The DAPA-HF Trial: A Momentous Victory in the War against Heart Failure.
In a randomized trial of patients with heart failure and reduced ejection fraction, the SGLT2 inhibitor dapagliflozin markedly reduced mortality and worsening heart failure (McMurray et al., 2019). Remarkably, these benefits seemed to be similar in people with and without diabetes. These data usher in a new paradigm in the treatment of heart failure.


Analgecine protects against cerebral ischemia-reperfusion through apoptosis inhibition and anti-neuroinflammation in rats.
Stroke influence the quality of life of patients and leave big public health issues as acute cerebrovascular disease all over the world. Analgecine (AGC) relieves pain and accelerates repair of nerve injury. This current study aims to observe the pharmacological effects and related mechanisms of AGC in cerebral ischemic stroke among middle cerebral artery ischemia-reperfusion (MCAO) rats. After seven days of AGC administration, motor function was enhanced as evidenced by the prehensile traction test. Morphological ameliorations were observed by immunohistochemistry analysis. The protein expression levels of HSP70, Bcl-2, Bax, TRAF-6, MyD88, BDNF, NGF, pCREB, CREB, pTrkB, TrkB, pAKT and AKT were estimated by western blot. Meanwhile, AGC alleviated MCAO-induced inflammation chiefly by decreasing inflammatory cytokines in rat brain tissues. These results above suggested that MCAO-caused brain infarction was obviously alleviated by AGC. The immunohistochemistry data showed that AGC reduced neuronal injury and apoptosis, and inhibited microglia and astrocytes activation. The protein results suggested the expression of apoptosis-relevant proteins decreased among AGC treated groups and the neurotrophin related proteins were obviously enhanced by CREB/BDNF/TrkB/AKT and HSP70/Bcl-2/Bax pathways. Collectively, the results demonstrated that AGC primarily promoted neuro-nutrition, reduced the injury of nerve apoptosis and ameliorated neuroinflammation. In summary, AGC played a neuroprotective role, which had provided reliable evidence for AGC to be a potential drug in treating stroke.


Geometry of population activity in spiking networks with low-rank structure.
Recurrent network models are instrumental in investigating how behaviorally-relevant computations emerge from collective neural dynamics. A recently developed class of models based on low-rank connectivity provides an analytically tractable framework for understanding of how connectivity structure determines the geometry of low-dimensional dynamics and the ensuing computations. Such models however lack some fundamental biological constraints, and in particular represent individual neurons in terms of abstract units that communicate through continuous firing rates rather than discrete action potentials. Here we examine how far the theoretical insights obtained from low-rank rate networks transfer to more biologically plausible networks of spiking neurons. Adding a low-rank structure on top of random excitatory-inhibitory connectivity, we systematically compare the geometry of activity in networks of integrate-and-fire neurons to rate networks with statistically equivalent low-rank connectivity. We show that the mean-field predictions of rate networks allow us to identify low-dimensional dynamics at constant population-average activity in spiking networks, as well as novel non-linear regimes of activity such as out-of-phase oscillations and slow manifolds. We finally exploit these results to directly build spiking networks that perform nonlinear computations.


Biomarkers in acute heart failure--state of the art.
The role of biomarkers in the management of patients with acute heart failure (HF) has evolved rapidly in the past several years. Representing a major burden on health systems, acute HF has increased the need for earlier diagnosis, better risk stratification, and cost-effective treatment to reduce rates of hospitalization. Biomarker-guided diagnosis and treatment have become essential, especially in the acute setting to which the majority of the patients with acute HF initially present. Studies clearly demonstrate the complexity of these patients, who commonly have multiple comorbidities necessitating an integrative approach. Several groundbreaking studies conducted in the past decade have demonstrated how biomarkers, individually or in combination, can outperform conventional laboratory tests used in the emergency department as well as in hospitalized patients with acute HF. In this Review, we will provide an update on biomarkers considered state of the art in the diagnosis and management of patients with acute HF.


Separation and analysis of mononuclear cells infiltrating the thyroid of patients with Graves' disease.
A simple method was established for separating lymphocytes infiltrating the thyroid from thyroid epithelial cells. Namely, suspensions of minced thyroid from patients with Graves' disease were layered on a Percoll two-step density gradient (p = 1.050 and 1.077 g/ml) and centrifuged (400g, 30 min, 4 degrees C). In this way 0.1-18 X 10(5) lymphocytes/g of thyroid tissue with a purity of 65-95% were obtained. Thyroid lymphocytes were analyzed quantitatively with monoclonal antibodies by laser flow cytometry and compared with peripheral lymphocytes. The proportion of OKT3+ cells was decreased with increase in OKIa+ cells. The percentage of OKIa+ cells was significantly correlated with that of Leu12+ cells. The percentages of OKT4+ cells and OKIa+ cells were higher when analyzed with an extended gate window, which was arranged for detection of activated, large-sized lymphocytes. The percentages of OKT8+ and Leu7+ cells were not significantly different from those in peripheral blood. From these results it was concluded that the proportion of B lymphocytes is increased and that of T lymphocytes is decreased, the proportion of activated B lymphocytes is increased, some helper/inducer T cells are activated in the thyroid gland in Graves' disease, and these activated lymphocytes may be important in local production of antithyroid autoantibodies.


ORAL N-ACETYL CYSTEINE VERSUS RECTAL INDOMETHACIN FOR PREVENTION OF POST ERCP PANCREATITIS: A MULTICENTER MULTINATIONAL RANDOMIZED CONTROLLED TRIAL.
This multicenter multinational RCT designed to compare the efficacy of suppository indomethacin and NAC for prevention of PEP. During a 6-month period, all of the ERCP cases in seven referral centers were randomly assigned to receive either 1200 mg oral NAC, indomethacin suppository 100 mg, 1200 mg oral NAC plus indomethacin suppository 100 mg or placebo 2 hours before ERCP. The primary outcomes were the rate and severity of any PEP. A total of 432 patients included (41.4% male). They were originally citizens of 6 countries (60.87% Caucasian). They were randomly allocated to receive either NAC (group A, 84 cases), rectal indomethacin (group B, 138 cases), NAC + rectal indomethacin (group C, 115 cases) or placebo (group D, 95 cases). The rate of PEP in groups A, B and C in comparison with placebo were 10.7%, 17.4%, 7.8% vs 20% (P=0.08, 0.614 & 0.01 respectively). The NNT for NAC, indomethacin and NAC + indomethacin was 11, 38 and 8 respectively. Oral NAC is more effective than rectal indomethacin when compared to placebo for prevention of PEP and the combination of NAC and Indomethacin had the lowest incidence of PEP and may have synergistic effect in preventing of PEP (IRCT20201222049798N1; 29/12/2020).


Evaluation of omeprazole as a cost-effective diagnostic test for gastro-oesophageal reflux disease.
There is a need for a simple, therapeutic test that is of diagnostic value and can also provide rapid symptom relief in patients who present with classic, mild symptoms suggestive of gastro-oesophageal reflux disease (GERD), when the diagnosis is based on symptom assessment alone. To assess the diagnostic value of a therapeutic trial of omeprazole 40 mg in a dyspeptic population. A total of 90 patients with symptoms suggestive of GERD entered the study. Patients underwent endoscopy and ambulatory oesophageal pH monitoring for 18-24 h. Patients then received omeprazole 40 mg o.m. for 2 weeks. There was a significant correlation between the diagnoses obtained from a trial of omeprazole and the diagnoses obtained from pH monitoring (P < 0. 05). There was no significant correlation between the diagnoses obtained from endoscopy and those obtained from pH monitoring. Both omeprazole and endoscopy were compared to pH monitoring as the 'gold standard' for the diagnosis of GERD and the cost per correct diagnosis with omeprazole was pound47 (95% CI: pound40- pound59) compared to pound480 (95% CI: pound396- pound608) with endoscopy. There was a complete absence of acid-related symptoms in the majority (59%) of patients after 3 days of omeprazole 40 mg therapy and, after 2 weeks, 82% of patients had experienced an improvement in overall symptoms ( 1 grade). We conclude that omeprazole can be used as a clinically effective tool in the initial management of GERD and that it is of diagnostic value in patients who present with typical symptoms, such as heartburn, when the diagnosis is based on symptom assessment alone.


Factors in predicting initial in-office therapeutic dosages of alprostadil for the treatment of organic impotence.
The use of intracavernous penile injections of alprostadil for treating organic impotence is well-established. Using blood pressure measurements, especially systolic BP and MABP as measured in a flat supine position, the dosage of alprostadil required to achieve satisfactory erections in men with organic impotence can be predicted. This guidance can significantly influence the outcome of therapy by reducing the number of titrated diagnostic injections and the time required for the patient to achieve satisfactory results.


Relationship of findings of clinical research and development of criteria: a researcher's perspective.
Simply more research will not answer the problem of evaluation of patient outcomes. Research in nursing related to clinical phenomena lacks a specific focus and sustained pursuit of subject matter. What is required is unifying theory, a recognition that the existence of ambiguity is essential to the creation of science, an open mind, and the ability to criticize oneself objectively.


Hormone measurements and histomorphological observations in male Bactrian camels.
The aim of this study was to investigate the effect of age on the hypothalamic-pituitary-gonadal (HPG) axis hormones and to determine the morphological changes of the testis. The Bactrian camels were divided into two groups based on their ages. The results showed that the testicular weight was significantly heavier in adult male camels than in pubertal male camels (P < 0.05). There were also significant differences between testicular length, testicular width, and testicular volume (P < 0.05). In the testes of both pubertal and adult male camels, Sertoli cells, spermatogonia, spermatocytes, round spermatids, and elongated spermatids were observed. Adult male camels had more Sertoli cells (P < 0.01) and elongated spermatids (P < 0.05). The concentrations of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were higher in the plasma and testes of adult camels than in pubertal camels (P < 0.05). E2 concentrations were lower in adult camels than in pubertal camels (P < 0.05). The testosterone levels in testicular tissue were higher than in blood plasma in both adult and pubertal stage (P < 0.05). In conclusion, these findings provide supportive knowledge and show the significant differences in terms of testicular volume, testicular hormone concentrations, and testicular morphology between different developmental stages in Bactrian camels.


