for water quality assessment and risk warning of water toxicity.


Real world study of ocrelizumab in multiple sclerosis: Kuwait experience.
Ocrelizumab is a humanized anti-CD20 antibody that has been approved for the treatment of patients with multiple sclerosis (MS). Real-world data in the Middle East is very limited. To describe the effectiveness and safety of ocrelizumab treatment in MS patients in a real clinical setting. This is an observational, registry-based study. MS patients who were treated with ocrelizumab and completed at least one-year follow-up post-treatment were included. Baseline clinical and radiological characteristics were collected before ocrelizumab initiation. The relapse rate, disability measures, magnetic resonance image (MRI) activity (new T2 lesions and/or GD+ enhancing T1 lesions), and adverse events (AE) at the last follow-up visits were assessed. Data from 447 patients were analyzed, of which 260 (58.2%) were females. The mean age and mean disease duration were 37.39 ± 11.61 and 9.38 ± 7.57 years respectively. Most of the cohort was of a relapsing form (74.3%; n = 332), whereas active secondary and primary progressive forms represented 15.4% (n = 69) and 10.3% (n = 46) respectively. In the relapsing cohort, Ocrelizumab was prescribed in 162 (48.8%) patients due to highly active disease, and in 99 (29.8%) patients due to disease breakthrough while on prior therapies. In the last follow-up visits, most of the relapsing cohort was relapse-free (95.8% vs. 27.4%; p <0.001), had no evidence of MRI activity (3.6% vs. 67.5%; p <0.001) while EDSS score was stable (1.80+1.22 vs. 1.87+1.16; p < 0.104) when compared to baseline. NEDA-3 was achieved in 302 (91%) of RRMS patients. Confirmed disability progression was 27.5% and 23.9% in SPMS and PPMS respectively. Adverse events were observed in 139 (31.1%); infusion reactions and infections represented the most. This study showed that ocrelizumab is an effective and safe treatment for MS patients in a real clinical setting similar to what was observed in clinical trials.


Survival in an era of organ preservation: an update on laryngeal cancer in Ireland.
Laryngeal cancer epidemiology has changed in recent years, with falling incidence observed internationally. Organ preservation therapies have revolutionised management, though some patients may be unsuitable and survival was noted to fall in the 2000s. This study examines trends in laryngeal cancer in Ireland. A retrospective cohort study of National Cancer Registry of Ireland data from 1994 to 2014. From a cohort of 2651, glottic disease was most common (62%, n = 1646). Incidence rose to 3.43 cases/100,000/year for 2010-2014. 5-year disease-specific survival (DSS) was 60.6% and did not change significantly over time. Overall survival (OS) for T3 disease managed with primary radiotherapy was similar to primary surgery (HR 0.98, p = 0.9). DSS for T3 disease improved with primary radiotherapy (HR 0.72, p = 0.045). Incidence of laryngeal cancer in Ireland rose despite international trends, while survival changed little. Radiotherapy improves DSS for T3 disease but does not improve OS, possibly secondary to poor organ function post-radiotherapy.


Chinese herbal medicine formulas as adjuvant therapy for osteonecrosis of the femoral head: A systematic review and meta-analysis of randomized controlled trials.
Osteonecrosis of femoral head (ONFH) is a disabling clinical entity affecting mainly young adults. Although Chinese Herbal Medicine (CHM) has been widely used as an adjunct therapy for ONFH in China, its effectiveness is not well defined. The purpose of this systematic review is to assess the effectiveness of CHM as an adjunct therapy to core decompression (CD) for patients with ONFH. A systematic literature search was conducted in 10 electronic databases. Randomized controlled trials involving CHM and CD for ONFH were included. Two authors independently assessed the studies for inclusion and extracted the data. A meta-analysis was conducted to estimate the safety and efficacy of CHM as an adjunct therapy. Twenty-three randomized controlled trials with 1815 participants were included. The formulas used in these studies were different and we only combined data of studies observing the same formulas. Patients treated with CHM additionally exhibited a better TER (total effective rate) compared with CD alone in different degree, with the risk ratio (RR) varies from 1.09 to 1.09. The Harris score and radiographic effective rate indicate a similar result, with the medicine (MD) varies from 17.35 to 14.94 and RR 1.40 to 1.27. The risk of side-effect was barely reported except only 2 study record that no complications were observed. This systematic review indicated that CHM as adjunctive therapy may improve the effectiveness of CD. However, a firm conclusion could not be reached because of overall high risk of bias in most domains. Further studies of higher quality are required, and other benefits of CHM remain to be determined.


