Live transgenic reporters of the vertebrate embryo's Segmentation Clock.
Imaging rapidly changing gene expression during embryogenesis is a challenge for the development of probes and imaging techniques. The vertebrate Segmentation Clock is a genetic network that controls the subdivision of the elongating embryonic body axis into somites, the precursors of adult segmented structures, such as vertebrae. Because of its rapid oscillations, direct observation of gene expression in this system has proven difficult, and so is a benchmark for transgene design and imaging in vivo. Transgenic approaches using destabilized reporter cassettes in the mouse embryo have provided the first glimpses of this dynamic expression system. Nevertheless, improvements in temporal and spatial resolution, paired with the ability to make precise quantifications, will be necessary to connect observations and theory.


Gender Differences in Recommended Treatment Decisions among Breast Cancer Patients: A Study Using the National Cancer Database.
Previous studies have explored surgery refusal among female breast cancer patients. However, little attention has been given to other therapies in both females and males. The goal of this study was to determine the potential role of gender on recommended hormone therapy, chemotherapy, radiation therapy, and surgery refusal and to describe other determinants of refusal. A retrospective study of the National Cancer Database (NCDB) between 2004 and 2016 was conducted. The outcome was whether patients accepted or refused the recommended treatment. We examined four different outcome variables (hormone therapy, chemotherapy, radiation therapy, and surgery) relation to gender and other factors. A total of 906,342 breast cancer patients met the eligibility criteria for hormone therapy, 1,228,132 for surgery, 596,229 for chemotherapy, and 858,050 for radiation therapy. The odds of refusing hormone therapy and surgery in males were 17% (AOR = 0.83; 95% CI: 0.75-0.92) and 33% (AOR=0.67; 95% CI: 0.50-0.90) lower compared to female patients, respectively. The odds of refusing radiation therapy were 14% higher in males compared to females (AOR=1.14; 95% CI:1.03-1.30). Older age and lack of insurance were significantly associated with each treatment refusal. Female patients tend to refuse hormone therapy and surgery compared to males. A marginally statistically significant gender differences was found for radiotherapy refusal. The providers and other stakeholders can utilize the current findings to identify the risk groups and barriers associated with refusal for each treatment and to develop interventions.


Kinetics and molecular docking studies of pimarane-type diterpenes as protein tyrosine phosphatase (PTP1B) inhibitors from Aralia continentalis roots.
Since insulin sensitivity to cells is attributed to phosphorylation of the insulin receptor (IR), protein tyrosine phosphatase 1B (PTP1B), which dephosphorylates the tyrosine residues of IR proteins, is primarily responsible for insulin resistance in type 2 diabetes. Therefore, PTP1B inhibitors ameliorating the insulin-dependent signaling pathway are potential therapeutic candidates for the treatment and prevention of diabetes. As part of our continuous search for diterpenes derived from Aralia continentalis as potent PTP1B inhibitors, five active diterpenoids, including ent-pimara-8(14),15-diene-19-oic acid (1); 7-oxo-ent-pimara-8(14),15-diene-19-oic acid (2); 7β-hydroxy-ent-pimara-8(14),15-diene-19-oic acid (3); ent-pimara-8(14),15-diene-19-ol (4); 8α-hydroxy-ent-pimara-15-en-19-ol (5); and ent-kaur-16-en-19-oic-acid (6) were investigated using the enzyme kinetic assay. With the exception of 1 showing mixed inhibition, compounds 2 and 4-6 exhibited noncompetitive inhibition against PTP1B with K i values ranging 3.29-12.86 μM. In particular, 2 with an oxo group in the C-7 position showed increased PTP1B inhibition compared to nonsubstituted 1. Based on the structure and activity relationship, the 3D docking simulations of 1, 2, and 3 were also performed. Compounds 1-3 showed negative binding energies of -5.3 to -6.1 kcal/mol and a high affinity to PTP1B residues (Phe182 and Asp181 in the WPD loop; Cys215 in the active sites; Tyr46, Arg47, Asp48, Val49, Ser216, Ala217, Gly218, Ile219, Gly220, Arg221, Gln262, and Gln266 in the pocket site), indicating that they may stabilize the open form and generate tighter binding to the catalytic sites of PTP1B. The enzymatic kinetics and docking results clearly indicate the promising potential of pimarane-type diterpenes as PTP1B inhibitors.


The kinetic properties and sensitivity to pyruvate inhibition of tissue lactate dehydrogenase in diving and nondiving reptiles.
The kinetic properties and susceptibility to pyruvate inhibition of lactate dehydrogenase (LDH) were examined in three tissues of the freshwater turtle, Pseudemys scripta, and two snake species, Elaphe obsoleta and Nerodia rhombifera. Brain and heart LDH activity of the snakes surpassed that of Pseudemys at pyruvate concentrations between 0.03 and 0.50 mM. The snakes also had lower apparent Km and higher Vmax values than Pseudemys. Liver LDH activity, apparent Km, and Vmax were highest in Elaphe, and there were no differences between Km or Vmax values of Nerodia and Pseudemys. In each tissue, snake LDH was less susceptible to pyruvate inhibition than was Pseudemys LDH. The results indicate that Pseudemys LDH is no better adapted to withstand anaerobic conditions than is that of Nerodia or Elaphe.


'Don't stop believing': The role of training beliefs in cognitive bias modification paradigms.
Cognitive Bias Modification (CBM) paradigms have previously been applied to target appetite (craving, hunger) and food intake, and are hypothesised to reduce unhealthy food consumption. However, inconsistencies in relation to training outcomes raise questions regarding the efficacy of CBM as a standalone intervention. Furthermore, individual level factors (such as belief in the intervention efficacy) may influence expectations of behaviour change following training. Across two pre-registered studies, our aim was to investigate how directly manipulating beliefs in relation to training purpose and effectiveness influenced food value and choice across two popular CBM paradigms (Inhibitory Control Training (ICT: Study 1) and Evaluative Conditioning (EC: Study 2)). In online studies, participants were presented with a paragraph describing the CBM technique positively (or an unrelated control message) prior to completing either active or control CBM training. Across both studies, the results revealed that active CBM training resulted in a reduction to unhealthy food value (relative to pre-training), but only when paired with a positive manipulation message. Participants who received a control message displayed no significant changes to food value, even where active CBM training was provided. These results suggest that participant beliefs and expectancies have important consequences for CBM effectiveness. Future research should further investigate these factors within CBM contexts to identify their role within successful behaviour change interventions.


Surface morphology effects on clathrate hydrate wettability.
Clathrate hydrates preferentially form at interfaces; hence, wetting properties play an important role in their formation, growth, and agglomeration. Experimental evidence suggests that the hydrate preparation process can strongly affect contact angle measurements, leading to the different results reported in the literature. These differences hamper technological progress. We hypothesize that changes in hydrate surface morphologies are responsible for the wide variation of contact angles reported in the literature. Experimental testing of our hypothesis is problematic due to the preparation history of hydrates on their surface properties, and the difficulties in advanced surface characterization. Thus, we employ molecular dynamics simulations, which allow us to systematically change the interfacial features and the system composition. Implementing advanced algorithms, we quantify fundamental thermodynamic properties to validate our observations. We achieve excellent agreement with experimental observations for both atomically smooth and rough hydrate surfaces. Our results suggest that contact line pinning forces, enhanced by surface heterogeneity, are accountable for altering water contact angles, thus explaining the differences among reported experimental data. Our analysis and molecular level insights help interpret adhesion force measurements and yield a better understanding of the agglomeration between hydrate particles, providing a microscopic tool for advancing flow assurance applications.


A review of unplanned admissions in head and neck cancer patients undergoing oncological treatment.
Non-surgical treatment for head and neck cancer (HNC) often results in severe toxicities, which are detrimental to a patient's health and quality of life. There is limited published UK data on unplanned hospital admissions and reasons associated with admission. We aim to identify frequencies and reasons for unplanned hospital admissions, highlighting those patient groups who are most vulnerable. A retrospective study of unplanned hospital admissions of HNC patients receiving non-surgical treatment was completed. An inpatient admission was defined as ≥ 1 night spent in the hospital. To test potential demographic and treatment predictors of inpatient admission, a multiple regression model was constructed using the endpoint measure (unplanned admission), as the dependent variable. A cohort of 216 patients was identified over a 7-month period, and 38 of these patients (17%) required an unplanned admission. Treatment type was the only statistically significant predictor of in-patient admission. The majority of admissions were patients receiving chemoradiotherapy (CRT) (58%) with predominant reasons for admission being nausea and vomiting (25.5%) and decreased oral intake/dehydration (30%). Of the patients admitted, 12 had a prophylactic PEG placed pre-treatment, and 18 of 26 admitted without prophylactic PEG required nasogastric tube feeding during their admission. Almost one-fifth of HNC patients over this time period required hospital admission; the majority of which can be attributed to treatment toxicities when receiving CRT. This is concurrent with other studies which review the impact of radiotherapy versus CRT. Increased support and monitoring, particularly focused on nutrition, are required for patients with HNC who receive CRT. This article describes a retrospective review of a patient undergoing non-surgical treatment for head and neck cancer. These patients frequently require unplanned hospital admission. The results indicate that patients undergoing (chemo)radiotherapy are most vulnerable to deterioration and additional support focused on nutrition for these patients is indicated.


Medial unicompartmental knee arthroplasty: does tibial component position influence clinical outcomes and arthroplasty survival?
In several recent studies, unicompartmental knee arthroplasty (UKA) produced better functional outcomes than did total knee arthroplasty with 10-year prosthesis survival rates greater than 95%. Nevertheless, UKA is still widely viewed as producing inconsistent results. Tibial component loosening is the leading cause of failure. We consequently sought to identify tibial component position criteria associated with outcomes of medial UKA. We conducted a retrospective multicentre study of 559 medial UKAs performed between 1988 and 2010 in 421 patients (262 females and 159 males) with a mean age of 69.51±8.72 years at surgery. We recorded the following radiographic parameters: joint space height, obliquity and slope of the tibial implant, whether the tibial component was perpendicular to the femoral component, and lower limb malalignment. The International Knee Society (IKS) score was used to assess clinical outcomes. Mean follow-up at re-evaluation was 5.17±4.33 years. The mean 10-year prosthesis survival rate was 83.7±3.5%. Factors associated with decreased prosthesis survival were a greater than 2-mm change in joint space height, a greater than 3° change in tibial component obliquity, a slope value greater than 5° or a change in slope greater than 2°, and more than 6° of divergence between the tibial and femoral components. Residual mechanical varus of 5° or more was also associated with mechanical failure. The only factor associated with worse functional score values was joint space elevation by more than 2mm. The high level of accuracy required for optimal positioning of the tibial component during medial UKA indicates a need for considerable technical expertise and emphasises the conservative nature of the procedure. Optimal positioning is crucial to restore normal knee kinematics and to prevent implant wear and lesions to adjacent compartments. IV, retrospective study.