Problems with prostate-specific antigen screening: a critical review.
The effect of population screening with regard to reduction of prostate cancer specific mortality and quality of life issues is not yet clear. Several national and international prospective studies are currently being conducted to answer these important questions. They include the trials in the Federal State of Tyrol, Austria and in the Quebec City area, Canada, as well as the Prostate, Lung, Colorectal and Ovarian (PLCO) trial in the United States and the European Randomized Study of Screening for Prostate Cancer (ERSPC). In the meantime, individual case finding (opportunistic screening) is recommended for men with a life-expectancy of at least 10 years.


Concerted localization-resets precede YAP-dependent transcription.
Yes-associated protein 1 (YAP) is a transcriptional regulator with critical roles in mechanotransduction, organ size control, and regeneration. Here, using advanced tools for real-time visualization of native YAP and target gene transcription dynamics, we show that a cycle of fast exodus of nuclear YAP to the cytoplasm followed by fast reentry to the nucleus ("localization-resets") activates YAP target genes. These "resets" are induced by calcium signaling, modulation of actomyosin contractility, or mitosis. Using nascent-transcription reporter knock-ins of YAP target genes, we show a strict association between these resets and downstream transcription. Oncogenically-transformed cell lines lack localization-resets and instead show dramatically elevated rates of nucleocytoplasmic shuttling of YAP, suggesting an escape from compartmentalization-based control. The single-cell localization and transcription traces suggest that YAP activity is not a simple linear function of nuclear enrichment and point to a model of transcriptional activation based on nucleocytoplasmic exchange properties of YAP.


Impact of global change on environmental hazards of different clays: A case study on Aliivibrio fischeri.
The effects of global change in marine ecosystems are expected to lower pH from the current 8.1-7.5-7.0, which will have significant impacts on marine species. The purpose of this study is to investigate whether the ecotoxicity of ten different natural clays change significantly in response to the acidification process and what factors are associated with the observed changes. In this study, the ecotoxicological response of a bacterium (Aliivibrio fischeri) was tested under current (pH= 8.1) and acidified (pH 7.5 and 7.0) conditions. The ecotoxicity detected in the solid phase test (SPT protocol) and in the contact water was affected by the pH, which increased the ecotoxicity from 2/10 clays (pH 8.10) to 7/10 clays (pH 7.00), also shifting the detected effects from low to high toxicity values. The analyses performed on the natural clays studied show that pH can affect the release of metals, metalloids and rare earths from the clays into the contact water phase, affecting the toxicity observed. This phenomenon depends on the type of clay and is closely related to its mineralogical composition. As consequence, in a globally changing scenario, ecotoxicity, even of natural materials such as clay, cannot be considered stable, but must be accurately revaluated depending on the mineralogical and chemical composition of the clay. Moreover, the mineralogical composition of clays showed different efficiency in absorbing bacteria on the surface of clay particles. It was found that live bacterial cells were absorbed on the clay surface in numbers that were dependent on both clay types and pH levels.


Photic- and pattern-induced seizures: a review for the Epilepsy Foundation of America Working Group.
This report summarizes background material presented to a consensus conference on visually provoked seizures, convened by the Epilepsy Foundation of America. A comprehensive review of literature was performed. Photosensitivity, an abnormal EEG response to light or pattern stimulation, occurs in approximately 0.3-3% of the population. The estimated prevalence of seizures from light stimuli is approximately 1 per 10,000, or 1 per 4,000 individuals age 5-24 years. People with epilepsy have a 2-14% chance of having seizures precipitated by light or pattern. In the Pokemon cartoon incident in Japan, 685 children visited a hospital in reaction to red-blue flashes on broadcast television (TV). Only 24% who had a seizure during the cartoon had previously experienced a seizure. Photic or pattern stimulation can provoke seizures in predisposed individuals, but such stimulation is not known to increase the chance of subsequent epilepsy. Intensities of 0.2-1.5 million candlepower are in the range to trigger seizures. Frequencies of 15-25 Hz are most provocative, but the range is 1-65 Hz. Light-dark borders can induce pattern-sensitive seizures, and red color also is a factor. Seizures can be provoked by certain TV shows, movie screen images, video games, natural stimuli (e.g, sun on water), public displays, and many other sources. Recommendations on reducing risk of seizures have been developed by agencies in the United Kingdom, Japan, and the International Telecommunications Union, affiliated with the United Nations. The Epilepsy Foundation of America has developed a consensus of medical experts and scientists on this subject, reported in an accompanying work.


Spatial practice, conceived space and lived space: Hong Kong's "Piers saga" through the Lefebvrian lens.
By applying the Lefebvrian lens, this paper tries to understand why unlike previous similar cases, the latest removal of the Star Ferry and Queen's Pier was so controversial. To Lefebvre, embedded in "spatial practices" that "secrete" a place are two contradicting spaces: "conceived spaces" produced by planners to create exchange values and "lived spaces" appropriated by citizens for use values. Applying Lefebvre's framework to examine the "Piers saga", it is found that the pre-Second World War (WWII) piers were "conceived" by spatial practices of a colonial and racially segregated trading enclave. The public space in the commercial heart that housed the previous generations of piers was not accessible to the Chinese community, thus denying them opportunities to appropriate them and turn them into "lived" spaces. It was only after WWII when the Government carried out further reclamation to meet the needs of an industrializing economy that inclusive public spaces were conceived in the commercial heart, enabling the general public to "appropriate" them as "lived" space. When the Government planned to remove this very first "lived" space in the political and economic heart of the city to conceive further reclamation for the restructuring economy, the more enlightened citizens were determined to defend it.


Quantitative reverse transcription polymerase chain reaction analysis of Porphyromonas gingivalis gene expression in vivo.
An etiological relationship between periodontitis, a significant oral health problem, and the anaerobe Porphyromonas gingivalis may be related to the expression of a variety of putative virulence factors. The objective of the experiments described here was to develop a quantitative reverse transcription polymerase chain reaction (QRT-PCR) method to examine P. gingivalis gene expression in human dental plaque from periodontitis subjects. PCR primers and probes for six target genes representing putative virulence factors were chosen and evaluated in vitro for specificity. A potential cross-reactivity level of only 10 copies/10(7) whole genomic equivalents was occasionally observed with non-P. gingivalis microbes. P. gingivalis cells stressed in vitro by a 5 degrees C temperature increase showed a rapid rise in the mRNA associated with the molecular chaperons (htpG, dnaK, groEL), SOD (sodA) and gingipain (rgp-1) genes. We examined the stability of bacterial RNA in plaque specimens and found no significant difference in the amount of RNA obtained before or after storage 3 months in a stabilizing buffer (p=0.786, t-test). Sixty-five percent of plaque samples obtained from two clinical locations contained P. gingivalis; there was a mean level of gene expression (fold increase) for all samples tested for groEL, dnaK, htpG, sodA, PG1431 and rgp-1 of 0.84+/-2.03 to 7.85+/-10.0. ANOVA showed that the levels of stress gene transcription for dnaK and htpG were significantly elevated (p<0.05) at diseased sites; groEL gene transcription approached statistically significant elevation (p=0.059). We found correlations between probing depth and increased transcription of groEL, htpG and rgp-1 and between attachment loss and htpG. When sorted by disease status, we detected correlations between disease status and elevated expression of dnaK and htpG.


Dimensionality and invariance of ADL, IADL, BI-M2/WG-SS, and GALI in large surveys in France (2008-2014) and implications for measuring disability in epidemiology.
The epidemiological investigation and surveillance of disability requires well-constructed, invariant, and, if possible, exchangeable measures. However, the current or recommended measures have not been thoroughly investigated with respect to these issues. Here we examined the dimensional structure and invariance of four measures across sociodemographic groups: Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Budapest Initiative Mark 2 (BI-M2) and Washington Group on Disability Statistics Short Set (WG-SS), and Global Activity Limitation Indicator (GALI). We used data from three large nationwide representative surveys conducted in France between 2008 and 2014. The surveys included these four measures and classical and modern approaches (correlations, principal component analysis, Rasch modeling) were used to assess their dimensional structure as well as their invariance through differential item functioning (DIF) for sociodemographic characteristics. Polytomous logistic regression models were used to assess gradients in health inequalities associated with these measures. For many items of ADL, IADL, and BI-M2/WG-SS, we consistently observed disordered response thresholds, rejection of unidimensionality, and DIF evidence for sociodemographic characteristics across the survey samples. Health inequality gradients were erratic. In addition, it was impossible to identify a common continuum for GALI, ADL, IADL, and BI-M2/WG-SS or their constituent items. This study warns against the current practice of investigating disability in epidemiology using measures that are unsuitable for epidemiological use, incommensurable, and inadequate regarding the basic requisites of dimensionality and invariance. Developing invariant measures and equating them along a common continuum to enlarge the common bases of measurement should therefore be a priority.


The impact of social connectedness on mental health in LGBTQ + identifying individuals during the COVID-19 pandemic in Germany.
Recent studies report that LGBTQ + people have experienced high levels of mental health problems during COVID-19-related social distancing. Given the well-established association between social isolation and mental health, the main aim of the current study was to investigate differences in mental health and (perceived) social isolation and social support in LGBTQ + individuals compared to heterosexual, cisgender people and to explore whether the hypothesized higher mental health burden in LGBTQ + individuals is (partly) mediated by (perceived) social isolation or social support. N = 531 participants indicating belonging to the LGBTQ + community and N = 1826 not identifying as LGBTQ + participated in a cross-sectional online survey during the initial COVID-19-related lockdown in Germany. Standardized questionnaires were used to assess depression, anxiety, suicidality, loneliness and social support. Further, perceived social isolation and face-to-face communication during the lockdown were assessed. LGBTQ + people had higher levels of depression, anxiety and suicidal thought, were lonelier and experienced less social support than non-LGBTQ + identifying individuals. Mediation analysis showed that the higher levels of mental health burden in LGBTQ + people were (partly) mediated by reduced social connectedness. Further face-to-face contact positively affected mental health by reducing feelings of loneliness. Given the high impact of loneliness on mental health, governmental actions should be taken to promote social connectedness particularly among LGBTQ + identifying individuals to ensure that the COVID-19 pandemic does not exacerbate the health inequalities that already exist between LGBTQ+-identifying and heterosexual, cisgender people.


