Induced pluripotent stem cells reprogramming: Epigenetics and applications in the regenerative medicine.
Induced pluripotent stem cells (iPSCs) are somatic cells reprogrammed into an embryonic-like pluripotent state by the expression of specific transcription factors. iPSC technology is expected to revolutionize regenerative medicine in the near future. Despite the fact that these cells have the capacity to self-renew, they present low efficiency of reprogramming. Recent studies have demonstrated that the previous somatic epigenetic signature is a limiting factor in iPSC performance. Indeed, the process of effective reprogramming involves a complete remodeling of the existing somatic epigenetic memory, followed by the establishment of a "new epigenetic signature" that complies with the new type of cell to be differentiated. Therefore, further investigations of epigenetic modifications associated with iPSC reprogramming are required in an attempt to improve their self-renew capacity and potency, as well as their application in regenerative medicine, with a new strategy to reduce the damage in degenerative diseases. Our review aimed to summarize the most recent findings on epigenetics and iPSC, focusing on DNA methylation, histone modifications and microRNAs, highlighting their potential in translating cell therapy into clinics.


Blood culture and conventional media for vitreous culture in infectious endophthalmitis.
To study culture of vitreous fluid specimens in patients with infectious endophthalmitis, using blood culture bottles compared with conventional culture media. Patients with infectious endophthalmitis, occurred within 6 weeks after ocular trauma or intraocular surgery, were prospectively studied. Vitreous fluid specimens were cultured in both blood culture bottles and conventional culture media. The measured outcome is the yield of positive culture and time to positive culture. The vitreous fluid culture was positive in 14 of 27 eyes (51.85%). Blood culture bottle was positive in 14 of 14 eyes (100%), whereas conventional culture media was positive in 7 of 14 eyes (50%). Most specimens in both techniques showed positive culture within 24 hours. Vitreous fluid culture with blood culture bottles is superior to conventional media with statistically significant difference. There was no significant difference in time to positive culture.


Evaluation of low-pressure gas chromatography-tandem mass spectrometry method for the analysis of >140 pesticides in fish.
A multiresidue method for the analysis of 143 pesticide residues in fish was developed and evaluated using fast, low-pressure gas chromatography/triple-quadrupole tandem mass spectrometry (LP-GC/MS-MS). The method was based on a QuEChERS (quick, easy, cheap, effective, rugged, safe) extraction with acetonitrile and dispersive solid-phase extraction (d-SPE) cleanup with zirconium-based sorbent. The developed method was evaluated at four spiking levels (1, 5, 50, and 100 ng/g) and further validated by analysis of NIST Standard Reference Materials (SRMs) 1974b and 1947 for selected pesticides with certified concentrations. Acceptable recoveries (70-120%) and standard deviations below 20% were achieved for the majority of pesticides from fortified samples. The measured values for both SRMs agreed with certified values (71-115% accuracy, 4-14% relative standard deviations) for all pesticides, except for p,p-DDD + o,p-DDT (45%) and heptachlor (133%) in SRM 1974b and except for mirex (58%) and trans-chlordane (136%) in SRM 1947. The developed method is fast, simple, and inexpensive with detection limits of 0.5-5 ng/g. Residues of dimethoate, hexachlorobenzene, BHC, lindane, nonachlor, chlorpyrifos, trifluralin, p,p-DDE, p,p-DDD, o,p-DDD, o,p-DDT, p,p-DDD, and chlordane were measured in catfish samples from the market.


[Heart and brain -- the influence of psychiatric disorders and their therapy on the heart rate variability].
Psychiatric disorders are associated with autonomic dys-regulations. There is evidence that these dys-regulations are partly responsible for the increased mortality in patients with psychiatric disorders. The determination of the heart rate variability (HRV) is a method easily applicable and allows the assessment of the autonomic control of the heart rate regulation. A multitude of HRV parameters with different physiological meanings have been introduced, the most widely used parameters are presented and characterized in this paper. Many studies have shown a reduced HRV in patients with major depression. Most studies found a reduced parasympathetic activity. However some authors discuss an elevated sympathetic activity. The magnitude of HRV reduction correlates to the severity of the depression. In patients with coronary diseases, major depression is an independent risk factor of mortality. Antidepressive therapy with serotonin reuptake inhibitors has failed to improve the prognosis of this patients. Patients with panic disorders also have a reduced HRV due to an elevated sympathetic control and reduced vagal control. In schizophrenic patients a reduced HRV was found in long term electrocardiogram recordings, whereas short term recordings did not show a reduced HRV. Patients with Alzheimer's disease also have a reduced HRV, which is limited to the low frequency component. Therapy with cholinesterase inhibitors further influences HRV by reducing the high frequency component and might increase the risk for arrhythmias. HRV analysis and integration in the assessment and monitoring of psychiatric patients before and during therapy elucidate the role of autonomic disturbances in such diseases and may help to optimize treatment.


Colorectal cancer in the young - outcomes following surgical management?
Colorectal cancer (CRC) is the third most common cancer, accounting for approximately 10% of all cancer deaths. The incidence of CRC in young adults and the adolescent population is increasing. This study aims to highlight short-term outcomes for young patients with CRC. Data were collected retrospectively for all patients aged less than 50 years diagnosed with CRC at a university teaching hospital between October 2012 and June 2018. The primary endpoints were disease-free survival (DFS) and overall survival (OS). A total of 120 patients (65 males, 55 females) with CRC aged under 50 years were initially included; 20 did not receive surgical treatment (12 metastatic adenocarcinoma, 5 metastatic squamous cell cancer (SCC), 3 neuroendocrine tumours (NET)), and 13 patients had insufficient data for analysis and were excluded. A total of 87 patients underwent surgical intervention and 66 with diagnosis of adenocarcinoma were included in survival analysis. Median age of patients was 42 years (19-49 years). Cancer recurrence was seen in 14 patients, 10 showing local, 3 liver and 1 lung metastasis. The median OS was 28 months (3-156 months). The median DFS was 13 months (3-85 months). Overall 5-year survival and DFS were 72% and 59%, respectively. Median survival in the group who did not undergo surgery was 4.5 months (1-15 months). CRC is often more advanced and aggressive in younger patients. Current guidelines can result in young patients being investigated/treated for other gastrointestinal conditions before referral for CRC investigation.


Tritylamine as an ammonia surrogate in the Ugi tetrazole synthesis.
The role of tritylamine is introduced as a convenient ammonia substitute in the Ugi tetrazole synthesis. Fifteen examples and their mild cleavage products are described in satisfactory to good yields. N-Unsubstituted α-aminotetrazoles are important compounds with annotated biological activities, and the described two-step synthesis provided an alternative route to otherwise difficult to access derivatives.


Dissecting immunity by germline mutagenesis.
The last decades have seen numerous approaches being used to decipher biological phenomena, notably the strategies we employ to defend ourselves against pathogenic attacks. From microarrays to genetics to computing technologies, all have supported a better but not yet comprehensive understanding of the pathways regulating our immune system. Limitations are notably exemplified by cases of immune deficiencies in humans that often result in high susceptibility to infections or even death, without the genetic cause being evident. To provide further insight into the mechanisms by which pathogen detection and eradication occur, several in vivo strategies can be used. The current review focuses on one of them, namely germline mutagenesis in the mouse. After describing the main technical aspects of this forward genetic approach, we will discuss particular germline mutants that have all been instrumental in deciphering innate or adaptive immune responses. Mutations in previously uncharacterized genes in the mouse, like Unc93B or Themis, have demonstrated the impartiality of forward genetics and led to the identification of new crucial immunity actors. Some mutants, like PanR1, have informed us on particular protein domains and their specific functions. Finally, certain mutations identified by this non-hypothesis-driven method have revealed previously unknown gene functions, as recently illustrated by memi, which links a particular nucleoside salvage enzyme to cell proliferation and apoptosis.


LysX2 is a Mycobacterium tuberculosis membrane protein with an extracytoplasmic MprF-like domain.
Aminoacyl-phosphatidylglycerol (aaPG) synthases are bacterial enzymes that usually catalyze transfer of aminoacyl residues to the plasma membrane phospholipid phosphatidylglycerol (PG). The result is introduction of positive charges onto the cytoplasmic membrane, yielding reduced affinity towards cationic antimicrobial peptides, and increased resistance to acidic environments. Therefore, these enzymes represent an important defense mechanism for many pathogens, including Staphylococcus aureus and Mycobacterium tuberculosis (Mtb), which are known to encode for lysyl-(Lys)-PG synthase MprF and LysX, respectively. Here, we used a combination of bioinformatic, genetic and bacteriological methods to characterize a protein encoded by the Mtb genome, Rv1619, carrying a domain with high similarity to MprF-like domains, suggesting that this protein could be a new aaPG synthase family member. However, unlike homologous domains of MprF and LysX that are positioned in the cytoplasm, we predicted that the MprF-like domain in LysX2 is in the extracytoplasmic region. Using genetic fusions to the Escherichia coli proteins PhoA and LacZ of LysX2, we confirmed this unique membrane topology, as well as LysX and MprF as benchmarks. Expression of lysX2 in Mycobacterium smegmatis increased cell resistance to human β-defensin 2 and sodium nitrite, enhanced cell viability and delayed biofilm formation in acidic pH environment. Remarkably, MtLysX2 significantly reduced the negative charge on the bacterial surface upon exposure to an acidic environment. Additionally, we found LysX2 orthologues in major human pathogens and in rapid-growing mycobacteria frequently associated with human infections, but not in environmental and non-pathogenic mycobacteria. Overall, our data suggest that LysX2 is a prototype of a new class within the MprF-like protein family that likely enhances survival of the pathogenic species through its catalytic domain which is exposed to the extracytoplasmic side of the cell membrane and is required to decrease the negative charge on the bacterial surface through a yet uncharacterized mechanism.


The pattern of distribution of encephalocele in University of Port Harcourt Teaching Hospital--a three year experience.
Encephalocele is a congenital anomaly that results from failure of complete neural tube closure during foetal development. It is a known cause of mortality and morbidity in infants. This study was carried out to highlight its distribution pattern in University of Port Harcourt Teaching Hospital over a three-year-period. This is a retrospective study of children with encephalocele admitted from January 2007 to December 2009. The following information were obtained from their medical records: sex, age at diagnosis, distribution pattern, place of origin, detailed antenatal history, maternal occupation/level of education, family history, associated anomalies and outcome of surgery. 17 cases (10 females and 7 males) were seen over this period. 12 presented as frontal encephalocele while 5 were occipital. Their ages at diagnosis were: prenatal (determinded by abdominal ultrasound) 5, 0-6 months 11, and 7-12 months 1. 9 of 17 mothers were unbooked. Pregnancy was uneventful in all cases. None had family history of encephalocele. 5 had multiple anomalies while 12 had only encephalocele. 10 patients had surgery, of which 9 were successful. 1 died in the immediate postoperative period. 7 patients did not have surgery. Among these, 3 died before surgery while the parents of 4 children refused operation. 10 mothers had primary education, 5 secondary, while 2 had attained tertiary education. Encephalocele may be frontal or occipital. The distribution pattern of our cases was in favour of frontal location, with slight female preponderance.