IL-37 mediates the antitumor activity in renal cell carcinoma.
Interleukin (IL)-37 is a natural suppressor of innate inflammatory and immune responses. IL-37 plays an important role in renal function and antitumor activity. The aim of this study was to investigate the role of IL-37 in renal cell carcinoma (Rcc). Serum IL-37 levels in 120 Rcc patients and 50 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). The Rcc cell lines A498 and Caki-1 were cultured with 0-100 ng/mL of recombinant human IL-37 protein (rhIL-37). Cancer cells were transfected with or without pcDNA3.1-IL-6 to alter IL-6 expression. Cell migration, proliferation, and apoptosis were tested by wound-healing assay, MTT, and flow cytometry, respectively. Levels of IL-6, pSTAT3 Y705, Bcl-2, cyclin D1, and HIF-1α were detected by qRT-PCR, ELISA, or western blot. Additionally, therapeutic effect of rhIL-37 was also confirmed in SCID mice. The expression of IL-37 was decreased in Rcc patients and was negatively correlated with tumor progression. In vitro, IL-37 markedly inhibited the migration and proliferation, and promoted apoptosis in Rcc cells. Furthermore, the expressions of IL-6, pSTAT3 Y705, HIF-1α, Bcl-2, and cyclin D1 were decreased by IL-37. However, these effects were reversed by the transfection of pcDNA3.1-IL-6. In vivo, tumor growth and gene expressions of IL-6 and HIF-1α were suppressed by IL-37. In conclusion, IL-37 might serve as a novel tumor suppressor in Rcc and exert its antitumor activity through inhibiting IL-6/STAT3 signaling.


Free and total 3-methoxy-4-hydroxyphenylethylene glycol in human cerebrospinal fluid: relationship to blood pressure in hypertensives and patients with neuropsychiatric disease.
The concentrations of free and total 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) in the cerebrospinal fluid of 43 patients were measured by selected ion monitoring gas chromatography-mass spectrometry using MHPG specifically labelled with deuterium as internal standard. Unpaired Wilcoxon comparisons of free and total MHPG concentrations in males and females showed no significant difference between the sexes. The relationships between free, conjugated and total MHPG concentrations and age, blood pressure, glucose and protein levels in cerebrospinal fluid were examined by linear regression analysis. The only significant correlations found were between free MHPG and glucose and between total MHPG and glucose.


Expression and evolutionary features of the hexokinase gene family in Arabidopsis.
Arabidopsis hexokinase1 (HXK1) is a moonlighting protein that has separable functions in glucose signaling and in glucose metabolism. In this study, we have characterized expression features and glucose phosphorylation activities of the six HXK gene family members in Arabidopsis thaliana. Three of the genes encode catalytically active proteins, including a stromal-localized HXK3 protein that is expressed mostly in sink organs. We also show that three of the genes encode hexokinase-like (HKL) proteins, which are about 50% identical to AtHXK1, but do not phosphorylate glucose or fructose. Expression studies indicate that both HKL1 and HKL2 transcripts occur in most, if not all, plant tissues and that both proteins are targeted within cells to mitochondria. The HKL1 and HKL2 proteins have 6-10 amino acid insertions/deletions (indels) at the adenosine binding domain. In contrast, HKL3 transcript was detected only in flowers, the protein lacks the noted indels, and the protein has many other amino acid changes that might compromise its ability even to bind glucose or ATP. Activity measurements of HXKs modified by site-directed mutagenesis suggest that the lack of catalytic activities in the HKL proteins might be attributed to any of numerous existing changes. Sliding windows analyses of coding sequences in A. thaliana and A. lyrata ssp. lyrata revealed a differential accumulation of nonsynonymous changes within exon 8 of both HKL1 and HXK3 orthologs. We further discuss the possibility that the non-catalytic HKL proteins have regulatory functions instead of catalytic functions.


Effect of hemoperfusion with polymyxin B-immobilized fiber on plasma endothelin-1 and endothelin-1 mRNA in monocytes from patients with sepsis.
Hemoperfusion using polymyxin B-immobilized fiber (PMX-F) is reported to be an effective treatment for sepsis. The aim of the present study is to assess whether plasma endothelin-1 (ET-1) and ET-1 messenger RNA (mRNA) levels in peripheral-blood monocytes are altered in patients with sepsis and whether PMX-F treatment affects plasma ET-1 and monocyte ET-1 mRNA levels. Sixteen patients with sepsis and 20 healthy volunteers were included in this study. Plasma ET-1 concentration was measured by radioimmunoassay (RIA), and plasma levels of transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured by enzyme-linked immunosorbent assay (ELISA). Sixteen patients with sepsis were treated with direct hemoperfusion using PMX-F columns. Blood endotoxin levels decreased significantly from 35 to 10 pg/mL after two treatments of direct hemoperfusion, each for 2 hours. Patients with sepsis showed significantly increased levels of plasma ET-1 (P < 0.001) and monocyte ET-1 mRNA (P < 0.001) compared with healthy volunteers. However, no differences in plasma levels of TGF-beta, TNF-alpha, and IL-1beta existed between patients with sepsis and healthy volunteers. Increased plasma ET-1 levels and monocyte ET-1 mRNA levels in patients with sepsis decreased significantly after PMX-F treatment (P < 0.01). These data suggest that the secretion of ET-1 from peripheral-blood monocytes may be stimulated by endotoxin, and PMX-F treatment may be effective in reducing ET-1 secretion in patients with sepsis.


Evolution of the sex-determining gene in the teleostean genus Oryzias.
In the genetic sex determination of vertebrates, the gonadal sex depends on the combination of sex chromosomes that a zygote possesses. Despite the discovery of the sex-determining gene (SRY/Sry) in mammals in 1990s, the sex-determining gene in non-mammalian vertebrates remained an enigma for over a decade. In most mammals, the male-inducing master sex-determining gene is located on the Y chromosome and is therefore absent from XX females. A second sex-determining gene, Dmy, was described in the Oryzias latipes in 2002 and has a DNA-binding motif that is different from the motif in the mammalian sex-determining gene SRY or Sry. Dmy is also located on the Y chromosome and is therefore absent in XX females. Seven other sex-determining genes, including candidate genes, are now known in birds, a frog species, and 5 fish species. These findings over the past twenty years have increased our knowledge of sex-determining genes and sex chromosomes among vertebrates. Here, we review recent advances in our understanding of sex-determining genes and genetic sex determination systems in fish, especially those of the Oryzias species, which are described in detail. The facts suggest some patterns of how new sex-determining genes emerged and evolved. We believe that these facts are common not only in Oryzias but also in other fish species. This knowledge will help to elucidate the conserved mechanisms from which various sex-determining mechanisms have evolved.


Characterization of the promoter region of the human insulin receptor gene. Evidence for promoter activity.
Recombinant clones containing the promoter region of the human insulin receptor gene were isolated from genomic libraries derived from nondiabetic persons. A 1.5-kilobase pair fragment of the 5'-flanking region was sequenced. One transcriptional start site, located at 203 bases upstream from the start of translation was identified by nuclease S1 mapping and the primer extension experiment using the human insulin receptor mRNA. The bacterial chloramphenicol acetyltransferase assay revealed that a 573-base pair fragment immediately preceding the ATG has promoter activity and that the transcript initiates from the normal start site of the insulin receptor gene in the COS cells. The promoter region contains neither a "TATA box" nor a "CAAT box," has an extremely high G + C content, and contains seven central components of potential Sp 1 binding sites (GGGCGG or CCGCCC). These features are common to those found in the regulatory regions of a class of constitutively expressed "housekeeping" genes. A comparison between the promoter sequence of the human insulin receptor and those of other "housekeeping" genes revealed the presence of homologous sequences among these genes, in addition to the potential Sp 1 binding sites.


Quantitative analysis of a novel glucosylated phospholipid by liquid chromatography-mass spectrometry.
Building upon the demonstrated presence of a new glyceroglycolipid, phosphatidylglucoside (PtdGlc), in rat embryonic brain tissues, we have developed a method to identify minute amounts of PtdGlc in cultured cells by using nano-flow high-performance liquid chromatography and negative-ion-mode electrospray linear-ion trap time-of-flight mass spectrometry (LC-MS). A normal-phase silica gel-based column enabled us to separate PtdGlc from other lipid classes. PtdGlc was identified from its tandem mass spectrometry spectrum and from its retention time in the column. Using an internal standard collection and LC-MS, we obtained the linearity of PtdGlc at a range of 6.3-800 fmol per injection. We applied this method to analyze quantitative changes in PtdGlc in C6 glioma cells after cellular differentiation into GFAP-positive glial cells. PtdGlc in C6 glioma cells consisted exclusively of C18:0/C20:0 fatty acyl chains. Differentiation induced by the addition of anti-PtdGlc antibody plus cAMP in culture medium significantly increased the glycolipid content.


Genetics of Vitiligo.
Vitiligo reflects simultaneous contributions of multiple genetic risk factors and environmental triggers. Genomewide association studies have discovered approximately 50 genetic loci contributing to vitiligo risk. At many vitiligo susceptibility loci, the relevant genes and DNA sequence variants are identified. Many encode proteins involved in immune regulation, several play roles in cellular apoptosis, and others regulate functions of melanocytes. Although many of the specific biologic mechanisms need elucidation, it is clear that vitiligo is an autoimmune disease involving a complex relationship between immune system programming and function, aspects of the melanocyte autoimmune target, and dysregulation of the immune response.