A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist.
Cytokine hormones have a short plasma half-life and require frequent administration. For example, growth hormone replacement involves daily injections. In common with other cytokines, the extracellular domain of the growth hormone receptor circulates as a binding protein, which naturally prolongs the biological half-life of growth hormone. Here we have studied the biological actions of a ligand-receptor fusion of growth hormone and the extracellular domain of its receptor. The genetically engineered ligand-receptor fusion protein was purified from mammalian cell culture. In rats, the ligand-receptor fusion had a 300-times reduced clearance as compared to native growth hormone, and a single injection promoted growth for 10 d, far exceeding the growth seen after administration of native growth hormone. The ligand-receptor fusion forms a reciprocal, head-to-tail dimer that provides a reservoir of inactive hormone similar to the natural reservoir of growth hormone and its binding protein. In conclusion, a ligand-receptor fusion of cytokine to its extracellular receptor generates a potent, long-acting agonist with exceptionally slow absorption and elimination. This approach could be easily applied to other cytokines.


Hypocholesterolaemic effects of an ethanol precipitate of Kabosu juice in stroke-prone spontaneously hypertensive rats fed a cholesterol-free diet.
1. We have previously identified strong inhibitory effects of Kabosu (Citrus sphaerocarpa Hort.) juice precipitate (KJP) on cholesterol elevation in stroke-prone spontaneously hypertensive rats (SHRSP) fed a cholesterol diet. In the present study, to elucidate the hypocholesterolaemic mechanism, we examined the effect of dietary KJP on lipid metabolism by using SHRSP fed a cholesterol-free diet. 2. Compositions of the experimental diet containing 10% KJP powder were adjusted to those of the control diet. Seven-week-old male SHRSP were fed control or experimental diet for 2 weeks with free access to the diet and water. 3. Serum levels of cholesterol, phospholipid and triglyceride of the KJP group were significantly reduced, which was due to decreases in the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions. 4. Serum concentrations of apolipoproteins A-I and E (apoA-I and E) of the KJP group were significantly lower than those of the control group, whereas no significant differences were observed in serum apoB and apoA-IV between the two groups. 5. In liver, there were no significant differences in the contents of lipids or relative liver weight between the two groups. The activity of microsomal cholesterol 7alpha-hydroxylase of the KJP group tended to increase, whereas that of microsomal acyl-coenzyme A : cholesterol acyltransferase was significantly reduced, compared with the control group. 6. These results indicate that dietary KJP produces reductions of serum lipid levels, which are due to reductions in VLDL, apoE HDL and apoA-I HDL, and may promote catabolism and excretion of hepatic cholesterol in SHRSP fed a cholesterol-free diet.


RNA binding proteins in the regulation of heart development.
In vivo, RNA molecules are constantly accompanied by RNA binding proteins (RBPs), which are intimately involved in every step of RNA biology, including transcription, editing, splicing, transport and localization, stability, and translation. RBPs therefore have opportunities to shape gene expression at multiple levels. This capacity is particularly important during development, when dynamic chemical and physical changes give rise to complex organs and tissues. This review discusses RBPs in the context of heart development. Since the targets and functions of most RBPs--in the heart and at large--are not fully understood, this review focuses on the expression and roles of RBPs that have been implicated in specific stages of heart development or developmental pathology. RBPs are involved in nearly every stage of cardiogenesis, including the formation, morphogenesis, and maturation of the heart. A fuller understanding of the roles and substrates of these proteins could ultimately provide attractive targets for the design of therapies for congenital heart defects, cardiovascular disease, or cardiac tissue repair.


Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway.
Previous studies have shown that hematopoietic cytokines, including erythropoietin (Epo) and interleukin (IL)-3, activate the Ras GTPase and the downstream Raf/Erk/Elk-1 signaling pathway. Here we report that Epo or IL-3 rapidly and transiently activates Rac, a Rho family GTPase, in hematopoietic cell lines, 32D/EpoR-Wt and UT-7. The cytokine-induced activation of Rac was augmented in a 32D/EpoR-Wt clone that inducibly overexpresses the adaptor protein CrkL or the Ras guanine nucleotide exchange factor C3G, which forms a complex with CrkL. Furthermore, the Rac activation was enhanced or inhibited in cells inducibly expressing an activated Ras mutant, H-Ras61L, or a dominant negative Ras mutant, H-Ras17N, respectively. In addition, the cytokine-induced Rac activation was inhibited by a phosphatidyl-inositol 3'-kinase (PI3K) inhibitor, LY294002, which also inhibited the Erk activation. A dominant negative Rac mutant, Rac17N, also inhibited the cytokine-induced activation of Erk as well as Elk-1. On the other hand, activation of Akt downstream of PI3K was found to play an inhibitory role in cytokine activation of Erk/Elk-1. Together, these results indicate that Rac is activated by Epo or IL-3 at downstream of the Ras/PI3K pathway in parallel with Akt and plays a role in activation of the Erk/Elk-1 signaling pathway in hematopoietic cells.


Intravenous diltiazem worsens regional function in compromised myocardium.
The effect of intravenous diltiazem on regional myocardial function was assessed in a canine model of critical constriction of the left anterior descending coronary artery (LAD). Maintenance anesthesia with fentanyl (1.5 micrograms.kg-1.min-1), 60% inspired nitrous oxide, and 0.7% inspired halothane resulted in regional dysfunction, measured as postsystolic shortening (20.6 +/- 10.7%), which was significantly worsened after 0.1 mg/kg (48.7 +/- 12.5%, P less than 0.05) and after 0.2 mg/kg (68.8 +/- 11.7%, P less than 0.05) intravenous diltiazem. Systolic shortening in the compromised LAD territory was substantially depressed after 0.1 mg/kg diltiazem (8.2 +/- 0.6% to 5.3 +/- 1.3%, P less than 0.05) and was essentially abolished after 0.2 mg/kg diltiazem (8.2 +/- 0.6% to 0.7 +/- 2.3%, P less than 0.05). At the higher dose of diltiazem, cardiac output was substantially decreased (1.37 +/- 0.23 L/min to 0.88 +/- 0.30 L/min, P less than 0.05) and LV dP/dtmax significantly depressed (1090 +/- 90 mm Hg/sec to 744 +/- 80 mm Hg/sec, P less than 0.05). These results demonstrate significant depression of regional systolic shortening and substantial worsening of regional dysfunction in myocardium with a compromised blood supply, in association with significant depression of left ventricular performance, with intravenous diltiazem administration during anesthesia.


Premovement silence in agonist muscles preceding maximum efforts.
Electromyographic silent periods (premovement silence) preceding the initial agonist burst were studied in 11 healthy subjects who performed rapid forearm flexions and extensions. Premovement silence occurred with higher frequency during self-paced movements when subjects produced maximum power efforts than during a reaction time paradigm. The occurrence and duration were significantly correlated with the peak acceleration of the movement. Premovement silence occurred specifically in those muscles involved in the intended movement, often in several synergists with different latencies and durations. The shortest latency of premovement silence was considerably briefer than that of the earliest voluntary increase in EMG. The findings suggest that premovement silence may increase peak muscular force by bringing motoneurons into a nonrefractory state prior to their activation. The fact that it occurred on some, but not all, trials within single subjects and had a variable duration from trial to trial suggests that it may be a learned, rather than automatic, motor response.


Nurse Practitioner Autonomy and Relationships with Leadership Affect Teamwork in Primary Care Practices: a Cross-Sectional Survey.
The Nurse Practitioner (NP) workforce represents a substantial supply of primary care providers able to contribute to meeting a growing demand for care. However, controversy exists regarding the expanding role of NPs in primary care in terms of challenging the teamwork between NPs and physicians. To date, no empirical evidence exists regarding how to promote teamwork in primary care between NPs and physicians. We investigated whether NP autonomy within primary care practices and the relationships they have with leadership affect teamwork between NPs and physicians. Using a cross-sectional survey design, data was collected from 163 primary care practices in Massachusetts. Three hundred and fourteen primary care NPs completed and returned the mail survey yielding a response rate of 40 %. The Autonomy and Independent Practice (AIP) and NP-Administration Relations (NP-AR) scales were used to measure NP independent practice and the relationships with leadership, respectively. These measures were aggregated to the practice level. Teamwork between NPs and physicians was measured at the individual NP level using the Teamwork (TW) scale. The multilevel linear regression models investigated the influence of practice-level NP autonomy and the relationship between NPs and leadership on teamwork. With every unit increase on the practice-level mean score of AIP centered at the grand mean, the mean TW score increased by 0.271 units (p < 0.0001). With every unit increase of NP-AR centered at the grand mean, the mean TW score increased by 0.375 (p < 0.001). Over one-third (41.3 %) of the variance in teamwork could be explained by the final model. The study findings demonstrate that NP autonomy and favorable relationships with leadership improve teamwork. Policy and organizational change should focus on promoting NP autonomy and improving the relationship between NPs and leadership to improve teamwork and consequently improve patient care and outcomes.


Normal strobe electroretinograms without pattern electroretinograms in albino rats.
Electroretinograms (ERGs) were obtained from pigmented and albino rats to step luminance changes of an unpatterned TV screen. Surround luminance was increased until the ERG became small and focal. In pigmented rats the ERG at on was positive, earlier, and about twice the amplitude of the negative ERG at off. All pigmented rats had pattern ERGs-0.5 cycles/deg in dark agouti rats and an octave less in hooded rats. Implicit peak times were similar to that of the sum of on plus off focal ERGs from the same animals (85 ms). In albino rats off responses were more like on. The resultant sum was consequently small. Both peak times were similar and did not move earlier than 120 ms as surround luminance increased. Pattern ERGs could not be recorded from albinos at any spatial frequency or surround luminance. These pigmented rat ERGs seem to have two major components. One follows luminance linearly; the other is a fully rectified nonlinearity with about one-third the amplitude. The albino rat retina apparently lacks the latter component. These deficiencies may occur in albinos of other species and be associated with their visual system abnormalities.


Brain transcriptome perturbations in the Hfe(-/-) mouse model of genetic iron loading.
Severe disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds the neurologic effects of milder, more common iron loading disorders such as hereditary hemochromatosis, which is usually caused by loss-of-function polymorphisms in the HFE gene. There is evidence from both human and animal studies that HFE gene variants may affect brain function and modify risks of brain disease. To investigate how disruption of HFE influences brain transcript levels, we used microarray and real-time reverse transcription polymerase chain reaction to assess the brain transcriptome in Hfe(-/-) mice relative to wildtype AKR controls (age 10 weeks, n≥4/group). The Hfe(-/-) mouse brain showed numerous significant changes in transcript levels (p<0.05) although few of these related to proteins directly involved in iron homeostasis. There were robust changes of at least 2-fold in levels of transcripts for prominent genes relating to transcriptional regulation (FBJ osteosarcoma oncogene Fos, early growth response genes), neurotransmission (glutamate NMDA receptor Grin1, GABA receptor Gabbr1) and synaptic plasticity and memory (calcium/calmodulin-dependent protein kinase IIα Camk2a). As previously reported for dietary iron-supplemented mice, there were altered levels of transcripts for genes linked to neuronal ceroid lipofuscinosis, a disease characterized by excessive lipofuscin deposition. Labile iron is known to enhance lipofuscin generation which may accelerate brain aging. The findings provide evidence that iron loading disorders can considerably perturb levels of transcripts for genes essential for normal brain function and may help explain some of the neurologic signs and symptoms reported in hemochromatosis patients.