Novel biomarkers for the assessment of paediatric systemic lupus erythematosus nephritis.
The discovery of serum biomarkers specific for paediatric lupus nephritis (pLN) will facilitate the non-invasive diagnosis, follow-up and more appropriate use of treatment. The aim of this study was to explore the role of serum high-mobility group box 1 (HMGB1) protein, antibodies against nucleosomes (anti-NCS), complement factor C1q (anti-C1q) and glomerular basement membrane (anti-GBM) in pLN. Serum samples of 42 patients with paediatric systemic lupus erythematosus (pSLE) (22 with pLN and 20 without renal involvement), 15 patients with other autoimmune nephritis (AN) and 26 healthy controls (HCs) were examined using enzyme-linked immunosorbent assay (ELISA). The activity of both pSLE and pLN was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) tool. The levels of all four biomarkers were significantly higher in pLN compared to AN and to HCs. The anti-NCS, anti-GBM and HMGB1 serum levels were significantly higher in pLN than in pSLE without renal involvement. The anti-C1q and the HMGB1 serum levels were correlated positively with pSLE activity. The HMGB1 serum levels were also correlated positively with pLN activity. These findings suggest that serum anti-NCS, anti-GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas anti-C1q only of pSLE activity.


Chronic inhibition of NOS does not prevent plasticity of rat somatosensory (S1) cortex following deafferentation.
Nitric oxide (NO) has been proposed as an intercellular messenger mediating postsynaptic to presynaptic information transfer in the induction of long-term potentiation. A number of studies support the possible involvement of NO in synaptic plasticity. NO may have a role in synaptogenesis and synaptic plasticity in developing rat brain and may play a fundamental part in the process of regeneration, plasticity, and retargeting of axons following injury. We examined the possible role of NO on plasticity in the rat first somatosensory cortex with [14C]2-deoxyglucose (2-DG) autoradiography in rats treated daily with l-nitroarginine (l-NA) following neonatal unilateral vibrissae deafferentation. After 6 weeks of l-NA treatment, the local cerebral glucose utilization (LCGU) and the spatial extent of the metabolic activation following stimulation of the spared whisker was measured. NOS catalytic activity exhibited significant inhibition throughout the treatment period. Vibrissae deafferentation produced a small but not statistically significant increase of LCGU in the vibrissa activated C3 barrel, and l-NA treatment did not alter the activation of LCGU in the deafferented cortex following whisker stimulation. Additionally, l-NA treatment did not alter the area of metabolic activation on either the non-deafferented side or the deafferented side. Deafferentation produced a 298% increase in the metabolic representation of the spared C3 barrel following stimulation in the saline treated animals, a 257% increase in the chronically l-NA treated animals, and a 256% increase in the short-term treated animals, all with respect to the response in the non-deafferented cortex. Metabolic plasticity in the barrel cortex was not attenuated by l-NA treatment. These results show that nitric oxide does not play a major role on developmental cortical plasticity induced by vibrissae deafferentation in the rat.


Therapeutic implications of acute lung injury.
Although there are no specific therapies for septic shock or acute lung injury that have proven efficacy in humans, a growing understanding of mechanisms of tissue injury has suggested interventions that may prevent or treat this injury. These therapies range from immunization against the glycopolysaccharide core of endotoxin to cyclooxygenase inhibitors to specific oxygen radical scavengers. Each of these treatments is effective in ameliorating at least one of the pathophysiologic manifestations of acute lung injury, although the effect of these agents in the prevention of the sequelae of fibrosis is unknown. Interaction between several factors and mediators is likely necessary for the development of acute lung injury. It is hoped that with additional knowledge regarding mechanisms of injury gained through basic science and clinical research, we can apply definitive therapy that may salvage patients who now die with sepsis and acute lung injury.


Structural and functional characterisation of recombinant human erythropoietin analogues.
Deletion mutants of a synthetic human erythropoietin-cDNA were transiently expressed in COS-7 cells and products analyzed using Western blots and a cell proliferation assay. Only two mutants with deletions affecting the N-terminal portion and the amino acid sequence 115-121 displayed biological activity. The exchange of hydrophilic, charged amino acids by alanine in two potential alpha-helical regions, the internal amino acid sequence 102-106 and the C-terminal sequence 154-159, causes a 2-11-fold loss of activity. The results suggest that both regions are involved in either maintaining the active structure of the hormone or interacting with the receptor.