[Epidemiological and anatomopathological profile of breast cancer at the Ibn Rochd University Hospital, Casablanca].
The present study aims to determine the various epidemiological characteristics among newly diagnosed patients with breast cancer in Casablanca during 2018. During that period, 668 cases were collected, the average age was 51.6 years, the female was the most represented with 662 cases (99.1%) and men with 6 cases (0.9%), a sex ratio (M/F) of 0.009. The average age of menopause was 49.8 years and the average age of menarche was 13.5 years, 31.7% had a history of cancer (breast 14.1%, stomach and 9% liver 7%). The average diagnosis delay was 10 months, the thyroid disease was the most represented pathology, the left breast was diagnosed in 50.2% and the right breast in 44.7% and 1.3% in the bilateral location. The most common histological type was invasive ductal carcinoma (73.2%). The vascular and lymphatic invasion was observed in 42.2%, axillary nodes were affected in 71.1% of cases. The histological prognosis (SBR) revealed a predominance of grade II in 55.9% of cases. The Luminal B continues to be the most common phenotype (46%) followed by Triple Negative (15.3%) and Luminal A (14.2%) and HER2 (7.4%). The immediate prognosis is a cause for concern because of delayed diagnosis. It seems urgent to develop the health information policy and education.


Opioid and cannabinoid synergy in a mouse neuropathic pain model.
Clinical studies have reported that pan-cannabinoid receptor agonists may have efficacy in neuropathic pain states and that this might be enhanced by co-administration with opioids. While cannabinoid-opioid analgesic synergy has been demonstrated in animal models of acute pain, it has not been examined in neuropathic pain models. We examined the effect of combination treatment with cannabinoid and opioid receptor agonists on allodynia and side effects in a nerve injury-induced neuropathic pain model. C57BL/6 mice were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of morphine and the pan-cannabinoid receptor agonist, WIN55212, on allodynia and side effects were examined at 7-10 days post-CCI surgery. Isobolographic analysis was used to determine whether the effects of the combination were synergistic. The opioid agonist morphine reduced CCI-induced mechanical and cold allodynia and produced motor incoordination, in a dose-dependent manner. WIN55212 reduced CCI-induced allodynia and produced motor incoordination, catalepsy and sedation, in a dose-dependent manner, as we have observed previously. When administered together, WIN55212 and morphine reduced allodynia in a synergistic manner but had only an additive effect on motor incoordination. These findings indicate that administration of a combination of a non-selective opioid and cannabinoid receptor agonist synergistically reduces nerve injury-induced allodynia, while producing side effects in an additive manner. This suggests that this combination treatment has an improved anti-allodynic potency and therapeutic index in a neuropathic pain model.


Supernumerary B Chromosomes of Tetragonisca fiebrigi Share Repeat Content with Standard Chromosome Set of both T. fiebrigi and Tetragonisca angustula (Apidae: Meliponini).
The stingless bees Tetragonisca angustula and Tetragonisca fiebrigi are widely distributed in Brazil, and both are commonly known as "jataí." Our goal was to investigate the possible origin of the B chromosomes in T. fiebrigi, a cytotaxonomic trait that differentiates T. fiebrigi from T. angustula. We analyzed diploid chromosome number (2n), B chromosome incidence, patterns of constitutive heterochromatin, and in situ localization of different repetitive DNA probes in T. angustula and T. fiebrigi. Both species displayed 2n = 34, with similar karyotype structures. One to three B chromosomes were observed in T. fiebrigi only. Constitutive heterochromatin was distributed on one arm of all chromosomes in both species, and T. fiebrigi B chromosomes were mainly heterochromatic with one euchromatic extremity. The (GA)15 and (CAA)10 microsatellite probes marked the euchromatic arms of all chromosomes in both species without marking the B chromosomes. The 18S ribosomal DNA (rDNA) probe marked 10 chromosomes in T. angustula and 6 A chromosomes in T. fiebrigi with an additional marking on 1B in individuals with 3B. The Tan-Bsp68I repetitive DNA probe marked the heterochromatic portion of all T. fiebrigi A and B chromosomes. This probe also marked the heterochromatic portion of all T. angustula chromosomes; therefore, both alternative hypotheses to the B chromosome origin are possible: (i) from the A chromosome complement of T. fiebrigi (intraspecific origin); or (ii) a by-product of genome reshuffling following the hybridization between T. fiebrigi and T. angustula (interspecific origin).


Optimizing administration of bisphosphonates in women with postmenopausal osteoporosis.
Bisphosphonates have been approved in the US as oral medication for the treatment of osteoporosis for about 10 years. Efficacy data exists for fracture reduction for the commonly used oral bisphosphonates but not for intravenous formulations. Based on the mechanism of action that appears to allow for longer intervals between doses, it has been possible to extend the treatment choices from the original more demanding daily oral dose to an array of options including oral weekly and more recently monthly treatment (so-called cyclical therapy) and intravenous treatment with various administration regimens. The possibility of treatment with an annual (or less frequent) intravenous administration with zoledronic acid exists. Compliance, adverse effects, and efficacy vary with each administration regimen.


Mutational Screening of Androgen Receptor Gene in 8224 Men of Infertile Couples.
Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity. The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males. A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses. We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic. This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.


Enhancement of the pressor response to norepinephrine by angiotensin in the conscious rabbit.
The pressor interactions between angiotensin II and norepinephrine were investigated in conscious New Zealand white rabbits receiving a low sodium diet. Angiotensin II was administered continuously by intraperitoneal osmotic pumps in a subpressor dose so as to avoid the potentially confounding effects of experimentally-induced hypertension. Norepinephrine challenges were given as a series of graded intravenous boluses. During the 3 days of study the baseline blood pressure in the angiotensin-treated rabbits (n=10) did not differ from that in controls (n=10) whose intraperitoneal pumps contained only diluent. After 24 hours the systolic and diastolic blood pressure responses to norepinephrine in the angiotensin-treated group were, on average, 45% and 30% higher than in the controls; after 72 hours, they were 46% and 34% higher. Although the pressor amplitudes were increased by angiotensin II, they were not prolonged. Thus, facilitation by the subpressor angiotensin II of the blood pressure responses to norepinephrine did not seem dependent upon alterations in endogenous sympathetic mechanisms or the uptake of norepinephrine; nor could it be explained by sodium retention. It is possible that angiotensin II exhibits its effect by enhancing contractile responsiveness to norepinephrine at the postreceptor level.


Cervical conization: when is uterine dilatation and curettage also indicated?
Although the primary goal of cervical cone biopsy is treatment of cervical intraepithelial neoplasia, conization plus uterine dilatation and curettage is usually considered as a single, standard procedure. We reviewed 128 cone biopsies (114 of these procedures included dilatation and curettage) over a 3-year period to see whether dilatation and curettage was necessary as an accompaniment to conization. The mean age for all patients was 32.8 years, and 6.25% (eight patients) had a history of abnormal uterine bleeding. There was no evidence of endometrial abnormality in any of the 114 dilatation and curettage specimens. These findings suggest that dilatation and curettage is not warranted as a routine adjunct to cone biopsy. We believe more precise criteria for combining dilatation and curettage with conization are required, and these include: patients in the peri- or postmenopausal period, suspected intrauterine abnormalities, and the presence of abnormal glandular cells in a cytologic sample. With the use of these guidelines, only 18 patients (14%) would have required dilatation and curettage.


EDTA and ethylurethan specifically interferes with the formation of normalDictyostelium fruiting bodies without inhibiting the cellular differentiation into spores and stalk cells. Thus differentiation is largely independent from the normal culmination process.On the other hand a preferential inhibition of the differentiation has been observed with 2-mercaptoethanol, the spores being more sensitive than the stalk cells.


Canada-Denmark MRI scoring system of the spine in patients with axial spondyloarthritis: updated definitions, scoring rules and inter-reader reliability in a multiple reader setting.
To validate the Canada-Denmark (CANDEN) MRI scoring system for the spine in axial spondyloarthritis with updated lesion definitions. Lesion definitions in the CANDEN system were updated and illustrated by a consensus set of reference images. Sagittal spine MRIs of 40 patients with axial spondyloarthritis obtained at baseline and at week 52 after initiation of treatment with the tumour necrosis factor inhibitor golimumab were evaluated in unknown chronology by seven readers blinded to all other data. CANDEN MRI spine inflammation score had very good reliability for status scores (single-measure intraclass correlation coefficient (ICC) of 21 reader pairs median of 0.91 (IQR 0.88-0.92)) and change scores (ICC 0.88 (0.86-0.92)). CANDEN MRI spine fat score had good to very good reliability for status scores (ICC 0.79 (0.75-0.86)) and moderate to good reliability for detecting change (ICC 0.59 (0.46-0.73)). CANDEN MRI spine bone erosion score and CANDEN MRI spine new bone formation score had slight to moderate reliability for status scores (ICC 0.38 (0.32-0.52) and 0.39 (0.27-0.49), respectively). The CANDEN MRI spine scoring system allows a comprehensive evaluation of inflammation, fat, bone erosion and new bone formation of the spine in patients with axial spondyloarthritis. It demonstrated very good reliability for detecting change in inflammation, moderate to good reliability for detecting change in fat, and slight to moderate reliability for detecting bone erosions and new bone formation. Studies with longer follow-up or patients with more advanced spinal involvement may be needed to reliably detect change in bone erosion and new bone formation scores. NCT02011386.


Remimazolam versus propofol for procedural sedation: a meta-analysis of randomized controlled trials.
To improve patient tolerability and satisfaction as well as minimize complications, procedural sedation has been widely used. Propofol is the most widely used agent for induction of anesthesia and sedation by anesthesiologists. With a different mechanism compared to propofol, remimazolam is a new short-acting GABA-A receptor agonist. It is an ester-based benzodiazepine. This meta-analysis aims to clarify the efficacy and safety of remimazolam versus propofol for procedure sedation. Electronic databases were searched for randomized controlled trials (RCTs) comparing efficacy or safety of remimazolam versus propofol. Meta-analysis were conducted using RStudio with "metafor" package with random-effects model. A total of twelve RCTs were included in the meta-analysis. The pooled results demonstrated that patients with remimazolam for procedural sedation had lower risk of bradycardia (OR 0.28, 95% CI [0.14-0.57]), hypotension (OR 0.26, 95% CI [0.22-0.32]), and respiratory depression (OR 0.22, 95% CI [0.14-0.36]). There was no difference in the risk of developing postoperative nausea and vomiting (PONV) (OR 0.65, 95% CI [0.15-2.79]) and dizziness (OR 0.93, 95% CI [0.53-1.61]) between the remimazolam and propofol groups. Using remimazolam for procedural sedation is significantly associated with less injection pain compared to propofol (OR 0.06, 95% CI [0.03-0.13]). Regarding the sedation efficacy, there was no difference in sedation success rate or time to loss of consciousness, recover and discharge between the remimazolam and the propofol groups. Based on our meta-analysis, patients receiving procedural sedation with remimazolam had lower risk of bradycardia, hypotension, respiratory depression and injection pain compared with propofol. On the other hand, there was no difference in sedation success rate, risk of PONV, dizziness, time to LOC, recovery and discharge between these two sedatives. CRD42022362950.