Juvenile myasthenia gravis with predominant facial weakness in a 7-year-old boy.
Myasthenia gravis is the most prevalent of the diseases of the neuromuscular junction in children. The most common clinical finding is ptosis, although ophthalmoplegia and facial weakness are commonly present. This paper reports juvenile myasthenia gravis in a 7-year-old boy with predominant facial muscle weakness without ophthalmoplegia and ptosis. This was detected post-operatively after adenotonsillectomy, as there was severe respiratory distress. Prompt diagnosis and treatment was life saving. A CT scan of the chest revealed thymoma. After the surgical removal of the thymoma, the child has been followed up for a year and is asymptomatic.


Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with breast cancer treated with HER2 blockade.
The association between human epidermal growth factor receptor-2 (HER2) blockades and risk of fatal adverse events (FAEs) has not been well described. We carried out a meta-analysis regarding this issue. An electronic search of Medline, Embase and The Cochrane Central Register of Controlled Trials was conducted to investigate the effects of anti-HER2 therapies on cancer patients. Only randomized controlled trials were included. Random or fixed-effect meta-analytical models were used to evaluate the risk ratio (RR) of FAEs due to the use of HER2 blockades. Twenty two trials were included. The incidence of FAEs related to HER2 blockades was 0.34%, and there was no statistically significant increase in the risk of FAEs for HER2 blockades versus control in overall population (RR = 1.16, 95%CI: 0.78-1.73). Furthermore, when we performed several subgroup analyses according to drug type (trastuzumab, lapatinib, and pertuzumab), treatment strategy (dual HER2 blockade vs. mono HER2 therapy), and study setting (adjuvant trials vs. metastatic trials), we did not observe any significant differences among the groups. No evidence of publication bias was observed. Compared with control, the addition of HER2 blockades may not increase the risk of FAEs among patients with breast cancer.


Temperature, relative humidity and sunshine may be the effective predictors for occurrence of malaria in Guangzhou, southern China, 2006-2012.
Malaria has been endemic in Guangzhou for more than 50 years. The goal of this study was to use a negative binomial regression to identify the relationship between meteorological variables and malaria reported. Our results revealed that each 1°C rise of temperature corresponds to an increase of 0.90% in the monthly number of malaria cases. Likewise, a one percent rise in relative humidity led to an increase of 3.99% and a one hour rise in sunshine led to an increase of 0.68% in the monthly number of cases. Our findings may be useful for developing a simple, precise malaria early warning system.


On the molecular mechanism of DNA translocation during in vitro packaging of bacteriophage T3 DNA.
The process of packaging of bacteriophage T3 DNA in a defined in vitro system can be separated into two stages: formation of a precursor complex (50 S complex) in the presence of adenosine-5'-O-(3'-thiotriphosphate) (ATP-gamma-S) and subsequent translocation of DNA into the head by the addition of ATP. Packaged DNA exits when DNA translocation is interrupted by the addition of ATP-gamma-S (M. Shibata, H. Fujisawa, and T. Minagawa, 1987, Virology, in press; M. Shibata, H. Fujisawa, and T. Minagawa, 1987, J. Mol. Biol., in press). The in vitro system packaged nicked and cross-linked DNAs but did not package single-stranded DNA. DNA packaging was inhibited by intercalating reagents such as ethidium bromide, acridine orange, and 4',6-diamino-2-phenylindole dihydrochloride. The inhibitory effect was proportional to the ability of intercalating agents to unwind DNA. Ethidium bromide did not inhibit the formation of 50 S complex but blocked translocation of DNA into and out of the capsid. DNA packaging was inhibited by actinomycin D and distamycin A which bind to the minor groove of the DNA helix. From these results, we conclude that DNA packaging mechanism utilizes the exterior structure of duplex DNA for translocating the DNA into the capsid.


Renal calcification incidence in very low birth weight infants.
Serial ultrasound examinations were performed on 31 neonates with birth weights of less than 1,500 g for the detection of renal calcifications. Renal calcifications occurred in 20 (64%) of the infants at a mean age of 39.3 +/- 26.7 days of life. Infants with renal calcifications had shorter gestations (28.2 +/- 1.8 v 31 +/- 1.4 weeks, P less than .004) and lighter birth weights (924 +/- 195 v 1,338 +/- 100 g, P less than .004) than those infants without renal calcifications (n = 11). Furosemide administration was more common in the infants with renal calcifications (65% v 9.1%, P less than .001). The mean total dose of furosemide administered before renal calcifications were noted was 9.59 +/- 7.25 mg/kg. The 20 neonates with renal calcifications had a mean urine calcium level of 12.0 +/- 6.8 mg/kg/24 hours, mean urine calcium to creatinine ratio of 1.32 +/- 1.03 (range 0.3 to 4.45), and a mean alkaline phosphatase concentration of 961 +/- 327 IU. Initial parathyroid hormone levels were not different between the two groups, and subsequent determinations in infants with renal calcifications did not differ significantly from initial values. Renal calcifications are fairly common among very low birth weight infants, particularly in those receiving supplemental calcium and furosemide therapy. Although long-term implications of such findings are not known, close monitoring of renal function by serial determinations of urine calcium and urine calcium to creatinine ratios may identify those infants at risk for renal calcifications.


Imaging recommendations for acute stroke and transient ischemic attack patients: a joint statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery.
In the article entitled "Imaging Recommendations for Acute Stroke and Transient Ischemic Attack Patients: A Joint Statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery", we are proposing a simple, pragmatic approach that will allow the reader to develop an optimal imaging algorithm for stroke patients at their institution.


Prevalence of low back pain in three occupational groups in Shanghai, People's Republic of China.
Low back pain (LBP) is one of the most prevalent work-related conditions affecting employed populations in developed countries, yet little is known about this condition among the world's largest, single-nation labor force: The People's Republic of China. This is a cross-sectional study of the prevalence of low back pain (LBP) among garment workers, battery/kiln workers, and teachers in Shanghai, People's Republic of China. Data were collected by personal interview and physical examination at six work sites. The overall response rate was 78%. The overall (N=383) self-reported annual prevalence of LBP symptoms lasting 24 hours or more was 50%. Garment workers had a higher annual prevalence of LBP (74%) than teachers (40%), prevalence ratio (PR=1.9, 95% CI=1.4-2.4). The overall annual prevalence of self-reported LBP (50%) was higher than that reported among 50 other Chinese employed study populations (30%). Healthy worker effects may have limited the conclusions from this cross-sectional study. These results suggest that LBP is a prevalent condition in Chinese workers and that more work should be done to estimate its impact on the Chinese workforce. The findings for garment workers were consistent with increased risk of LBP among persons doing work in fixed, sedentary postures.


Long-term sorption and solubility of bulk-fill and conventional resin-composites in water and artificial saliva.
To assess sorption and solubility of several bulk-fill and conventional resin-composites after one-year storage in water and artificial saliva (AS). Six bulk-fill (SureFil SDR, Venus Bulk Fill, X-tra base, Filtek Bulk Fill flowable, Sonic Fill, and Tetric EvoCeram Bulk Fill) and eight conventional resin-composites (Grandioso Flow, Venus Diamond Flow, XFlow, Filtek Supreme XTE, Grandioso, Venus Diamond, TPH Spectrum, and Filtek Z250) were tested. Disc shaped samples (n=5) were randomly immersed into distilled water and AS for one-year period and weighed at different time intervals. Data were analysed using repeated measures ANOVA, one-way ANOVA, and Tukey's post hoc test (α=0.05). In water, all materials (with the exception of X-Flow) reached a stable mass within three months with a slow increase observed in AS up to one year. Sorption values in water and AS for most materials were not significantly different (p≥0.2). Sorption and solubility values in water ranged from (6.5 μg/mm(3) and -1.77 μg/mm(3) respectively) for X-tra base to (78.8 μg/mm(3) and 44.77 μg/mm(3) respectively) for X-Flow (p<0.005). Sorption of the polymer matrix in water ranged from 1.18% for XB to 9.95 % for XF. Water sorption and solubility of resin-composites are material-dependent and highly affected by the filler loading and hydrophilicity of the resin matrix. BisEMA and UDMA-BisEMA based resins appeared to be more hydrophobic than BisGMA based systems. Water and AS, are generally comparable as storage media in terms of water sorption. Bulk-fill materials and conventional resin-composites tested varied in terms of sorption and solubility but both were considered stable in longterm water storage. The composition of each material is critical and can affect the long-term clinical performance of either type of resincomposites.


Methyl carbamates of phosphatidylethanolamines and phosphatidylserines reveal bacterial contamination in mitochondrial lipid extracts of mouse embryonic fibroblasts.
The occurrence of methyl carbamates of phosphatidylethanolamines and phosphatidylserines in the lipid extract of mitochondria obtained from mouse embryonic fibroblasts was ascertained by hydrophilic interaction liquid chromatography with electrospray ionization single and multi-stage mass spectrometry, performed using sinergically a high resolution (quadrupole-Orbitrap) and a low resolution (linear ion trap) spectrometer. Two possible routes to the synthesis of methyl carbamates of phospholipids were postulated and evaluated: (i) a chemical transformation involving phosgene, occurring as a photooxidation by-product in the chloroform used for lipid extraction, and methanol, also used for the latter; (ii) an enzymatic methoxycarbonylation reaction due to an accidental bacterial contamination, that was unveiled subsequently on the murine mitochondrial sample. A specific lipid extraction performed on a couple of standard phosphatidyl-ethanolamines/-serines, based on purposely photo-oxidized chloroform and deuterated methanol, indicated route (i) as negligible in the specific case, thus highlighting the enzymatic route related to bacterial contamination as the most likely source of methyl carbamates. The unambiguous recognition of the latter might represent the starting point toward a better understanding of their generation in biological systems and a minimization of their occurrence when an artefactual formation is ascertained.


