Lower Viral Loads and Slower CD4+ T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02.
HLA strongly influences human immunodeficiency virus type 1 (HIV-1) disease progression. A major contributory mechanism is via the particular HLA-presented HIV-1 epitopes that are recognized by CD8(+) T-cells. Different populations vary considerably in the HLA alleles expressed. We investigated the HLA-specific impact of the MRKAd5 HIV-1 Gag/Pol/Nef vaccine in a subset of the infected Phambili cohort in whom the disease-susceptible HLA-B*58:02 is highly prevalent. Viral loads, CD4(+) T-cell counts, and enzyme-linked immunospot assay-determined anti-HIV-1 CD8(+) T-cell responses for a subset of infected antiretroviral-naive Phambili participants, selected according to sample availability, were analyzed. Among those expressing disease-susceptible HLA-B*58:02, vaccinees had a lower chronic viral set point than placebo recipients (median, 7240 vs 122 500 copies/mL; P = .01), a 0.76 log10 lower longitudinal viremia level (P = .01), and slower progression to a CD4(+) T-cell count of <350 cells/mm(3) (P = .02). These differences were accompanied by a higher Gag-specific breadth (4.5 vs 1 responses; P = .04) and magnitude (2300 vs 70 spot-forming cells/10(6) peripheral blood mononuclear cells; P = .06) in vaccinees versus placebo recipients. In addition to the known enhancement of HIV-1 acquisition resulting from the MRKAd5 HIV-1 vaccine, these findings in a nonrandomized subset of enrollees show an HLA-specific vaccine effect on the time to CD4(+) T-cell count decline and viremia level after infection and the potential for vaccines to differentially alter disease outcome according to population HLA composition. NCT00413725, DOH-27-0207-1539.


Spectroscopic investigation on the binding of bioactive pyridazinone derivative to human serum albumin and molecular modeling.
The interaction between a novel promising pyridazinone derivative (5-chloro-2-nitro-N-(4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)benzamide (CNPB)) and human serum albumin (HSA) under physiological conditions has been investigated systematically by fluorescence spectroscopy, UV absorption spectroscopy, circular dichroism (CD) and molecular modeling. From the spectra obtained, it was observed that CNPB had a strong ability to quench the intrinsic fluorescence of HSA through a static quenching procedure. The site binding constants (K(b)) were 4.22 x 10(4) and 3.32 x 10(4)M(-1) at 290 and 300 K, respectively. The alterations of protein secondary structure in the presence of CNPB were qualitative and quantitative calculated by the results from CD and synchronous fluorescence. In addition, the thermodynamic standard enthalpy (DeltaH) and standard entropy (DeltaS) for the reaction were calculated to be -17.35 kJ mol(-1) and 9.57 J mol(-1)K(-1), respectively. These results showed that the binding of CNPB to HSA was mainly of hydrophobic interaction, but the hydrogen bonding and electrostatic interaction could not be excluded. Furthermore, the study of molecular modeling also indicated that CNPB could strongly bind to the site I (subdomain IIA) of HSA mainly by hydrophobic interaction and there were hydrogen bond interactions between CNPB and the residue His242.


Chronic intermittent hypoxia enhances glycinergic inhibition in nucleus tractus solitarius.
Chronic intermittent hypoxia (CIH), an animal model of sleep apnea, has been shown to alter the activity of second-order chemoreceptor neurons in the caudal nucleus of the solitary tract (cNTS). Although numerous studies have focused on excitatory plasticity, few studies have explored CIH-induced plasticity impacting inhibitory inputs to NTS neurons, and the roles of GABAergic and glycinergic inputs on heightened cNTS excitability following CIH are unknown. In addition, changes in astrocyte function may play a role in cNTS plasticity responses to CIH. This study tested the effects of a 7-day CIH protocol on miniature inhibitory postsynaptic currents (mIPSCs) in cNTS neurons receiving chemoreceptor afferents. Normoxia-treated rats primarily displayed GABA mIPSCs, whereas CIH-treated rats exhibited a shift toward combined GABA/glycine-mediated mIPSCs. CIH increased glycinergic mIPSC amplitude and area. This shift was not observed in dorsal motor nucleus of the vagus neurons or cNTS cells from females. Immunohistochemistry showed that strengthened glycinergic mIPSCs were associated with increased glycine receptor protein and were dependent on receptor trafficking in CIH-treated rats. In addition, CIH altered astrocyte morphology in the cNTS, and inactivation of astrocytes following CIH reduced glycine receptor-mediated mIPSC frequency and overall mIPSC amplitude. In cNTS, CIH produced changes in glycine signaling that appear to reflect increased trafficking of glycine receptors to the cell membrane. Increased glycine signaling in cNTS associated with CIH also appears to be dependent on astrocytes. Additional studies will be needed to determine how CIH influences glycine receptor expression and astrocyte function in cNTS.NEW & NOTEWORTHY Chronic intermittent hypoxia (CIH) has been used to mimic the hypoxemia associated with sleep apnea and determine how these hypoxemias influence neural function. The nucleus of the solitary tract is the main site for chemoreceptor input to the CNS, but how CIH influences NTS inhibition has not been determined. These studies show that CIH increases glycine-mediated miniature IPSCs through mechanisms that depend on protein trafficking and astrocyte activation.


Prenatal diagnosis of beta-thalassemia by reverse dot-blot hybridization in southern China.
Beta-thalassemia (thal) is the most common genetic disease and is widely distributed in southern China. Prenatal diagnosis is needed to prevent the birth of thalassemic offspring in couples at-risk. This can be performed in the first or second trimester of pregnancy by DNA analysis using polymerase chain reaction (PCR). As there are more than 30 mutations causing beta-thal in Chinese, the point mutation detection by reverse dot-blot for common mutations together with direct DNA sequencing was developed for prenatal diagnosis. Using reverse dot-blot, we were able to offer complete diagnosis in 315 (99.4%) of 317 pregnancies. Only two fetuses needed the DNA sequencing technique for diagnosis. Of the 319 at-risk fetuses, 82 (25.7%) were found to be normal, 143 (44.8%) to be heterozygous for beta-thal and 94 (29.5%) to be affected with beta-thal. Therefore, the combination of reverse dot-blot with direct DNA sequencing can perform prenatal diagnosis by DNA analysis in almost all cases at- risk of beta-thal in southern China.


Acute severe hypoxia induces apoptosis of human pluripotent stem cells by a HIF-1α and P53 independent mechanism.
Human embryonic and induced pluripotent stem cells are self-renewing pluripotent stem cells (hPSCs) that can differentiate into a wide range of specialized cells. Although moderate hypoxia (5% O2) improves hPSC self-renewal, pluripotency, and cell survival, the effect of acute severe hypoxia (1% O2) on hPSC viability is still not fully elucidated. In this sense, we explore the consequences of acute hypoxia on hPSC survival by culturing them under acute (maximum of 24 h) physical severe hypoxia (1% O2). After 24 h of hypoxia, we observed HIF-1α stabilization concomitant with a decrease in cell viability. We also observed an increase in the apoptotic rate (western blot analysis revealed activation of CASPASE-9, CASPASE-3, and PARP cleavage after hypoxia induction). Besides, siRNA-mediated downregulation of HIF-1α and P53 did not significantly alter hPSC apoptosis induced by hypoxia. Finally, the analysis of BCL-2 family protein expression levels disclosed a shift in the balance between pro- and anti-apoptotic proteins (evidenced by an increase in BAX/MCL-1 ratio) caused by hypoxia. We demonstrated that acute physical hypoxia reduced hPSC survival and triggered apoptosis by a HIF-1α and P53 independent mechanism.


Is a murder charge an occupational hazard of intensive care nursing?
When nurses are accused of harming their patients there is an understandable wave of concern. When nurses kill their patients there is disbelief and horror. After all, killing patients is so far from the traditional image of the nurse as to cause distress and disorientation. When the nurse in question is a woman and when the charge amounts to serial killing, our most cherished assumptions about gender roles and professional responsibility are called into question. Yet in this decade nurses have been accused of killing patients, attempting to kill patients and causing grievous bodily harm to others. In the UK, of the nurses accused of attempting to murder their patients two came from the same specialism. Two of the three accusations centred on Intensive Care Units (ICU); the case of Amanda Jenkinson (Kenny 1996) and the case of Kath Atkinson, an ICU sister in Newcastle (Porter 1998a). In the most notorious case of nurse homicide in the UK this decade, that of paediatric nurse Beverly Allitt, the profession and society at large were shaken by accusations so serious as to defy belief.


The role of microRNA-185 in the pathogenesis of human diseases: A focus on cancer.
MicroRNAs (miRNAs) are a widely-studied class of non-coding RNAs characterized by their short length (18-25 nucleotides). The precise functions of miRNAs are not well-elucidated; however, an increasing number of studies suggest their involvement in various physiologic processes and deregulation in pathologic conditions. miRNA-185 (miR-185) is among the mostly-studied miRNAs in human diseases, which is found to play putative roles in conditions like metabolic disorders, asthma, frailty, schizophrenia, and hepatitis. Notably, many cancer studies report the downregulation of miR-185 in cell lines, tumor tissues, and plasma specimens of patients, while it demonstrates a suppressing role on the malignant properties of cancer cells in vitro and in vivo. Accordingly, miR-185 can be considered a tumor suppressor miRNA in human malignancies, while a few studies also report inconsistent findings. Being suggested as a prognostic/diagnostic biomarker, mi-185 is also found to offer clinical potentials, particularly for early diagnosis and prediction of the prognosis of cancer patients. In this review, we have outlined the studies that have evaluated the functions and clinical significance of miR-185 in different human diseases with a particular focus on cancer.


Managing Chronic Headache Disorders.
Headaches are a very common disorder, more common than asthma and diabetes combined. Migraine is the most common headache disorder, but it remains underdiagnosed and therefore undertreated. The treatment of migraines is divided into acute and prophylaxis. Patients who are experiencing 8 or more headaches a month or those who experience disability with their headaches as determined by the Migraine Disability Assistance Score or MIDAS should be placed on prophylaxis.


Cerebellar Transcranial Direct Current Stimulation Does Not Alter Somatosensory Temporal Discrimination Threshold.
This study aimed to explore the role of the cerebellum on the somatosensory temporal discrimination (STD) process. Twenty healthy volunteers were enrolled in the study. Each participant was included in three different transcranial direct current stimulation (tDCS) sessions as anodal, cathodal, and sham sessions in randomised order. Anodal and cathodal cerebellar tDCS (cTDCS) were given for 20 min at an intensity of 2 mA. The results of the study indicate no effect of cTDCS on STD. Although the study results show that cTDCS does not affect STD, because of the restricted sample size of the study, it is useful and necessary to investigate this relationship more in depth in a larger healthy subject population using different cTDCS methodologies.