Correlation of estrogen and androgen receptor status in prostatic disease measured by high pressure liquid chromatography.
To further characterize human prostatic estrogen receptors (ER) determined by high pressure liquid chromatography (HPLC), we checked our procedure by which we nullify estrogen binders (including testosterone binding globulin, TeBG) other than ER by preincubation of cytosols with dihydrotestosterone (DHT). We also showed that the ER exhibited ligand specificity and that ER is present in BPH nuclear extract at 10-fold its concentration in the corresponding cytosols. Of seven prostates with localized cancer determined preoperatively, only 3 showed localization; ER concentration in the cancer parts was lower than in the corresponding surrounding BPH. A total of 22 specimens were evaluated for ER and androgen receptors (AR). Statistically, AR had higher values than ER but there was no correlation between the corresponding AR and ER for each tissue.


ERRATUM.
Due to an overlook on the author's side, author's name in the article entitled as: "Neurodegeneration and the Brain Tumor Microenvirnment: Glutamate in the Limelight" by Dr. Nicolai E. Savaskan (Co-author) published in the journal "Current Neuropharmacology" Volume 13, No 2, Page no 258-265, was wrong. The correct title is as follows: Neurodegeneration and the Brain Tumor Microenviornment. Curr. Neuropharmacol., 2015, 13(2), 258 - 265.


An in silico analysis of robust but fragile gene regulation links enhancer length to robustness.
Organisms must ensure that expression of genes is directed to the appropriate tissues at the correct times, while simultaneously ensuring that these gene regulatory systems are robust to perturbation. This idea is captured by a mathematical concept called r-robustness, which says that a system is robust to a perturbation in up to r - 1 randomly chosen parameters. r-robustness implies that the biological system has a small number of sensitive parameters and that this number can be used as a robustness measure. In this work we use this idea to investigate the robustness of gene regulation using a sequence level model of the Drosophila melanogaster gene even-skipped. We consider robustness with respect to mutations of the enhancer sequence and with respect to changes of the transcription factor concentrations. We find that gene regulation is r-robust with respect to mutations in the enhancer sequence and identify a number of sensitive nucleotides. In both natural and in silico predicted enhancers, the number of nucleotides that are sensitive to mutation correlates negatively with the length of the sequence, meaning that longer sequences are more robust. The exact degree of robustness obtained is dependent not only on DNA sequence, but also on the local concentration of regulatory factors. We find that gene regulation can be remarkably sensitive to changes in transcription factor concentrations at the boundaries of expression features, while it is robust to perturbation elsewhere.


A prognostic systemic inflammation score (SIS) in patients with advanced intrahepatic cholangiocarcinoma.
Systemic-inflammatory response parameters (SIR) are known prognostic markers in different tumour entities, but have not been evaluated in patients with iCCA treated with systemic chemotherapy. Therefore, we evaluated the impact of different SIR markers on the clinical course of patients with advanced iCCA treated at our center. SIR markers were retrospectively evaluated in 219 patients with iCCA at the West-German-Cancer-Center Essen from 2014 to 2019. Markers included neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), CRP, and the modified Glasgow-Prognostic-Score (mGPS), which were correlated with clinico-pathological findings, response to chemotherapy (ORR), progression-free (PFS) and overall survival (OS) using Kaplan-Meier analyses, and Cox proportional models. Median overall survival (OS) of the entire cohort was 14.8 months (95% CI 11.2-24.4). Median disease-free survival (DFS) in 81 patients undergoing resection was 12.3 months (95% CI 9.7-23.1). The median OS from start of palliative CTX (OSpall) was 10.9 months (95% 9.4-14.6). A combined Systemic Inflammatory Score (SIS) comprising all evaluated SIR markers correlated significantly with ORR, PFS, and OSpall. Patients with a high SIS (≥ 2) vs. SIS 0 had a significantly inferior OSpall (HR 8.7 95% CI 3.71-20.38, p < 0.001). Multivariate analysis including known prognostic markers (ECOG, CA19-9, LDH, and N- and M-status) identified the SIS as an independent prognostic factor. Inflammatory markers associate with inferior survival outcomes in patients with iCCA. A simple SIS may guide treatment decisions in patients treated with systemic chemotherapy.


Patient-reported outcomes and patient voices.
Online hemodiafilration (HDF) treatment may be associated with better quality of life due to improved clearance of middle-molecular-weight uremic toxins and hemodynamic stability in dialysis patients, in addition to better overall survival.


BILATERAL CHOROIDAL VASCULAR MALFORMATIONS IN HEREDITARY HEMORRHAGIC TELANGIECTASIA.
To describe a case of bilateral choroidal vascular malformations in a patient with hereditary hemorrhagic telangiectasia. Case report. A 78-year-old man with hereditary hemorrhagic telangiectasia was incidentally noted to have focal, large deep choroidal vessels on optical coherence tomography with corresponding elevation of the overlying retina. Indocyanine green angiography revealed dilated, intensely fluorescent vessels in arterial phase emptying into massively dilated choroidal veins consistent with choroidal arteriovenous malformation. This case presents multimodal imaging findings of choroidal arteriovenous malformations in hereditary hemorrhagic telangiectasia. Choroidal vascular malformations may represent an underrecognized clinical feature of this syndrome.


Alteration of hepatic phospholipids in rats and mice by feeding di-(2-ethylhexyl)adipate and di-(2-ethylhexyl)phthalate.
Effects of di-(2-ethylhexyl)adipate (DOA) and di-(2-ethylhexyl)phthalate (DEHP), plasticizers for polyvinylchloride products, on concentrations and compositions of hepatic phospholipids were studied in rats. When administered to rats at a 2% level for 2 wk, both DOA and DEHP caused a hepatomegaly, an increase in hepatic phospholipids and a decrease an increase in hepatic phospholipids and a decrease in the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE). In the comparable study with mice, the alkyl moiety of DOA was found to be responsible for these alterations. DOA and DEHP specifically altered fatty acid compositions of PC and PE: there was an increase in oleic and palmitic acids and a decrease in stearic and docosahexaenoic acids in PC and an increase in arachidonic acid at the expense of docosahexaenoic acid in PE. In addition, DOA caused an increase in the trienoic and tetraenoic molecular species in PC and an increase in the 1-palmitoyl-2-arachidonyl (16:0@20:4) species in PE. Thus, the effects of DOA on the lipid dynamics resembled those observed with DEHP, although the magnitude was slightly moderated.


Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells.
Present guidelines for the treatment of type 2 diabetes recommend HbA1c values of less than 7%. As beta cell function worsens during progress of the disease, insulin therapy is often necessary to achieve this ambitious goal. However, due to peripheral insulin resistance, many patients need rather high insulin dosages. In the light of the extremely high cardiovascular risk of diabetic patients, it is important to determine whether high concentrations of insulin or its frequently used analogues are harmful to the cardiovascular system. We therefore investigated the modulatory effects of regular human insulin and its analogue glargine on proliferation and apoptosis of human coronary artery endothelial cells (HCAECs) and human coronary artery smooth muscle cells (HCASMCs). Cells were treated with regular human insulin or insulin glargine. Proliferation was determined by [3H]thymidine incorporation and by flow cytometric analysis of Ki-67 expression. Apoptosis was assessed by flow cytometry (cell cycle analysis and annexin V staining) and determination of caspase-3 activity. HCAECs and HCASMCs treated with regular human insulin or insulin glargine did not show significant increases in DNA synthesis or Ki-67 expression. Administration of regular human insulin or insulin glargine did not modulate the extent of apoptotic events. No influence of insulin on lipoapoptotic vascular cell death could be detected. Taken together, neither regular human insulin nor insulin glargine influences growth and apoptosis of human coronary artery cells in vitro. Our data do not suggest that regular human insulin or insulin glargine promote atherosclerosis through mechanisms affecting the cellularity of human coronary arteries.


In vitro activity in deptomycin (LY-146032) compared with other antimicrobial agents against gram-positive cocci.
A comparison was made of the activity of deptomycin (LY-146032) with that of ampicillin, cephalexin, cefamandole, cephalothin, erythromycin, teicoplanin, tetracycline, and vancomycin. The minimal inhibitory concentration (MICs) for greater than or equal to 90% of 356 Gram-positive cocci, against deptomycin, were less than or equal to 2 micrograms/ml. The MICs for the other antimicrobials varied greatly depending on the compound. A slight and unexplained inoculum effect was observed for LY-146032.


In ovo injection of CHIR-99021 promotes feather follicles development via activating Wnt/β-catenin signaling pathway during chick embryonic period.
The Wingless-types/beta-catenin (Wnt/β-catenin) signaling pathway plays an important role in embryonic development and affects the physiological development processes of feather follicles. To investigate the role of Wnt/β-catenin pathway in regulating feather follicles morphogenesis, in ovo injection of CHIR-99021, an activator of the Wnt/β-catenin signaling pathway, was conducted in chick embryo model. Initially, a total of 40 embryos were used to assess feather follicles morphogenesis and the expression of β-catenin (E9-E17). The histological results showed that feather follicle morphogenesis was mainly completed from E9 to E17. β-catenin was involved in the processing of the appearance of dermal cell condensation (E9) and the completion of the feather follicles morphogenesis (E17). Next, a total of 160 fertilized eggs were randomly divided into 8 groups for in ovo injection at E9, including a Normal Saline injected group (CON) and the 500, 1,000, 2,000, 5,000, 10,000, 50,000, and 100,000 ng CHIR-99021 groups. Dorsal skin tissue samples were collected at E17 for investigating feather follicles morphology and expressions of β-catenin and lymphoid enhancerbinding factor-1 (LEF1) at gene and protein levels. The results showed that feather follicle diameter in the injected groups were significantly (P < 0.05) increased with limit dose-independence compared to the CON group. CHIR-99021 significantly (P < 0.05) influenced the mRNA expressions of catenin beta-1 (CTNNB1) and downstream target LEF1. In ovo injection of CHIR-99021 caused that β-catenin and LEF1 were significantly (P < 0.05) increased followed the increased doses as determined by western blotting. The immunochemical results showed that β-catenin was detected in the dermal papilla of feather follicles. Given these results, this study suggests to developmental biology that in ovo injection of CHIR-99021 promoted feather follicles morphogenesis and development via activating Wnt/β-catenin signaling pathway and upregulating downstream target LEF1 during embryonic period in chick embryo model. Moreover, CHIR-99021 may be a strong candidate to promote the animal feather/hair industry, especially as a reference for bird feather production.