On the relationship between pregnancy weight gain and chorioamnionitis.
Chorioamnionitis refers to infection of the amniotic fluid by such agents as Streptococcus sp., E. coli and Ureaplasma sp. It has not only been linked to the risk of premature rupture of the membranes and preterm delivery, but also to increased morbidity and mortality among neonates born to mothers with such infections. The possible association between maternal gestational weight gain and chorioamnionitis was examined in data using a case sample of 62 and control sample of 168 Israeli women. Univariate analysis demonstrated a significant increase in the incidence of chorioamnionitis among mothers delivering before 33 weeks gestation who displayed inadequate gestational weight gain according to the IOM standards. Comparison of logistic regression analyses between mothers who developed chorioamnionitis at different stages of their pregnancies, controlling for the effects of maternal anthropometric, sociodemographic, and obstetric factors, showed that inadequate weight gain significantly increased the risk of chorioamnionitis among those delivering very prematurely. The differences in significant risk factors suggest the possibility that pre- and full-term chorioamnionitis may not have the same etiologies. Am. J. Hum. Biol. 9:545-553, 1997. © 1997 Wiley-Liss, Inc.


[Ocular toxoplasmosis. Utilization of immunohistochemical reaction for diagnosis].
The diagnosis of ocular toxoplasmosis is based primarily on clinical presentation and laboratory tests described else where. Eventually, unusual clinical presentation, as well unusual pathologic findings occur, mainly in immunosuppressed individuals. The authors report a case of a female patient from Paraná with a progressive ocular disease, for at least three years, without definite diagnosis. After an exhaustive clinical and laboratory investigation, as well empiric medical treatment, without success, it was decided to enucleate the atrofic organ and to proceed to a histologic examination. It revealed a cronic and inspecific inflammatory process without any specific agent. However the immunohistochemical technique was able to detect Toxoplasma gondii antigens in the ocular tissue. This technique provides an alternative method for the diagnosis of unusual forms of toxoplasmosis.


Comparative in Vitro and in Vivo Evaluation of the Estrogenic Effect of Hexafluoropropylene Oxide Homologues.
As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide (HFPO) homologues, including hexafluoropropylene oxide dimer acid (HFPO-DA), hexafluoropropylene oxide trimer acid (HFPO-TA), and hexafluoropropylene oxide tetramer acid (HFPO-TeA), have been used in the fluoropolymer industry for a long period of time. These compounds have attracted widespread attention in recent years due to their environmental ubiquity and high bioaccumulation capability, as well as their toxicity. In our study, we evaluated the potential estrogenic effects of HFPOs in comparison to PFOA by ligand binding, transcriptional activity, and in vivo assays. Fluorescence ligand binding assays showed that both HFPO-TA and HFPO-TeA exhibited higher binding affinity to estrogen receptor ligand binding domains (ER-LBDs) than PFOA, with 2.5- and 57.5-fold higher affinity to ERα-LBD and 2.6- and 41.8-fold higher affinity to ERβ-LBD, respectively, whereas HFPO-DA exhibited weaker binding affinity than PFOA. Unlike PFOA, HFPO-TA and HFPO-TeA exhibited antagonistic activity toward the ERs' signaling pathway, with HFPO-TeA displaying the strongest potency. In silico study revealed that while PFOA binds with ERs in a similar fashion as 17β-estradiol, the HFPOs display an antagonistic binding mode. Using a zebrafish model, we further found that exposure to HFPO homologues significantly altered the levels of sex steroid hormones and vitellogenin. In general, both in vivo and in vitro results indicate that HFPO homologues might exert higher estrogenic effects than PFOA.


Increased maternal nutrition increases leptin expression in perirenal and subcutaneous adipose tissue in the postnatal lamb.
The present study tested the hypothesis that exposure to an increased level of maternal nutrition before birth results in altered expression of adipogenic, lipogenic, and adipokine genes in adipose tissue in early postnatal life. Pregnant ewes were fed either at or approximately 50% above maintenance energy requirements during late pregnancy, and quantitative RT-PCR was used to measure peroxisome proliferator-activated receptor (PPAR)-gamma, lipoprotein lipase (LPL), glycerol-3-phosphate-dehydrogenase (G3PDH), adiponectin, and leptin mRNA expression in perirenal (PAT) and sc adipose tissue (SCAT) in the offspring on postnatal d 30. Relative SCAT mass was higher in lambs of well-fed ewes (40.0 +/- 4.0 vs. 22.8 +/- 3.3 g/kg, P < 0.05) and was directly related to plasma insulin in the first 24 h after birth and to G3PDH and LPL expression. The expression of leptin mRNA in both the SCAT and PAT depots was higher (P < 0.05) in lambs of well-fed ewes. PPARgamma adiponectin, LPL, and G3PDH mRNA expression were not, however, different between well-fed and control groups in either depot. Relative PPARgamma expression in SCAT was directly related to plasma insulin concentrations in the first 24 h after birth (r(2) = 0.23; P < 0.05), and G3PDH and LPL expressions were also positively correlated with PPARgamma expression (r(2) = 0.27; P < 0.05). We have demonstrated that exposure to increased prenatal nutrition increases leptin expression at 1 month of age in both PAT and SCAT. The results of this study provide evidence that the nutritional environment before and immediately after birth can influence the development of adipose tissue in early postnatal life.


A new species of Leptolalax (Anura: Megophryidae) from Gunung Mulu National Park, Sarawak, East Malaysia (Borneo).
We describe a new species of Leptolalax from Gunung Mulu National Park in eastern Sarawak, Malaysian Borneo. The new species had been assigned to Leptolalax dringi and Leptolalax gracilis in the past. It is shown to differ from both these species and from all other species of the genus by a unique combination of morphological characters including large body size, rounded snout, interorbital distance being smaller than width of upper eyelid, bipartite subgular vocal sac in males, basal toe webbing, shagreened skin with tiny tubercles on dorsum and dorsal side of head, angled supratympanic fold, small pectoral glands, absence of supraaxillary glands and ventrolateral glandular ridges, spotted venter, advertisement call consisting of long series of 8-289 notes, each composed of three or four pulses, and dominant frequency at 7225-9190 Hz, with prominent frequency modulation.


Vibronic coupling models for donor-acceptor aggregates using an effective-mode scheme: Application to mixed Frenkel and charge-transfer excitons in oligothiophene aggregates.
A reduced-dimensional effective-mode representation is developed in order to efficiently describe excited-state dynamics of multichromophoric donor-acceptor aggregates within a linear vibronic coupling model. Specifically, we consider systems where vibrational modes pertaining to a given molecular fragment couple both to local excitations of Frenkel type and delocalized states of charge transfer exciton type. A hierarchical chain representation is constructed which is suitable to describe correlated fluctuations, leading to a set of correlated spectral densities. An application is shown for a first-principles parameterized model of an oligothiophene H-type aggregate whose properties are modified due to the presence of charge transfer excitons. Within a pentamer model comprising 13 electronic states and 195 normal modes, good convergence of the effective-mode representation of the spectral densities is achieved at the eighth order of the hierarchy with 104 modes, and a qualitatively correct picture is obtained at the sixth order with 78 modes.


Effects of posterior pericardiotomy on the incidence of pericardial effusion and atrial fibrillation after coronary revascularization.
The aim of this prospective, randomized study was to assess the efficacy of posterior pericardiotomy in decreasing the prevalence of pericardial effusion and postoperative atrial fibrillation (AF). The study was performed in 100 patients who underwent elective coronary artery bypass grafting surgery (CABG) between October 2003 and July 2005. They were randomized to receive posterior pericardiotomy (Group A) or no posterior pericardiotomy (Group B). A 4-cm longitudinal incision was made parallel and posterior to the left phrenic nerve, extending from the left inferior pulmonary vein to the diaphragm in group A patients. Posterior pericardiotomy was not performed in group B patients. Early pericardial effusion developed in 6 patients (12%) of group A and 21 patients (42%) of group B; no late pericardial effusion developed in group A, but did in 3 patients (6%) of group B. The number of patients who developed postoperative AF was significantly lower in the fenestration group compared with the control group (10% vs. 30%, p < 0.010). The overall incidence of supraventricular tachycardia in patients with early pericardial effusion was significantly higher than in patients without early pericardial effusion (18 patients vs. 9 patients). These findings suggest that posterior pericardiotomy reduces the prevalence of early pericardial effusion and related AF by improving pericardial drainage in patients undergoing coronary artery bypass surgery.


Actinomyces denticolens Dent & Williams sp. nov: a new species from the dental plaque of cattle.
Six strains of actinomyces isolated from the dental plaque of cattle were assigned presumptively to the genus Actinomyces on the basis of Gram reaction, cellular and colony morphology and acid end-products of metabolism. This assignment was confirmed by the peptidoglycan composition which is shared with Actinomyces species from dental plaque. These cattle strains formed a homogeneous group on the basis of cell wall carbohydrate components, DNA base composition, polypeptide molecular weight distribution and physiological reactions but could not be classified with any recognised species of Actinomyces. A new taxon Actinomyces denticolens is proposed for these strains.


Activation of the calcium/calmodulin-dependent protein kinases as a consequence of oxidative stress.
Oxygen radicals have diverse effects on cells. In many cases, exposure to reactive oxygen intermediates (ROI) can induce cell death. Conversely, there is also evidence that suggests oxygen radicals can activate signaling pathways that are thought to prevent cell death. In this review, the authors discuss the finding that hydrogen peroxide and ROI-generating treatments trigger the activation of the calcium/calmodulin-dependent kinases (CaM-kinases), and the potential role this activation has in preventing apoptosis. Evidence is presented that CaM-kinase activation occurs by both calcium dependent- and independent-pathways in response to ROIs. In addition, the idea is discussed that ROIs have the potential to lead to the phosphorylation of calmodulin and through this mechanism potentiate the activation of the CaM-kinases. The concept that inhibition of the CaM-kinases as a mechanism to sensitize cells to the damaging effects of ROIs is also presented. Contrasting these studies, evidence is presented that exposure of the CaM-kinases directly to hydrogen peroxide also has the apparent ability to inhibit their activity.