Effects of interferential current electrical stimulation (IFCS) on mastication and swallowing function in healthy young adults: A preliminary study.
This study aimed to investigate the effects of interferential current electrical stimulation (IFCS) on masticatory and swallowing function. Twenty healthy young adults were enrolled. The measurement items were spontaneous swallowing frequency (SSF), voluntary swallowing frequency (VSF), saliva secretion volume (SSV), glucose elution volume (GEV), and velocity of chew (VOC). All participants underwent both IFCS and sham stimulation (without stimulation, sham). Two sets of independent IFCS electrodes were placed on the bilateral neck. The precise location of the upper electrodes was just below the angle of the mandible, while the lower electrodes were placed at the anterior border of the sternocleidomastoid muscle. The intensity of IFCS was determined to be one level below the perceptual threshold that all participants felt discomfort. Statistical analysis was performed using a two-way repeated measures analysis of variance. For IFCS, the results of each measurement before and during stimulation were SSF: 1.16 and 1.46, VSF: 8.05 and 8.45, SSV: 5.33 and 5.56 g, GEV: 171.75 and 208.60 mg/dL, and VOC: 87.20 and 95.20, respectively. SSF, GEV, and VOC during stimulation were significantly increased by IFCS (SSF, p = .009; GEV, p = .048; and VOC, p = .007). Following sham stimulation, the results were SSF: 1.24 and 1.34, VSF: 7.75 and 7.90, SSV: 5.65 and 6.04 g, GEV: 176.45 and 187.35 mg/dL, and VOC: 91.35 and 88.25, respectively. While no significant differences were observed in the sham group, our findings suggest that IFCS of the superior laryngeal nerve may impact not only the swallowing function but also the masticatory function.


Effect of prostacyclin and adenosine triphosphate on vasospasm of canine basilar artery.
Cerebral vasospasm is one of the most important factors influencing morbidity and mortality of intracranial operations or diseases. Platelet aggregation and adhesion is increased in spastic vessels. Degradation of platelets liberates mediators, which in turn increase vasospasm, thus creating a vicious cycle. Healthy vessels cope with this by increasing the synthesis of prostacyclin. The purpose of this study was to increase experimentally the levels of arterial prostacyclin and adenosine triphosphate (ATP) in animals through intraarterial injection of these substances because they are lower in spastic vessels. Prostacyclin promotes antiaggregation and dilatation, increases blood flow, inhibits thromboxane A2, and prevents synthesis of angiotensin II. Most of these effects were done by increasing cyclic adenosine monophosphate (cAMP). After injecting autogenous blood into the cisterna magna of male dogs, both the acute and chronic phases of vasospasm and the degenerative changes in the arterial wall were observed. Injecting ATP increased the severity of vasospasm. During vasospasm it was found that when prostacyclin is used intraarterially, vasodilatation began, but degeneration of the arterial wall could not be prevented. In the group of animals in which both ATP and prostacyclin were used, there was no degeneration of the arterial wall and the basilar artery was seen to be normal when viewed under the electron microscope.


Unexpected walking perturbations: Reliability and validity of a new treadmill protocol to provoke muscular reflex activities at lower extremities and the trunk.
Instrumented treadmills offer the potential to generate standardized walking perturbations, which are particularly rapid and powerful. However, technical requirements to release adequate perturbations regarding timing, duration and amplitude are demanding. This study investigated the test-retest reliability and validity of a new treadmill perturbation protocol releasing rapid and unexpected belt perturbations to provoke muscular reflex responses at lower extremities and the trunk. Fourteen healthy participants underwent two identical treadmill walking protocols, consisting of 10 superimposed one-sided belt perturbations (100ms duration; 2m/s amplitude), triggered by a plantar pressure insole 200ms after heel contact. Delay, duration and amplitude of applied perturbations were recorded by 3D-motion capture. Muscular reflex responses (within 200ms) were measured at lower extremities and the trunk (10-lead EMG). Data was analyzed descriptively (mean±SD). Reliability was analyzed using test-retest variability (TRV%) and limits of agreement (LoA, bias±1.96∗SD). Perturbation delay was 202±14ms, duration was 102±4ms and amplitude was 2.1±0.01m/s. TRV for perturbation delay, duration and amplitude ranged from 5.0% to 5.7%. LoA reached 3±36ms for delay, 2±13ms for duration and 0.0±0.3m/s for amplitude. EMG amplitudes following perturbations ranged between 106±97% and 909±979% of unperturbed gait and EMG latencies between 82±14ms and 106±16ms. Minor differences between preset and observed perturbation characteristics and results of test-retest analysis prove a high validity with excellent reliability of the setup. Therefore, the protocol tested can be recommended to provoke muscular reflex responses at lower extremities and the trunk in perturbed walking.


Comparison of the upfront surgery and neoadjuvant therapy in resectable and borderline resectable pancreatic cancer: an updated systematic review and meta-analysis.
Pancreatic cancer is a malignant disease with a dismal prognosis. While neoadjuvant therapy has shown promise in the treatment of pancreatic cancer, its role remains a subject of controversy among physicians. We aimed to evaluate the benefits of neoadjuvant therapy in patients with resectable and borderline resectable pancreatic cancer. Eligible studies were identified from MEDLINE, Embase, Cochrane Library, and Web of Science. Studies comparing neoadjuvant therapy with upfront surgery (with or without adjuvant therapy) in resectable and borderline resectable pancreatic cancer were included. The primary endpoint assessed was overall survival. A total of 10,022 studies were identified, and the meta-analysis finally enrolled 50 revealed studies. The meta-analysis suggested that neoadjuvant therapy significantly improved the overall survival (HR 0.74, p < 0.001) and recurrence-free survival (HR 0.75, p = 0.006) compared to the upfront surgery approach. Furthermore, neoadjuvant therapy leads to favorable postoperative outcomes, with an enhanced R0 resection rate (OR 1.90, p < 0.001) and reduced lymph node metastasis (OR 0.36, p < 0.001) and perineural invasion (OR 0.42, p < 0.001), although it is associated with a reduced resection rate (OR 0.42, p < 0.001). In addition, patients treated with neoadjuvant therapy experience superior survival benefits compared to those undergoing adjuvant therapy (HR 0.87, p = 0.019). These results are further corroborated by the subgroup analysis of randomized controlled trials. Neoadjuvant therapy has the potential to provide survival benefits and improve postoperative long-term outcomes for patients with resectable and borderline resectable pancreatic cancer. However, to validate and reinforce these findings, further well-designed and large trials are required.


Promotion of trained innate immunity by nanoparticles.
The dogma that immunological memory is an exclusive trait of adaptive immunity has been recently challenged by studies showing that priming of innate cells can also result in modified long-term responsiveness to secondary stimuli, once the cells have returned to a non-activated state. This phenomenon is known as 'innate immune memory', 'trained immunity' or 'innate training'. While the main known triggers of trained immunity are microbial-derived molecules such as β-glucan, endogenous particles such as oxidized low-density lipoprotein and monosodium urate crystals can also induce trained phenotypes in innate cells. Whether exogenous particles can induce trained immunity has been overlooked. Our exposure to particulates has dramatically increased in recent decades as a result of the broad medical use of particle-based drug carriers, theragnostics, adjuvants, prosthetics and an increase in environmental pollution. We recently showed that pristine graphene can induce trained immunity in macrophages, enhancing their inflammatory response to TLR agonists, proving that exogenous nanomaterials can affect the long-term response of innate cells. The consequences of trained immunity can be beneficial, for instance, enhancing protection against unrelated pathogens; however, they can also be deleterious if they enhance inflammatory disorders. Therefore, studying the ability of particulates and biomaterials to induce innate trained phenotypes in cells is warranted. Here we analyse the mechanisms whereby particles can induce trained immunity and discuss how physicochemical characteristics of particulates could influence the induction of innate memory. We review the implications of trained immunity in the context of particulate adjuvants, nanocarriers and nanovaccines and their potential applications in medicine. Finally, we reflect on the unanswered questions and the future of the field.


Morphological characterization of slow and fast pyramidal tract cells in the cat.
In adult cats the morphology of slow and fast pyramidal tract (Pt) neurons was studied following intracellular HRP injections and Golgi impregnation. Both types of neurons are pyramidal cells and their soma are all located in the fifth layer of the motor area. As a rule, fast Pt neurons have large somata and their basal and apical dendrites occupy a larger territory in the tangential plane. In layer I, terminal apical dendrites of fast Pt neurons are smooth and divide poorly while those of slow Pt neurons bear a moderate amount of spines and branch profusely. Midway between the pia and layer V, in the third layer, the apical shafts of both types of Pt cells run upward with little branching. These shafts are more numerous in fast Pt cells (7 to 16) and they are almost devoid of spines. Those of slow Pt cells in layer III number between 5 and 9 and are densely covered with spines. Oblique and horizontal branches of slow and fast Pt neurons extend in layer V and some of them invade the lower part of layer III. It is suggested that this zone corresponds to a true fourth layer in the motor area. In both types of cells oblique and lateral branches bear numerous spines. Within the basal dendritic territory of Pt cells, one has to distinguish two dendritic systems: a short and a long one. The former spreads downward obliquely and appears to remain within layer V. The latter is made up of long descending vertical (antiapical) and oblique dendrites (tap root). While both types of cells may have long antiapical dendrites that run down radially to the lower part of layer VI, tap root dendrites which expand laterally below the cell body for considerable distances are a distinctive feature of fast Pt neurons. Though basal dendrites of all Pt cells bear spines, their number, distribution and shape are very variable in fast Pt cells.


Effect of direction of pressure change on obtaining airtight seals in tympanometry.
To determine the effect of change in pressure direction on obtaining a seal during tympanometry, an ascending approach (-/+) was attempted when the traditional, descending approach (+/-) was unsuccessful in maintaining an airtight seal. Results revealed that a seal was achieved using the ascending direction in twelve ears when the descending method failed; in only four ears, neither method was successful.