A review assessing the quality of reporting of risk factor research in implant dentistry using smoking, diabetes and periodontitis and implant loss as an outcome: critical aspects in design and outcome assessment.
To assess, using a structured review, the quality of reporting (design and outcome assessment) of risk factor research using the STROBE statements. The outcome was implant loss, and the risk factors assessed were smoking, diabetes and periodontitis. Literature search was performed individually for each of the risk factors and the outcome using three sets of database: (a) MEDLINE, (b) references derived from relevant reviews and (c) references derived from identified manuscripts. Only case-control and cohort studies were included and assessed using the STROBE statements. A total of 104 papers were retrieved, three of which were found to be cohort studies (one in the diabetes and two in the periodontitis review) and none was a case-control study. A total of 101 of 104 papers were case series or cross-sectional study. Risk factor research in implant dentistry is mostly comprised of case series studies. These are used to generate hypotheses, but are the wrong tool to test these hypotheses. In the near future, well-designed observational studies are needed and should be reported according to the proposed checklist.


Prediction of the severity of acute pancreatitis on admission by carboxypeptidase-B activation peptide: A systematic review and meta-analysis.
The assessment of acute pancreatitis severity on admission currently remains a challenge to clinicians. A single, rapid biochemical marker would be preferable to clinical and radiological scoring systems. The aim of this study was to undertake a meta-analysis on the value of carboxypeptidase-B activation peptide (CAPAP) in predicting severity of acute pancreatitis on admission. Major databases and trial registries were searched to identify all relevant studies from January 1998 to March 2015. Pooled sensitivity, specificity and the diagnostic odds ratios (DOR) with 95% confidence interval (CI) were calculated for each study and were compared to other biomarkers, if included, within the same study. Summary receiver-operating curves (ROC) were conducted and the area under the curve (AUC) was evaluated. In total, six studies were included. At the time of admission, the AUC of serum CAPAP for predicting severity of acute pancreatitis was 0.86 with pooled sensitivity, specificity and DOR of 0.90, 0.70 and 19.08, respectively. When serum CAPAP was compared with urinary CAPAP, the AUC, pooled sensitivity, specificity and DOR were 0.69 vs 0.88, 0.90 vs 0.81, 0.68 vs. 0.77 and 17.96 vs. 18.58, respectively. Similarly, the AUC, pooled sensitivity, specificity and DOR of serum CAPAP vs maximal serum C-reactive protein within the first 3 days of admission were found to be 0.97 vs. 0.82, 0.92 vs. 0.88, 0.81 vs 0.68 and 37.90 vs. 18.80, respectively. Both serum and urinary CAPAP have the potential to act as a stratification marker on admission in predicting severity of acute pancreatitis.


In chronic spontaneous urticaria, IgE and C-reactive protein are linked to distinct microRNAs and interleukin-31.
Chronic spontaneous urticaria (CSU) is a common and disabling disease. Assessments of IgE and C-reactive protein (CRP) are recommended in the diagnostic work-up, but the role and clinical relevance of these biomarkers are not well characterized. Moreover, it remains unknown if elevated levels of IgE or CRP are linked to CSU microRNA (miRNA) signatures or interleukin 31 (IL-31). We measured IgE and CRP serum levels in 47 CSU patients (and 45 healthy controls) and determined CSU disease activity using the urticaria activity score (UAS7). Expression levels of miR-155 and miR-221 were assessed by RT-PCR, and IL-31 levels were determined by ELISA. Total IgE and CRP levels were independently increased in CSU patients. IgE and CRP levels were highest and lowest in patients with high and mild disease activity. IgE levels correlated with miR-155 levels, whereas CRP levels correlated with miR-221 levels. miR-155 and miR-221 were significantly overexpressed in CSU patients. ROC analyses linked miRNA-155 and CSU with a sensitivity of 79% and specificity of 87%, and miRNA-221 and CSU with a sensitivity of 75% and specificity of 91%. High CRP and miR-221 expression levels were linked to elevated levels of IgG anti-TPO and IL-31. IgE and CRP are useful biomarkers for disease activity in CSU, with distinct miRNA profiles. High CRP and miR-221 levels may point to autoimmune CSU and a role for IL-31.