Impact of Mobile Phone-Based Interventions on Methamphetamine Use and High-risk Sexual Behaviors in Men Who Have Sex with Men (MSM): A Systematic Review.
Today, increased use of methamphetamine in homosexual men is associated with high-risk sexual behaviors and (HIV) epidemic. Mobile phone-based interventions are an accessible and rapid method to provide healthcare services to this population. This study aimed to systematically review the effects of mobile phone-based interventions on methamphetamine use and high-risk sexual behaviors in homosexual men. This systematic review was conducted by two researchers via searching in PubMed, Google Scholar, Web of Science, Scopus, and PsycINFO databases to retrieve the published articles regarding the effects of mobile phone-based interventions on the control of methamphetamine use and high-risk sexual behaviors. Among 250 unique articles that were retrieved, only five cases met all the inclusion criteria of the study. Accordingly, some of the applied interventions included text messaging (n = 4) and mobile apps (n = 1). In this regard, the use of text messaging significantly decreased the rates of methamphetamine use, condomless anal intercourse (CAI), and HIV transmission among homosexual men. According to the results, short-term interventions based on text messaging could decrease the rates of methamphetamine use and the high-risk sexual behaviors associated with HIV infection in homosexual men. Despite the positive impact of these interventions, long-term follow-ups are required for individuals using methamphetamine in different communities.


Magnetic resonance imaging of large and giant intracranial aneurysms.
Twelve large or giant intracranial aneurysms were studied with magnetic resonance (MR) imaging, and the findings were compared with those from computed tomographic (CT) scanning. Characteristic MR features of such aneurysms are: round, extra-axial mass with hypointensity rim; signal void, paradoxical enhancement, or even-echo rephasing due to blood flow; and laminated, eccentric thrombus with increased signal intensity when fresh, perianeurysmal hemorrhage occurs in the acute or subacute stage after aneurysmal rupture. MR imaging, however, often fails to identify or characterize the area of calcification. For the diagnosis of large or giant intracranial aneurysms, MR imaging is apparently superior to CT scanning in differentiating aneurysms from tumors, delineating the blood flow and intraluminal thrombus, and detecting the exact size of the aneurysm. It may also provide useful information concerning the growth mechanisms of aneurysms with or without thrombus formation.


Profile of patients with essential blepharospasm and hemifacial spasm in the two largest ophthalmology reference centers in Brazil.
Information is scarce regarding the comprehensive profile of patients with essential blepharospasm and hemifacial spasm in Brazil. The present study aimed to assess the clinical features of patients with these conditions, followed up in two reference centers in Brazil. The study included patients with essential blepharospasm and hemifacial spasm, followed up at the Departments of Ophthalmology at Universidade Federal de São Paulo and Universidade de São Paulo. Apart from demographic and clinical features, past stressful events related to the first symptoms (triggering event), aggravating factors, sensory tricks, and other ameliorating factors for the eyelid spasms were assessed. A total of 102 patients were included in this study. Most patients were female (67.7%). Essential blepharospasm was the most frequent movement disorder [51/102 patients (50%)], followed by hemifacial spasm (45%) and Meige's syndrome (5%). In 63.5% of the patients, the onset of the disorder was associated with a past stressful event. Ameliorating factors were reported by 76.5% of patients; 47% of patients reported sensory tricks. In addition, 87% of the patients reported the presence of an aggravating factor for the spasms; stress (51%) was the most frequent. Our study provides information regarding the clinical features of patients treated in the two largest ophthalmology reference centers in Brazil.


[Confocal laser endomicroscopy in the diagnosis of diseases of biliary ducts].
Are clinical observations of various diseases of the bile ducts, including cholangiocarcinoma, developed with chronic diseases pancreato-biliary zone. Reflected the complexity of instrumental diagnostics at an early stage of the disease. For the first time at the given pathology diagnostic purposes was applied the method of probe confocal laser endomicroscopy allowed in all cases to clarify and verify the diagnosis. Describes the technique of the research, its results are compared with other diagnostic methods. The authors suggest that in the diagnosis of pancreatic and biliary zone method probe confocal laser endomicroscopy can be crucial in inefficiency or uninformative other methods.


Depression and cigarette smoking behavior: A critical review of population-based studies.
Smoking and depression are both leading causes of disability, mortality and morbidity around the world. Using epidemiologic data to study the association between depression and the severity, course, and persistence of smoking in the general population is important for understanding the scope of the problem of smoking among people with depression. The current paper aims to critically review existing epidemiologic research on the smoking behaviors of persons with depressive symptoms and disorders and to identify gaps in the literature that warrant further study. Literature searches of Medline and EMBASE were used to identify articles that analyzed epidemiologic data and examined an aspect of smoking behavior in persons with depressive symptoms or disorders. Six hundred ninety-three abstracts were reviewed and 45 studies met all of the inclusion criteria to be included in the review. Persons with depression, compared to those without depression, are more likely to smoke, and meet criteria for nicotine dependence, are less likely to quit smoking, and are more likely to relapse. Little is known about the association between depression and smoking behavior by age, socioeconomic status, or race/ethnicity or with regard to the use of tobacco products other than cigarettes. Persons with depression are more likely to smoke cigarettes and have greater difficulty quitting smoking. Community-based and public health approaches may need to begin considering the links between depression and smoking in order to best target the current smokers in the population and develop more effective tobacco control campaigns.


Cytomegalovirus in pregnancy and the neonate.
Congenital cytomegalovirus (CMV) remains a leading cause of disability in children. Understanding the pathogenesis of infection from the mother via the placenta to the neonate is crucial if we are to produce new interventions and provide supportive mechanisms to improve the outcome of congenitally infected children. In recent years, some major goals have been achieved, including the diagnosis of primary maternal CMV infection in pregnant women by using the anti-CMV IgG avidity test and the diagnosis and prognosis of foetal CMV infection by using polymerase chain reaction real-time tests to detect and quantify the virus in amniotic fluid. This review summarises recent advances in our understanding and highlights where challenges remain, especially in vaccine development and anti-viral therapy of the pregnant woman and the neonate. Currently, no therapeutic options during pregnancy are available except those undergoing clinical trials, whereas valganciclovir treatment is recommended for congenitally infected neonates with moderately to severely symptomatic disease.


Interplay between PEO tether length and ligand spacing governs cell spreading on RGD-modified PMMA-g-PEO comb copolymers.
The effects of tether length on cell adhesion to poly(methyl methacrylate)-graft-poly(ethylene oxide), PMMA-g-PEO, comb copolymer films functionalized with the adhesion peptide RGD were investigated. Copolymers having PEO tether lengths of 10 and 22 EO segments were synthesized and coupled with a synthetic peptide that contained both RGD and the synergy sequence PHSRN. Cell spreading assays revealed that the longer polymer tethers increased the rate of spreading and reduced the time required for fibroblasts to form focal adhesions. Fluorescence resonance energy transfer (FRET) measurements indicated a mean separation between integrin-bound peptides of 15.6 +/- 1.4 nm for combs with long (22-mer) tethers, compared with 17.5 +/- 1.3 nm for short (10-mer) tethers, on films of comparable peptide density (approximately 2500 peptides/microm2). The results suggest that the added mobility afforded by the more extensible tethers encouraged the formation of focal adhesions by allowing cells to reorganize tethered peptides on the nanometer length scale. In addition, adhesion peptides were selectively coupled to 10-mer or 22-mer PEO tethers within a bimodal brush to investigate stratification effects on cell adhesion. Peptides bound by short tethers in a bed of long unsubstituted chains resulted in surfaces that resisted, rather than promoted, cell adhesion. By contrast, when long peptide tethers were employed with short unsubstituted chains, cell attachment and spreading were comparable to that found on a monomodal brush of long chains at equivalent peptide density.


Clinical use of computational modeling for surgical planning of arteriovenous fistula for hemodialysis.
Autogenous arteriovenous fistula (AVF) is the best vascular access (VA) for hemodialysis, but its creation is still a critical procedure. Physical examination, vascular mapping and doppler ultrasound (DUS) evaluation are recommended for AVF planning, but they can not provide direct indication on AVF outcome. We recently developed and validated in a clinical trial a patient-specific computational model to predict pre-operatively the blood flow volume (BFV) in AVF for different surgical configuration on the basis of demographic, clinical and DUS data. In the present investigation we tested power of prediction and usability of the computational model in routine clinical setting. We developed a web-based system (AVF.SIM) that integrates the computational model in a single procedure, including data collection and transfer, simulation management and data storage. A usability test on observational data was designed to compare predicted vs. measured BFV and evaluate the acceptance of the system in the clinical setting. Six Italian nephrology units were involved in the evaluation for a 6-month period that included all incident dialysis patients with indication for AVF surgery. Out of the 74 patients, complete data from 60 patients were included in the final dataset. Predicted brachial BFV at 40 days after surgery showed a good correlation with measured values (in average 787 ± 306 vs. 751 ± 267 mL/min, R = 0.81, p < 0.001). For distal AVFs the mean difference (±SD) between predicted vs. measured BFV was -2.0 ± 20.9%, with 50% of predicted values in the range of 86-121% of measured BFV. Feedbacks provided by clinicians indicate that AVF.SIM is easy to use and well accepted in clinical routine, with limited additional workload. Clinical use of computational modeling for AVF surgical planning can help the surgeon to select the best surgical strategy, reducing AVF early failures and complications. This approach allows individualization of VA care, with the aim to reduce the costs associated with VA dysfunction, and to improve AVF clinical outcome.


Simulation of Wire Arc Additive Manufacturing in the Reinforcement of a Half-Cylinder Shell Geometry.
Wire arc additive manufacturing (WAAM) is an additive manufacturing process based on gas metal arc welding. It allows the fabrication of large-volume metal components by the controlled deposition and stacking of weld beads. Next to the near-net-shape manufacturing of metal components, WAAM is also applied in the local reinforcement of structural parts, such as shell geometries. However, this procedure can lead to undesired thermally induced distortions. In this work, the distortion caused by the WAAM reinforcement of half-cylinder shell geometries was investigated through experiments and transient thermo-mechanical finite element simulations. In the experiments, the weld beads were applied to the specimen, while its thermal history was measured using thermocouples. The developing distortions were registered using displacement transducers. The experimental data were used to calibrate and validate the simulation. Using the validated model, the temperature field and the distortions of the specimens could be predicted. Subsequently, the simulation was used to assess different deposition patterns and shell thicknesses with regard to the resulting part distortions. The investigations revealed a non-linear relation between shell thickness and distortion. Moreover, the orientation and the sequence of the weld beads had a significant impact on the formation of distortion. However, those effects diminished with an increasing shell thickness.