MSAL-Net: improve accurate segmentation of nuclei in histopathology images by multiscale attention learning network.
The digital pathology images obtain the essential information about the patient's disease, and the automated nuclei segmentation results can help doctors make better decisions about diagnosing the disease. With the speedy advancement of convolutional neural networks in image processing, deep learning has been shown to play a significant role in the various analysis of medical images, such as nuclei segmentation, mitosis detection and segmentation etc. Recently, several U-net based methods have been developed to solve the automated nuclei segmentation problems. However, these methods fail to deal with the weak features representation from the initial layers and introduce the noise into the decoder path. In this paper, we propose a multiscale attention learning network (MSAL-Net), where the dense dilated convolutions block captures more comprehensive nuclei context information, and a newly modified decoder part is introduced, which integrates with efficient channel attention and boundary refinement modules to effectively learn spatial information for better prediction and further refine the nuclei cell of boundaries. Both qualitative and quantitative results are obtained on the publicly available MoNuseg dataset. Extensive experiment results verify that our proposed method significantly outperforms state-of-the-art methods as well as the vanilla Unet method in the segmentation task. Furthermore, we visually demonstrate the effect of our modified decoder part. The MSAL-Net shows superiority with a novel decoder to segment the touching and blurred background nuclei cells obtained from histopathology images with better performance for accurate decoding.


Tamoxifen protects clonal mouse hippocampal (HT-22) cells against neurotoxins-induced cell death.
In the present work using an established clonal mouse hippocampal (HT-22) cell line, we have examined whether the estrogen antagonist tamoxifen antagonizes the observed neuroprotective effects of estrogen against glutamate and amyloid beta protein neurotoxicity. Results obtained suggest that like estrogen, tamoxifen protects HT-22 cells against both 5mM glutamate and 2 microM amyloid beta protein induced cell death in a concentration dependent manner. Optimum protection was obtained at 500 nM tamoxifen. Tamoxifen was found to offer more potent protection at this dose against amyloid beta protein induced neurotoxicity when compared with glutamate neurotoxicity. We were unable to detect either estrogen receptor (ER)--ER alpha or ER beta presence in HT-22 cells using western blot technique. However, amyloid beta protein treatment significantly increases total glucocorticoid receptors (GRs) as determined by western blot technique, while prior treatment with estrogen or tamoxifen followed by amyloid beta protein resulted in the reduction of total GRs to the levels comparable to that observed for the control untreated cells. In addition, using confocal immunoflourescence microscopy technique, we observed that 20 h of treatment with 2 microM amyloid beta protein resulted in enhanced nuclear localization of GRs in HT-22 cells as compared to control untreated cells or 500 nM tamoxifen alone treated cells. Interestingly, 500 nM tamoxifen treatments for 24h, followed by 20 h treatment with 2 microM amyloid beta protein resulted in dramatic reduction in GRs nuclear localization. In conclusion, tamoxifen (i) protects HT-22 cells against amyloid beta protein neurotoxicity and (ii) neuroprotective effect is independent of ERs.


Cinnamon modulates the pharmacodynamic & pharmacokinetic of amlodipine in hypertensive rats.
The objective of this study was to investigate the effects of cinnamon on the pharmacodynamic (PD) & pharmacokinetic (PK) of amlodipine in hypertensive rats. The hypertensive control group of Wistar rats received L-NAME (40 mg/kg, daily, orally) only. The cinnamon group of rats was treated with cinnamon (200 mg/kg, daily, orally) along with L-NAME. Following 14 days treatment period, blood pressures of rats were monitored at designated intervals over 24 h utilizing a tail-cuff system for measuring blood pressure. To assess the oral PK; amlodipine was administered as a single oral dose of 1 mg/kg to rats and blood samples were collected at specified intervals over 24 h and analysed by UPLC-LC MS/MS. Synergistic decreased in rat's blood pressure was observed in presence of cinnamon + amlodipine. Simultaneous administration of cinnamon ameliorates the Cmax and AUC0-t of amlodipine, the Cmax and AUC0-t was 11.04 ± 1.01 ng/ml and 113.76 ± 5.62 ng h/ml for the cinnamon + amlodipine group as compared to 4.12 ± 0.49 ng/ml and 48.59 ± 4.28 ng h/ml for the amlodipine alone group. The study demonstrates that the use of cinnamon considerably decreases the blood pressure levels and enhances the PK parameters of amlodipine in hypertensive rats.


Metals and metalloids in Antarctic krill and water in deep Weddell Sea areas.
The study on the concentration of trace elements in Antarctic krill and in water in the deep areas of the Atlantic sector of the Antarctic was performed. Concentrations of 22 trace elements were studied to determine their spatial distribution in krill, and to assess the accumulation ability of the krill against 8 of them. The trace elements concentration in krill diminished in the following order: Fe > Cu > Zn > Bа > B > Se > As > Cr > Ni > Ag > Li > Mn > V > Mo > Cd > Co > Hg > Be. Concentrations of Pb, Ti, Tl, Sb were below their detection limits. Concentration factors of trace elements by krill varied from n × 102 to n × 104. The Cu and As concentrations in dry krill exceeded their MPC. Concentrations of all trace elements in wet mass of krill were not exceeded established regulative values.


Lung surfactant: a biotechnological challenge.
The genes for all three of the bona fide surfactant associated proteins have been cloned, allowing their production by recombinant DNA technology. In addition, improved protocols for the isolation of the natural surfactant proteins (NSP) made them available in larger quantities. Whereas, the NSP are often mixtures of allelic variants or functional isomers from gene families, the recombinant proteins (RSP) are obtained as single pure protein species. Antibodies directed against the N/RSP in combination with DNA probes have allowed new approaches to analyze the formation, location, transport, structure and functional capacities of these molecules as well as their interactions with one another and the phospholipids.


Moraxella bacteremia. Report of a case resembling gonococcemia with cutaneous manifestations.
A case of a Moraxella osloensis bacteremia mimicking a case of gonococcemia, complete with cutaneous manifestations, is presented. The importance of confirming all positive smears with inhibitory and noninhibitory culture media is stressed.


The impact of nonmotor symptom burden on sexual function.
Sexual dysfunction (SD) is defined as a combination of reduction in libido, and problems with a person's ability to have sex. It is a frequent but neglected and poorly recognized nonmotor symptom (NMS) in Parkinson's disease (PD) which correlates with reduced quality of life (QoL). Hypersexuality forms another spectrum of SD and is an impulse control disorder (ICD) of behavior, which also affects the sexual desires of people with Parkinson's (PwP) and impacts their partner, family, and QoL. NMS occur in various forms and represents a range of symptoms, from cognitive dysfunction to pain and SD, and this chapter explores the relationship of comorbid NMS with SD and also how NMS, motor symptoms, and hypersexuality experienced by patients may impact sexual function in people with Parkinson's (PwP).


Kinetics of arsenic release from naturally contaminated soils at half saturation moisture by various extractants.
Kinetic studies on arsenic (As) release from soils are commonly performed using soils spiked or artificially contaminated with As at soil to solution ratios of 1:10 to 1:50 by mass, which make the conditions of study very different from the prevailing field situations. In this study, the kinetics of As release were investigated using different extractants including 1MK2HPO4, 0.5MNa3C6H5O7, 1MNaOH, 1MNH4F, and [Formula: see text] in five naturally As-contaminated soils (80-1680 mg total As/kg) at half saturation moisture over a long period of time (15 min-60 d). Six kinetic models were employed to fit the data. Results indicated that the trend of As release was initially rapid followed by a slow release with K2HPO4, [Formula: see text] and Na3C6H5O7 solutions, whereas with NaOH and NH4F an increasing As release was followed by a decreasing trend at longer times, and a considerable amount of the released As was re-adsorbed or precipitated. The order of the cumulative amounts of As released by extractants was [Formula: see text] . The percentage of total As released during the reaction time was less than 3% for all extractants except K2HPO4, which was between 4.0 and 8.5% in different soils. Therefore, much lower extractability of As occurred in the naturally As-contaminated soils at half saturation moisture than has previously been reported for soils spiked or artificially contaminated with As at lower soil to solution ratios (1:10 to 1:50) suggests that caution should be exercised in extending or applying the results of As release studies on artificially contaminated soils to naturally contaminated soils for remediation purposes. Finally among six kinetic models, only the power function and the simplified Elovich models described the release data satisfactorily.


Glucocorticoids for Management of Polymyalgia Rheumatica and Giant Cell Arteritis.
Diagnosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) is based on typical clinical, histologic, and laboratory features. Ultrasonographic imaging in PMR with assessment especially of subdeltoid bursitis can aid in diagnosis and in following response to treatment. In GCA, diagnosis and disease activity are supported with ultrasonographic, MRI, or [(18)F]fluorodeoxyglucose PET evaluation of large vessels. Glucocorticoids are the primary therapy for PMR and GCA. Methotrexate may be used in patients at high risk for glucocorticoid adverse effects and patients with frequent relapse or needing protracted therapy. Other therapeutic approaches including interleukin 6 antagonists are under evaluation.


Glycosylated zein as a novel nanodelivery vehicle for lutein.
Glucosamine-glycosylated zein (GLZ) generated by transglutaminase was developed as a novel delivery vehicle to prepare lutein-loaded glycosylated zein nanoparticles (GLZ-LUT). GLZ-LUT exhibited a polydispersed spherical microstructure, lutein was embedded into GLZ to form nanocomplexes via self-assembly, they had a lower zeta potential and an average particle size of less than 200 nm. Compared to lutein-loaded zein nanoparticles (Zein-LUT), the lutein entrapment efficiency of GLZ-LUT was increased from 81.55% to 89.60%. Infrared spectroscopy (FTIR) analysis results confirmed that zein was successfully modified and that lutein was encapsulated by hydrophobic zein and GLZ. Moreover, GLZ showed significantly higher solubilization of lutein than Zein-LUT and significantly improved the in vitro release of lutein in the simulated gastrointestinal tract. The in vitro antioxidant activity of lutein was also enhanced by the encapsulation of zein and glycosylated zein. These findings indicated that GLZ represent a potentially efficient and promising nanodelivery carrier for lutein compounds.


Carboxymethyl chitosan/sodium alginate hydrogel films with good biocompatibility and reproducibility by in situ ultra-fast crosslinking for efficient preservation of strawberry.
Strawberry is a seasonal and regional fruit. Thus, strawberry waste caused by spoilage and decay is an urgent problem that must be solved. Developing hydrogel films (HGF) for multifunctional food packaging can effectively slow down strawberry. Based on the carboxymethyl chitosan/sodium alginate/citric acid with excellent biocompatibility, preservation effect, and ultrafast (10 s) coating on the strawberry surface, HGF specimens were designed and prepared through the electrostatic interaction of opposite charges between polysaccharides. The prepared HGF specimen exhibited excellent low moisture permeability and antibacterial properties. Its lethality rates against both Escherichia coli and Staphylococcus aureus were more than >99 %. The HGF could keep strawberries fresh for up to 8, 19, and 48 days at 25.0, 5.0, and 0 °C, respectively, by delaying the fruits' ripening, dehydration, microbial invasion, and respiration rate. The HGF dissolved and regenerated five times still exhibited good performance. The water vapor transmission rate of the regenerative HGF could reach 98 % of that of the original HGF. The regenerative HGF could maintain the freshness of strawberries for up to 8 days at 25.0 °C. This study provides new insight into an alternative film design for convenient, green, and renewable alternative films to delay perishable fruit spoilage.