Rapid detection of Escherichia coli O157:H7 using immuno-magnetic flow cytometry in ground beef, apple juice, and milk.
A rapid method combining flow cytometry and immunomagnetic bead separation (IMFC) was effective for detecting low populations of Escherichia coli O157:H7 inoculated into ground beef, apple juice, and raw milk samples. Modified buffered peptone was most effective for enrichment of E. coli O157:H7 in ground beef. Using IMFC in combination with a 6-h enrichment, as few as four E. coli O157:H7 cells/g of ground beef were detected in as little as a 7-h total analysis time. Our results demonstrate the possibility of using flow cytometry and immunomagnetic bead separation to detect low concentrations of E. coli O157:H7 in ground beef, apple juice and milk.


Changes in hemopoiesis of mice of the C3H strain following transplantation of Gardner lymphosarcoma and infection with LDH-virus. II. Spleen and bone marrow.
Cytological examination of spleens of mice with growing Gardner lymphosarcoma contaminated with LDH virus indicates the augmentation of erythropoiesis and granulopoiesis, as well as the decrease of lymphopoiesis. Similar changes were observed after infection with LDH-virus. The counts from the bone marrow smear showed more pronounced changes only in tumorous mice, in which repeatedly increased granulopoiesis was found. When the mice bearing Gardner lymphosarcoma were treated with L-asparaginase, then the cytological findings in the spleens and marrows of femors were almost normal. The examination of spleen and bone marrow smears revealed no tumor cells. Histologically examined spleens of mice with 12-day-growing Gardner lymphosarcoma demonstrated infiltration of the follicles with tumor cells. In the marrow of sternum no infiltration of tumor cells could be established.


Macrophage turnover, division and activation within developing, peak and "healed" tuberculous lesions produced in rabbits by BCG.
This review is a synthesis and analysis of our nine experimental pathology papers on macrophage kinetics in dermal tuberculous lesions produced in rabbits by BCG. It is presented at this time to summarize the macrophage kinetics in both active and essentially healed tuberculous lesions and to suggest that the bacilli frequently multiply and are destroyed in the viable granulation tissue of many small arrested tuberculous lesions. The turnover of mononuclear cells (MN)-which were mostly macrophages with some medium and large lymphocytes-was most rapid in BCG lesions at 2-3 weeks (when tuberculin sensitivity and acquired cellular resistance were at their peaks). At this time, more macrophages entered, more died or left, more remained at the site, and more became activated than before or afterwards. Before this time, the host had no delayed-type hypersensitivity (DTH) and cell-mediated immunity (CMI), so that no antigen-specific enhancement of the inflammatory response occurred. After this time, the bacilli and their antigenic products had decreased, so that the stimuli for cell infiltration and activation were reduced. In "healed" lesions, the MN turnover still occurred, but was decreased. The continuous entry of live non-activated macrophages into the viable parts of tuberculous lesions provides fresh intracellular sites where tubercle bacilli may multiply before they are again inhibited by the DTH and CMI of the host. In tuberculosis, bacillary dormancy of long duration may only be present in caseous necrotic tissue where no live host cells exist.


Critically ill patients with acute cholecystitis are at increased risk for extensive gallbladder inflammation.
Acute cholecystitis is a common diagnosis and surgery is the standard of care for young and fit patients. However, due to high risk of postoperative morbidity and mortality, surgical management of critically ill patients remains a controversy. It is not clear, whether the increased risk of perioperative complications associated with the management of critically ill patients with acute cholecystitis is secondary to reduced physiologic reserve per se or to the severity of gallbladder inflammation. A retrospective analysis of prospectively collected data of patients undergoing laparoscopic cholecystectomy for acute cholecystitis in a university hospital over a three-year-period was performed. The ASA scores at the time of presentation were used to categorize patients into two groups. The study group consisted of critically ill patients with ASA 3 and 4, while the control group was made up of fit patients with ASA 1 and 2. Both groups were compared with regard to perioperative data, postoperative outcome and extent of gallbladder inflammation on histopathology. Two hundred and seventeen cases of acute cholecystitis with complete charts were available for analysis. The study group included 67 critically ill patients with ASA 3 and 4, while the control group included 150 fit patients with ASA 1 and 2. Both groups were comparable with regard to perioperative data. Histopathology confirmed severe cholecystitis in a significant number of cases in the study group compared to the control group (37 % vs. 18 %, p = 0.03). Significantly higher rates of morbidity and mortality were recorded in the study group (p < 0.05). Equally, significantly more patients from the study group were managed in the ICU (40 % vs. 8 %, p = 0.001). Critically ill patients presenting with acute cholecystitis are at increased risk for extensive gallbladder inflammation. The increased risk of morbidity and mortality seen in such patients might partly be secondary to severe acute cholecystitis.


The ubiquitin-like protein Plic-1 enhances the membrane insertion of GABAA receptors by increasing their stability within the endoplasmic reticulum.
Gamma-aminobutyric acid receptors (GABA(A)R) are the major sites of fast inhibitory neurotransmission in the brain, and a critical determinant for the efficacy of neuronal inhibition is the number of these receptors that are expressed on the neuronal cell surface. GABA(A)Rs are heteropentamers that can be constructed from seven subunit classes with multiple members; alpha, beta, gamma(1-3), delta, epsilon(1-3), theta, and pi. Receptor assembly occurs within the endoplasmic reticulum, and it is evident that transport-competent combinations exiting this organelle can access the cell surface, whereas unassembled subunits are ubiquitinated and subject to proteasomal degradation. In a previous report the ubiquitin-like protein Plic-1 was shown to directly interact with GABA(A)Rs and promote their accumulation at the cell surface. In this study we explore the mechanisms by which Plic-1 regulates the membrane trafficking of GABA(A)Rs. Using both recombinant and neuronal preparations it was apparent that Plic-1 increased the stability of endoplasmic reticulum resident GABA(A)Rs together with an increase in the abundance of poly-ubiquitinated receptor subunits. Furthermore, Plic-1 elevated cell surface expression levels by selectively increasing their rates of membrane insertion. Thus, Plic-1 may play a significant role in regulating the strength of synaptic inhibition by increasing the stability of GABA(A)Rs within the secretory pathway and thereby promoting their insertion into the neuronal plasma membrane.


Flow cytometric analysis of chromosomes and cells using a modified BrdU-Hoechst method.
Chromosomes and interphase cells were harvested from cultures of the Chinese hamster line B14 F28 grown in medium containing BrdU up to four cell cycles and stained with the fluorescent dye 33342 Hoechst for flow cytometry. The newly synthetized BrdU-DNA is not stainable by the Hoechst dye which is highly specific for thymidine. The temporal development of the DNA fluorescence after addition of BrdU to the growth medium has been investigated. The chromosomal fluorescence intensity is reduced one step per generation. The extent of the intensity decrease by BrdU incorporation is proportional to the amount of new DNA and it is realized by repeated measurement following an UV-exposure. This UV-illumination stops the quenching by BrdU of the Hoechst stain induced DNA fluorescence. Therefore, the entire DNA content of these chromosomes now becomes measurable. The obtained intensity gain serves as a measure of the extent of the previous BrdU caused intensity shift. In this way we could establish 3 successive mitoses. Principally, this method is suitable also for measurement of whole cells in order to obtain both the number of generations in the experimental period and the phase distribution of the cell cycle.


Understanding social engagements: A comparative analysis of user and text features in Twitter.
Information is spread as individuals engage with other users in the underlying social network. Analysis of social engagements can therefore provide insights to understand the motivation behind how and why users engage with others in different activities. In this study, we aim to understand the driving factors behind four engagement types in Twitter, namely like, reply, retweet, and quote. We extensively analyze a diverse set of features that reflect user behaviors, as well as tweet attributes and semantics by natural language processing, including a deep learning language model, BERT. The performance of these features is assessed in a supervised task of engagement prediction by learning social engagements from over 14 million multilingual tweets. In the light of our experimental results, we find that users would engage with tweets based on text semantics and contents regardless of tweet author, yet popular and trusted authors could be important for reply and quote. Users who actively liked and retweeted in the past are likely to maintain this type of behavior in the future, while this trend is not seen in more complex types of engagements, reply, and quote. Moreover, users do not necessarily follow the behavior of other users with whom they have previously engaged. We further discuss the social insights obtained from the experimental results to understand better user behavior and social engagements in online social networks. The online version contains supplementary material available at 10.1007/s13278-022-00872-1.


Investigating the modulation of stimulus types on language switching costs: Do semantic and repetition priming effect matter?
In the present study, I investigated the influence of stimulus types on bilingual control in the language switching process. The commonly employed stimuli in language switching studies - Arabic digits and objects - were compared to further investigate the way in which inhibitory control could be modulated by semantic and repetition priming effects. The digit stimuli have two unique characteristics in the language switching paradigm, for example, they are present repeatedly and are semantically related to each other, compared with pictural stimuli. Thus, these unique characteristics might influence the operation of inhibitory control in bilingual language production, modulating the size and asymmetry of switching costs. Two picture control sets were set up to match those characteristics: (1) a semantic control set, in which picture stimuli belong to the same category group, such as, animals, occupations or transportation and specific semantic categories were presented in a blocked condition; and (2) a repeated control set, in which nine different picture stimuli were repeatedly presented like the Arabic digits from 1 to 9. When comparing the digit condition and the standard picture condition, analyses of naming latencies and accuracy rates revealed that switching costs were reliably smaller for digit naming than for picture naming and the L1 elicited more switching costs for picture naming than for digit naming. On the other hand, when comparing the digit condition and the two picture control sets, it was found that the magnitude of switching costs became identical and the asymmetry in switching costs became much smaller between the two languages.