Neural maturation of breastfed and formula-fed infants.
Human milk provides infants with a full complement of all polyunsaturated fatty acids, including docosahexaenoic acid (DHA) and arachidonic acid (AA). Formula milks only contain the precursors of DHA, AA and linoleic acid, and hence formula-fed infants must synthesize their own DHA and AA. To evaluate the effect of feeding--whether breastfeeding or formula-feeding--in early infancy upon subsequent neurodevelopment and achievement of optimum brain function. The study included 53 normal, healthy infants (30 exclusively breastfed infants and 23 exclusively formula-fed infants) at the age of 1 y (+/-1 mo). Each infant was subjected to a full physical and neurological examination together with neurophysiological studies including flash visual evoked potential (FVEP), brainstem auditory evoked potential (BAEP) and somatosensory evoked potential (SSEP). There was significant prolongation of P100 wave latency of FVEP in formula-fed infants, together with significant prolongation of absolute latency of waves I, III and V of BAEP in formula-fed infants compared with breastfed infants. There was significant prolongation in inter-peak latencies between cortical and Erb's components in formula-fed infants compared with breastfed infants. We can conclude that VEP, BAEP and SSEP are more mature in breastfed infants relative to formula-fed infants at 1 y of age, and thus breast milk helps earlier development and maturation of some aspects of the nervous system than milk formulas.


Phase behavior of charged colloids at a fluid interface.
We study the phase behavior of a system of charged colloidal particles that are electrostatically bound to an almost flat interface between two fluids. We show that, despite the fact that our experimental system consists of only 10^{3}-10^{4} particles, the phase behavior is consistent with the theory of melting due to Kosterlitz, Thouless, Halperin, Nelson, and Young. Using spatial and temporal correlations of the bond-orientational order parameter, we classify our samples into solid, isotropic fluid, and hexatic phases. We demonstrate that the topological defect structure we observe in each phase corresponds to the predictions of Kosterlitz-Thouless-Halperin-Nelson-Young theory. By measuring the dynamic Lindemann parameter γ_{L}(τ) and the non-Gaussian parameter α_{2}(τ) of the displacements of the particles relative to their neighbors, we show that each of the phases displays distinctive dynamical behavior.


Easy preparation of self-assembled high-density buckypaper with enhanced mechanical properties.
A controlled assembly and alignment of carbon nanotubes (CNTs) in a high-packing density with a scalable way remains challenging. This paper focuses on the preparation of self-assembled and well-aligned CNTs with a densely packed nanostructure in the form of buckypaper via a simple filtration method. The CNT suspension concentration is strongly reflected in the alignment and assembly behavior of CNT buckypaper. We further demonstrated that the horizontally aligned CNT domain gradually increases in size when increasing the deposited CNT quantity. The resultant aligned buckypaper exhibited notably enhanced packing density, strength, modulus, and hardness compared to previously reported buckypapers.


Long-term follow-up of bulking agents for stress urinary incontinence in older patients.
Implantation of bulking agents represents a noninvasive procedure for the treatment of stress urinary incontinence (SUI) in all patients where a more invasive procedure may increase perioperative risks. The primary aim of this retrospective study was to evaluate the efficacy over time of bulking agent implantation. As secondary aims, we evaluated long-term (patients' subjective) satisfaction rate, rate of de novo urinary symptoms, and the impact of urinary incontinence on the quality of life. All patients who underwent implantation of bulking agents between 1999 and 2013 at Campus Bio-Medico of Rome were retrospectively considered eligible for this study. Patients were interviewed using two standardized questionnaires: International Consultation on Incontinence Questionnaire Short Form and Patient Global Impression of Improvement. Cure rate, improvement rate, failure rate, and the onset of new symptoms were also investigated through specific questions. The original group of patients was then divided into two subgroups according to follow-up time (group A: shorter than median follow-up; group B: longer than median follow-up). Sixty-three patients were enrolled. Mean follow-up was 8.3 ± 3.5 years with a range of 3.5 to 18 years. Fifteen (24%) cured patients (cure rate), 12 (19%) improved patients (improvement rate), 36 (57%) failed treatment (failure rate). We reported an overall success rate of 43%. No differences were reported among groups in terms of overall success rate (42% vs 44% for group A and group B, respectively). Bulking agent implantation is an effective treatment for people with intrinsic sphincter deficiency (type III SUI) and it is a valid alternative to more invasive surgeries in older patients. Moreover, it shows an overall success rate (43%) that remains high even after many years.


Incidence of BVDV1 and BVDV2 infections in cattle submitted for necropsy in Northern Germany.
The incidence of bovine viral diarrhoea virus (BVDV) 1 and 2 infections was determined in calves, young cattle and older cattle with signs of mucosal disease (MD) submitted for necropsy to three laboratories in Northern Germany between June 2000 and May 2001. At necropsy, tonsils, retropharyngeal lymph nodes, mesenteric lymph nodes, ileal Peyer's patch and spleen were collected and examined by immunohistochemistry and virus isolation. From 311 animals examined, 30 (9.6%) were positive for BVDV. All viral isolates were typed by polymerase chain reaction after reverse transcription using species-specific primers and determined to be BVDV1. Based on the distribution of lesions and viral antigen, animals with MD, persistent infection (PI) and acute, transient infection could be distinguished. Twelve of the positive animals had characteristic signs of MD: severe diarrhoea, erosive to ulcerative lesions throughout the digestive tract and severe depletion of all lymphoid tissues. Viral antigen was present in all tissues and cell types, but particularly in depleted lymphoid follicles and altered epithelium. In seven calves, viral antigen was detectable in all tissues and cell types, but lesions were mild or missing. This is typical for PI. The remaining 11 calves most likely represent animals with acute, transient infection. Distribution of antigen was more variable, predominantly restricted to lymphoid follicles and often not seen in all tissues examined. Clinical findings were combined bronchopneumonia and enteritis. The detection of BVDV1 in young calves with pneumonia and enteritis emphasizes the importance of BVDV1 and not only BVDV2 for severe respiratory and enteric diseases of calves.


A carbapenem-resistant Acinetobacter baumannii outbreak associated with a polymyxin shortage during the COVID pandemic: an in vitro and biofilm analysis of synergy between meropenem, gentamicin and sulbactam.
During the COVID-19 pandemic, the burden of nosocomial infections caused by MDR pathogens has caused a shortage of polymyxins. Thus, we evaluated the in vitro synergism and antibiofilm activity of antimicrobial combinations and propose a test kit for synergism against carbapenem-resistant Acinetobacter baumannii (CRAB). Fifty-six CRAB isolates were tested for synergy between meropenem, gentamicin and ampicillin/sulbactam. MICs were determined by broth microdilution. Synergism was tested using chequerboard analysis, followed by a time-kill curve. Additionally, minimum biofilm eradication concentration was determined and the antibiofilm activity of the combinations was evaluated by MTT assay and biomass reduction. A test kit was developed for routine laboratory testing to detect synergism. All CRAB isolates were resistant to gentamicin and ampicillin/sulbactam. Chequerboard synergism occurred against 75% of the isolates. Meropenem + ampicillin/sulbactam was the most frequent combination with synergism (69%), followed by ampicillin/sulbactam + gentamicin (64%) and meropenem + gentamicin (51%). All combinations presented only bacteriostatic activity and no bactericidal or antibiofilm effects. The routine laboratory test showed 100% accuracy compared with other in vitro assays. Our study demonstrates the potential role of antibiotic combinations against planktonic bacteria. In vitro synergism is possible and can be an alternative treatment for patients with CRAB infection during a polymyxin shortage.


Immunological parameters associated with the severity of COVID-19 pneumonia in kidney transplant recipients.
An outbreak of a novel respiratory disease due to coronavirus species was emerged in 2019 and named as Coronavirus Disease-2019 (COVID-19). Clinical and immunological factors affecting the course of COVID-19 in kidney transplant recipients (KTR) are not well-known. In this prospective observational study, we presented 20 KTR with COVID-19 pnemonia and examined the factors predicting the severity of COVID-19. A total of 10 KTR without COVID-19 was used as control group. Lymphocyte subsets were determined by flow cytometry. In 13/20 patients, immunophenotyping was repeated 1 week later. Mean age of the patients was 50 ± 9 years. Patients were classified as mild-moderate (oxygen saturation: SO2 > 90%) and severe disease groups (SO2 ≤ 90%). Serum albumin and hemoglobin were lower and CRP, fibrinogen and peak D-dimer were higher in severe group. Peak CRP was inversely associated with nadir SO2 (r = - 0.68, p = 0.001). Neutrophil/lymphocyte ratio was higher in severe group (p = 0.01). CD3 + and CD4 + cells were lower and NK cell percentage (CD16 + 56 +) was higher in severe group. Percentage of spontaneously activated CD8 cells (CD8 + CD69 +) was higher in severe group. In comparison of KTR with and without COVID-19, CD8 + cells were lower but NK cell percentage was higher in KTR with COVID-19. In this pilot study, increased NK cells, activated CD8 + cells and decreased CD3 + and CD4 + cells were associated with severity of COVID-19 in KTR. Peripheral immunophenotyping of lymphocyte subtypes may provide prognostic information about the clinical course of COVID-19 in KTR.


Development of backlighting sources for a Compton radiography diagnostic of inertial confinement fusion targets (invited).
We present scaled demonstrations of backlighter sources, emitting bremsstrahlung x rays with photon energies above 75 keV, that we will use to record x-ray Compton radiographic snapshots of cold dense DT fuel in inertial confinement fusion implosions at the National Ignition Facility (NIF). In experiments performed at the Titan laser facility at Lawrence Livermore National Laboratory, we measured the source size and the bremsstrahlung spectrum as a function of laser intensity and pulse length from solid targets irradiated at 2x10(17)-5x10(18) W/cm(2) using 2-40 ps pulses. Using Au planar foils we achieved source sizes down to 5.5 microm and conversion efficiencies of about 1x10(-13) J/J into x-ray photons with energies in the 75-100 keV spectral range. We can now use these results to design NIF backlighter targets and shielding and to predict Compton radiography performance as a function of the NIF implosion yield and associated background.