[Waardenburg's syndrome. Four cases in an Iranian family (author's transl)].
4 cases of Waardenburg's syndrome in an Iranian family are presented and discussed. The patients, a 34-year-old father with his 6-month-old and 3-year-old sons and 2-year-old daughter, show symptoms of this syndrome in varying degrees of expression except for deafness.


An insight into the potent medicinal plant Phyllanthus amarus Schum. and Thonn.
Phyllanthus amarus Schum. and Thonn., a globally distributed herb is known for its several therapeutic potentials. P. amarus has a long history of use in the traditional system of medicine for over 2000 years owing to its wide array of secondary metabolites that confer significant medicinal attributes. Research on various aspects including ethnobotany, phytochemistry to bioactivity, or pharmacological studies has been conducted over the past several decades on this potent herb. P. amarus extracts have shown a broad range of pharmacological activities like hepatoprotective, antioxidant, antiviral, antimicrobial, antidiabetic, anti-inflammatory, anticancer, antimalarial, nephroprotective, diuretic, and several other properties. The present review compiles and covers literature and research of several groups across past decades to date and focuses on how the therapeutic significance of this plant can be further explored for future research either as herbal formulations, alternative medicine, or in the pharmaceutical industry. The online version contains supplementary material available at 10.1007/s13237-022-00409-z.


[Endografts (or stent-grafts) and diseases of the descending thoracic aorta].
The endovascular treatment of aorta diseases with S-Graft is considered as an alternative to surgery, especially interesting in patients with severe comorbidities. Indeed, the mid-term morbidity and mortality are comparable to surgery in relatively large series, and S-Graft implantation appeared as a safe, less invasive and efficient treatment for different affections of the thoracic aorta. This article reviews technical aspects, indications and results of endovascular repairs of thoracic aorta lesions. We will also assess the advantages and limitations of S-Graft therapy.


Shared and distinct changes in local dynamic functional connectivity patterns in major depressive and bipolar depressive disorders.
Distinguishing bipolar depressive disorder (BDD) from major depressive disorder (MDD) solely relying on clinical clues is a challenge. Evidence in neuroimaging have revealed potential neurological markers for the differential diagnosis. We aimed to characterize common and specific alterations in the dynamic local functional connectivity pattern in BDD and MDD by using the dynamic regional phase synchrony (DRePS), a newly developed method for assessing intrinsic dynamic local functional connectivity. A total of 98 patients with MDD and 56 patients with BDD patients, and 97 age-, gender-, and education-matched healthy controls (HC) were included and underwent the resting-state functional magnetic resonance imaging. Compared with HC, patients with two disorders shared decreased DRePS value in the bilateral orbitofrontal cortex (OFC) extends to insula, the right insula extends to hippocampus, the left hippocampus, the right inferior frontal gyrus (IFG), the left thalamus extends to caudate, the right caudate, the bilateral superior frontal gyrus (SFG), and the right medial frontal gyrus (MFG). Furthermore, patients with MDD exhibited specific decreased DRePS value in the left caudate. Moreover, voxel signals in these regions during the support vector machine analysis contributed to the classification of the two diagnoses. Our findings provided new insight into the neural mechanism of patients with MDD and BDD and could potentially inform the diagnosis and the treatment of this disease.


Infection rate in total hip arthroplasty as a function of air cleanliness and antibiotic prophylaxis. 10-year experience with 2,384 cementless Lord madreporic prostheses.
To separate the respective effects of sterile air and antibiotic prophylaxis in orthopedic surgery, the authors reviewed 2,384 cementless total hip replacements performed from 1975 to 1984 for incidence of deep sepsis. During this period, a conventionally ventilated room (100 particle-forming units (pfu)/m3) and a laminar vertical flow (1 pfu/m3) were alternately used, without significant difference in the sepsis rate. Beginning in 1979, a prophylactic antibiotic regimen was added, which from 1979 to 1984 reduced the incidence of deep sepsis from 2.78% to 0.52%. There was also a change in common infecting organisms, from sensitive to resistant strains, which is not an insignificant consequence.


Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog recombination.
An essential feature of meiosis is interhomolog recombination whereby a significant fraction of the programmed meiotic double-strand breaks (DSBs) is repaired using an intact homologous non-sister chromatid rather than a sister. Involvement of Mec1 and Tel1, the budding yeast homologs of the mammalian ATR and ATM kinases, in meiotic interhomlog bias has been implicated, but the mechanism remains elusive. Here, we demonstrate that Mec1 and Tel1 promote meiotic interhomolog recombination by targeting the axial element protein Hop1. Without Mec1/Tel1 phosphorylation of Hop1, meiotic DSBs are rapidly repaired via a Dmc1-independent intersister repair pathway, resulting in diminished interhomolog crossing-over leading to spore lethality. We find that Mec1/Tel1-mediated phosphorylation of Hop1 is required for activation of Mek1, a meiotic paralogue of the DNA-damage effector kinase, Rad53p/CHK2. Thus, Hop1 is a meiosis-specific adaptor protein of the Mec1/Tel1 signaling pathway that ensures interhomolog recombination by preventing Dmc1-independent repair of meiotic DSBs.


Impact of the circadian nuclear receptor REV-ERBα in dorsal raphe 5-HT neurons on social interaction behavior, especially social preference.
Social interaction among conspecifics is essential for maintaining adaptive, cooperative, and social behaviors, along with survival among mammals. The 5-hydroxytryptamine (5-HT) neuronal system is an important neurotransmitter system for regulating social behaviors; however, the circadian role of 5-HT in social interaction behaviors is unclear. To investigate whether the circadian nuclear receptor REV-ERBα, a transcriptional repressor of the rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) gene in 5-HT biosynthesis, may affect social interaction behaviors, we generated a conditional knockout (cKO) mouse by targeting Rev-Erbα in dorsal raphe (DR) 5-HT neurons (5-HTDR-specific REV-ERBα cKO) using the CRISPR/Cas9 gene editing system and assayed social behaviors, including social preference and social recognition, with a three-chamber social interaction test at two circadian time (CT) points, i.e., at dawn (CT00) and dusk (CT12). The genetic ablation of Rev-Erbα in DR 5-HTergic neurons caused impaired social interaction behaviors, particularly social preference but not social recognition, with no difference between the two CT points. This deficit of social preference induced by Rev-Erbα in 5-HTDR-specific mice is functionally associated with real-time elevated neuron activity and 5-HT levels at dusk, as determined by fiber-photometry imaging sensors. Moreover, optogenetic inhibition of DR to nucleus accumbens (NAc) 5-HTergic circuit restored the impairment of social preference in 5-HTDR-specific REV-ERBα cKO mice. These results suggest the significance of the circadian regulation of 5-HT levels by REV-ERBα in regulating social interaction behaviors.


Synthesis, In vitro Antifungal and Antitumour Activity of Some Triorganotin(IV) N,C,N-Chelates.
The in vitro antifungal activity of compounds 1-3 ({[(CH3)2NCH2]2C6H3}R2SnX; (where X=Cl, R=n-Bu for 1, X=Br, R=n-Bu for 2 and x=PF6, R=n=Bu for 3)) was estimated with the help of a modified microdilution format of the M27-A guidelines and was compared with in vitro activity of their diphenyltin(IV) analogues 4 and 5 (where X=Br, R=Ph for 4 and X=PF6, R=Ph for 5), and of drugs currently in clinical use (ketoconazole, fluconazole and amphotericin B). It was found that in coordinating solvents the more soluble derivative 2 is less active than the phenyl one (4), and compounds 1 and 3 are even inactive.In this paper, the in vitro antitumour activity of ionic diphenyltin(IV) complexes 4 and 5 against seven tumoural cell lines of human origin is also reported. The preparation and characterization (H1, C13 and Sn119 NMR spectroscopy and electrospray ionization mass spectrometry) of the novel compound 3 is mentioned too.


A comparative ultrastructural study of blood cells from nine insect orders.
An ultrastructural study of hemocytes from 9 different insect orders has led to the identification of 8 cell types: (1) Plasmatocytes, whose cytoplasm is filled with small dense lysosomes and large heterogeneous structures, are phagocytic cells. (2) Granulocytes, filled with uniformly electron dense granules, are involved in capsule formation. (3) Coagulocytes, which contain granules and structured globules and which possess a well developed RER, are involved in phagocytosis. (4) Spherule cells are filled with large spherical inclusions. (5) Oenocytoids are large cells with few cytoplasmic organelles. These 5 hemocyte types represent the majority of insect blood cells. (6) Prohemocytes, blastic cells which are one of the stem cells a hemocytes, are very few in number in each species investigated. (7) Thrombocytoids and (8) Prodocytes are restricted to a small number of insect species. The ultrastructural characteristics of these hemocyte types are discussed.


Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network meta-analysis.
Androgen deprivation therapy (ADT) has long been the gold standard for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trials have demonstrated significant survival benefits when docetaxel (DOC) or abiraterone acetate (AA) and prednisone (P) are added to ADT, necessitating comparison of these combination treatments. A systematic review of randomised controlled trials (RCTs) of AA-/ADT-/DOC-containing treatment regimens in newly diagnosed patients with high-risk and/or high-volume mHSPC identified three RCTs (LATITUDE, CHAARTED and GETUG-AFU 15). Network meta-analyses (NMAs) using fixed effects Bayesian methods were performed to compare relative benefits of each treatment on overall survival (OS), radiographic progression-free survival (rPFS) and quality of life (QoL) measured by the Brief Pain Inventory, and the Functional Assessment of Cancer Therapy-Prostate questionnaire. One trial, STAMPEDE, was assessed in exploratory OS analyses. The hazard ratio (HR) for OS ranged from 0.85 to 0.92, with the Bayesian probability of AA + P + ADT being better than DOC + ADT ranging between 72% and 87%. For rPFS, the HR ranged between 0.71 and 0.76 (Bayesian probability range: 93%-97%). Exploratory analyses including STAMPEDE found similar trends. AA + P + ADT also showed improved QoL compared with DOC + ADT for at least 1 year of therapy, with results being more pronounced at 3 months. Our findings suggest that AA + P + ADT is at least as effective as DOC + ADT in reducing the risk of death in men with mHSPC and better at preventing disease progression and improving QoL. The NMA provides useful insights to clinicians and other decision-makers on the relative efficacy of treatment options for men with mHSPC.


The impact of childhood parental loss on risk for depression and anxiety in adulthood: A community-based study in Southwest China.
Lack of parental raising is an important reason for parental loss in China due to urbanization. We aimed to explore the association between parental loss (including parental death, divorce, alcoholism, crime, drug addiction, bedridden, and lack of parental raising) before 17 years old and mental health disorders in adulthood in Southwest China. Childhood parental loss, age, gender, socioeconomic status, smoking, drinking, and medical history were self-reported. Patient Health Questionnaire 9 (PHQ-9) and Generalized Anxiety Disorder 7 (GAD-7) were used for identifying depression and anxiety, respectively. We use logistic regression with inverse probability weighting according to the propensity score to assess the risk of childhood parental loss on mental health disorders in adulthood. A total of 8014 adults were enrolled in this study. Childhood parental loss increased the risk of adulthood depression (OR, 1.60, 95%CI, 1.30-1.98) but not anxiety (p= 0.07) after adjustment of all covariates. Sensitivity analyses including logistic regression with original data, nearest neighbor matching, full matching, and propensity score as the only covariate all yielded similar results. Recall bias could not be fully eliminated due to the retrospective nature of study design. Our study had been conducted in a less-prosperous area in Southwest China and the results may not be representative at nation level. Childhood parental loss was associated with depression in adulthood in Southwest China, highlighting the need for early intervention in children with parental loss, to prevent long-term negative effects on their mental health.


Significance of traumatology in abdominal and vascular surgery.
Frequency of polytrauma accounts for the numerous abdominal traumas. Abdominal injuries should be treated by an abdominal surgeon. Three hundred and seventy traumas of the abdomen were checked regarding other injuries and their percentages given. Mortality rate was 16.6 percent. The different steps of diagnosis are shown with special reference to intraperitoneal lavage and sonography. Frequency of possible organ injuries in patients at Göttingen Medical Center is noted and the special surgical care is explained. The importance and urgency of vascular injuries are discussed with reference to different types of arterial and venous injuries in the abdominal cavity and in retroperitoneal spaces.