Ultraviolet A sunscreen evaluations in normal subjects.
We have used a specially modified xenon arc solar simulator to examine ultraviolet A (UVA) protection of a research sunscreen formulation. UVA doses were given to sunscreen-protected and unprotected skin with the use of irradiance values of 50 mW/cm2 and 100 mW/cm2. Erythemal responses were evaluated 5.2 +/- 0.9 hours later and again 24.4 +/- 1.8 hours later. The overall mean unprotected UVA minimal erythema dose (MED) was 23.6 joules/cm2 (SD = 4.8) and the mean UVA protection factor (APF) was 3.2 (SD = 0.78). Neither irradiance nor evaluation time significantly affected MED or APF. These preliminary findings indicate that the modified solar simulator permits convenient determination of sunscreen APF. The APF of a sunscreen is analogous to SPF: APF refers to UVA protection, while SPF refers to protection from the entire solar spectrum, predominantly from the effects of UVB.


[The genome instability in the descendants of the Chinese hamster of the cells, irradiated by the low dose and by various intensities of gamma-radiation].
The V-79 Chinese hamster cells were irradiated by gamma-rays in dose of 0.5 Gy at powers of doses 0.48 Gy/min (an acute irradiation) and 0.0485 MGy/min (a prolonged irradiation). The acute and prolonged irradiation in a dose of 0.5 Gy enlarges frequency of the appearance of micronucleus (MN). Subsequent cultivation of the irradiated cells during 20 generations enlarges frequency of MN, and for prolonged an irradiation the boosted frequency of MN, is saved during 40-60 generations. After an acute irradiation the number of MN starts to reduce after 20 doublings.


The influence of l-carnitine on the expression of miRNAs in asthenospermia spermatozoa and the network regulation of the associated molecules.
l-carnitine is a natural compound that is indispensable for energy metabolism in mammals. The efficiency and safety of l-carnitine in improving sperm activity, enhancing epididymal function and treating male infertility has been widely acknowledged by clinicians. CircRNAs can regulate gene expression at the transcriptional or post-transcriptional level by serving as a molecular sponge of miRNAs with miRNA response elements. However, the detailed mechanism linking miRNA, circRNA and asthenospermia remains unclear. The present study demonstrated that hsa-miR-27b-3p, hsa-miR-151a-5p and hsa-miR-206 play an important role in the effects of l-carnitine treatment of the spermatozoa in asthenospermia patients. Furthermore, the target mRNAs of hsa-miR-206 were analysed by GO and KEGG. The results show that the target mRNAs of hsa-miR-206 may change the activity of ATP synthase and participate in the cAMP signalling pathway and the calcium signalling pathway, which may play an important role in sperm motility.


Melanopsin: The Tale of the Tail.
In this issue of Neuron, Mure et al. (2016) demonstrate that two mechanisms-phosphorylation of a C-terminal intracellular region, and mechanism involving the whole of the C terminus-oppositely shape the kinetics and sensitivity of the nonvisual photoreceptor melanopsin.


Phosphoramidate-Supported Cp*Ir(III) Aminoborane H2 B=NR2 Complexes: Synthesis, Structure, and Solution Dynamics.
Reaction of aminoboranes H2 B=NR2 (R=iPr or Cy) with the cationic Cp*Ir(III) phosphoramidate complex [IrCp*{κ(2) -N,O-Xyl(N)P(O)(OEt)2 }][BAr(F) 4 ] generates the aminoborane complexes [IrCp*(H){κ(1) -N-η(2) -HB-Xyl(N)P(OBHNR2 )(OEt)2 }][BAr(F) 4 ] (R=iPr or Cy) in which coordination of a P=O bond with boron weakens the B=N multiple bond. For these complexes, solution- and solid-state, as well as DFT computational techniques, have been employed to substantiate B-N bond rotation of the coordinated aminoborane.


Acute gangrenous cholecystitis due to metastatic melanoma detected by cholescintigraphy.
A case of acute gangrenous cholecystitis due to cystic duct obstruction by a metastasis from malignant melanoma detected by cholescintigraphy is presented.


Conformational analysis of peptide T and of its C-pentapeptide fragment.
The synthetic peptide of sequence H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH, termed peptide T, a competitor of the Human Immunodeficiency Virus in the binding to human T cells, and its C-terminal pentapeptide fragment, were studied by 1H-nmr in DMSO solution to determine conformational preferences. The observation of nuclear Overhauser enhancements (NOEs) for both peptides, and unusual finding for small linear peptides, allowed complete sequence-specific resonance assignments. Long-range NOEs, ring-current shifts, and the very small temperature coefficient of the Thr8 NH chemical shift suggest, for the zwitterionic form of peptide T, the presence in solution of a beta-turn involving Thr5, Asn6, Tyr7 and Thr8. This conformational feature is consistent with previous structure-activity relationship studies indicating the invariance of the same residues in several potent pentapeptide analogues. The studied pentapeptide fragment, although less structured, shows some tendency to fold even in a polar solvent such as DMSO. Preliminary chemotaxis data on some pentapeptide analogues are consistent with our structural model.


Minimally invasive in tumor multidrug comparative analysis with contrast-enhanced MRI in mice.
To facilitate decision making in the oncology clinic, technologies have recently been developed to independently inject and assess multiple anticancer agents directly in a patient's tumor. To increase the flexibility of this approach beyond histological readouts of response, contrast-enhanced MRI was evaluated for the detection of cell death in living tumors after injection. A six-needle arrayed microinjection device designed to provide head-to-head comparisons of chemotherapy responses in living tumors was used. Xenografted non-Hodgkin lymphoma tumors in athymic Nude-Foxn1(nu) mice were injected either with different doses of vincristine or with one needle each of vincristine, doxorubicin, bendamustine, prednisolone, mafosfamide, and a vehicle control. To assess drug responses, measurements of enhancement by T1-weighted contrast-enhanced MRI were made for individual sites at 24, 48, and 72 h after injection. For comparison, histological evaluations of cell death were obtained after tumor resection. Measurements of MRI enhancement at injection sites showed a significant (P < 0.001) positive regression slope as a function of vincristine dose. Average MRI measurements were closely correlated with cell death by hematoxylin and eosin staining (R = 0.81; P = 0.001). Contrast-enhanced MRI has the potential to replace or augment histological analyses of tumor responses to microinjected doses of chemotherapy agents with potential application in selecting optimal chemotherapy regimens. Magn Reson Med 76:946-952, 2016. © 2015 Wiley Periodicals, Inc.


EEG phase-amplitude coupling to stratify encephalopathy severity in the developing brain.
Neonatal hypoxic ischemic encephalopathy (HIE) is difficult to classify within the narrow therapeutic window of hypothermia. Neurophysiological biomarkers are needed for timely differentiation of encephalopathy severity within the short therapeutic window for initiation of hypothermia therapy. A novel analysis of mean Phase Amplitude Coupling index, PACm, of amplitudes high frequencies (12-30 Hz) coupled with phases of low (1,2 Hz) frequencies was calculated from the 6 h EEG recorded during the first day of life. PACm values were compared to identify differences between mild versus higher-grade HIE, respectively, for each of the EEG electrodes. A receiver operating characteristic curve was generated to examine the performance of PACm. 38 newborns with different HIE grades were enrolled in the first 6 h of life. Threshold PACm 0.001 at Fz, O1, O2, P3, and P4 had AUC >0.9 to differentiate HIE severity and predict the persistence of moderate to severe encephalopathy that requires treatment with hypothermia. PAC is a promising biomarker to identify mild from higher severity of HIE after birth.


ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression.
ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient neonatal cholestasis (TNC). Neonatal intrahepatic cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic cholestasis [PFIC] group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes. The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow-up of TNC patients was 44 months (12 months-168 months). At presentation, hepatobiliary-injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non-null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan-Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study. Neonatal cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non-null PPV or with liver BSEP expression.


Application of Liposomes in Cancer Therapy: An Assessment of the Advancement of Technology Through Patent Documents.
Cancer is caused by mutations in oncogenes and loss of tumor suppressor activity. Despite the efforts of the pharmaceutical industry to fight cancer, it is necessary to investigate new methods to enhance the action against this disease. In this scenario, liposome technology has emerged as a drug delivery system for cancer treatment. The objective of this study was to evaluate the use of liposome technology in the treatment of cancer through analysis of patent documents. We analyzed prospective documents in the Derwent Innovation Index database. A total of 203 patent documents were related to the area of interest, published between 2000 and 2020, and the USA and Japan were shown as countries with the largest number of publications. Moreover, most of these publications came from companies, however, also with the representation of important universities, mainly the University of California. According to the International Patent Classification, the codes most applicable to the documents were in the areas of human necessities and chemistry. The results of this study showed that the study and application of liposomes for the development of cancer treatment tended to grow, along with the number of related patents.


[Prognosis of patients with primary liver carcinoma treated with local resection].
To discuss the prognosis of primary liver carcinoma treated with local resection and factors affecting prognosis. The data on 130 patients who had been treated from October 1989 to October 1995 were reviewed retrospectively. Curative local resection was performed in 130 patients. Death rate of operation was 0.7%, and the incidence of complications 16.1% (n = 18). The overall 1-, 3- and 5-year survival rates were 82.1%, 60.6% ,48.2%, respectively. Involvement of blood vessels or liver capsules as well as the increase of AST before operation are the significant factors affecting prognosis (P < 0.05). Local resection is a method characterized by little damage, less bleeding, less complication and good prognosis.