Correlation between calcium carbonate content and emission characteristics of incense.
In Taiwan and China, calcium carbonate is commonly added as a filler during incense production to lower the cost. This study has found an unexpected benefit for this practice: it reduces particulate emission. Nine types of the popular incense on the local market were chosen for this study. The calcium content in raw material incense was analyzed by inductively coupled plasma atomic emission spectrometry, followed by X-ray diffraction (XRD) spectroscopy. The correlation between the calcium content and emission characteristics of incense was investigated. The calcium content varied from 1.8 to 60 mg/g (incense burned) among those nine different types of incense. Very little calcium (< 1%) was found in natural wood or plants, which is mainly the raw material of incense. Instead, most calcium was artificially added in the form of CaCO3 during manufacturing. The combustion characteristics, including burning rate, emission factors of particulate, ash, and solid-phase polycyclic aromatic hydrocarbons (S-PAHs), varied significantly among the nine types of incense. Incense containing 2% calcium would emit 30% less S-PAHs, compared with those with little (< 0.2%) calcium. More importantly, increasing the calcium content from 0.5 to 5% by adding CaCO3 reduced the particulate emission from incense by approximately 50%.


Distribution of genetic variants of transcobalamin II in Nigerian black populations.
Transcobalamin II ( TC2 ) phenotyping was performed in Nigerian black males from several ethnic groups, using polyacrylamide gel electrophoresis in combination with autoradiography. The TC2 gene frequencies in the total Nigerian sample amounted to .064 (X), .124 (S), .498 (M), and .313 (F). Compared to white populations, the frequency of TC2 *X is low while the frequencies of TC2 *S and TC2 *F are high, which confirms previous studies on blacks. In some of the rare phenotypes we found, in addition to common TC2 variants, TC2 gene products with an electrophoretic mobility intermediary to X and S, and to M and F, indicative of further microheterogeneity in the genetic system of TC2 . The TC2 gene frequency data indicate interpopulation heterogeneity for this marker. Major differences were found between the Sudan and Guinea Savanna Group ( SGSG ) and the Middle Belt Group, and between the SGSG and the Ibos . The results of our comparative study confirm to some extent similar surveys, which have been based on the distribution of the ABO blood groups.


The effect of manual forestripping on milking performance of Holstein dairy cows.
The objective of this study was to evaluate the effects of forestripping as a premilking stimulation technique on milk yield, milking unit attachment time, and milk flow rates in Holstein dairy cattle. Multiparous Holstein cows (n = 24) were divided into two groups (HPE, high producing, early lactation; LPL, low producing, late lactation) based on prestudy milk yield and stage of lactation. Within the production group, cows were randomly assigned into treatment (n = 6) and control groups (n = 6) in a switchback design. Cows were milked twice daily and treatments were switched after 20 milkings. Premilking udder preparation for the treatment group was as follows: forestripping, predipping with 0.5% iodine, and drying with paper towels followed by unit attachment. Udder preparation for the control group was identical except forestripping was not performed. Data were analyzed by using the PROC Means and PROC Mixed models described by SAS. During the study, cows in the HPE group produced significantly more milk and had longer milking unit attachment times compared with cows in the LPL group. The milk flow rate was 0.36 kg/min faster for the HPE cows compared with the LPL cows. There was no significant effect of order of treatment administration on any outcome variable. There were no significant differences in milk yield, milk unit attachment time, or milk flow for animals that were forestripped compared with animals that were not forestripped. In this study, the addition of forestripping to an otherwise acceptable premilking udder preparation routine did not increase milking performance of multiparous Holstein dairy cows.


The effects of procaine/haematoporphyrin on age-related decline: a double-blind trial.
A randomized, double-blind study of procaine/haematoporphyrin (KH3) has been carried out over two years in a selected population of healthy elderly subjects. The period of study exceeds 500 patient years. The trial population was weighted to contain a larger proportion of subjects aged over 75 years than a standard population; those receiving active KH3 had similar characteristics on entry to those receiving placebo. Over the course of two years, KH3 was shown to be an active substance in that: (a) decrement in the consolidation of new learning was prevented in the treatment group (less than 1.0%, as against 38% in the placebo group); (b) the prevalence of incontinence increased significantly in the placebo group, but not in the active group (P less than 0.05); (c) there was a significant increase in grip strength in the active treatment group (+22%, P less than 0.01 v. placebo); (d) more adverse reactions were observed on treatment with KH3 (P less than 0.005).


STAT3 Signaling Axis and Tamoxifen in Breast Cancer: A Promising Target for Treatment Resistance.
Signal transducers and activators of transcription 3 (STAT 3) have been proposed to be responsible for breast cancer development. Moreover, evidence depicted that upregulation of STAT3 is responsible for angiogenesis, metastasis, and chemo-resistance of breast cancer. Tamoxifen (TAM) resistance is a major concern in breast cancer management which is mediated by numerous signaling pathways such as STAT3. Therefore, STAT3 targeting inhibitors would be beneficial in breast cancer treatment. The information on the topic in this review was gathered from scientific databases such as PubMed, Scopus, Google Scholar, and ScienceDirect. The present review highlights STAT3 signaling axis discoveries and TAM targeting STAT3 in breast cancer. Based on the results of this study, we found that following prolonged TAM treatment, STAT3 showed overexpression and resulted in drug resistance. Moreover, it was concluded that STAT3 plays an important role in breast cancer stem cells, which correlated with TAM resistance.


Biobleaching of industrial important dyes with peroxidase partially purified from garlic.
An acidic peroxidase was extracted from garlic (Allium sativum) and was partially purified threefold by ammonium sulphate precipitation, dialysis, and gel filtration chromatography using sephadex G-200. The specific activity of the enzyme increased from 4.89 U/mg after ammonium sulphate precipitation to 25.26 U/mg after gel filtration chromatography. The optimum temperature and pH of the enzyme were 50°C and 5.0, respectively. The Km and V max for H2O2 and o-dianisidine were 0.026 mM and 0.8 U/min, and 25 mM and 0.75 U/min, respectively. Peroxidase from garlic was effective in decolourizing Vat Yellow 2, Vat Orange 11, and Vat Black 27 better than Vat Green 9 dye. For all the parameters monitored, the decolourization was more effective at a pH range, temperature, H2O2 concentration, and enzyme concentration of 4.5-5.0, 50°C, 0.6 mM, and 0.20 U/mL, respectively. The observed properties of the enzyme together with its low cost of extraction (from local sources) show the potential of this enzyme for practical application in industrial wastewater treatment especially with hydrogen peroxide. These Vat dyes also exhibited potentials of acting as peroxidase inhibitors at alkaline pH range.


Genu amoris.
Intractable pain in a patient with chondromalacia patellae was found to be related to an unusual type of repetitive trauma.


Differentiation of human breast-milk stem cells to neural stem cells and neurons.
Objectives. Human breast milk contains a heterogeneous population of cells that have the potential to provide a noninvasive source of cells for cell therapy in many neurodegenerative diseases without any ethical concern. The objectives of this study were to differentiate the breast milk-derived stem cells (BMDSC) toward neural stem cells and then into the neurons and neuroglia. Materials and Methods. To do this, the BMDSC were isolated from human breast milk and cultured in Dulbecco's modified Eagle medium/F12 (DMEM/F12) containing fibroblast growth factor (bFGF). The cells were then characterized by evaluation of the embryonic and stem cell markers. Then, the cells were exposed to culture medium containing 1% B27 and 2% N2 for 7-10 days followed by medium supplemented with B27, N2, bFGF 10 µg/mL, and endothelial growth factor (EGF) 20 µg/mL. Then, the sphere-forming assay was performed. The spheres were then differentiated into three neural lineages by withdrawing growth factor in the presence of 5% FBS (fetal bovine serum). The immunofluorescence was done for β-tubulin III, O4, and GFAP (glial fibrillary acidic protein). Results. The results indicated that the cells expressed both embryonic and mesenchymal stem cell (MSC) markers. They also showed neurospheres formation that was nestin-positive. The cells were also differentiated into all three neural lineages. Conclusion. The BMDSC can behave in the same way with neural stem cells. They were differentiated into oligodendrocytes, and astrocytes as well as neurons.


Reactions of copper(II) chloride in solution: facile formation of tetranuclear copper clusters and other complexes that are relevant in catalytic redox processes.
Mixing CuCl2⋅2 H2O with benzylamine in alcoholic solutions led to an extremely colorful chemistry caused by the formation of a large number of different complexes. Many of these different species could be structurally characterized. These include relatively simple compounds such as [Cu(L(1))4Cl2] (L(1) = benzylamine) and (HL(1))2[CuCl4]. Most interestingly is the easy formation of two cluster complexes, one based on two cluster units Cu4OCl6(L(1))4 connected through one [Cu(L(1))2Cl2] complex and one based on a cubane-type cluster ([Cu4O4](C11H14)4Cl4). Both clusters proved to be highly reactive in a series of oxidation reactions of organic substrates by using air or peroxides as oxidants. Furthermore, it was possible to isolate and structurally characterize ([Cu(L(1))Cl]3 and [Cu(benz2mpa)2]CuCl2 (benz2mpa = benzyl-(2-benzylimino-1-methyl-propylidene)-amine), two copper(I) complexes that formed in solution, demonstrating the high redox activity of the cluster systems. In addition, it was possible to solve the molecular structures of the compounds Cu4OCl6(MeOH)4, [Cu(MeOH)2Cl2], [Cu(aniline)2Cl2], and an organic side product (HC13 H19 NOCl). In fact all determined structures are of a known type but the chemical relation between these compounds could be explained for the first time. The paper describes these different compounds and their chemical equilibria. Some of these complexes seem to be relevant in catalytic oxidation reactions and their reactivity is discussed in more detail.


Hypothyroidism among Pregnant Women Attending the Outpatient Department of Obstetrics in a Tertiary Care Centre: A Descriptive Cross-sectional Study.
Hypothyroidism is a common endocrine disorder occurring in pregnancy. Maternal and fetal complications are present in these patients. Timely identification and treatment help in the prevention of complications. The aim of this study was to find out the prevalence of hypothyroidism among pregnant women attending the Outpatient Department of Obstetrics in a tertiary care centre. A descriptive cross-sectional study was conducted in a tertiary care centre after taking ethical approval from the Institutional Review Committee (Reference number: 08/2021). Data from 1 January 2016 to 31 December 2020 were collected between 1 November 2021 to 31 November 2021. All pregnant women who had undergone thyroid level assessment in each trimester (first, second and third) and had delivered in the same centre were included in the study. However, pregnant women with comorbidities like hypertension, overt diabetes mellitus, hyperthyroidism, renal disease, cardiac disease, and neurological disorder were excluded. Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated. Among 216 pregnant patients, the prevalence of hypothyroidism was 74 (34.25%) (27.92-40.57, 95% Confidence Interval). Maternal complications were seen in 33 (44.59%). The commonest complication was oligohydramnios 10 (13.51%) followed by preterm delivery 8 (10.81%). The prevalence of hypothyroidism among pregnant women was found to be higher than other studies done in similar settings. complications; hypothyroidism; miscarriage; pregnancy; thyroid.