The insulinoma-associated 1: a novel promoter for targeted cancer gene therapy for small-cell lung cancer.
The insulinoma-associated 1 (INSM1) gene is expressed exclusively during early embryonal development, but has been found re-expressed at high levels in neuroendocrine tumors. The regulatory region of the INSM1 gene is therefore a potential candidate for regulating expression of a therapeutic gene in transcriptionally targeted cancer gene therapy against neuroendocrine tumors. We analyzed expression of a reporter gene from a 1.7 kb region of the INSM1 promoter in a large number of small-cell lung cancer (SCLC) cell lines. This INSM1 promoter region showed very high levels of expression in most of the SCLC cell lines and expression was absent in cell lines of non-neuroendocrine origin. Inclusion of the general transcriptional enhancer from SV40 compromised the specificity of the promoter and did not enhance transcription in most of the SCLC cell lines. For comparison, the region of the gastrin releasing peptide (GRP) previously suggested for SCLC gene therapy was analyzed in a similar manner. High expression was observed for a number of cell lines, but unlike for the INSM1 promoter, reporter gene expression from the GRP promoter did not correlate to the relative GRP mRNA levels, demonstrating that this region may not contain all necessary regulatory elements. Expression of the suicide gene herpes simplex virus thymidine kinase (HSV-TK) from the INSM1 promoter in combination with treatment with the prodrug ganciclovir (GCV) caused a significant increase in GCV sensitivity specifically in INSM1-expressing cell lines. The INSM1 promoter is therefore a potential novel tool for transcriptionally targeted gene therapy for neuroendocrine tumors.


Effect of nitric oxide on the daunorubicin efflux mechanism in K562 cells.
NO (nitric oxide) donating drugs have been investigated for their important role in the sensitization of neoplastic cells to chemotherapy drugs. The goal of this work was to investigate the involvement of NO in the resistance of K562 cells to DNR (daunorubicin). Only simultaneous addition of DNR and SNAP (S-nitroso-N-acetyl-dl-penicillamine) caused significant cell death by apoptosis. Combination of the compounds decreased Bcl-2 and survivin, and increased Bax and active-caspase 3 expression. Fluorescence microscope and cytometric analysis showed that DNR and SNAP together caused DNR intracellular accumulation in K562 cells. RT-PCR (reverse transcription-PCR) analysis showed that DNR and SNAP, alone or in association, produced significant decreases in lrp expression. abcc1 gene expression was unaffected by the presence of SNAP, but when treated with DNR there was a small reduction that was intensified by DNR and SNAP in combination. The transport mechanism involved in the resistance to DNR in K562 cells involves ABCC1 and LRP (lung resistance protein) resistance proteins. DNR and SNAP inhibition of the expression of these proteins occurs by distinct mechanisms, and this disrupts the K562 resistance to DNR.


Factors influencing oral anticoagulant use in patients newly diagnosed with atrial fibrillation.
We investigated factors that influenced oral anticoagulant (OAC) initiation and choice in Australian general practice patients newly diagnosed with AF. Using an Australian nationally representative general practice dataset, MedicineInsight, we identified patients newly diagnosed with AF between January 2009 and April 2019. Logistic regression analyses were used to examine factors associated with OAC initiation and choice. A total of 63 212 patients with AF (53.7% males, mean age 72.4 years) were identified. Nearly two-thirds of these patients (40 854 [64.6%]) were initiated on an OAC, at a median time of 6 days after the documented diagnosis date. The proportion of patients who were initiated an OAC increased from 44.8% in 2009 to 72.2% in 2019 (P < .001). High risk of stroke (CHA2 DS2 -VASc, adjusted odds ratio (AOR), 4.39 [95% CI, 3.99-4.83]), low risk of bleeding (ORBIT, AOR, 1.87 [95% CI, 1.72-2.03]), not having a recorded history of dementia (AOR, 1.81 [95% CI, 1.65-1.98]) and male sex (AOR, 1.29 [95% CI, 1.22-1.35]) were independently associated with OAC initiation. Direct-acting oral anticoagulant (DOAC) use increased from 11.9% in 2011 to 94.0% of all OAC initiations in April 2019 (P < .001). The proportion of newly diagnosed patients with AF initiated on OAC increased markedly following the introduction of the DOACs. Of those initiated, 9 in 10 were receiving a DOAC at the end of the study period. There is potential underuse in women and individuals with dementia.


Effects of hypothalamic and preoptic lesions on reproductive behavior in male rats.
Adult male rats, which were selected on the basis of showing complete patterns of male copulatory behavior on two prior tests, were castrated six weeks prior to brain surgery. Animals were divided into three groups and given small bilateral lesions in the dorsomedial preoptic area (POA), ventromedial hypothalamus (VMH), or sham operations. Starting 10 days postsurgery, all animals were injected with estrogen alone and estrogen plus progesterone, and tested twice for lordosis behavior. Ten days following the female behavior tests, animals were injected daily with testosterone propionate for 13 days and tested for masculine sexual behavior on injection 5, 9 and 13. Low levels of lordotic behavior were observed for POA and VMH animals on both tests for female sex behavior and were comparable to sham operated animals. However, in terms of all dependent measures of male copulatory behavior, animals with VMH lesions showed significantly higher levels of male sex behavior with shorter latencies than sham animals across all three behavior tests. In contrast, POA lesioned rats showed little or no male sex behavior on any test and were significantly inferior to sham operated animals. Thus, the POA and VMH appear to exert excitatory and inhibitory control, respectively, over male copulatory behavior in male rats.


A randomized controlled trial examining the effects of behavioral weight loss treatment on hippocampal volume and neurocognition.
Obesity in midlife is an established risk factor for dementia. In middle-aged adults, elevated body mass index (BMI) is associated with lower neurocognition and smaller hippocampal volumes. It is unclear whether behavioral weight loss (BWL) can improve neurocognition. The purpose of this study was to evaluate whether BWL, compared to wait list control (WLC), improved hippocampal volume and neurocognition. We also examined if baseline hippocampal volume and neurocognition were associated with weight loss. We randomly assigned women with obesity (N = 61; mean±SD age=41.1 ± 9.9 years; BMI=38.6 ± 6.2 kg/m2; and 50.8% Black) to BWL or WLC. Participants completed assessments at baseline and follow-up including T1-weighted structural magnetic resonance imaging scans and the National Institutes of Health (NIH) Toolbox Cognition Battery. The BWL group lost 4.7 ± 4.9% of initial body weight at 16-25 weeks, which was significantly more than the WLC group which gained 0.2 ± 3.5% (p < 0.001). The BWL and WLC groups did not differ significantly in changes in hippocampal volume or neurocognition (ps>0.05). Baseline hippocampal volume and neurocognition scores were not significantly associated with weight loss (ps>0.05). Contrary to our hypothesis, we found no overall benefit of BWL relative to WLC on hippocampal volumes or cognition in young- and middle-aged women. Baseline hippocampal volume and neurocognition were not associated with weight loss.


Nosology and Pathology of Langerhans Cell Histiocytosis.
The classification of the histiocytoses has evolved based on new understanding of the cell of origin as a bone marrow precursor. Although the pathologic features of the histiocytoses have not changed per se, molecular genetic information now needs to be integrated into the diagnosis. The basic lesions of the most common histiocytoses, their patterns in different sites, and ancillary diagnostics are now just one part of the classification. As more is understood about the cell of origin and molecular biology of the histiocytoses, future classifications will be refined.


The mental health and adjustment of immigrant and refugee children.
Although parents may make decisions to leave their homes, either willingly in the hope of improving their lives or involuntarily to escape danger and seek safety for themselves and their families, it is never a voluntary decision for the child. The economic, political, social, and other contextual issues associated with migration are as significant in predicting the child's adjustment to his or her new circumstances as his or her physical and psychological endowment. This article addresses these issues and suggests that particular consideration be given to children whose migration was punctuated by life-threatening danger or whose families were overwhelmed by the stresses of migratory experiences. Child and adolescent psychiatrists and other well-trained mental health professionals can further the understanding of the interactions among the child, family, and new community, which can promote or hinder the process of adaptation to the new setting.


Computational investigation of a ternary model of SnoN-SMAD3-SMAD4 complex.
The transforming growth factor β (TGFβ) plays an essential role in the regulation of cellular processes such as cell proliferation, migration, differentiation, and apoptosis by association with SMAD transcriptional factors that are regulated by the transcriptional regulator SnoN. The crystal structure of SnoN-SMAD4 reveals that SnoN can adopt two binding modes, the open and closed forms, at the interfaces of SMAD4 subunits. Accumulating evidence indicates that SnoN can interact with both SMAD3 and SMAD4 to form a ternary SnoN-SMAD3-SMAD4 complex in the TGFβ signaling pathway. However, how the interaction of SnoN with the SMAD3 and SMAD4 remains unclear. Here, molecular dynamics (MD) simulations and molecular modeling methods were performed to figure out this issue. The simulations reveal that SnoNopen exists in two, open and semi-closed, conformations. Molecular modeling and MD simulation studies suggest that the SnoNclosed form interferes with the SMAD3-SMAD4 protein; in contract, the SnoNopen can form a stable SnoN-SMAD3-SMAD4 complex. These mechanistic mechanisms may help elucidate the detailed engagement of SnoN with two SMAD3 and SMAD4 transcriptional factors in the regulation of TGFβ signaling pathway.


Alleviation of drought stress of marigold (Tagetes erecta) plants by using arbuscular mycorrhizal fungi.
The effect of an arbuscular mycorrhizal fungus "AMF" (Glomus constrictum Trappe) on growth, pigments, and phosphorous content of marigold (Tagetes erecta) plant grown under different levels of drought stress was investigated. The applied drought stress levels reduced growth vigor (i.e. plant height, shoot dry weight, flower diameter as well as its fresh and dry weights) of mycorrhizal and non-mycorrhizal plant as compared to control plant (non-drought stressed plant). The presence of mycorrhizal fungus, however, stimulated all growth parameters of the treated plant comparing to non-mycorrhizal treated plant. The photosynthetic pigments (carotene in flowers and chlorophylls a and b in leaves) were also stimulated by the mycorrhizal fungi of well-watered as well as of water-stressed plants. The total pigments of mycorrhizal plants grown under well-watered conditions were higher than those of non-mycorrhizal ones by 60%. In most cases, drought-stressed mycorrhizal plants were significantly better than those of the non-mycorrhizal plants. So, the overall results suggest that mycorrhizal fungal colonization affects host plant positively on growth, pigments, and phosphorous content, flower quality and thereby alleviates the stress imposed by water with holding.