Devitalized Stem Cell Microsheets for Sustainable Release of Osteogenic and Vasculogenic Growth Factors and Regulation of Anti-Inflammatory Immune Response.
The objective of this work was to investigate the effect of devitalized human mesenchymal stem cells (hMSCs) and endothelial colony-forming cells (ECFCs) seeded on mineralized nanofiber microsheets on protein release, osteogenesis, vasculogenesis, and macrophage polarization. Calcium phosphate nanocrystals were grown on the surface of aligned, functionalized nanofiber microsheets. The microsheets were seeded with hMSCs, ECFCs, or a mixture of hMSCs+ECFCs, cultured for cell attachment, differentiated to the osteogenic or vasculogenic lineage, and devitalized by lyophilization. The release kinetic of total protein, bone morphogenetic protein-2 (BMP2), and vascular endothelial growth factor (VEGF) from the devitalized microsheets was measured. Next, hMSCs and/or ECFCs were seeded on the devitalized cell microsheets and cultured in the absence of osteo-/vasculo-inductive factors to determine the effect of devitalized cell microsheets on hMSC/ECFC differentiation. Human macrophages were seeded on the microsheets to determine the effect of devitalized cells on macrophage polarization. Based on the results, devitalized undifferentiated hMSC and vasculogenic-differentiated ECFC microsheets had highest sustained release of BMP2 and VEGF, respectively. The devitalized hMSC microsheets did not affect M2 macrophage polarization while vascular-differentiated, devitalized ECFC microsheets did not affect M1 polarization. Both groups stimulated higher M2 macrophage polarization compared to M1.


Nanostructured Materials for Energy Storage and Conversion.
The conversion and storage of renewable energy sources is an urgent challenge that we need to tackle to transition from a fossil fuel-based economy to a low-carbon society [...].


Effectiveness of microwave diathermy on pain, functional capacity, muscle strength, quality of life, and depression in patients with subacromial impingement syndrome: a randomized placebo-controlled clinical study.
The aim of this clinical trial was to evaluate the effectiveness of therapeutic MD on pain, functional capacity, muscle strength, quality of life, and depression in patients with subacromial impingement syndrome (SIS). A total of 40 inpatient subjects with definite SIS were included in this study. These patients were sequentially randomized into 2 groups. Group 1 (n = 20) received therapeutic MD. Group 2 (n = 20) was served as control group and received sham MD. Superficial heat and exercise program were given to both groups. Both of the programs were performed 5 times weekly for 3 weeks. Patients were assessed before treatment (BT), after treatment (AT), and at a 1-month follow-up (F). Outcome measures included visual analogue scale, goniometry, Shoulder Pain and Disability Index, Shoulder Disability Questionnaire, shoulder isokinetic muscle testing, handgrip strength, Short Form 36, and Beck Depression Index. The patients with SIS in each group had significant improvements in pain, shoulder ROM, disability, shoulder muscles and grip strength, quality of life, and depression AT and F when compared with their initial status (P < 0.05). There was no statistically significant difference between the groups according to all the parameters regarding the change scores between AT-BT test and F-BT test (P > 0.05). A 2,450-MHz MD regimen showed no beneficial effects in patients with SIS, so the superficial heat and exercise program, as it is efficient, may be preferable for the treatment of SIS, alone.


Activation of tumor-associated macrophages by thymosin alpha 1.
It was shown earlier that the progressive growth of a transplantable T-cell lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), in a murine host is associated with an inhibition of macrophages (TAM) along with an involution of thymus. However, it remained unclear if a decline in the level of thymic peptides in DL-bearing host, due to thymic regression, has any implications in the inhibited responses of TAM. Therefore, the present investigation was under taken to study whether the TAM of DL-bearing host can be activated to tumoricidal state by peptides of thymic origin. It was observed that intraperitoneal administration of thymosin alpha 1 to DL-bearing mice resulted in activation of TAM. Such TAM were found to produce enhanced amount of interleukin-1 (IL-1), tumor necrosis factor (TNF), reactive oxygen intermediates (ROI), nitric oxide (NO) and showed an increased abilities of pinocytosis, phagocytosis, antigen presentation and tumor cytotoxicity. The TAM were found to be directly responsive to thymosin alpha1 as in vitro treatment with thymosin alpha 1 could activate TAM to tumoricidal state. Treatment of TAM with thymosin alpha 1 also enhanced their LPS responsiveness for an augmented state of activation. The findings of this study demonstrate for the first time that the TAM of a T cell lymphoma can be activated to tumoricidal state by thymosin alpha 1.


Neurotransmitter content of mouse brain after inactivation by microwave heating.
Mice were sacrificed by either microwave inactivation of brain enzymes or by cervical dislocation. The norepinephrine, serotonin, 5-hydroxyindoleacetic acid and homovanillic acid content of the brains of the irradiated animals was significantly greater than that of the conventionally sacrificed controls.


Management of the Morel-Lavallée Lesion.
Morel-Lavallée lesions are closed degloving injuries sustained during violent soft tissue shear that separate the subdermal fat from its strong underlying fascia. Lesions most often occur in the peritrochanteric region, and patients may have concomitant polytrauma. As a result, a hematoma develops that has a high rate of acute bacterial colonization and chronic recurrence. Conservative treatment outcomes are best for those managed acutely. However, diagnosis is often delayed or missed. Furthermore, there is no universally accepted treatment algorithm. Diagnosis and treatment depend on a surgeon's thorough understanding of the cause, pathophysiology, imaging characteristics, and treatment options of Morel-Lavallée lesions.


Breast feeding--when nature fails to satisfy.
Human milk is the ideal source of nutrition for the healthy neonate. Milk from the mother whose diet is sufficient will supply the necessary nutrients. It is a considerable problem to discern if the milk supply is the adequate quantity for the infant. If the infant's water and caloric needs are not met for several days, signs and symptoms of hypernatremic dehydration >10% may develop. This report presents a case of a 15-day-old, breast-fed infant who developed significant hypernatremic dehydration.


[Smoking cessation in older smokers. A retrospective study in 181 older smokers managed in a smoking cessation clinic].
Smoking is a factor associated with premature death, including in older people. Stopping smoking reduces related mortality even after the age of 60. The aim of this study, conducted in a smoking cessation clinic, was to describe the characteristics of these older smokers and their quit attempts. A retrospective study was performed from the patient files of a smoking cessation clinic between 1999/01/01 and 2009/12/31; "older" smokers (≥60 years; n=181) were compared to "young" smokers (<60 years; n=1425). Compared to young smokers, older smokers had a higher frequency of cardio-pulmonary diseases (82.3 % vs. 46.7 %; P<0.0001) and current depressions (45.3% vs. 35.7%; P=0.012); their abstinence rate at 12 months was higher (44.2% vs. 32.9%; P=0.0025). An age over 60 years was associated with a higher success rate (OR=1.83; CI 95%: 1.29-2.59). Cessation smoking attempts are as likely to be successful in older smokers as in younger smokers. Physicians should advise and assist older smokers to quit and if necessary refer them to smoking cessation clinics. Smoking cessation guidelines therefore will apply without reserve in seniors.


Intraocular fibrous proliferation as an incisional complication in pars plana vitrectomy.
We enucleated an eye of a 39-year-old white man four weeks after partial pars plana vitrectomy was carried out for removal of an amagnetic foreign body which failed. Vitreous clouding complicated the perforating injury. Histological findings included massive ingrowth of fibrous tissue into the vitreous space and along preretinal planes, total retinal detachment with degenerations, and localized proliferations of the pigmentary epithelium. All proliferations originated at the site of the sclerotomy incision.


Mechanical thrombectomy in stroke in nonagenarians: useful or futile?
Mechanical thrombectomy is the standard treatment in acute ischemic stroke due to large vessel occlusion, but there is limited evidence about its efficacy in very old patients. We sought to analyse safety and effectiveness of mechanical thrombectomy in nonagenarian versus octagenarian patients. We included consecutive patients with acute ischemic stroke due to large vessel occlusion subjected to mechanical thrombectomy, during 29 months in a tertiary center. Patients were divided into two sub-groups, according to age: 80-89 and >90 years old. Recanalization, complications, functional outcome and mortality at discharge and at 3 months were compared. Multivariable analysis was performed to identify independent predictors of functional outcome at 3 months of follow-up, assessed by the modified Rankin Scale. A total of 128 octogenarians (88.9%) and 16 nonagenarians (11.1%) met the inclusion criteria. Successful revascularization was achieved in 87.5% of octagenarians and in 81.3% of nonagenarians (p = 0.486). Symptomatic hemorrhage occurred in 3.1% and 6.3% of younger and older patients, respectively (p = 0.520). Cerebral edema occured in 35.2% of octagenarians versus 25.0% of nonagenarians (p = 0.419). Functional independence (mRS ≤ 2) at 3 months was achieved in 28 (22.6%) and 5 (31.3%) of octagenarians and nonagenarians, respectively (p = 0.445). Mortality at 3 months was not significantly higher in nonagenarians (37.5%) versus octagenarians (33.9%, p = 0.773). No significant diferences were found in functional outcome, mortality, recanalization and complication rates between octagenarians and nonagenarians submitted to mechanical thrombectomy, underlining that patients should not be excluded from mechanical thrombectomy based on age alone.


Frozen Section or Intraoperative Cytology: Are We Ready for a Paradigm Shift in Thoracic Surgery?
Intraoperative frozen sections of specimens taken during thoracic surgery are widely seen as the gold standard. However, the accuracy of intraoperative cytology remains contentious. The study aims to estimate the value of intraoperative cytology by analyzing feasibility, accuracy, time requirements, and possible limitations when compared to standard frozen sections. To this end, we examined a total of 532 intraoperatively harvested specimens out of the 518 resected thoracic tumors from 360 patients between August 2016 and August 2017. The specimens were subject to intraoperative rapid cytology that was later counter compared to the final histology results. The mean time between the intraoperative harvesting and arrival at the laboratory was 2.23 min, and it took a further 3.5 min until the results were communicated to the surgeon. Cytologically, 218 cases (41%) were classified as malignant, 291 (55%) as benign, and 23 (4%) remained unclear. In 55 malignant cases, we observed additional benign formations. The final histological examination performed later yielded 267 malignant and 265 benign cases. Therefore, the sensitivity and specificity of rapid intraoperative cytology were 82% and 99%, respectively, with a negative/positive predictive value of 86%/99%. We conclude that the intraoperative rapid cytology is a fast, accurate, sensitive, and specific procedure for intraoperative decision making and is a distinctly helpful alternative or adjunct for the thoracic surgeon, providing that one is aware of the plausible limitations of this technique.