Idarubicin: a brief overview on pharmacology and clinical use.
Idarubicin exhibits features rendering this drug unique among anthracyclines. The higher lipophilicity leads to faster accumulation in the nuclei, superior DNA-binding capacity and consequently greater cytotoxicity compared to daunorubicin. A major advantage over this reference drug is its ability to overcome MDR at least partially. Its major metabolite idarubicinol is as active as the parent compound and crosses the blood-brain barrier. Furthermore, idarubicin can be administered orally reaching sufficient plasma levels. Compared to other anthracyclines, the risk of cardiotoxicity as the main side effect for this group of drugs is reduced with idarubicin, when administered in a therapeutical dose. Thus, IDA has become an important drug in the treatment of acute leukemias and its potency in lymphomas, plasmocytomas and other solid tumors such as breast cancer is currently under investigation in several clinical studies.


[Temporary skin replacement with lyophilized swine skin and foam substances--comparative experimental studies].
Using the skin replacement materials Corethium 2, Coldex, Epigard and SYSpur-derm, both fresh wound and wounds up to 6 days old were covered in rats. The histological work-up 1-7 days later showed material-dependent differences in the wound reaction. Under Corethium 2, a heavy layer of wound exudate formed on the first day both on fresh and granulating wound surfaces. Beneath this layer granulation tissue formed that was of regular thickness and well vascularized, filling the defect. Reepithelialization of the wound surface was not hindered by the material. In contrast, a strong connection was established between the wound base and the covering material when using the three foam substances Coldex, Epigard and SYSpur-derm, through the formation of granulation tissue. This process was dependent on the age of the wound. Thickening of the granulation tissue under the covering material was suppressed by the foam substances. Reepithelialization of the surface of the wound was disturbed by the growth of granulation tissue. The netlike structure of Epigard and the properties of the cover layer (fluid-resistant and protective against bacteria) make it possible for the granulation tissue to infiltrate evenly in the whole area of the wound covering and permit growth within the material right up to the surface. In addition to granulation tissue, epithelium also grows into the foam and spreads evenly. Epigard is suitable for long-term covering of large wounds. SYSpur-derm has a different fine structure than Epigard, which hinders the growth of granulation tissue, so that there are only cone-shaped connections between the wound base and the covering material. Rapid desiccation of the wound exudate cannot be prevented. Leukocytes and granulation tissue cannot spread in the foam. With SYSpur-derm an intermediate layer of wound exudate was observed more frequently than with Epigard. SYSpur-derm should be changed regularly in order to remove the detritus and exsudate from the wound. In comparison with polyurethane foam material the polyvinyl-alcohol foam (Coldex) was more complicated to handle, did not adapt as well to the wound, and dried up within a few hours. Between the base of the wound and Coldex, an intermediate layer often formed and, because of the rapid drying-out process, there was appreciably less infiltration with leukocytes and granulation tissue than with SYSpur-derm. With Coldex, as a rule the granulation tissue was more generously vascularized than in the other three materials.


Evaluation of alveolar bone support around incisors in patients with unilateral cleft lip, alveolus, and palate in late mixed dentition using cone beam computed tomography.
To evaluate alveolar bone support around cleft-adjacent maxillary central incisors (U1) in patients with unilateral cleft lip, alveolus and palate (UCLAP) in the late mixed dentition and to investigate the correlation between the alveolar bone thickness (ABT) and tooth inclination. Cone beam computed tomography scans of 45 subjects with UCLAP (29 boys, 16 girls; mean age = 10.74 ± 1.08 years) were assessed. The distance between the cementoenamel junction (CEJ) and alveolar bone crest (AC), and the ABTs at 3 mm, 6 mm, and the apex were measured on the labial, lingual and distal surfaces of U1. The cleft and normal sides were compared using a paired t-test and Pearson's χ2 test. Pearson's correlation was used to explore the association between the ABT and tooth inclination of cleft-adjacent U1 in the labiolingual and mesiodistal dimensions. The CEJ-AC distances were significantly greater in cleft-adjacent U1 ( P < .01), with more bone height reduction observed labially and distally ( P < .001). The labial, lingual, and apico-distal ABTs were decreased on the cleft side ( P < .01). A positive correlation was found between the apico-labial ABT and the labiolingual inclination ( r = 0.568, P < .01). Patients with UCLAP have reduced alveolar bone support around the cleft-adjacent U1, and the apico-labial ABT tends to decrease with increasing lingual tooth inclination; however, the correlation was weak.


What is Known About Cow's Milk Protein Allergy in Preterm Infants?
Background: Cow's milk protein allergy (CMPA) is well described in term infants, as opposed to preterm infants. In preterm infants, CMPA shares many gastrointestinal symptoms with necrotizing enterocolitis (NEC). Objectives: To evaluate the presentation of CMPA in preterm infants and to investigate the different diagnostic and therapeutic options. Materials and Methods: We searched for the relevant literature using the medical databases PubMed, Web of Science, and the Cochrane Library. We performed a post hoc analysis on the 25 case reports included in this study. Results: Literature was scarce and heterogeneous. The majority of preterm infants with CMPA were exposed to bovine-based milk proteins before the development of symptoms. The most common clinical manifestations were bloody stools, vomiting, and abdominal distension. Of the 25 cases, only 7 (28%) retained human milk in their diet after diagnosis. In the larger studies, no study has human milk as primary feeding choice after diagnosis. Conclusions: Preterm infants exposed to a type of cow's milk-based formula in their first days of life have a higher risk of developing CMPA. Most of the preterm infants are no longer fed with human milk after the diagnosis of CMPA is made, which is in contrast with current nutrition guidelines in preterm infants. We strongly advocate that human milk with mothers on a cow's milk-free diet is the first choice of feed after the diagnosis of CMPA. Prospective studies are necessary to obtain more information regarding clinical presentation, diagnostic tools, and therapeutic approaches.


Cardiovascular properties of medroxalol, a new antihypertensive drug.
Medroxalol is a new antihypertensive agent that is presently undergoing clinical trial. Its cardiovascular properties were studied using spontaneously hypertensive rats (SHR), anesthetized dogs, and isolated tissues. Medroxalol produced a long-lasting fall in blood pressure when given by the oral route to SHR. It was more potent than phentolamine in antihypertensive effectiveness. Given intravenously to dogs, medroxalol reduced the blood pressure and heart rate of doses that did not greatly reduce cardiac output. The hypotensive effect of medroxalol was reduced but not abolished following alpha- and beta-adrenergic-receptor blockade. Medroxalol inhibited heart rate and blood pressure responses to isoproterenol and phenylephrine in dogs. In vitro medroxalol resembled a competitive antagonist at alpha-adrenergic receptors in rabbit aortic strips (pA2 6.09) and beta-adrenergic receptors in guinea pig atria (pA2 7.73). It was 0.02 as potent as phentolamine at alpha-receptors and 0.09 as potent as propranolol at beta-receptors. It was concluded that the principal action of medroxalol was to produce a fall in blood pressure by decreasing peripheral vascular resistance more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does not satisfactorily explain the hypotension. A contribution by an active vasodilatory component appears likely.


Coupled solute fluxes in toad skin.
Net inward flux of mannitol across toad skin induced by making the outside solution hypertonic with urea has been investigated. No significant relation between net mannitol flux and net Na flux could be detected when both fluxes were measured simultaneously. In addition, the net mannitol flux caused by hypertonic solution was not altered by inhibition of Na transport with ouabain or by replacement of all Na in the bathing solutions by choline. The rate of net mannitol flux was dependent on the magnitude of the urea concentration difference across the skin and the direction of net flux could be reversed by reversing the direction of the urea concentration difference. These observations suggest that the mannitol transfer is the result of a coupling between the flows of urea and mannitol.


Structure-activity relationships in cinnamamides. 1. Synthesis and pharmacological evaluation of some (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamides.
Two series of (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamide derivatives were prepared and the biological activity of these compounds was investigated in a series of pharmacological tests. All compounds tested had clear activity on the CNS; generally, this was depressant with E isomers, while Z isomers always caused marked stimulation (tremors and convulsions). Some of the E isomers also had a clear-cut anticonvulsant activity as shown by the antagonistic effect on pentylenetetrazole-induced seizures in the mouse. The NMR spectra of these compounds, which confirm their configurations, are discussed.


9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor-Dependent Transforming Growth Factor β Regulation of p16 Expression in Human Aortic Smooth Muscle Cells.
The mechanism whereby the 9p21.3 locus confers risk for coronary artery disease remains incompletely understood. Risk alleles are associated with reduced expression of the cell cycle suppressor genes CDKN2A (p16 and p14) and CDKN2B (p15) and increased vascular smooth muscle cell proliferation. We asked whether risk alleles disrupt transcription factor binding to account for this effect. A bioinformatic screen was used to predict which of 59 single nucleotide polymorphisms at the 9p21.3 locus disrupt (or create) transcription factor binding sites. Electrophoretic mobility shift and luciferase reporter assays examined the binding and functionality of the predicted regulatory sequences. Primary human aortic smooth muscle cells (HAoSMCs) were genotyped for 9p21.3, and HAoSMCs homozygous for the risk allele showed reduced p15 and p16 levels and increased proliferation. rs10811656 and rs4977757 disrupted functional TEF-1 TEC1 AbaA domain (TEAD) transcription factor binding sites. TEAD3 and TEAD4 overexpression induced p16 in HAoSMCs homozygous for the nonrisk allele, but not for the risk allele. Transforming growth factor β, known to activate p16 and also to interact with TEAD factors, failed to induce p16 or to inhibit proliferation of HAoSMCs homozygous for the risk allele. Knockdown of TEAD3 blocked transforming growth factor β-induced p16 mRNA and protein expression, and dual knockdown of TEAD3 and TEAD4 markedly reduced p16 expression in heterozygous HAoSMCs. Here, we identify a novel mechanism whereby sequences at the 9p21.3 risk locus disrupt TEAD factor binding and TEAD3-dependent transforming growth factor β induction of p16 in HAoSMCs. This mechanism accounts, in part, for the 9p21.3 coronary artery disease risk.