Role of mitochondrial complexes I and II, reactive oxygen species and arachidonic acid metabolism in deoxycholate-induced apoptosis.
Bile acids are promoters of colon cancer; however, the mechanism(s) of action of this tumor promoter are largely unknown. Bile acids induce apoptosis in colon epithelial cells and it is probable that the modulation of apoptosis contributes, in part, to colon carcinogenesis. We tested the hypothesis that damage to mitochondria is an upstream event in sodium deoxycholate (NaDOC)-induced apoptosis and that a pro-oxidant state of the cell favors survival. NaDOC-induced damage to mitochondria was assessed by a decrease in mitochondrial membrane potential using flow cytometry and an increase in megamitochondria formation using transmission electron microscopy. We found that inhibition of mitochondrial complexes I and II with rotenone and thenoyltrifluoroacetone, respectively, dramatically protected HT-29 cells against NaDOC-induced apoptosis. Antioxidants (e.g. lazaroids U-74389G and U-8389G), however, sensitized cells to NaDOC-induced apoptosis, in spite of a reduction in reactive oxygen/nitrogen species. Lazaroid pre-treatment caused a marked decrease in NaDOC-induced activation of the anti-apoptotic transcription factor, NF-kappaB, which may provide the basis for the sensitization to apoptosis caused by these antioxidants. Inhibitors of arachidonic acid metabolism (e.g. esculetin, sulindac sulfide, NS-398) also sensitized HT-29 cells to NaDOC-induced apoptosis. These results indicate that the life/death decision is the result of a shift in the balance between specific anti-apoptotic and pro-apoptotic factors, respectively, that may have significance to colon carcinogenesis.


Dose-dependent regulation of macrophage differentiation by mos mRNA in a human monocytic cell line.
The proto-oncogene c-mos was expressed during differentiation of the human monocytic cell line U937 into macrophages. To investigate a possible role of the mos oncogene, we introduced the v-mos gene under an inducible promoter, MT-I, into U937 cells. The v-mos transformed cells expressed mos mRNA at an amount proportional to the concentration of Zn2+ ions. The induction of the v-mos gene caused growth inhibition and macrophage differentiation in these cells. The differentiation of v-mos transformed monocytes into macrophages required continuous expression of the v-mos gene. The extent of expression of phenotypic characteristics of macrophages, such as phagocytosis, cell surface antigens and typical morphology, depends on the amount of mos mRNA present. We were therefore able to demonstrate that the expression of only one oncogene, mos, determines monocyte differentiation into macrophages.


Effect of chlorpyrifos on healing of cutaneous leishmaniasis lesions after treatment with Pentostam(®).
The insecticide chlorpyrifos (CPF) is widely used in the Kingdom of Saudi Arabia (KSA) to control agricultural pests. The present work is a preliminary investigation of the effect of CPF on healing of cutaneous leishmaniasis (CL) lesions, caused by Leishmania major in farmers exposed to this insecticide, after treatment with Pentostam(®). Lesion diameters were measured and CPF concentrations in the blood plasma of farmer and non-farmer CL patients in Al-Ahsa were detected by gas chromatography/mass spectrometry/mass spectrometry before and 6 weeks after treatment with Pentostam(®). CPF concentrations in the blood of farmer patients ranged between 4.570 and 7.096 ng/μl (mean = 6.19 ± 0.881 ng/μl) before and after treatment with Pentostam(®). The mean lesion diameter in these patients decreased by a factor of 2.21 after treatment with Pentostam(®); they measured 1.85-11.75 mm, (mean = 6.165 ± 3.500 mm) before treatment and 0.22-6.10 mm (mean = 2.796 ± 2.102 mm) after treatment. Lesion diameter increased exponentially with the increase of CPF concentration in the patients' blood. CPF was not detected in the non-farmer patients before or after treatment. Their mean lesion diameter decreased by a factor of 6.86 after treatment with Pentostam(®); they measured 1.33-7.10 mm (mean = 2.882 ± 1.764 mm) before treatment and 0.11-0.92 mm (mean = 0.425 ± 0.277 mm) after treatment. The mean lesion diameter in farmer patients was much greater than that of non-farmer patients both before (2.14×) and after (6.657×) treatment with Pentostam(®). Chronic exposure to low levels of the pesticide aggravates the development and delays the healing of CL lesions due to immunotoxicity and/or peripheral neurotoxicity caused by CPF. Further detailed studies would assess CPF effect on the severity of infection with CL in agricultural workers continuously exposed to this insecticide in different areas of KSA in conformity of their finding.