Minimal Model of Plankton Systems Revisited with Spatial Diffusion and Maturation Delay.
This study revisits the minimal model for a plankton ecosystem proposed by Scheffer with spatial diffusion of plankton and the delay of the maturation period of herbivorous zooplankton. It deepens our understanding of effects of the nutrients and the predation of fish upon zooplankton on the dynamical patterns of the plankton system and also presents new phenomena induced by the delay with spatial diffusion. When the nutrient level is sufficient low, the zooplankton population collapses and the phytoplankton population reaches its carrying capacity. Mathematically, the global stability of the boundary equilibrium is proved. As the nutrient level increases, the system switches to coexistent equilibria or oscillations depending on the maturation period of zooplankton and the predation rate of fish on herbivorous zooplankton. Under an eutrophic condition, there is a unique coexistent homogeneous equilibrium, and the equilibrium density of phytoplankton increases, while the equilibrium density of herbivorous zooplankton decreases as the fish predation rate on herbivorous zooplankton is increasing. The study shows that the system will never collapses under the eutrophic condition unless the fish predation rate approaches infinite. The study also finds a functional bifurcation relation between the delay parameter of the maturation period of herbivorous zooplankton and the fish predation rate on herbivorous zooplankton that, above a critical value of the fish predation rate, the system stays at the coexistent equilibrium, and below that value, the system switches its dynamical patterns among stable and unstable equilibria and oscillations. The oscillations emerge from Hopf bifurcations, and a detailed mathematical analysis about the Hopf bifurcations is carried out to give relevant ecological predications.


Prognosis of Japanese encephalitis: a multivariate analysis.
To evaluate the role of various clinical neurophysiological laboratory and radiological parameters in the prognosis of Japanese encephalitis (JE), 28 patients were prospectively evaluated. Their age ranged between two and 54 years, with eight of them being female and 11 children. The outcome was defined, at the end of a six-month period, as being poor (bed-ridden), partial (partial dependence for activity for daily life) and complete recovery (independent for activities of daily life). A number of clinical (age, degree of coma, decerebration or decortication and reflex changes), laboratory (CSF cell and protein content, and haemagglutination inhibition titre in the serum), neurophysiological (EEG, EMG, sensory and motor evoked potentials) and the extent of radiological changes were subjected to stepwise multivariate logistic regression analysis. By the end of six months, four patients had died, seven had poor, ten partial and seven had complete recovery. The best set of predictors of outcome included age, Glasgow coma scale and reflex changes.


Risk factors for subclinical atherosclerosis in firefighters.
Heart disease is the leading cause of firefighter line-of-duty deaths. The study objectives were to identify early atherosclerotic disease through ultrasound measurement of carotid intima-media thickness (CIMT) and risk factors predicting increased CIMT and carotid plaque. Following ultrasound evaluation of 597 Phoenix and Tucson firefighters, logistic regression was used to identify risk factors for mean CIMT greater than 75th percentile and for carotid plaque. Age, low-density lipoprotein cholesterol (LDL-C) of 100 mg/dL or more, and high-density lipoprotein cholesterol were significant independent predictors of increased CIMT. Age, hypertension, LDL-C, and plasma soluble P-selectin were significant predictors of carotid plaque. This study supports an emphasis on traditional risk factors for atherosclerotic disease in firefighters, in particular maintaining LDL-C less than 100 mg/dL. Plasma soluble P-selectin may help identify firefighters at increased risk for carotid plaque.


Some biochemical responses of rat skeletal muscle to a single subcutaneous injection of a toxin (notexin) isolated from the venom of the Australian tiger snake Notechis scutatus scutatus.
1. Some biochemical responses of mammalian skeletal muscle to a single subcutaneous injection of a purified toxin from the venom of the Australian tiger snake, Notechis scutatus scutatus, have been investigated to determine the role of changes in peptide hydrolase enzymes in the muscle wasting caused by notexin administration. 2. Within 6 h of injection, serum creatine kinase activity was increased by five- to ten-fold, and remained elevated for at least 24 h. 3. There was an initial inflammatory response in the muscle adjacent to the site of injection; by 12 h after injection, muscle wet weight increased by 60%. 4. After the initial increase, wet weight fell to about 50% of normal at 7 days. Normal wet weight was achieved by 20 days after the injection. Over the period 1-20 days after the injection of the toxin, the changes in wet weight were mirrored by changes in non-collagen protein content. 5. The activities of cathepsin B and acid proteinase were increased following the injection of the toxin. By 2 days after injection, there was a ten-fold increase in the activity of cathepsin B, and a seven-fold increase in the activity of acid proteinase. The activity of both enzymes become normal by 20 days. 6. Experiments utilizing a variety of cytotoxic drugs suggested that the acid proteinase and cathespin B are primarily located within invading phagocytic cells. 7. The results are discussed with reference to the previously described pathology of toxin-damaged skeletal muscle.


Viscum album prevents haematological changes, electrolyte imbalance, changes in liver function enzymes and histological alterations in some selected tissues in cadmium chloride-intoxicated rats.
The use of Viscum album to treat different diseases is popular in the practise of alternative medicine. We investigated the ability of the aqueous extract of V. album to protect against the toxic effects of cadmium. Thirty rats used for the experiment were treated as follows; Group 1 - no cadmium or extract. Group 2-10 mg/kg body weight of cadmium chloride. Group 3-10 mg/kg body weight of cadmium chloride and 200 mg/kg body weight of aqueous extract of V. album. Group 4-10 mg/kg body weight of cadmium chloride and 400 mg/kg body weight of aqueous extract of V. album. Group 5-10 mg/kg body weight of cadmium chloride with 800 mg/kg body weight of aqueous extract of V. album. Group 6-10 mg/kg body weight of cadmium chloride and atorvastatin (100 mg/kg body weight). Apart from WBC and platelets, other haematological parameters and electrolytes, urea and creatinine levels were not significantly affected by the administration of cadmium chloride along with the aqueous extract of V. album. Treatment with the extract caused significant decreases in the hepatosomatic index, cardiosomatic index, and increase in renosomatic index of the test rats. It also resulted in significant (P < 0.05) decrease in AST level. Histological report also shows that treatment with the extract restored the normal myocardium and vascular architecture of the heart, normal portal and vascular architecture of the liver and normal glomerular and tubular architecture of the kidney, in the cadmium-intoxicated experimental rats. V. album protects against the toxic effects of cadmium chloride.


Klotho inhibits the formation of calcium oxalate stones by regulating the Keap1-Nrf2-ARE signaling pathway.
Oxidative damage is important in calcium oxalate (CaOx) stone development but occurs via multiple pathways. Studies have shown that klotho plays an essential role in ameliorating oxidative damage. This study aims to explore the role of klotho in CaOx stones and whether the underlying mechanism is related to the regulation of Keap1-Nrf2-ARE signaling. The levels of GSH, SOD, CAT, MDA, and ROS were examined by ELISA. The klotho, Bcl-2, caspase-3, Keap1, Nrf2, HO-1, and NQO1 mRNA levels were measured by qRT‒PCR, and their protein levels were detected by Western blotting. Renal tissue apoptosis was examined by TUNEL staining, and crystal cell adherence and apoptosis in HKC cells were assessed based on the Ca2+ concentrations and by flow cytometry. The renal pathological changes and the adhesion of CaOx crystals in the kidneys were examined by hematoxylin-eosin and von Kossa staining, respectively. We constructed a CaOx kidney stone model in vitro. By regulating the klotho gene, klotho overexpression inhibited the CaOx-induced promotion of crystal cell adherence and apoptosis in HKC cells, and these effects were reversed by klotho knockdown. Moreover, our in vivo assay demonstrated that klotho overexpression alleviated glyoxylate administration-induced renal oxidative damage, renal apoptosis, and crystal deposition in the kidneys of mice, and these effects were also associated with activation of the Keap1-Nrf2-ARE pathway. Klotho protein inhibits the oxidative stress response of HKC cells through the Keap1-Nrf2-ARE signaling pathway, reduces the apoptosis of and adhesion of CaOx crystals to HKC cells, and decreases the occurrence of CaOx kidney stones. 20220304.


Seasonal Variation Analysis for Weekly Cases, Deaths, and Hospitalizations of COVID-19 in the United States.
Knowing the seasonality of COVID-19 helps decision-makers to take suitable interventions against the pandemic. In this study, we performed the Brown-Forsythe variance analysis on seasonal variations on different indicators based on the data on COVID-19 for the United States provided publicly by WHO. Our study finds that the seasonality of weekly cases and deaths of COVID-19 are strongly statistically supported by the data. The weekly total cases(/deaths) in winter are three to seven times(/two to three times) more than the other three single seasons. The ICU patients in winter and autumn are four to five times more than spring. The weekly hospital admissions in winter are four times more than spring. The mean of the positive rate in winter is five times more than spring. The findings of this research can be a reference in decision-making when taking interventions against the pandemic, such as taking stricter interventions in winter while considering less strict interventions in summer, etc.


[Reversible metabolic syndrome].
A 52-year-old male patient was admitted to the emergency department with dyspnea and hypertensive urgency. During the previous 6 months, the patient had noticed leg edema, weight gain (particularly in the face and abdomen), and impotence. 1.5 years ago, he was diagnosed with hypertension resistant to medication. After an accident at work 1 year ago, osteoporosis was diagnosed with vertebral and rib fractures. Measurement of sleeping midnight salivary cortisol levels together with 24-h urine free cortisol excretion and an overnight low-dose 1-mg dexamethasone suppression test proved overt hypercortisolism. The high-dose 8-mg dexamethasone suppression suggested an adrenal or ectopic source of hypercortisolism. By contrast, elevated adreno-corticotropic hormone (ACTH) levels and a corticotropin-releasing hormone stimulation test gave evidence for a pituitary source of hypercortisolism. However, pituitary magnetic resonance imaging failed to reveal a pituitary adenoma. Moreover, computed tomography scans of thorax and abdomen were negative. In this situation, an inferior petrosal vein sampling was performed and revealed an ACTH gradient (central-systemic) >3 with lateralization to the right side. The patient underwent a selective, partial, transsphenoidal resection and was cured from clinical signs and symptoms caused by hypercortisolism. Subsequent hormonal replacement therapy of postoperative pituitary insufficiency was necessary.


Current and emerging chemotherapy treatment strategies for Wilms tumor in North America.
Wilms tumor is the most common primary renal malignancy occurring in childhood. Approximately 500 children are diagnosed with Wilms tumor annually in the US alone, most of whom are aged <5 years. Several prognostic factors have been identified, including stage of disease, tumor histology, patient age, tumor weight, and tumor-specific loss of heterozygosity for chromosomes 1p and 16q. During the period from 1969 to 2002, the National Wilms Tumor Study Group coordinated five multicenter Wilms tumor studies. The overall survival rate for Wilms tumor has risen to >90% for patients with tumors of favorable histology. However, the treatment of patients with Wilms tumor with anaplastic histology remains challenging. The optimal treatment strategies for Wilms tumor in relapse will be studied via international collaboration in the near future. Goals of emerging studies include minimizing toxicity while maintaining the outstanding cure rates for patients with a good prognosis and, through advancing biologic understanding and developing novel therapeutic approaches, improving the prognosis for those patients in whom effective cure of their disease continues to elude physicians.