Loss of heterozygosity on chromosome 4q32-35 in sporadic basal cell carcinomas: evidence for the involvement of p33ING2/ING1L and SAP30 genes.
Studies on basal cell carcinoma (BCC) have demonstrated that patched gene and p53 gene located at 9q22.3 and 17p13 are the main genes responsible for the onset of this tumor. In order to identify a possible involvement of other tumor suppressor genes, we screened 19 cases of BCCs for loss of heterozygosity (LOH). The analysis was performed on tumoral tissue and on corresponding normal tissue by using a panel of 37 polymorphic markers spanning 26 chromosomal regions. We observed that only four chromosomal regions, 4q32 (30.00%), 4q35 (27.27%), 9q21-22 (28.57%), and 9q22-qter (35.71%), demonstrated a significative LOH (>20%), even if others show a borderline percentage (15-20%) of imbalance (1q32, 3p24, 10p22.1, and 17q21.3). Our findings suggest that a new chromosomal region mapping in the long arm of chromosome 4 could be involved in sporadic BCC carcinogenesis. Further analyses indicate that the minimal deleted region in 4q32-35 includes p33ING2/ING1L and SAP30, whose deletion could impair the G1-phase checkpoint control and favor gene silencing, respectively.


[Rhabdomyosarcoma of the hand. Apropos of a case confined to the thenar eminence].
A case of alveolar rhabdomyosarcoma of the hand in a 21-year-old patient is reported. In the light of this case, the authors review the literature and analyse the therapeutic implications.


Reduced baroreflex sensitivity and cardiorespiratory transfer in amyotrophic lateral sclerosis.
Clinically relevant autonomic disturbances have been reported for respirator-dependent ALS patients while subclinical involvement may be present in the early course. Eighteen patients with early-stage ALS and 18 age-matched controls were studied by means of standard autonomic tests (heart off + response to deep breathing and tilt-table testing), and spectral analysis of heart rate (HR) and arterial blood pressure (ABP), using the associated transfer function as a measure of baroreflex sensitivity for the mid-frequency band (MF band, 0.05-0.15 Hz) and as a measure of cardiorespiratory transfer for the high-frequency band (HF band, 0.15-0.33 Hz). Mean HR and ABP were increased in ALS, while results of standard autonomic tests were similar for ALS and controls. Transfer function analysis revealed reduced baroreflex sensitivity and diminished cardiorespiratory transfer during normal breathing. Cardiovascular autonomic functions are intact in patients with ALS. There is evidence of sympathetic enhancement and vagal withdrawal, accompanied by reduced baroreflex sensitivity. These findings are similar to those reported for essential hypertension and may point to a common central autonomic derangement in both disorders.


A pH-dependent N, P co-doped carbon dots as fluorescent probe for malachite green assay and its visual application based on fluorescent hydrogel kit.
A pH-dependent red fluorescent N, P co-doped carbon dots (N, P-CDs) was firstly developed for rapid, sensitive and visual detection of the toxic dye malachite green (MG). The synthesis of N, P-CDs was carried out by hydrothermal treatment of o-phenylenediamine and phosphoric acid, and the low cytotoxicity of N, P-CDs was verified by Cell Counting Kit-8 (CCK-8) method. The linear decrease of N, P-CDs fluorescence in the pH range of 3.8-5.6 was attributed to the reduction of protonation of nitrogen-containing groups on the surface. And the sensing mechanism for MG was constructed based on the inner filter effect (IFE). The obtained linear ranges were 0.08-1 and 1-50 µmol·L-1 with limit of detections (LODs) of 0.07 and 0.74 µmol·L-1. The proposed method has been successfully applied to the determination of MG in water and fish samples. In addition, a kind of N, P-CDs fluorescent hydrogel kit was prepared for the visual analysis of MG. This method is not only simple, rapid and accurate, but also the prepared fluorescent hydrogel has potential application prospects for on-site qualitative identification and semi-quantitative analysis of MG, which also provides a new idea for monitoring MG in water environment and fish products.


Role of Serum Markers in Benign Paroxysmal Positional Vertigo: Are They Useful?
Benign Paroxysmal Positional Vertigo is a peripheral labyrinthine disease and is one of the most common causes of dizziness in the general population. The proposed study was conducted in the Department of Otorhinolaryngology - Head and Neck Surgery at Indira Gandhi Medical College and Hospital, Shimla, Himachal Pradesh for a period of one year. About 44 patients aged between 14 and 60 years who came out positive on Dix Hallpike test and were willing for study were included in case group, whereas 44 patients aged 14-60 years who came out negative on Dix Hallpike test and with no complaint of vertiginous feeling were included in control group. Cases and controls were subjected to blood investigations like complete hemogram, calcium, vitamin D and uric acid. The mean Vitamin D was found to be significantly less in Case group (27.90 ± 15.89) compared to the Control group (39.05 ± 21.15) while no significant difference in mean Serum Calcium was observed between the Case group (8.48 ± 1.28) and Control group (8.88 ± 1.25). Serum uric acid levels were also compared and no significant difference was found between Case group (4.12 ± 1.15) and the Control group (4.06 ± 0.95). Our study found that there is relation between low vitamin D levels and occurrence of BPPV. Which supports the hypothesis that supplementation of Vitamin D might be helpful in preventing the occurrence and more frequent recurrence of BPPV. However in our study no association was found between serum calcium and uric acid levels with BPPV.


Bilateral autologous breast reconstruction with deep inferior epigastric artery perforator flaps: Review of a single surgeon's early experience.
The purpose of this study is to describe the early experience of a single surgeon just out of training, including preoperative conditioning, surgical approach, and outcomes in bilateral deep inferior epigastric artery perforator (DIEP) flap breast reconstruction patients. We retrospectively reviewed 54 consecutive patients who underwent 108 DIEP flap breast reconstructions performed by a single surgeon over an initial 2.5-year period. There was 100% overall flap survival. The unplanned reoperation rate was 7.6% (n = 4). Minor complications including nonoperative infection, minor wound dehiscence, and donor site seroma occurred in 26% of patients (n = 14). Significant late complications were abdominal wall bulge (n = 1) and fat necrosis < 10% of volume (n = 1). Tissue expander explantation due to infection occurred in 25% of attempted staged patients (two of eight); this did not seem to compromise their oncologic treatment or final reconstruction outcome. This study demonstrates the efficacy of the DIEP flap for bilateral autologous breast reconstruction in the immediate, staged, and delayed settings.


A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome.
A novel causative variant (c.608G>A, p.Arg203Gln) in PACS1.


Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations.
Cardiovascular risk factors (CVRF) possibly contribute to the emergence of Alzheimer's disease (AD). Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been widely used to demonstrate specific patterns of reduced cerebral metabolic rates of glucose (CMRgl) in subjects with AD and in non-demented carriers of the apolipoprotein ε4 (APOE ε4) allele, the major genetic risk factor for AD. However, functional neuroimaging studies investigating the impact of CVRF on cerebral metabolism have been scarce to date. The present FDG-PET study investigated 59 cognitively preserved elderlies divided into three groups according to their cardiovascular risk based on the Framingham 10-year risk Coronary Heart Disease Risk Profile (low-, medium-, and high-risk) to examine whether different levels of CVRF would be associated with reduced CMRgl, involving the same brain regions affected in early stages of AD. Functional imaging data were corrected for partial volume effects to avoid confounding effects due to regional brain atrophy, and all analyses included the presence of the APOE ε4 allele as a confounding covariate. Significant cerebral metabolism reductions were detected in the high-risk group when compared to the low-risk group in the left precuneus and posterior cingulate gyrus. This suggests that findings of brain hypometabolism similar to those seen in subjects with AD can be detected in association with the severity of cardiovascular risk in cognitively preserved individuals. Thus, a greater knowledge about how such factors influence brain functioning in healthy subjects over time may provide important insigths for the future development of strategies aimed at delaying or preventing the vascular-related triggering of pathologic brain changes in the AD.


Investigating the ability of astrocytes to drive neural network synchrony.
Recent experimental works have implicated astrocytes as a significant cell type underlying several neuronal processes in the mammalian brain, from encoding sensory information to neurological disorders. Despite this progress, it is still unclear how astrocytes are communicating with and driving their neuronal neighbors. While previous computational modeling works have helped propose mechanisms responsible for driving these interactions, they have primarily focused on interactions at the synaptic level, with microscale models of calcium dynamics and neurotransmitter diffusion. Since it is computationally infeasible to include the intricate microscale details in a network-scale model, little computational work has been done to understand how astrocytes may be influencing spiking patterns and synchronization of large networks. We overcome this issue by first developing an "effective" astrocyte that can be easily implemented to already established network frameworks. We do this by showing that the astrocyte proximity to a synapse makes synaptic transmission faster, weaker, and less reliable. Thus, our "effective" astrocytes can be incorporated by considering heterogeneous synaptic time constants, which are parametrized only by the degree of astrocytic proximity at that synapse. We then apply our framework to large networks of exponential integrate-and-fire neurons with various spatial structures. Depending on key parameters, such as the number of synapses ensheathed and the strength of this ensheathment, we show that astrocytes can push the network to a synchronous state and exhibit spatially correlated patterns.