Can sleep questionnaires predict adenotonsillectomy outcome for children with sleep disordered breathing?
Adenotonsillar hypertrophy is the main cause of childhood sleep disordered breathing (SDB) and adenotonsillectomy (TA) the most common treatment. Polysomnography (PSG) for diagnosing SDB is often difficult to obtain with Otolaryngologists usually relying on history and examination when recommending TA. Questionnaires assessing quality of life (QoL) may assist the Otolaryngologists decision making. To explore changes in QoL tools following TA for SDB in children aged 3 to 15 with the aim of identifying whether the Pediatric Sleep Questionnaire (PSQ) or Obstructive Sleep Apnoea -18 (OSA-18) is a better predictor of outcome following TA. QoL was assessed using OSA-18, PSQ and the Pediatric Quality of Life Inventory™ (PedsQL™). Four groups were recruited from three research databases, those with: SDB, recurrent tonsillitis (RT), SDB and RT, or no disease (controls). Children either received TA or underwent observation. QoL questionnaires were administered at recruitment and 3 months later. Test-retest reliability was assessed using Bland-Altman plots. Pre-intervention scores were plotted against changes in scores, with pre-established cut-offs and cut-offs indicated by control group variability. There were 120 children, 25 had no intervention, and 19 were controls. All questionnaires showed test-retest reliability over time. Using the distribution of scores from the control group we estimated the 95th percentile to redefine the cut-off for OSA-18 (reduced from 60 to 46) and PSQ (unchanged from 0.33). Higher pre-operative scores predicted greater reduction following TA, with OSA-18 the most consistent predictor of QoL change. The PSQ classified 86.8% of children undergoing TA above the 0.33 cut-off; whereas OSA-18 classified 73.7% above the 46 cut-off. Of these, 71.2% and 87.5% showed improvement after TA, respectively. Using the 95% confidence interval for change in the control group to identify a 'meaningful' change in score, children with OSA-18 scores >46 had a 93% chance of a meaningful improvement, whereas PSQ scores >0.33 were associated with an 80% chance of a meaningful improvement. OSA-18 is a better predictor of improved QoL than PSQ for TA in children with SDB. We propose a new cut off score (>46) for OSA-18. This may assist Otolaryngologists' decision making when assessing a child with SDB.


Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice.
The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson's disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD. In this study, live Pg were orally administrated to animals, three times a week for 1 month. Pg-derived lipopolysaccharide (LPS) was used to stimulate mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression. Dopaminergic neurons in the substantia nigra were reduced, and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) was detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice. These findings suggest that oral Pg-induced inflammation may play an important role in the pathophysiology of LRRK2-associated PD.


Routine reversed-phase high-performance liquid chromatographic measurement of urinary vanillylmandelic acid in patients with neural crest tumors.
A rapid and simple reversed-phase high-performance liquid chromatographic procedure for the determination of vanillylmandelic acid (VMA) is described. This method was applied in the determination of the VMA content in urine from normal subjects and patients with neural crest lesions. Sample preparation is minimal and the analysis is short (20 min) and reproducible. The sensitivity of the UV detection is in the ng range. By this technique, fourteen adult control subjects were found to excrete a mean of 2.86 microgram VMA per mg creatinine, whereas twelve patients with pheochromocytoma excreted a mean of 15.7 microgram VMA per mg creatinine.


Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle.
Skeletal and cardiac muscle depend on high turnover of ATP made by mitochondria in order to contract efficiently. The transcriptional coactivator PGC-1alpha has been shown to function as a major regulator of mitochondrial biogenesis and respiration in both skeletal and cardiac muscle, but this has been based only on gain-of-function studies. Using genetic knockout mice, we show here that, while PGC-1alpha KO mice appear to retain normal mitochondrial volume in both muscle beds, expression of genes of oxidative phosphorylation is markedly blunted. Hearts from these mice have reduced mitochondrial enzymatic activities and decreased levels of ATP. Importantly, isolated hearts lacking PGC-1alpha have a diminished ability to increase work output in response to chemical or electrical stimulation. As mice lacking PGC-1alpha age, cardiac dysfunction becomes evident in vivo. These data indicate that PGC-1alpha is vital for the heart to meet increased demands for ATP and work in response to physiological stimuli.


Central neurocytoma.
Central neurocytomas (CN) are rare intraventricular tumors with prominent neuronal differentiation. CN commonly arise in the lateral ventricles of young adults who predominantly present with raised intracranial pressure. Few studies have described the clinical, pathological, and radiological features of these tumors, and those that have are typically single case reports. Herein, we report ten patients with CN with variable clinical and pathological features and discuss the management of these tumors. Nine tumors occupied the lateral ventricle and only one was located in the sellar region. On MRI, all 10 tumors showed heterogeneous hypo-or iso-intensity on T1-weighted and hyperintensity on T2-weighted MRI. Contrast enhancement varied greatly from very slight to intense. All patients were surgically treated by macroscopic total or subtotal removal. Postoperative radiotherapy was given to six patients (four of whom had undergone subtotal resection and two of whom had undergone total resection). The surgical and histopathological data of these patients were reviewed and analyzed. No recurrences were noted although we were unable to contact two patients for follow-up. A brief review of the literature concerning differential diagnosis and therapeutic aspects of these tumors is also presented.


Zotarolimus compared with everolimus eluting stents-angiographic and clinical results after recanalization of true coronary chronic total occlusions.
To evaluate angiographic and clinical results of ZES compared with EES after recanalization of CTOs. ZES and EES showed similar clinical results in non-CTO lesions. Whether ZES and EES are also comparable in true CTO lesions (TIMI 0 flow, duration of occlusion of more than 3 months) with a higher risk of restenosis has not been addressed so far. 125 patients with successful CTO recanalization via antegrade or retrograde approach were included. EES were implanted in 68 patients and ZES in 57 patients. Dual antiplatelet therapy was prescribed for 12 months. Follow-up angiography was scheduled at 9 months and clinical follow-up at 12 months. The primary angiographic outcome measure was in-stent late lumen loss. Primary clinical outcome measures were target lesion revascularization rate (TLR) and major adverse cardiac events (MACE) as a composite of cardiac death, TLR and myocardial infarction not clearly attributable to a non-target vessel. Baseline characteristics were similar in both groups. Mean stent length was 72.8 ± 33.0mm with EES and 70.8 ± 31.5 mm with ZES (P = 0.72). In-stent late lumen loss was 0.50 ± 0.71 mm for EES compared with 0.59 ± 0.72 (P = 0.52) for ZES. There were similar rates for TLR (EES 10.3% versus ZES 10.5%, P = 0.97) and MACE (EES 10.3% versus ZES 12.3%). No definite or probable stent thrombosis occurred. Stent length but not type of stent was predictive for in-stent late loss and TLR. ZES and EES showed similar angiographic and clinical outcomes for treatment of CTOs. © 2016 Wiley Periodicals, Inc.


Pneumothoraces complicating systemic lupus erythematosus with nephritis.
Pneumothorax is an infrequently reported complication of systemic lupus erythematosus (SLE) and carries with it a grave prognosis. We report a patient with SLE and nephritis who developed pneumothorax that responded to aggressive and prolonged therapy. Surgical management with prolonged evacuation, judicious immunosuppression, and aggressive diagnosis and treatment of infection can improve the outcome for these patients.


What We Can Learn from Artificial Lateral Line Sensor Arrays.
The lateral line system of fish is important for many behaviors, including spatial orientation, prey detection, intraspecific communication, and entraining. With aid of the lateral line, fish perceive minute water motions. The smallest sensory unit of the lateral line is the neuromast, which occurs freestanding on the skin and in fluid-filled canals. We have built artificial lateral line canal systems that can be used to measure spatiotemporal flow patterns. Those patterns can, for instance, be used to distinguish between different environments and upstream objects.


Brief report: clonazepam behavioral side effects with an individual with mental retardation.
Behavioral side effects associated with clonazepam may include agitation, aggression, hyperactivity, irritability, property destruction, and temper tantrums. These side effects may be inadvertently confused with other behavioral or psychiatric conditions, especially if exacerbation of existing challenging behavior occurs. This report describes an individual with mental retardation who experienced behavioral exacerbation associated with clonazepam prescribed at 2 mg/day (0.02 mg/kg/day) to treat aggression, self-injurious behavior, property destruction, and screaming, which was measured with a 15-minute partial interval recording measurement method. When clonazepam was reduced and discontinued, these behaviors significantly decreased from 3.1% of intervals (95% confidence band = 1.6% to 4.6%) to 0.1% of intervals (95% confidence band = 0% to 0.1%). Indicators suggesting review by appropriate medical personnel for possible clonazepam behavioral side effects are provided.


Effectiveness of a desensitizing agent before in-office tooth bleaching in restored teeth.
The aim of this clinical trial was to evaluate the effectiveness and tooth sensitivity associated with bleaching in patients with composite restorations in anterior teeth after the application of a desensitizing agent. Bleaching was performed with 35 % hydrogen peroxide gel in 30 patients with composite restorations in anterior teeth, divided according to the prior application of a desensitizing agent (De), or a placebo (Pl), on maxillary superior teeth. Color was recorded at baseline, 1 week after each session and 6 months after treatment. The experience of tooth sensitivity (TS) was recorded on an NRS (0-4) during bleaching and 24 h after each session. Bleaching effectiveness was evaluated by one-way ANOVA and Tukey's tests (α = 0.05). The percentage of TS was evaluated by Fisher's exact test. For each treatment, periods were compared using the Wilcoxon signed-rank test (α = 0.05), and at each period, treatments were compared using Mann-Whitney U test. Both groups showed similar tooth color enhancement and color stability after 6 months (p < 0.05). No significant difference in prevalence of sensitivity was detected between groups (p < 0.001). Higher TS intensity (median [first/third quartiles]) was observed for Pl (1.5 [1/1.75]) compared with De (0.5 [0/1]) during treatment (p < 0.05). The use of a desensitizing gel (5 % potassium nitrate, 2 % sodium fluoride) before tooth bleaching in patients with composite restorations did not reduce the prevalence of tooth sensitivity, but reduced the intensity of TS during bleaching. Although the use of a desensitizing agent before bleaching, in patients with composite resin restorations, did not reduce the prevalence of TS, a reduction of the TS intensity during the protocol was observed without jeopardizing the whitening outcome.