A comparative agreement evaluation of two subaxial cervical spine injury classification systems: the AOSpine and the Allen and Ferguson schemes.
We performed an agreement study using two subaxial cervical spine classification systems: the AOSpine and the Allen and Ferguson (A&F) classifications. We sought to determine which scheme allows better agreement by different evaluators and by the same evaluator on different occasions. Complete imaging studies of 65 patients with subaxial cervical spine injuries were classified by six evaluators (three spine sub-specialists and three senior orthopaedic surgery residents) using the AOSpine subaxial cervical spine classification system and the A&F scheme. The cases were displayed in a random sequence after a 6-week interval for repeat evaluation. The Kappa coefficient (κ) was used to determine inter- and intra-observer agreement. Inter-observer: considering the main AO injury types, the agreement was substantial for the AOSpine classification [κ = 0.61 (0.57-0.64)]; using AO sub-types, the agreement was moderate [κ = 0.57 (0.54-0.60)]. For the A&F classification, the agreement [κ = 0.46 (0.42-0.49)] was significantly lower than using the AOSpine scheme. Intra-observer: the agreement was substantial considering injury types [κ = 0.68 (0.62-0.74)] and considering sub-types [κ = 0.62 (0.57-0.66)]. Using the A&F classification, the agreement was also substantial [κ = 0.66 (0.61-0.71)]. No significant differences were observed between spine surgeons and orthopaedic residents in the overall inter- and intra-observer agreement, or in the inter- and intra-observer agreement of specific type of injuries. The AOSpine classification (using the four main injury types or at the sub-types level) allows a significantly better agreement than the A&F classification. The A&F scheme does not allow reliable communication between medical professionals.


Changes in brain biogenic monoamines induced by the nootropic drugs adafenoxate and meclofenoxate and by citicholine (experiments on rats).
1. The effects of Adafenoxate (Adf), meclofenoxate (Mf) and citicholine (CCh) administered at a daily dose of 100 mg/kg for 7 days on the levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the frontal cerebral cortex, striatum, hippocampus and hypothalamus of rats were studied. 2. Adafenoxate increased the NA level in the striatum and decreased it in the hypothalamus; it increased the DA level in the cerebral cortex and hypothalamus and decreased it in the striatum; it increased the 5-HT level in the cerebral cortex and decreased it in the hippocampus. 3. Meclofenoxate decreased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the hippocampus and hypothalamus and the 5-HT level in the cerebral cortex, striatum, hippocampus and hypothalamus. 4. Citicholine increased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the striatum and the 5-HT level in the cerebral cortex, striatum and hippocampus. 5. An attempt is made to explain some similarities and differences in the behavioral effects of the drugs tested (and those observed in other studies) by the changes they induce in brain biogenic monoamines.


Properties of isolated human islets of Langerhans: insulin secretion, glucose oxidation and protein phosphorylation.
In the present study, human islets were isolated by collagenase digestion from the pancreases of three kidney donors. Maintainance of the islets in tissue culture enabled insulin release, glucose oxidation and Ca2+ -calmodulin-dependent protein phosphorylation to be determined using the same islets. Increasing glucose over a range 0-20 mmol/l resulted in a sigmoidal stimulation of insulin release (28.8 +/- 5.2 to 118.4 +/- 25.8 microU . islet-1 . h-1, n = 10; threshold less than 4 mmol/l). There was a marked correlation between the insulin secretory response of the islets to glucose and their rate of glucose oxidation (5.9 +/- 0.3 at glucose 2 mmol/l up to 25.8 +/- 1.8 pmol . islet-1 . h-1 at 20 mmol/l, r = 0.98). N-acetylglucosamine (20 mmol/l) failed to elicit a secretory response from the islets. Stimulation of insulin secretion by glucose was dependent upon the presence of extracellular Ca2+. Extracts of the islets contained a Ca2+ -calmodulin-dependent protein kinase which phosphorylated a 48-kdalton endogenous polypeptide. Myosin light-chain kinase activity was demonstrated in the presence of exogenous myosin light chains. This report demonstrates for the first time the sigmoidal nature of glucose-stimulated insulin release from isolated human islets, and its correlation with enhanced glucose oxidation. Furthermore, this is the first report of the presence of Ca2+ -dependent protein kinases in human islets.


Poverty, dignity, and forgotten skin care: dermatology in the stream of human mobile population.
Skin diseases represent the greatest public health care problem in all developing countries. Tropical diseases tend to cluster in poor populations and often are defined as "neglected" because the investments made to combat them seem negligible compared with the massive amounts expended globally on the health problems of developed countries. After reviewing the worldwide situation, this article explains the principles of community dermatology and discusses the work of the San Gallicano Institute in Rome, which has developed a model for reducing the number of people suffering from dermatologic and other diseases and has established the first dermatologic hospital in Ethiopia.


Extensive versus focal lymphovascular invasion in squamous cell carcinoma of the cervix: A comprehensive international, multicenter, retrospective clinicopathologic study.
We evaluated clinicopathologic parameters of patients with cervical squamous cell carcinoma (SCC) who were treated with initial surgical management and assessed their relation to survival outcomes. Specifically, we evaluated the relation between extent of lymphovascular invasion (LVI) and survival outcomes. All available tumor slides from patients with initially surgically treated cervical SCC were collected from 10 institutions and retrospectively analyzed. Standard clinicopathological parameters, tumor stroma, and extent of LVI were assessed (focal: <5 spaces, extensive: ≥5 spaces). PFS and OS were evaluated using Kaplan-Meier methodology. Univariable and multivariable Cox proportional hazards models were created to determine prognostic survival-related risk factors. A total of 670 tumor samples were included in the analysis. Median age at diagnosis was 47 years (IQR: 38-60), 457 patients (72%) had a 2018 International Federation of Gynecology and Obstetrics (FIGO) stage I tumor, and 155 tumors (28%) were flat and/or ulcerated. There were 303 nonkeratinizing tumors (51%), 237 keratinizing tumors (40%), and 356 histologic grade 2 tumors (61%). Quantifiable LVI was present in 321 cases (51%; 23% focal and 33% extensive). On multivariable analysis for PFS, extensive and focal LVI had worse outcomes compared to negative LVI (HR: 2.38 [95% CI: 1.26-4.47] and HR: 1.54 [95% CI: 0.76-3.11], respectively; P = 0.02). The difference did not reach statistical significance for OS. Presence of LVI is a prognostic marker for patients with cervical SCC. Quantification (extensive vs. focal vs. negative) of LVI may be an important biomarker for oncologic outcome.


The center for integration of medicine and innovative technologies (CIMIT): a proven model to speed the cycle of healthcare innovation.
CIMIT is a Boston-wide consortium of premier clinical, research and academic institutions dedicated to improving patient care through application of innovative enabling technology.


The nasal distribution of metered dose inhalers.
The intranasal distribution of aerosol from a metered dose inhaler has been assessed using a radiotracer technique. Inhalers were prepared by adding 99Tcm-labelled Teflon particles (simulating the drug particles) to chlorofluorocarbon propellants, and scans of the head (and chest) taken with a gamma camera. Ten healthy subjects (age range 19-29 years) each performed two radioaerosol studies with the inhaler held in two different ways: either in a single position (vial pointing upwards) or in two positions (vial pointing upwards and then tilted by 30 degrees in the sagittal plane). The vast majority of the dose (82.5 +/- 2.8 (mean +/- SEM) per cent and 80.7 +/- 3.1 per cent respectively for one-position and two-position studies) was deposited on a single localized area in the anterior one-third of the nose, the initial distribution pattern being identical for each study. No significant radioaerosol was detected in the lungs. Only 18.0 +/- 4.7 per cent and 15.4 +/- 4.1 per cent of the dose had been removed by mucociliary action after 30 minutes, and it is probable that the remainder had not penetrated initially beyond the vestibule. Since the deposition pattern was highly localized and more than half the dose probably failed to reach the turbinates it is possible that the overall effect of nasal MDIs is suboptimal for the treatment of generalized nasal disorders.


Highly engineered biocatalysts for efficient small molecule pharmaceutical synthesis.
Technologies for the engineering of biocatalysts for efficient synthesis of pharmaceutical targets have advanced dramatically over the last few years. Integration of computational methods for structural modeling, combined with high through put methods for expression and screening of biocatalysts and algorithms for mining experimental data, have allowed the creation of highly engineered biocatalysts for the efficient synthesis of pharmaceuticals. Methods for the synthesis of chiral alcohols and amines have been particularly successful, along with the creation of non-natural activities for such desirable reactions as cyclopropanation and esterification.


Synthesis and properties of phosphorylated 3'-O-beta-D-ribofuranosyl-2'-deoxythymidine.
A strategy was developed for the synthesis of 3'-O-beta-D-ribofuranosyl 2'-deoxythymidine derivatives using three different protecting groups, which allows the synthesis of a phosphoramidite building block for oligonucleotide synthesis. Likewise the 5'-O- and 5''-O-phosphorylated analogues were synthesized and their conformation was determined using NMR spectroscopy.


Carotid artery dissection revealed by an oculosympathetic spasm.
Internal carotid dissection can be responsible for stroke and lead to severe neurological and functional complications. Thus, it must be diagnosed and treated with heparin as soon as possible. Horner syndrome is one of the most usual manifestations of internal carotid dissection. We report the case of a patient who presented with a unilateral non-reactive enlargement of the right pupil that did not last longer than 30 s. As a carotid dissection was not recognized from this atypical symptomatology, magnetic resonance angiography was performed only a few days later when Horner syndrome occurred. It disclosed a dissection of the internal carotid artery ipsilateral from its origin. The evolution and the duration of the pupil involvement suggest that the initial episode of mydriasis was caused by an oculosympathetic spasm, a rare form of sympathetic dysfunction that can be observed when the sympathetic nerve or the pericarotid plexus is irritated. It is important to recognize this oculosympathetic spasm because it has equal value as Horner syndrome for the diagnosis of internal carotid dissection.