A Case of Hemorrhagic Ovarian Cyst Rupture Necessitating Surgical Intervention.
Despite the relatively high incidence of ovarian cysts, particularly in premenopausal women, cyst rupture may on occasion present painfully and require surgical intervention to resolve. Particularly in the case of ruptured hemorrhagic ovarian cysts, resulting hemoperitoneum can create a risk of further adverse events including hypovolemic shock; proper identification and management of such cases are therefore critical. This case focuses on a 22-year-old female that presented to the emergency department (ED) with suprapubic pain in the lower left quadrant of the abdomen. Ultrasonography and computed tomography of the abdomen and pelvis revealed a ruptured hemorrhagic corpus luteum cyst of the left ovary and secondary hemoperitoneum. Patient treatment required laparoscopic left ovarian cyst wall removal, with the removal of hemoperitoneum.


Hyperpyrexia in children. Eight-year emergency room experience.
In an eight-year period, 100 children were seen in a pediatric emergency room with a temperature of 41.1 C or higher, hereafter called hyperpyrexia. There was a significantly greater occurrence of bacterial meningitis in the hyperpyrexia group, compared to a group of 264 children with temperatures of 40.5 to 41.0 C. Bacteremia and seizures were also more common. Children with hyperpyrexia require careful evaluation, especially of the central nervous system.


Temporal factors in tactile spatial acuity: evidence for RA interference in fine spatial processing.
We investigated the extent to which subjects' ability to perceive the fine spatial structure of a stimulus depends on its temporal properties (namely the frequency at which it vibrates). Subjects were presented with static or vibrating gratings that varied in spatial period (1-8 mm) and vibratory frequency (5-80 Hz) and judged the orientation of the gratings, presented either parallel or perpendicular to the long axis of the finger. We found that the grating orientation threshold (GOT)-the spatial period at which subjects can reliably discriminate the orientation of the grating-increased as the vibratory frequency of the gratings increased. As the spatial modulation of SA1 and RA afferent fibers has been found to be independent of vibratory frequency, the frequency dependence of spatial acuity cannot be attributed to changes in the quality of the peripheral signal. Furthermore, we found GOTs to be relatively independent of stimulus amplitude, so the low spatial acuity at high flutter frequencies does not appear to be due to an inadequacy in the strength of the afferent response at those frequencies. We hypothesized that the RA signal, the strength of which increases with vibratory frequency, interfered with the spatially modulated signal conveyed by SA1 fibers. Consistent with this hypothesis, we found that adapting RA afferent fibers improved spatial acuity, as gauged by GOTs, at the high flutter frequencies.


Sociodemographic Predictors of HIV Infection among Pregnant Women in Botswana: Cross-Sectional Study at 7 Health Facilities.
To determine the prevalence and sociodemographic predictors of HIV among pregnant women in Botswana. This was a cross-sectional study of randomly enrolled women aged 18 to 49 years, attending 7 health facilities in Botswana. Data were gathered from November 2017 to March 2018 and analyzed using SPSS version 24. Of the 429 women enrolled, 407 (96.4%) were included in the analysis. The HIV prevalence was 17%; 69 of 407 (95% CI: 13.4- 21.0). Women aged 35 to 49 years had higher HIV prevalence than those 18 to 24 years (adjusted odds ratio [AOR] = 6.2; 95% CI: 2.7-14.4). Illiterate and elementary school educated women had higher HIV prevalence than those with a tertiary education (AOR = 8.5; 95% CI: 1.8-39.1). Those with a history of alcohol intake had a higher HIV prevalence than those without (AOR = 2.6; 95% CI: 1.3-5.3). HIV prevalence was lower than it was in 2011. Age, level of education, and history of alcohol intake were strong predictors for HIV infection calling for targeted behavioral change interventions.


Pharmacological modification of pulmonary vascular injury: possible role of cAMP.
Experiments were designed to test the hypothesis that drugs which increase adenosine 3',5'-cyclic monophosphate (cAMP) in the lung would prevent the pulmonary hypertension and the increase in vascular permeability caused by the infusion of the oxidant lipid peroxide, tert-butyl hydroperoxide (t-bu-OOH), in isolated rabbit lungs perfused with Krebs-Henseleit buffer. Pretreatment with indomethacin or verapamil was also studied, since these drugs block the increase in pulmonary arterial pressure caused by t-bu-OOH. Indomethacin or verapamil prevented the pulmonary hypertension but did not prevent the increase in permeability caused by t-bu-OOH. Consequently, indomethacin or verapamil treatment partially reduced the gain in lung weight caused by t-bu-OOH. In contrast, pretreatment with isoproterenol, prostaglandin E1, or a cAMP analogue not only prevented the pulmonary hypertension but also inhibited the increase in vascular permeability caused by t-bu-OOH. Consequently, these drugs completely blocked the gain in lung weight caused by t-bu-OOH. Posttreatment with aminophylline or the cAMP analogue also significantly reduced the gain in lung weight caused by t-bu-OOH. These results indicate that pharmacological therapy can reduce the pulmonary hypertension and the increase in vascular permeability caused by the infusion of a lipid hydroperoxide. Since isoproterenol, aminophylline, prostaglandin E1, and a cAMP analogue all had similar effects, the results suggest that the likely common mechanism for their protective effect is an increase in cAMP.


Enterohormonal disturbances in colorectal cancer patients.
Gastrointestinal (GI) hormonal peptides play a role in the development of gastrointestinal malignancies, and their abnormal levels may contribute to dysmotility. The aim of this study was to analyze plasma concentrations of enterohormones (motilin, ghrelin, gastrin and pancreatic polypeptide) and to verify if their abnormal levels may contribute to the severity of dyspeptic symptoms in colorectal cancer patients. The study included 60 patients with colorectal malignancies (22 men and 38 women), among them 30 individuals with colon cancers (group A) and 30 subjects with rectal tumors (group B). Fasting plasma levels of pancreatic polypeptide (PP), motilin, gastrin and ghrelin were determined by means of ELISA. The results were compared with the respective parameters of healthy volunteers. Colon cancer patients presented with significantly lower concentrations of ghrelin than the subjects with rectal tumors and healthy controls (156.8±86.7 vs. 260.2±87.6 vs. 258.4±94.2 pg/ml, p=0.02), as well as with significantly higher levels of PP (265.5±66.3 vs. 154.1±54.6 vs. 148.3±64.3 pg/ml, p=0.005). Also the levels of motilin turned out to be lower in colon cancer patients than in the subjects with rectal malignancies and healthy controls. No statistically significant intergroups differences were found in plasma levels of gastrin (388.2±98.6 vs. 475.6±88.7 vs. 428.2±91.2 pg/ml, p>0.05). Epigastric bloating was the most frequent dyspeptic symptom, reported by 63.3% and 40% of patients with colon and rectal tumors, respectively. Our findings imply that colon cancer patients may present with abnormal plasma levels of enterohormones significantly more often than individuals with rectal malignancies. Dysmotility observed in colon cancer patients may result not only from anticancer surgery, but also from abnormal release of enterohormones, induced either by neoplastic process or by changes within the autonomic nervous system.


Intracranial Hemorrhage Secondary to Vaping: A Case Report and Literature Review.
Vaping and marijuana use are becoming more common and accessible in young adults. However, questions remain regarding their long-term health implications. Current literature does not suggest that vaping causes intracranial hemorrhages. Here, we present a case of a 32-year-old male with no medical history other than vaping and marijuana use, who was found to have an acute intraventricular hemorrhage presenting as syncope. This paper explores the relationships between vaping, marijuana use, and strokes in the general population, and further elaborates on the effects of vaping in young adults. We hope to raise awareness of the negative health implications vaping has on otherwise healthy patients and encourage clinicians to take thorough histories and identify those who vape so that comprehensive education can be provided.


Predictive Factors for Hearing Outcomes After Canaloplasty in Patients With Congenital Aural Atresia.
The aim of this study was to determine the most important factors in preoperative imaging, including components of Jahrsdoefer score (J score), and favorable prognostic factors for postoperative hearing results after canaloplasty for congenital aural atresia. Retrospective review of medical records. One hundred eight patients who underwent canaloplasty by a single surgeon between January 2011 and July 2014 were included. The influence of the following factors on the success for restoring of hearing was evaluated by univariable and multivariable logistic regression analyses: sex, atretic side, total J score, each component of Jahrsdoerfer grading scale, incudostapedial joint angle, inferior displacement of the tegmen, middle ear height, and inner ear anomaly. Successful hearing outcome was defined as postoperative air conduction ≤40 dB at 3 months after surgery, and it was achieved in 74 of 108 ears (70.5%). Univariable analysis revealed that the total J score, course of the facial nerve, presence of the malleus-incus complex, pneumatization of the mastoid, and middle ear height were significant as favorable predictive factors. Multivariable analysis revealed that middle ear height and inferior displacement of the tegmen were significant as favorable predictive factors. Inferior displacement of the tegmen was the most significant factor by the stepwise selection method in the final model. Middle ear height and inferior displacement of the tegmen are useful factors in predicting favorable hearing results after canaloplasty for congenital aural atresia. These factors might have a useful prognostic value supplementary to the J score.


A review of performance and symptom validity testing with pediatric populations.
Growing recognition and concerns of non-credible performance in pediatric populations have led clinicians to investigate the utility of performance and symptom validity tests (PVT/SVTs) among children and adolescents. Yet current research has indicated that a minority of clinicians routinely utilize a free-standing PVT in pediatric neuropsychological evaluations. The current article investigates the rationale for using PVT/SVTs, and the impact that failure of such exams have on other neurocognitive tests. A review of common adult PVTs and their appropriateness for use with specific pediatric clinical populations is presented, as well as empirical evidence for evaluating embedded validity indicators. The limited literature on SVTs with youth is also reviewed and provides additional insight into symptom exaggeration. There are various reasons children would provide noncredible performance, many of which are different from adults. A review of how the clinician should handle this behavior in pediatric evaluations is provided and what patient populations may present with a higher base rate of failure. Finally, various approaches are offered on how to explain these results to children and their caregivers.