Changes in the quality of life of early breast cancer patients and comparison with the normative Slovenian population.
We aimed to identify changes in quality of life after breast cancer treatment and compare them with the normative population data for the Slovenian population. A prospective, single-group, cohort design was used. A total of 102 early breast cancer patients treated with chemotherapy at the Institute of Oncology Ljubljana were included. Of those, 71% returned the questionnaires after one-year post-chemotherapy. The Slovenian versions of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and BR23 questionnaires were used. Primary outcomes were a comparison of global health status/quality of life (GHS) and C30 Summary Score (C30-SumSc) at baseline and one-year post-chemotherapy with the normative Slovenian population. The exploratory analysis evaluated the differences in symptoms and functional scales of QLQ C-30 and QLQ BR-23 between baseline and one-year post-chemotherapy. At baseline and one-year post-chemotherapy, C30-SumSc of patients was lower than the predicted C30-SumSc from the normative Slovenian population by 2.6 points (p = 0.04) and 6.5 points (p < 0.001), resp. On the contrary, GHS was not statistically different from predicted either at baseline or after one year. Exploratory analysis revealed that one-year post-chemotherapy compared to the beginning of chemotherapy, patients had statistically significantly and clinically meaningful lower scores in body image and cognitive functioning, and increased symptom scores for pain, fatigue, and arm symptoms. The C30-SumSc is reduced one-year post-chemotherapy. Early interventions should be directed toward the prevention of the decline of cognitive functioning and body image, and to alleviate fatigue, pain, and arm symptoms.


The diagnosis and management of neurofibromatosis 2 in childhood.
Neurofibromatosis 2 (NF2) is an autosomal-dominant condition that causes multiple benign nervous system tumors, especially vestibular schwannoma. Although frequently confused with the more common neurofibromatosis 1, NF2 presents a distinct set of diagnostic, genetic, and management issues. The presentation and natural history of NF2 differs in children and adults, with eighth nerve dysfunction often overshadowed by the effects of other tumors on the nervous system. Molecular diagnostics is an important tool for early recognition of NF2, and when performed in the context of appropriate counseling and follow-up, may lead to a better final outcome of the disease. Further research into the molecular genetic etiology of NF2 promises to broaden the possibilities of therapy for this devastating disorder.


Studies in the field of pyridazine compounds. Part 21. Structural studies on 6-H-pyrimido[1,2-b]-1,2,4-triazolopyridazines.
The structure of 7,8-dihydro-6H-pyrimido [1,2-b]-1,2,4-triazolo [3,4-f] pyridazine (2a) was confirmed by 1H and 13C NMR spectroscopy and by preparation of the isomeric [5,1-f] pyridazine 3. Some derivatives of 6H-pyrimido [1,2-b]-1,2,4,-triazolo [3,4-f]pyridazine were prepared. Compounds 2a, 2b and 9a showed a positive inotropic effect.


Estrogen receptor in uteri of mice of different H-2 genotypes.
A relationship between the amount of available estradiol receptors in uteri of inbred mice and their H-2 genotype is suggested by study in congenic animals.


Metaphyseal chondrodysplasia, Schmid type. Clinical and radiographic delineation with a review of the literature.
Analysis of 20 cases of metaphyseal chondrodysplasia, Schmid type as well as a review of the world literature reveals a specific autosomal dominant disorder that was often over-diagnosed in the past, sometimes resulting in incorrect genetic counselling. Significant radiologic features include an enlarged capital femoral epiphysis in early childhood, coxa vara, greater involvement of the distal femoral metaphysis than the proximal, anterior rib changes and a normal spine. Chondroosseous morphology is not specific. Presentation in nonfamilial cases is no earlier than the second year of life.


Effects of spatial variation in water quality and hydrological factors on environmental flows.
Environmental flow is the quantity, timing, and quality of water flows required to sustain freshwater and estuarine ecosystems and the human livelihoods and well-being that depend on these ecosystems. Environmental flows (e-flows) are crucial parameters for ecosystem restoration. Understanding the effects of spatial variation in the hydrological and water quality factors on e-flows aids the determination of recovery prior areas and helps to improve the success rate of ecosystem restoration projects. However, few studies have investigated the effects, which severely hinder the restoration of aquatic ecosystems and the sustainable use of water resources in inland waters. This paper therefore presents a framework for studying such effects. Spatial autocorrelation, a geostatistical method, is used to analyze the spatial variation in the hydrological and water quality factors and to further analyze the effects of various factors on the spatial heterogeneity of e-flows. Four different methods including the Tennant method, wetted perimeter method, AEHRA, and integrated water quality method are integrated to comprehensively evaluate e-flows. The former three methods consider the demands of biota on the streamflow, whereas the latter considers the demands on both the streamflow and the water quality. The results show that the Tennant and wetted perimeter methods, which focus on the statistics of only streamflow, result in similar spatial distribution of e-flows; the AEHRA and integrated water quality method, which consider the effects of water quality and other hydrological factors such as flow velocity and water depth on fish, also result in a similar spatial variation. Consideration of both demands on the hydrological factors and the water quality environmental factors makes the integrated water quality method more practical, particularly in developing regions with excessive pollutant discharge into rivers. In addition, spatial variation in the hydrological and water quality factors influenced the presence of principal fish species and consequently affected the e-flows. Of the 37 water quality factors identified, water transparency had a negative impact on e-flow because the increase in transparency could reduce the number of principal fish species. Of the four hydrological factors, flow velocity and river width had positive impacts on fish because the increase in flow velocity can provide breeding sites and habitats for more fish, respectively, both of which result in increases in the numbers of principal fish species. We found that spatial variation in the hydrology and water quality factors had a profound impact on the living environments of aquatic organisms; negative changes in these factors lowered the survival probability of principal species, which changed the hierarchy and structure of the ecosystems and thus led to variation in e-flows. The results can provide priori knowledge for e-flow methods selection and a reference for ecosystem restoration helping improve the success rate of project elsewhere in the world.


Two-photon-activated ligand exchange in platinum(II) complexes.
Two photons are better than one: a square-planar Pt(II) complex with derivatized pyridine ligands was synthesized, which undergoes two-photon-induced ligand substitution with 600-740 nm light. Linear and quadratic density functional response theory allowed identification of the electronic transitions involved.


A novel combined radiological method for evaluation of the response to chemotherapy for primary bone sarcoma.
In the treatment of bone sarcoma, evaluation of chemotherapeutic effects is extremely important. In this study, we compared radiological evaluations and histological response, and developed a combined radiological scoring system for assessing the response to chemotherapy. A total of 79 patients with primary bone sarcomas were examined by X-ray photography (Xp), angiography, MRI, 201Tl scintigraphy (Tl) and 99mTc-MIBI scintigraphy (MIBI) to evaluate their response to preoperative chemotherapy. Patients were classified as responders and non-responders according to radiological images. All resected tumors were evaluated histologically and classified as a good response (≥90% necrosis) or a poor response (≤90% necrosis). The sensitivity, specificity, accuracy, and kappa values in radiological evaluation were calculated. Furthermore, we developed a combined radiological scoring system that correlated the results of radiological images with histological response. Sensitivity, specificity, and accuracy were 90.9%, 38.2%, and 67.5% (K = 0.31), respectively, for Xp; 91.7%, 33.3%, and 66.7% (K = 0.27) for angiography; 81.0%, 67.6%, and 75.0% (K = 0.49) for MRI; 78.9%, 72.4%, and 76.1% (K = 0.51) for Tl; 85.3%, 69.2%, and 78.3% (K = 0.55) for MIBI; and 93.3%, 76.5%, and 86.1% (K = 0.71) for combined radiological scoring. Combined radiological evaluations showed high correlation with histological response for assessing the effects of chemotherapy.


The Continuing Evolution of Precision Health in Type 2 Diabetes: Achievements and Challenges.
The purpose of this review was to summarize recent advances in the genomics of type 2 diabetes (T2D) and to highlight current initiatives to advance precision health. Generation of multi-omic data to measure each of the "biologic layers," developments in describing genomic function and annotation in T2D relevant tissue, along with the increasing recognition that T2D is a heterogeneous disease, and large-scale collaborations have all contributed to advancing our understanding of the molecular basis of T2D. Substantial advances have been made in understanding the molecular basis of T2D pathogenesis, such that precision health diabetes is increasingly becoming a reality. For precision diabetes to become a routine in clinical and public health, additional large-scale multi-omic initiatives are needed along with better assessment of our environment to delineate an individual's diabetes subtype for improved detection and management.


Effect of tumor necrosis factor-α blockade on mucosal addressin cell-adhesion molecule-1 in Crohn's disease.
Mucosal addressin cell-adhesion molecule (MAdCAM)-1, which is overexpressed on gut endothelium in active Crohn's disease (CD), promotes intestinal recruitment of integrin α(4)β(7)(*) T cells that sustain chronic inflammation. As tumor necrosis factor alpha (TNF)-α, a cytokine centrally involved in CD, modulates gut endothelial adhesion molecules, we here explored the in vivo and ex vivo effects of TNF-α blockade on MAdCAM-1 expression in CD. MAdCAM-1 was determined by immunoblotting in colonic biopsies collected before and 10 weeks after either infliximab or adalimumab treatment in CD patients, and in CD biopsies incubated with either infliximab or adalimumab or control IgG(1). Integrin β(7)(*) circulating T cells were analyzed by flow cytometry. MAdCAM-1 significantly decreased after either infliximab or adalimumab treatment in responder but not in nonresponder patients. In parallel, an increase of circulating β(7)(*) T cells was found in responder patients only. A marked downregulation of MAdCAM-1 was observed in CD biopsies cultured with either infliximab or adalimumab in comparison to IgG(1)-treated biopsies. Our findings showing that MAdCAM-1 is downregulated by TNF-α blockade point to a novel mechanism of action of anti-TNF-α antibodies in CD.