Thein utero initiation with DMN alters the complement of cytosolic glutathione S-transferases and the phenobarbital-induced expression ofc-jun andc-myc oncogenes in primary neonatal rat hepatocytes.
As revealed by a novelin utero-in vitro hepatocarcinogenesis model, a single exposure to dimethylnitrosamine (DMN) elicited in postnatal (and fetal) primary rat hepatocytes (i) immunocytochemically detectable, widespread increases in their complement of thealpha, mu and especiallypi classes of cytosolic glutathione S-transferases (GST's); and (ii) changed patterns (with respect to controls) of the phenobarbital (PB)-evoked increases in steady state levels ofc-jun andc-myc mRNA's. These results indicate that DMN causes both transient cytotoxic effects and a broad, permanent initiation in fetal proliferating hepatocytes.


[Aortometric correlations in normal and pathological subjects].
The chest roentgenograms of 691 normal, arteriosclerotic and hypertensive patients have been reviewed for measurements of the aortic knob. There is a significant correlation between the width of the aorta and age, but no such correlation was found with the degree of hypertension. The comparison between average widths of the aorta in the 3 categories of subjects has shown its increase in arteriosclerotic and hypertensive patients.


From adolescence to late aging: A comprehensive review of social behavior, alcohol, and neuroinflammation across the lifespan.
The passage of time dictates the pace at which humans and other organisms age but falls short of providing a complete portrait of how environmental, lifestyle and underlying biological processes contribute to senescence. Two fundamental features of the human experience that change dramatically across the lifespan include social interactions and, for many, patterns of alcohol consumption. Rodent models show great utility for understanding complex interactions among aging, social behavior and alcohol use and abuse, yet little is known about the neural changes in late aging that contribute to the natural decline in social behavior. Here, we posit that aging-related neuroinflammation contributes to the insipid loss of social motivation across the lifespan, an effect that is exacerbated by patterns of repeated alcohol consumption observed in many individuals. We provide a comprehensive review of (i) neural substrates crucial for the expression of social behavior under non-pathological conditions; (ii) unique developmental/lifespan vulnerabilities that may contribute to the divergent effects of low-and high-dose alcohol exposure; and (iii) aging-associated changes in neuroinflammation that may sit at the intersection between social processes and alcohol exposure. In doing so, we provide an overview of correspondence between lifespan/developmental periods between common rodent models and humans, give careful consideration to model systems used to aptly probe social behavior, identify points of coherence between human and animal models, and point toward a multitude of unresolved issues that should be addressed in future studies. Together, the combination of low-dose and high-dose alcohol effects serve to disrupt the normal development and maintenance of social relationships, which are critical for both healthy aging and quality of life across the lifespan. Thus, a more complete understanding of neural systems-including neuroinflammatory processes-which contribute to alcohol-induced changes in social behavior will provide novel opportunities and targets for promoting healthy aging.


Characterization of a novel tyrosinase inhibitor, (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384).
We synthesized (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384) as a potential tyrosinase inhibitor and investigated its antityrosinase activity. The structure of MHY384 was established using (1)H and (13)C NMR spectroscopy and mass spectral analyses. To investigate dual mechanisms of action of MHY384 for the inhibition of melanin synthesis, we confirmed the inhibitory effect of tyrosinase catalytic activity of MHY384. Then, we confirmed the inhibitory effect of MHY384 on transcription of tyrosinase mRNA through alpha-MSH-induced cAMP-PKA-MITF signaling. In addition, we supported the inhibitory mechanism of MHY384 against tyrosinase using a kinetic study and docking programs. To determine how MHY384 regulates melanogenesis, we measured melanin levels and expression of the genes for microphthalmia-associated transcription factor (MITF) and tyrosinase in α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 melanoma cells. MHY384 potently inhibited tyrosinase activity and melanin production in B16F10 melanoma cells. Through docking models, we were able to construct the tertiary structure of mushroom tyrosinase and simulate its docking with MHY384. The result supports that MHY384 strongly interacts with tyrosinase residues in the active site and it can directly inhibit tyrosinase. To investigate additional mechanisms of action of MHY384, we confirmed that the inhibition of tyrosinase activity was found to be due to the modulation of the expression of tyrosinase and its transcription factor, MITF, through cAMP, which regulates protein kinase A. This study strongly indicates that the depigmenting effect of MHY384 results from the down-regulation of MITF and tyrosinase through direct tyrosinase inhibition. Our findings suggest that MHY384 can be an effective skin-whitening agent.


Molecular evaluation of PIK3CA gene mutation in breast cancer: determination of frequency, distribution pattern and its association with clinicopathological findings in Indian patients.
Somatic mutations in the PIK3CA gene are common in breast cancer and represent a clinically useful marker for prognosis and therapeutic target. Activating mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in 18-40 % of breast carcinomas. In this study, we evaluated PIK3CA mutation in 185 Indian breast cancer patients by direct DNA sequencing. PIK3CA mutations were observed in 23.2 % (43/185) of breast tumor samples. PIK3CA mutations were more frequent exon 30 (76.8 %) than in exon 9 (23.2 %). Mutations were mostly clustered within two hotspot region between nucleotides 1624 and 1636 or between 3129 and 3140. Sequencing analysis revealed four different missense mutations at codon 542 and 545 (E542K, E545K, E545A and E545G) in the helical domain and two different amino acid substitutions at codon 1047 (H1047R and H1047L) in the kinase domain. None of the cases harbored concomitant mutations at multiple codons. PIK3CA mutations were more frequent in older patients, smaller size tumors, ductal carcinomas, grade II tumors, lymph node-positive tumors and non-DCIS tumors; however, none of the differences were significant. In addition, PIK3CA mutations were common in ER+, PR+ and HER2+ cases (30 %), and a comparatively low frequency were noted in triple-negative tumors (13.6 %). In conclusion, to our knowledge, this is the largest study to evaluate the PIK3CA mutation in Indian breast cancer patients. The frequency and distribution pattern of PIK3CA mutations is similar to global reports. Furthermore, identification of molecular markers has unique strengths and can provide insights into the pathogenic process of breast carcinomas.


Case Report : Li-Fraumeni Syndrome with Central Nervous System Tumors in Two Siblings.
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations. It is characterized by high risk of early-onset cancer, and has been confirmed as associated with multiple tumors clinically. So pediatricians should be more alert to LFS in children with tumors. Choroid plexus carcinoma (CPC) is a rare, malignant tumor which account for less than 1% of all central nervous system (CNS) tumors. However, when such tumorigenesis occurs, it is important to be vigilant for the presence of LFS. The first patient is a 32-month-old boy admitted for convulsions and then was found intracranial space-occupying lesion. Underwent operation, he was diagnosis as choroid plexus carcinoma (WHO Grade III). After 5 months, his elder sister, a 13-year-old girl, was brought to emergency department for confusion and intermittent convulsions. Surgery was performed immediately after head CT examination found the lesion. The pathology result indicated glioblastoma. Because the siblings of the same family have successively suffered from malignant tumors, we performed genetic testing on this family. TP53 gene mutation occurred in both children of these two cases from their father, and their other brother was not spared either. So the two siblings both met the diagnostic criteria of LFS. Then they all received systematic anti-tumor therapy, and follow-up hitherto. Here we reported a rare LFS case that two siblings were inherited the same TP53 germline mutations from their father. They suffered from choroid plexus carcinoma and glioblastoma and were finally diagnosed with LFS. In this LFS family, the primary tumors of the two children were both central nervous system tumors, which were not reported in the previous literature. It is suggested that clinicians should be alert to LFS related tumors, which is helpful for early diagnosis. Timely detection of TP53 gene is an important way for early diagnosis of LFS, especially in children with tumor. The incidence of secondary tumor in LFS patients is significantly higher, and other family members of the LFS patient also have an increased risk of suffering from the tumors. Therefore, early diagnosis and timely tumor surveillance can obtain better therapeutic effect and prognosis for both proband and their family.


1700 nm and 1800 nm band tunable thulium doped mode-locked fiber lasers.
This paper presents short wavelength operation of tunable thulium-doped mode-locked lasers with sweep ranges of 1702 to 1764 nm and 1788 to 1831 nm. This operation is realized by a combination of the partial amplified spontaneous emission suppression method, the bidirectional pumping mechanism and the nonlinear polarization rotation (NPR) technique. Lasing at emission bands lower than the 1800 nm wavelength in thulium-doped fiber lasers is achieved using mode confinement loss in a specially designed photonic crystal fiber (PCF). The enlargement of the first outer ring air holes around the core region of the PCF attenuates emissions above the cut-off wavelength and dominates the active region. This amplified spontaneous emission (ASE) suppression using our presented PCF is applied to a mode-locked laser cavity and is demonstrated to be a simple and compact solution to widely tunable all-fiber lasers.


Targeting proteostasis network in osteoporosis: Pathological mechanisms and therapeutic implications.
As the most common bone disease, osteoporosis (OP) increases bone fragility and makes patients more vulnerable to the threat of osteoporotic fractures. With the ageing population in today's society, OP has become a huge and growing public health problem. Unfortunately, the clear pathogenesis of OP is still under exploration, and effective interventions are still scarce. Therefore, exploring new targets for pharmacological interventions to develop promising therapeutic drugs for OP is of great clinical value. Previous studies have shown that normal bone remodeling depends on proteostasis, whereas loss of proteostasis during ageing leads to the dysfunctional proteostasis network (PN) that fails to maintain bone homeostasis. Nevertheless, only a few studies have revealed the pathophysiological relationship between bone metabolism and a single component of PN, yet the role of PN as a whole in the pathogenesis of OP is still under investigation. This review comprehensively summarized the role of PN in the pathogenesis of OP and further discussed the potential of PN as innovative drug targets for the therapy of OP.


How could aortic arginase activity enhancement be involved in DOCA-salt hypertension?
This study was to examine whether the increase in aortic arginase activity observed in DOCA-salt hypertensive rats is involved in the mechanism of physiological hypertension by participating to vessel hypertrophy and/or to the impairment of endothelium-dependent relaxation to acethylcholine. We measured polyamine content and relaxation-response to acethylcholine in aortic rings isolated from control and DOCA-salt treated Sprague-Dawley rats after in vitro modification of arginase activity. Polyamine content was significantly increased in aorta from DOCA-salt hypertensive rats compared with controls. In the normotensive rats, the addition of L-valine (an inhibitor of arginase) decreased the relaxation response to acethylcholine whereas the addition of arginase increased the relaxation dependent response. On the contrary, in DOCA-salt hypertensive rats, the addition of L-valine or of arginase did not change the endothelium dependent relaxation. The results obtained suggest that the increase in aortic arginase activity in DOCA-salt hypertension could contribute to vascular hypertrophy but not to the impairment of endothelium-dependent relaxation.