Endoilluminator phototoxic maculopathy associated with combined ICG-assisted epiretinal membrane and internal limiting membrane peeling.
Phototoxic maculopathy caused by endoillumination during macular surgery is uncommon. Previously identified risk factors have included intensity of the light source, proximity to the retinal surface, and length of exposure. In the era of indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling, the use of ICG, and the technique of ILM peeling may both contribute to subsequent phototoxic maculopathy. We present cases of routine chromovitrectomy who developed phototoxic maculopathy in the precise discrete distribution of the ILM rhexes, and discuss potential mechanisms and implications.


Injury to anterior optic pathways.
Fourteen patients with injury to the anterior optic pathways have been presented and analysed. Their clinical profile, radiological data and problems involved therein have been discussed. Since an expectant policy has been the rule so far, an attempt has been made to define the role of surgery in such cases.


Characterization of heterogeneity of haemophilia B for the detection of carriers.
Factor IX activity (IX:C) and antigern (IX:Ag) as well as factor VII, prothrombin time, Normotest and Thrombotest were determined in 37 haemophiliacs B from 26 kindreds, in 30 carriers of haemophilia B and in 40 healthy subjects. In 15 obligatory carriers from 9 kindreds, in which haemophiliacs did not exhibit IX:Ag in excess of IX:C, IX:C was parallel with IX:Ag, but in 4 from 4 kindreds, in which haemophiliacs exhibit excess of IX:Ag, there was a discrepancy between IX:C and IX:Ag. Among the obligatory carriers 6 from 3 kindreds, in which haemophiliacs did not have IX:Ag in excess of IX:C, showed that the anomaly M is not a sign of genetic variability of haemophilia B.


An antisense oligonucleotide on the mouse Shaker-like potassium channel Kv1.1 gene prevents antinociception induced by morphine and baclofen.
Inactivation of the Kv1.1 gene, which codes for a member of the Shaker-like potassium channels by an antisense oligodeoxyribonucleotide (aODN), was carried out in mice. The effect of this inactivation on analgesia induced by morphine (5-9 mg kg-1 s.c.) and baclofen (2-5 mg kg-1 s.c.) was investigated in the mouse hot-plate test. Mice received a single intracerebroventricular injection of mKv1.1 aODN (0.5, 1.0, 2.0 or 3.0 nmol per injection), degenerated ODN or vehicle on days 1, 4 and 7. A dose-dependent inhibiton of morphine and baclofen antinociception was observed 72 h after the last intracerebroventricular aODN injection, whereas degenerated ODN and vehicle, used as controls, did not affect morphine- and baclofen-induced antinociception. Sensitivity to both analgesic drugs returned to the normal range 7 days after the end of the aODN treatment, which indicated the absence of any irreversible damage or toxicity caused by aODN. Quantitative reverse transcription-polymerase chain reaction analysis demonstrated that a decrease in mKv1.1 mRNA levels occurred only in the aODN-treated group, being absent in all control groups. Furthermore, neither aODN, degenerated ODN nor vehicle produced any behavioral impairment of mice. These results indicate that the mKv1.1 potassium channel, whose gene expression we specifically modulated by means of the antisense ODN strategy, plays an important role in central analgesia induced by morphine and baclofen.


[Comparative Assessment of Effects of Free and Fixed Combinations of Hypotensive Drugs on Quality of Life of Patients With Arterial Hypertension of High and Very High Risk].
comparative assessment of effects of free and fixed combinations of hypotensive drugs on quality of life (QL) of patients with arterial hypertension (AH) of high and very high risk of cardiovascular complications. Study group comprised 120 patients (70% men, 30% women, age 45-65 years) with degree II (20.9%) and III (79.1%) A. Duration of AH was 10.6+/-2.89 years. Risk was high in 58 (48.3%), very high - in 62 (51.7%) patients. Patients were randomized into 3 groups with different second step therapy. Patients of group 1 received amlodipine + ramipril, group 2 - amlodipine + lisinopril, group 3 - fixed amlodipine/lisinopril combination. If necessary bisoprolol and indapamide were added at 3-rd and 4-th step, respectively. Assessment of QL was carried out prior to therapy and at the end of 14-th week of intervention by means of Short Form-36 (SF-36). Use of fixed amlodipine/lisinopril combination in patients with AH with high and very high risk of cardiovascular complications compared with free combinations of amlodipine and lisinopril or ramipril was associated with statistically significant improvement of a number of QL parameters as assessed by SF-36 questionnaire: physical functioning, bodily pain, general health, social functioning, and mental health.


Erratum.
Stachler RJ, Francis DO, Schwartz SR, et al. Clinical practice guideline: hoarseness (dysphonia) (update). Otolaryngol Head Neck Surg. 2018;158:S1-S42. (Original DOI: 10.1177/0194599817751030) Stachler RJ, Francis DO, Schwartz SR, et al. Clinical practice guideline: hoarseness (dysphonia) (update) executive summary. Otolaryngol Head Neck Surg. 2018;158:409-426. (Original DOI: 10.1177/0194599817751031) Krouse HJ, Reavis CW, Stachler RJ, Francis DO, O'Connor S. Plain language summary: hoarseness (dysphonia). Otolaryngol Head Neck Surg. 2018;158:427-431. (Original DOI: 10.1177/0194599817751137) In the March 2018 clinical practice guideline and associated articles David O. Francis and Seth R. Schwartz's affiliations were listed incorrectly. Dr Francis should have been affiliated with University of Wisconsin, Madison, Wisconsin, USA. Dr Schwartz should have been affiliated with Virginia Mason Medical Center, Seattle, Washington, USA. Additionally, in the Plain Language Summary the location of Wayne State University was listed as Allen Park, Michigan; it should have been Detroit, Michigan. These have been updated in the online issues.


The platform GrowScreen-Agar enables identification of phenotypic diversity in root and shoot growth traits of agar grown plants.
Root system architecture and especially its plasticity in acclimation to variable environments play a crucial role in the ability of plants to explore and acquire efficiently soil resources and ensure plant productivity. Non-destructive measurement methods are indispensable to quantify dynamic growth traits. For closing the phenotyping gap, we have developed an automated phenotyping platform, GrowScreen-Agar, for non-destructive characterization of root and shoot traits of plants grown in transparent agar medium. The phenotyping system is capable to phenotype root systems and correlate them to whole plant development of up to 280 Arabidopsis plants within 15 min. The potential of the platform has been demonstrated by quantifying phenotypic differences within 78 Arabidopsis accessions from the 1001 genomes project. The chosen concept 'plant-to-sensor' is based on transporting plants to the imaging position, which allows for flexible experimental size and design. As transporting causes mechanical vibrations of plants, we have validated that daily imaging, and consequently, moving plants has negligible influence on plant development. Plants are cultivated in square Petri dishes modified to allow the shoot to grow in the ambient air while the roots grow inside the Petri dish filled with agar. Because it is common practice in the scientific community to grow Arabidopsis plants completely enclosed in Petri dishes, we compared development of plants that had the shoot inside with that of plants that had the shoot outside the plate. Roots of plants grown completely inside the Petri dish grew 58% slower, produced a 1.8 times higher lateral root density and showed an etiolated shoot whereas plants whose shoot grew outside the plate formed a rosette. In addition, the setup with the shoot growing outside the plate offers the unique option to accurately measure both, leaf and root traits, non-destructively, and treat roots and shoots separately. Because the GrowScreen-Agar system can be moved from one growth chamber to another, plants can be phenotyped under a wide range of environmental conditions including future climate scenarios. In combination with a measurement throughput enabling phenotyping a large set of mutants or accessions, the platform will contribute to the identification of key genes.


Combined treatment of epigallocatechin gallate and Coenzyme Q10 attenuates cisplatin-induced nephrotoxicity via suppression of oxidative/nitrosative stress, inflammation and cellular damage.
Cisplatin (CP), a platinum based anticancer drug is used as one of the first-line therapy for the treatment of different types of solid tumors. However, CP-induced side effects particularly, nephrotoxicity is a major concern. A single nephrotoxic dose (7 mg/kg body weight) of CP was administered in rats with or without, pre and post combined multidoses of epigallocatechin gallate (EGCG) and coenzyme Q10 (CoQ10) (15 and 5 mg/kg body weight respectively). CP administration resulted in marked increase in the nephrotoxic parameters with alterations in the oxidative and nitrosative stress markers. The concentration of inflammatory, as well as apoptotic markers were markedly up-regulated in the kidney of the CP-treated group. Furthermore, CP resulted in histological injury in the renal tissues. Combined antioxidant treatment significantly (p < 0.01) attenuated CP-induced oxidative stress, nitrosative stress, inflammatory and apoptotic parameters. Moreover, an improvement in the histopathological changes confirmed the nephroprotective effect of antioxidant treatment. In conclusion, our study indicates that the combinatorial multidoses of EGCG and CoQ10 ameliorate the cisplatin-mediated pathogenesis by improving renal oxidative/nitrosative status, inflammation and apoptosis and thus can be used as a promising protective agent to increase the efficacy of the drug by minimizing its major side effect i.e. nephrotoxicity.


Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia.
Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity.


Prospective study of hormonal contraception and women's risk of HIV infection in South Africa.
Many women using hormonal contraceptives are also at risk of sexually transmitted HIV infection, but data are mixed on whether hormonal contraception increases women's risk of HIV. We investigated associations between HIV incidence and use of combined oral contraceptives (COC), norethindrone enanthate (NET-EN) or depot medroxyprogesterone acetate (DMPA) in a cohort of South African women. Participants were 4200 HIV-negative women aged 35-49 years enrolled into a cervical cancer screening trial. At enrollment, women were tested for sexually transmitted infections and reported on their sexual behaviour and contraceptive use. During the 24 months of follow-up, women reported on their sexual behaviours and contraceptive use and underwent repeat HIV testing. During the 5010 person-years of follow-up, 111 incident HIV infections were observed (HIV incidence, 2.2 infections/100 person-years). At enrollment, 21% of women reported using hormonal contraception, primarily DMPA (14% of all women) or NET-EN (5%). After adjusting for sexual risk behaviours and sexually transmitted infections, the incidence of HIV was similar among women using COC, NET-EN or DMPA compared with women not using any hormonal method [incidence rate ratios and 95% confidence intervals, 0.65, 0.16-2.66; 0.79, 0.31-2.02 and 0.96, 0.58-1.59, respectively]. There was also no association between increased duration of DMPA use and HIV incidence (P-value for trend, 0.51). These findings contribute to the evidence from general population cohorts of women that hormonal contraceptive use is not associated with increased risk of HIV acquisition. Nonetheless, family planning services are an important venue for HIV prevention activities.