Early spontaneous recanalization following acute carotid occlusion.
Occlusion of the internal carotid artery (ICA) and stroke may be the consequence of either local thrombosis due to atherosclerosis or massive embolism. Up to date, there are only few reports of subsequent recanalization. We report 12/76 cases of acute ICA occlusion leading to ischemic stroke, in which early recanalization was identified. Ultrasound and stroke MRI findings, therapeutic options, and outcome are described. 10/12 patients showed an- or hypoechogenic morphology of occlusion. While in 7/12 cases complete recanalization was seen, in 5/12 patients partial recanalization with filiform flow (4) or residual high-grade stenosis (1) was detected. 10/12 patients had territorial or subcortical infarction, while two showed small cortical lesions only. In 7/12 cases, a potential cardiac source of embolism was found. Five patients received tPA; four patients underwent early carotid endarterectomy of the partially recanalized ICA within 48 hours. In the 10-day follow-up examination 10/12 patients showed clinical improvement as measured by the NIHSS. Spontaneous recanalization after occlusion of the ICA may occur and might be more frequent than hitherto assumed. Echogenicity analysis and serial examinations of symptomatic ICA occlusion is useful for identifying a patient subgroup that might benefit from further therapy.


Changing epidemiology of methicillin-resistant Staphylococcus aureus in Alberta, Canada: population-based surveillance, 2005-2008.
SUMMARYIncreasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been reported in Canada. We report the results of a prospective surveillance of MRSA infections in Alberta over a consecutive 3-year period. A total of 8910 unique clinical MRSA isolates was analysed from July 2005 to June 2008. The incidence of MRSA infection increased over the study period and was highest in males, age group ⩾85 years, and the Calgary Area. CMRSA10 (USA300) and CMRSA2 (USA100/800) were the most common PFGE strain types, representing 53·0% and 27·9% of all isolates, respectively. Significant differences were noted between MRSA strains in the source of infection and antimicrobial susceptibility. The incidence of MRSA infection in Alberta has nearly doubled in the last 3 years; this is attributed to the emergence of CMRSA10 as the predominant strain.


The safety of carotid endarterectomy in patients with preoperative renal dysfunction.
Recent published data suggest that performing carotid endarterectomy (CEA) in patients with renal dysfunction is associated with a prohibitively high perioperative stroke and death rate. On the basis of our experience, we hypothesized that CEA is a safe procedure in patients with renal insufficiency. A retrospective review of one surgeon's CEA experience from 1988 to 1998 was performed. A total of 398 procedures performed on 370 patients were reviewed for patient demographics and adverse events in the 30-day perioperative period. Risk factors, indications for procedure, and degree of stenosis, as well as intraoperative use of shunts, patch angioplasty, drains, completion angiography, and EEG monitoring were compared. Patients were categorized by preoperative creatinine (Cr) levels as normal (Cr <or= 1.5) or abnormal (Cr > 1.5). All data were subjected to statistical analysis. Our results showed that CEA can be performed safely in patients with renal dysfunction with no increase in perioperative stroke or death rate. Performing CEA in patients with renal insufficiency does require preoperative cardiac evaluation and close cardiac monitoring, as there appears to be an increased rate of myocardial infarction in our series.


Demonstration of Epstein-Barr virus genome in neoplastic cells of Hodgkin's disease by in situ hybridization, in paraffin-embedded tissue using biotinylated probes. A study of 46 cases.
Paraffin-embedded tissue specimens from 46 cases of Hodgkin's disease (HD) were studied by in situ hybridization with biotinylated probes for the presence of EBV genomes. EBV specific DNA sequences were detected in the nuclei of Reed-Sternberg (RS) and Hodgkin cells (H), in 14 of these 46 cases. There was no correlation between positive hybridization and morphological subtype or site of tumor. By demonstrating an exclusive localization of the viral DNA in the tumor cells of HD, our study adds to the growing body of evidence to suggest an involvement of EBV in the pathogenesis of at least some cases of HD.


Cortical morphological heterogeneity of schizophrenia and its relationship with glutamatergic receptor variations.
Recent genetic evidence implicates glutamatergic-receptor variations in schizophrenia. Glutamatergic excess during early life in people with schizophrenia may cause excitotoxicity and produce structural deficits in the brain. Cortical thickness and gyrification are reduced in schizophrenia, but only a subgroup of patients exhibits such structural deficits. We delineate the structural variations among unaffected siblings and patients with schizophrenia and study the role of key glutamate-receptor polymorphisms on these variations. Gaussian Mixture Model clustering was applied to the cortical thickness and gyrification data of 114 patients, 112 healthy controls, and 42 unaffected siblings to identify subgroups. The distribution of glutamate-receptor (GRM3, GRIN2A, and GRIA1) and voltage-gated calcium channel (CACNA1C) variations across the MRI-based subgroups was studied. The comparisons in clinical symptoms and cognition between patient subgroups were conducted. We observed a "hypogyric," "impoverished-thickness," and "supra-normal" subgroups of patients, with higher negative symptom burden and poorer verbal fluency in the hypogyric subgroup and notable functional deterioration in the impoverished-thickness subgroup. Compared to healthy subjects, the hypogyric subgroup had significant GRIN2A and GRM3 variations, the impoverished-thickness subgroup had CACNA1C variations while the supra-normal group had no differences. Disrupted gyrification and thickness can be traced to the glutamatergic receptor and voltage-gated calcium channel dysfunction respectively in schizophrenia. This raises the question of whether MRI-based multimetric subtyping may be relevant for clinical trials of agents affecting the glutamatergic system.


In situ localization of murine c-Ki-ras-2 oncogene: preliminary evidence for conservation of telomeric territory of oncogenes?
The use of a human cDNA probe and a Robertsonian translocation marker allowed us to localize the murine c-Ki-ras-2 oncogene to 6F-G at the telomere. Our finding provides support for the hypothesis that oncogenes have a preferred telomeric territory that is evolutionarily conserved. Given our physical mapping of c-Ki-ras-2 to 6F-G, the role of this oncogene in the genesis and/or maintenance of granulocytic leukemias can now be explored by correlating the oncogenic site to that of the structural rearrangement of chromosome 6 seen in the tumors.


Severe jaundice after rupture of abdominal aortic aneurysm.
Eight patients after operation for ruptured abdominal aortic aneurysm developed severe jaundice. The jaundice became clinically apparent by the sixth postoperative day, and the average peak total bilirubin level reached 28.4 mg/100 ml, alkaline phosphatase level 8.6 BL units/l, and SGOT 95 Karmen units/ml. In addition to the hepatic dysfunction, all patients developed acute renal failure, seven of eight patients experienced hypovolemic shock, and six of eight patients had respiratory insufficiency requiring ventilatory support. The overall mortality was 83 per cent. The most probable causes for the severe jaundice were increased bile pigment load and hepatocellular dysfunction due to ischemic hypoxic injury of hepatocytes secondary to shock. Morphologically, a picture of cholestasis existed with severe bile-staining of hepatocytes and intracanalicular and intraductal bile thrombi. No evidence of recent or resolving hepatic necrosis was observed.


[Conventional contrast media examinations and computer tomography in space-occupying processes (author's transl)].
In 1977, more than 2,000 patients were examined in our department of neuroradiology by means of angiography, computed tomography, and in some cases also by pneumoencephalography. The value of the various neuroradiological examinations is discussed taking as an example two patients suffering from intracranial space-occupying processes of different etiologies. Consequently, the differential diagnostic problems occurring are discussed casuistically. It is demonstrated that correct diagnosis can often be achieved only by use of all the results of the different neuroradiological methods, together with precise knowledge of the course and the clinical symptoms.


Immune-Mediated Central Nervous System Disease-Current Knowledge and Recommendations.
Immune-mediated inflammation is responsible for about 25% of central nervous system disease in dogs. The disease can affect all ages and breeds, but young to middle-aged small breed dogs are over-represented for most forms. Diagnosis consists of advanced imaging (MRI), cerebrospinal fluid analysis, and infectious disease testing, but biopsy is required for definitive diagnosis and classification of the disease into one of the many subtypes. Treatment consists of immunosuppressive medication with the goal being to control and/or improve clinical signs. Current literature shows that prognosis is variable.


Heterodimer HLA-DM Fused with Constant Fragment of the Heavy Chain of the Human Immunoglobulin Accelerates Influenza Hemagglutinin HA306-318 Loading to HLA-DR1.
Major histocompatibility complex class II (MHC II) plays an important role not only in the adaptive immune responses to foreign pathogens, but also in the development of some autoimmune diseases. Non-classical MHC, HLA-DM is directly involved in MHC II loading with the peptide. To study this process, we synthesized recombinant proteins HLA-DR1 and HLA-DM. α/β-Chains of DR1 heterodimer contained C-terminal leucine domains of the fos and jun factors, respectively. Each DM chain contained constant fragment of human antibody heavy chain fused via a long linker domain. In addition, DM α-chain carried N165D substitution suppressing potential glycosylation at this site. We observed significant acceleration of DR1 peptide loading with influenza HA306-318 hemagglutinin in the presence of DM, which indicates functionality of recombinant DR1-DM protein couple. Our results can be used to study the presentation of other viral and self-antigens and can become the basis for the development of new drug modeling.


Evaluation of joint toxicity of heavy metals and herbicide mixtures in soils to earthworms (Eisenia fetida).
It is widely acknowledged that a simplified and robust approach to evaluating thecombined effects of chemical mixtures is critical for ecological risk assessment (ERA) of contaminated soil. The earthworm (Eisenia fetida) was used as a model to study the combined effects of polymetallic contamination and the herbicide siduron in field soil using a microcosm experiment. The responses of multiple biomarkers, including the activities of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR) and acetylcholine esterase (AChE), the concentrations of glycogen, soluble protein (SP), malonaldehyde (MDA), and metallothionein (MT), and the neutral red uptake test (NRU), were investigated. Multivariate analysis, Principal Component Analysis (PCA) and Spearman's Rank Correlations analysis (BVSTEP) revealed that the activities of AChE and CAT and the NRU content were the prognostic biomarkers capturing the minimum data set of all the variables. Internal Cd (tissue Cd) in earthworms was closely related to the health status of worms under combined contamination of heavy metals and siduron. The integrated effect (Emix) calculated based on the activities of AChE and CAT and NRU content using the stress index method had significantly linear regression with internal Cd (p<0.01). Emix(10), Emix(20), and Emix(50) were then calculated, at 1.27, 1.63 and 2.71 mg/kg dry weight, respectively. It could be concluded that a bioassay-based approach incorporating multivariate analysis and internal dose was pragmatic and applicable to evaluating combined effects of chemical mixtures in soils under the guidance of the top-down evaluation concept of combined toxicity.


Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy.
Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133+ putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model.