Thermal conditions for successful breeding in Great Tits (Parus major L.) : II. Thermal properties of nests and nesthoxes and their implications for the range of temperature tolerance of Great Tit broods.
A model is described in which the thermal properties of nests and nestboxes are integrated with allometric equations describing the metabolic properties of Great Tit broods. These allometric equations were presented and discussed in the preceding paper.The effect of changing certain dimensions of the nest and the nestbox and the size of the brood is discussed in relation to the over-all conductance of the whole system and the influence of these factors on the range of temperature tolerance of Great Tit broods. It seems likely that the over-all conductance of the nest and nestbox system, and consequently the rate of heat loss of the brood, are roughly proportional to the 2/3 power of the brood weight. This is explained by the fact that the value of the over-all conductance is mainly determined by the heat transport due to radiation and convection from the upper surface of the brood. The fact that Great Tits build their nests mainly of moss is discussed in relation to special properties of this nest material by which the upper limit of the range of temperature tolerance can rise under conditions of heat stress.


Extratubular Tamm-Horsfall protein deposits induced by ureteral obstruction in mice.
The effects of unilateral ureteral obstruction were studied in mice. Obstruction for 24 hr led to the formation of extratubular Tamm-Horsfall protein (TH) aggregates within the renal interstitium and at the base of distal convoluted tubular (DCT) cells. These DCT deposits were shown by ultrastructural analysis to be entirely extracellular. They had the fibrillar substructure characteristic of TH and had not been seen after urinary obstruction in other species. As a consequence of retrograde flow of urine to glomeruli, obstruction also caused TH aggregates to form within Bowman's spaces. These glomerular casts of TH were detected throughout the 3-week period of study after the release of unilateral obstruction. High serum titers of IgG antibodies to TH developed in mice intradermally immunized with TH but were not observed after obstruction alone. Circulating anti-TH antibodies combined with TH present on the basal surfaces of the thick ascending limb of the loop of Henle cells and DCT cells to form immune complexes in situ. Interstitial inflammation in the areas surrounding subepithelial tubular immune deposits was not present in the kidneys of immunized mice and was not selectively induced by temporary obstruction. However, foci of inflammation were seen in all obstructed kidneys. At later times, inflammatory foci in previously obstructed kidneys were associated with progressive scarring, primarily in polar regions. The location and severity of these changes within kidneys produced by obstruction in immunized mice did not differ from those in unimmunized mice. The titers of anti-TH antibodies in immunized mice were not enhanced or depressed as a consequence of unilateral ureteral obstruction. These studies demonstrate that complete obstruction of urinary flow in the mouse for periods as short as 24 hr may lead to progressive segmental renal scarring. These studies further indicate that increasing the quantities of extracellular TH by obstruction does not facilitate inflammatory responses to TH immune complexes formed in situ. While exposure of renal tissue to highly toxic components of extravasated urine may play a crucial role in inflammatory responses, autoimmunity to TH was not implicated as a contributing factor by the present studies in mice.


Genetic polymorphisms in phase II metabolizing enzymes in alcoholic and idiopathic chronic pancreatitis: Indian scenario.
To study polymorphisms in glutathione-S-transferases (GST-T1, GST-M1, GST-P1) and uridine-5'-diphosphate-glucuronosyl-transferases (UGT1A7) genes and the risk of developing chronic pancreatitis (CP) associated with these polymorphisms. This study included 49 alcoholic and 51 idiopathic chronic pancreatitis patients, 50 alcohol addicts and 50 healthy controls. Polymorphism(s) in GST-T1 and GST-M1 genes were assessed by multiplex polymerase chain reaction (PCR), while PCR-radiofrequency lesioning (RFLP) was employed to assess the same in GST-P1 and UGT1A7 genes. The differences in polymorphism frequency between groups and the risk of developing pancreatitis were assessed by the odds ratio. Strong association of the null genotype of GST-T1 with CP susceptibility was observed. Alcoholics with the Val allele of GST-P1 have higher chances of having pancreatitis. Idiopathic pancreatitis patients with higher age at the onset of pain were found to have the null genotype of GST-M1. Alcoholics with the null genotype of the GST-T1 gene and the Valine allele of the GST-P1 gene are at a higher risk of developing CP. Thus, genotyping of these genes may serve as an important screening tool for the identification of high-risk groups among alcoholics.


Prevention of distal embolization following the treatment of late stent occlusion.
We report the use of the AngioGard system in the treatment of acute, late in-stent occlusion of the circumflex coronary artery. This case shows that late stent occlusion can in part be due to in-stent thrombosis and the use of an embolization protection device should be considered in this context.


[Does PSA of less than 20 ng/ml exclude the diagnosis of metastatic prostate cancer?].
To demonstrate the considerable risk of bone metastases from clinically localized prostatic cancer with PSA greater than 20 ng/ml. Patients presenting an indication for radical prostatectomy (younger than 70, with localized prostate cancer, less than 6 out of 9 positive biopsies) and PSA less than 20 ng/ml (Tandem) were selected for this intent-to-treat study. Seven of the 210 patients corresponding to the selection criteria presented with bone metastases and 4 of them had a PSA less than 10 ng/ml. None had lymph node metastases. The risk of bone metastases despite PSA less than 20 ng/ml is therefore not negligible. In our opinion, it is necessary therefore to continue to include bone scan in the staging assessment of clinically localized prostate cancer.


[Effects of transcorneal electrical stimulation in patients with Stargardt's disease].
Stargardt's disease is an autosomal recessive inherited juvenile macular degeneration and at present no acknowledged science-based therapy is available for these patients. Recently, reports have been published on the effectiveness of electrical stimulation in experimental animal models and in patients with neurodegenerative ocular disease, particularly retinitis pigmentosa. This study included 12 patients with Stargardt's disease who were randomized into one of three groups (n = 4) with 0% (sham), 66% or 150% of the individual electrically stimulated phosphene threshold. Outcome measures of the study were safety and efficacy of transcorneal electrical stimulation (TES) with DTL electrodes in subjective and objective parameters of visual function under therapy. In general TES was well tolerated and no adverse or serious events were noted. Neither Ganzfeld, multifocal ERG, OCT nor visual field testing showed statistically significant changes in any group.


Computed tomography after severe COVID-19 pneumonia: findings at 6 months and beyond.
Parenchymal bands and ground-glass opacities consistent with a pattern of late organising pneumonia are frequently observed 6 months after ICU admission for #COVID19, whereas fibrotic changes of limited extent are only observed in about 1/3 of patients https://bit.ly/2UGOsbr.


Microhabitat identity of two species of sheet-web spiders: field experimental demonstration.
Descriptive studies reveal that web-site characteristics of two sympatric species of sheet-web spiders, Linyphia triangularis and L. tenuipalpis are similar, even though their body sizes and web sizes are significantly different. The hypothesis of identical web-sites were tested by a species exchange experiment in the field. Here the residence times of adult females of each species released in webs of the other species were compared to the residence times of other females released in own species' webs. As there was no differences between the species-exchange series and the control series, the experimental results supported the conclusions of the descriptive studies. The utility of testing habitat parameter differences experimentally, and the significance of the results to the ecology of the species, in particular to their interspecific interactions, are discussed.


Adverse childhood experiences exacerbate the association between day-to-day discrimination and mental health symptomatology in undergraduate students.
Adverse childhood experiences (ACEs) and day-to-day discrimination (hereafter, "discrimination") both contribute to mental health symptomatology in young adulthood, but how these constructs interact and whether they are associated with mental health remains unclear. This study evaluated whether the relation between discrimination in young adulthood and mental health symptomatology varied as a function of ACEs exposure. Undergraduates (n = 251) completed self-report measures related to ACEs, discrimination, and mental health symptomatology (i.e., depression, anxiety, somatization, and psychological distress). Linear and logistic regression models were implemented to test for potential exacerbation effects of ACEs on the relation between discrimination and mental health symptomatology. Participants with greater discrimination exposure and ACEs reported significantly more depression, anxiety, and somatic symptoms, along with more psychological distress, relative to those with less discrimination exposure and few or no ACEs. Data were cross-sectional, thus, causality cannot be inferred. ACEs and discrimination measures examined ACE counts and general discrimination, respectively, which did not allow for examination of possible differences across specific ACEs (e.g., childhood sexual abuse vs. neglect) or specific types of discrimination (e.g., sexual-orientation-based discrimination vs. race-based discrimination). These results are among the first to inform the conceptualization of ACEs and discrimination in etiological models of young adults' mental health. Both ACEs and discrimination, rather than exposure to only one of these stressors, may be synergistically associated with young adults' mental health symptomatology. Clinicians could address stress-sensitive mental health issues by assessing for both ACEs and discrimination exposure.


Induction of teratocarcinoma cell differentiation. Effect of the inhibitors of DNA synthesis.
Induction of teratocarcinoma cell (F9) differentiation was studied by using inhibitors of DNA synthesis and several agents known to be differentiation inducers. Inhibition of DNA synthesis induced changes in cell surface marker F9 and stimulated the production of plasminogen activator (PA) in a manner that is dependent upon de novo synthesis of RNA and protein. The results thus indicate close association between inhibition of DNA synthesis and induction of cell differentiation. This approach will be useful in investigating the mechanism of teratocarcinoma cell differentiation.


Plasma connective tissue growth factor is a novel potential biomarker of cardiac dysfunction in patients with chronic heart failure.
Connective tissue growth factor (CTGF) has been recently reported as a mediator of myocardial fibrosis; however, the significance of plasma CTGF concentration has not been evaluated in patients with heart failure. The aim of this study was to investigate the clinical utility of plasma CTGF concentration for the diagnosis of heart failure. We evaluated fifty-two patients with chronic heart failure. The plasma concentration of CTGF and other markers of fibrosis were assessed and compared with clinical and echocardiographic data. Plasma CTGF was significantly elevated in symptomatic patients in proportion to their NYHA classes and was significantly correlated with plasma brain natriuretic peptide (BNP) concentration (r=0.395, P<0.01). Plasma CTGF was also correlated with plasma transforming growth factor beta (TGF-beta) (r=0.512, P<0.01), matrix metalloproteinase (MMP)-2 (r=0.391, P<0.05) and tissue inhibitor of MMP (TIMP)-2 (r=0.354, P<0.05) concentrations. Interestingly, plasma CTGF was correlated with E/E' value evaluated by tissue Doppler echocardiography (r=0.593, P=0.012), but not with systolic function and left ventricular mass. Our study suggests that plasma CTGF concentration is a novel diagnostic marker for cardiac dysfunction and may provide additional specific information about myocardial fibrosis in chronic heart failure patients.


Long-term complications associated with permanent dermal fillers.
We report a case series of patients with serious long-term complications associated with the injection of permanent dermal fillers. Although such complications are relatively rare, the consequences are potentially life-long, and the psychological and medical effects can often have a profound impact on the patient. The continued routine offering of these treatments will require doctors to communicate effectively with patients about the nature of the complications and the probability of risk compared with alternative treatments.


Difficulties experienced by nurses in older patient care and their attitudes toward the older patients.
There is little known about nurses' attitudes toward older people in Turkish society, particularly within centers providing care to older patients. This research was conducted to determine nurses' attitudes toward older patient care and the difficulties they experience. A descriptive research design was used. The research population comprised 282 nurses working in the clinics of public hospitals in central Erzurum that mostly accommodate older patients. Participants completed questionnaires regarding descriptive characteristics, the type of difficulties they experienced in older patient care, and the Turkish version of Kogan's Attitudes Toward Old People Scale. Data were evaluated by using percentage, Kruskal-Wallis variance analysis, t test and Mann-Whitney U test. The study revealed that nurses experienced difficulties due to the inadequacy of physical conditions and technical equipment in hospitals; administrative problems; communication problems; and insufficient knowledge, skills and experience in older patient care. The nurses' overall attitude toward the older people was found to be positive (98.83 ± 11.19). The difficulties experienced by nurses in this sample resulted from the lack of technically equipped hospitals or clinics for older patients and the inadequacy of nurses' gerontology education. Despite these factors, the nurses' attitude toward older people was positive.


Sex-Based Differences in Unrecognized Myocardial Infarction.
Background Myocardial infarction is an important cause of morbidity and mortality in both men and women. Atypical or the absence of symptoms, more prevalent among women, may contribute to unrecognized myocardial infarctions and missed opportunities for preventive therapies. The aim of this research is to investigate sex-based differences of undiagnosed myocardial infarction in the general population. Methods and Results In the Lifelines Cohort Study, all individuals ≥18 years with a normal baseline ECG were followed from baseline visit till first follow-up visit (≈5 years, n=97 203). Individuals with infarct-related changes between baseline and follow-up ECGs were identified. The age- and sex-specific incidence rates were calculated and sex-specific cardiac symptoms and predictors of unrecognized myocardial infarction were determined. Follow-up ECG was available after a median of 3.8 (25th and 75th percentile: 3.0-4.6) years. During follow-up, 198 women experienced myocardial infarction (incidence rate 1.92 per 1000 persons-years) compared with 365 men (incidence rate 3.30; P<0.001 versus women). In 59 (30%) women, myocardial infarction was unrecognized compared with 60 (16%) men (P<0.001 versus women). Individuals with unrecognized myocardial infarction less often reported specific cardiac symptoms compared with individuals with recognized myocardial infarction. Predictors of unrecognized myocardial infarction were mainly hypertension, smoking, and higher blood glucose level. Conclusions A substantial proportion of myocardial infarctions are unrecognized, especially in women. Opportunities for secondary preventive therapies remain underutilized if myocardial infarction is unrecognized.


Efficient calculation of the principal components of imaging data.
Principal components analysis (PCA) of images is important in many applications such as positron emission tomography and functional magnetic resonance imaging. PCA is difficult for image data because the correlation matrix is very large. We present a direct method of calculating the PCA of the voxels from the small matrix expressing the correlations between images, instead of the larger matrix representing the correlations between voxels. The method is fast and accurate. It is faster and requires less memory than a singular value decomposition, although it is less accurate. It is much faster and more accurate than iterative and other approximate methods developed for this problem.


Genetic polymorphism of XRCC1 correlated with response to oxaliplatin-based chemotherapy in advanced colorectal cancer.
In this study, we investigated the association between genetic polymorphisms of XRCC1 Arg399Gln (G→A) and response to oxaliplatin-based chemotherapy in advanced colorectal cancer. XRCC1 genotypes of totally 99 patients (37 stage III and 62 stage IV) with advanced colorectal cancer treated with oxaliplatin-based chemotherapy were detected by the TaqMan-MGB probe allelic discrimination method, and clinical response of 62 patients in stage IV after 2 to 3 cycles of chemotherapy were evaluated. Also, time to progression (TTP) of all patients was evaluated. The results showed that of the genotype frequencies in all patients, up to 52.53% were G/G genotype, 9.09% were A/A genotype, and 38.38% were G/A genotype. The response rate (CR + PR) of 62 patients in stage IV was 61.29% (19/31). Patients with G/G genotype showed enhanced response to chemotherapy compared with those with G/A + A/A (x(2) = 5.6, p = .029; Odds Ratio (OR) = 3.845, 95% Confidence Interval (CI) = 1.231 ∼ 12.01, p = .018). Individuals with the G/G genotype had a TTP of 10.0 (8.88-11.12) months, and those with the G/A + A/A genotype had a TTP of 5.0 (4.26-5.74) months. The Log-Rank test was marginally significant (x(2) = 29.20, p < .01). The Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen showed that only XRCC1 G/G genotype increases the OR significantly (OR = 3.555; 95% CI, 2.119 ∼ 5.963; p < .01). These results indicate that XRCC1 Arg399Gln polymorphism is associated with response to oxaliplantin-based chemotherapy and TTP in advanced colorectal cancer in Chinese population. It is proposed that the XRCC1 Arg399Gln polymorphism should be routinely detected to screen patients who are more likely to benefit from oxaliplantin-based treatment.


Effect of different stunning methods on rigor mortis, shape, energetic status and physical characteristics of Salmo carpio fillets.
Consumer interest in safeguarding animal welfare and increased demand for fresh aquatic products support the need to understand the effects of stunning methods used in aquaculture on the biochemical process affecting fish fillet quality. The present paper aimed at comparing electrical stunning (ES) and cold shock (ICE) in Salmo carpio, an Italian endemic under-investigated species. Rigor mortis evolution, fillet adenosine 5'-triphosphate (ATP), shape, colour, pH and water holding capacity were assessed by integrating chemical and image analyses. Seventy-two fish (24 fish per treatment) were stunned by ES, ICE or anaesthesia (AN, used as control), then percussively slaughtered. ES and ICE hastened rigor mortis onset and resolution (21 and 28 h post mortem) compared to AN. This was confirmed by the faster ATP degradation in ES and ICE. Fillet shape features varied during rigor mortis, according to the stunning method, with the perimeter showing irreversible variation in ES and ICE groups. Initial circularity was recovered only in AN, while ICE and ES fillets showed significantly different values, between 0 and 192 h. ES is a promising stunning technique for S. carpio, but parameters should be optimized, because of the adverse effect on muscle activity which caused a fast pH drop, and the presence of blood spots in the fillets. Further studies are needed to understand whether fillet shape changes can interfere with filleting or fillet processing and consumer appreciation. © 2022 Society of Chemical Industry.


Colonic epithelial response to injury requires Myd88 signaling in myeloid cells.
Proper colonic injury response requires myeloid-derived cells and Toll-like receptor/Myd88 signaling. However, the precise role of Myd88 signaling specifically in myeloid-derived cells that occurs during tissue damage is unclear. Therefore, we created a mouse line with Myd88 expression restricted to myeloid lineages (Myd88(-/-); LysM(Cre/+); ROSA26(Myd88/+); herein Mlcr). In these mice, Myd88 was appropriately expressed and mediated responses to bacterial ligand exposure in targeted cells. Importantly, the severe colonic epithelial phenotype observed in dextran sodium sulfate-injured Myd88(-/-) mice was rescued by the genetic modification of Mlcr mice. During injury, myeloid cell activation and enrichment of Ptsg2-expressing stromal cells occurred within the mesenchyme that surrounded the crypt bases of Mlcr and Myd88(+/-) mice but not Myd88(-/-) mice. Interestingly, these cellular changes to the crypt base mesenchyme also occurred, but to a lesser extent in uninjured Mlcr mice. These results show that Myd88 expression in myeloid cells was sufficient to rescue intestinal injury responses, and surprisingly, these cells appear to require an additional Myd88-dependent signal from a non-myeloid cell type during homeostasis.


Socioeconomic Position is Positively Associated with Monoclonal Gammopathy of Undetermined Significance in a Population-based Cohort Study.
Knowledge of social inequalities in monoclonal gammopathy of undetermined significance (MGUS) will contribute to understanding multiple myeloma (MM) etiology, as MGUS consistently precedes MM. The aim of the present study was to examine whether socioeconomic position (SEP) is associated with MGUS in a population-based cohort including information on potential MGUS risk factors. Overall, 4787 study participants aged 45-75 years with information on MGUS were included. SEP indicators (education, income) and potential risk factors (i.e., body mass index, diabetes, smoking, dietary factors) were assessed at baseline. Overall, 260 MGUS cases were detected at baseline and prospectively over a 10-year follow-up. In age-adjusted logistic regression models, a lower chance of having MGUS at baseline or developing MGUS during 10 years of follow-up was indicated for groups of low SEP with odds ratios (OR) of 0.39 (95% confidence interval [95%-CI] 0.19-0.76) for women and 0.48 (95% CI 0.10-1.16) for men in the lowest compared to the highest educational group. After additionally including potential mediating risk factors in the regression models, the estimated ORs changed only slightly in magnitude. Similar results were obtained for income. Current smoking and low fruit consumption were associated with MGUS independently of SEP in women, but not in men. The present study indicates a lower MGUS risk in lower SEP groups. Supporting evidence is given that smoking and diet play a role in the development of MGUS independently of SEP, while it has to be assumed that risk factors unknown to date are responsible for the observed social inequalities in MGUS.


High consistency cellulase treatment of hardwood prehydrolysis kraft based dissolving pulp.
For enzymatic treatment of dissolving pulp, there is a need to improve the process to facilitate its commercialization. For this purpose, the high consistency cellulase treatment was conducted based on the hypothesis that a high cellulose concentration would favor the interactions of cellulase and cellulose, thus improves the cellulase efficiency while decreasing the water usage. The results showed that compared with a low consistency of 3%, the high consistency of 20% led to 24% increases of cellulase adsorption ratio. As a result, the viscosity decrease and Fock reactivity increase at consistency of 20% were enhanced from 510 mL/g and 70.3% to 471 mL/g and 77.6%, respectively, compared with low consistency of 3% at 24h. The results on other properties such as alpha cellulose, alkali solubility and molecular weight distribution also supported the conclusion that a high consistency of cellulase treatment was more effective than a low pulp consistency process.