[Value of multi-slice spiral CT in preoperative diagnosis of pancreatic cancer].
Objective: To analyze the diagnostic value of multi-slice spiral computed tomography (MSCT) in preoperative tumor staging, lymphatic metastasis, vascular invasion and perineural invasion. Methods: From January 2013 to December 2015, MSCT images of 87 patients from the Second Hospital of Harbin Medical University who were examined by contrast-enhanced MSCT and diagnosed as pancreatic cancer by surgical pathology within 2 weeks were collected.MSCT images were retrospectively analyzed to evaluate the tumor staging, lymphatic metastasis, vascular invasion and perineural invasion and then compared with surgical pathology.Kappa test and receiver operation characteristic (ROC) curve were used to evaluate the diagnostic value of MSCT in pancreatic cancer. Results: The overall accuracy of MSCT in T staging of pancreatic cancer was 85.1% (kappa =0.67, P<0.01); the accuracy of T1, T2, T3 and T4 staging were 75.0%, 57.1%, 95.0% and 66.7%; the sensitivity were 75.0%, 80.0%, 87.7% and 75.0%; the specificity were 98.8%, 92.2%, 86.4% and 96.2%; the positive predictive value (PPV) were 75.0%, 57.1%, 95.0% and 66.7%; the negative predictive value (NPV) were 98.8%, 97.3%, 70.4% and 97.4%.The accuracy, sensitivity, specificity, PPV and NPV of MSCT in diagnosing lymphatic metastasis were 62.1%, 62.3%, 61.5%, 79.2% and 41.0%.The accuracy, sensitivity, specificity, PPV and NPV of MSCT in diagnosing vascular invasion were 94.3%, 78.6%, 97.3%, 84.6% and 95.9%.The accuracy, sensitivity, specificity, PPV and NPV of MSCT in diagnosing MSCT perineural invasion were 80.5%, 81.1%, 76.9%, 95.2% and 41.7%.The area under curve (AUC) was 0.79(95%CI 0.68-0.90, P=0.001). Conclusion: Contrast-enhanced MSCT plays important roles in evaluation of preoperative tumor staging, vascular invasion and perineural invasion of pancreatic cancer while it has little value on diagnosis of lymphatic metastasis.


Magnet-Retained Two-Mini-Implant Overdenture: Clinical and Mechanical Consideration.
Two-implant overdentures have become the accepted treatment for restoring mandibular edentulism. The dimensions of regular implants sometimes limit their use, such as in the case of narrow ridges. Mini-implants with reduced diameters (less than 3.0 mm) enable insertion into narrow ridges. A magnet-retained two-mini-implant overdenture system was developed and is described in this paper. Additionally, we describe a clinical mandibular procedure using the system and evaluate its biomechanical performance.


Gamete donation and parental responsibility.
Unlike surrogacy and cloning, reproduction via gamete donation is widely assumed to be morally unproblematic. Recently, a number of authors have argued that this assumption is mistaken: gamete donors, they claim, have parental responsibilities that they typically treat too lightly. In this paper I argue that the 'parental neglect' case against gamete donation fails. I begin by examining and rejecting the view that gamete donors have parental responsibilities; I claim that none of the current accounts of parenthood provides good reason for ascribing parenthood to gamete donors. I then argue that even if gamete donors do have parental responsibilities for 'their' children, it is not clear that they treat these responsibilities too lightly. I conclude the paper by examining the wider question of just what kind of responsibilities gamete donors might have towards the children that they have a role in creating.


Chemotherapy for head and neck cancer relapsing after radiotherapy.
Thirty-nine patients (28 men and 11 women, ages 43 to 83 years) with advanced head and neck epidermoid carcinoma (33 had relapsed from previous radiotherapy) were treated with a three-day bleomycin administration (30 by continuous intravenous infusion and nine by subcutaneous route) followed on the fifth day by intravenous administration of cyclophosphamide + methotrexate + 5-fluorouracil (Bleo-CMF). This drug schedule was based on the cell cycle synchrony principle. Twenty-one of 39 patients (54%) responded (seven complete, 14 partial remission) lasting from 4 to 20 months. The median duration of survival for complete remission, partial remission, and disease progression was 15, ten, and four months, respectively. The Bleo-CMF was well tolerated with minimal toxicity. The effectiveness of this regimen in previously irradiated patients compels us to pursue its application in a randomized study as an adjuvant for Stages III and IV head and neck cancer following maximum eradication of the local disease by surgery and/or radiotherapy.


Adsorption of O2 and oxidation of CO at Au nanoparticles supported by TiO2(110).
Density functional theory calculations are performed for the adsorption of O2, coadsorption of CO, and the CO+O2 reaction at the interfacial perimeter of nanoparticles supported by rutile TiO2(110). Both stoichiometric and reduced TiO2 surfaces are considered, with various relative arrangements of the supported Au particles with respect to the substrate vacancies. Rather stable binding configurations are found for the O2 adsorbed either at the trough Ti atoms or leaning against the Au particles. The presence of a supported Au particle strongly stabilizes the adsorption of O2. A sizable electronic charge transfer from the Au to the O2 is found together with a concomitant electronic polarization of the support meaning that the substrate is mediating the charge transfer. The O2 attains two different charge states, with either one or two surplus electrons depending on the precise O2 adsorption site at or in front of the Au particle. From the least charged state, the O2 can react with CO adsorbed at the edge sites of the Au particles leading to the formation of CO2 with very low (approximately 0.15 eV) energy barriers.


A review: Mechanism of action of antiviral drugs.
Antiviral drugs are a class of medicines particularly used for the treatment of viral infections. Drugs that combat viral infections are called antiviral drugs. Viruses are among the major pathogenic agents that cause number of serious diseases in humans, animals and plants. Viruses cause many diseases in humans, from self resolving diseases to acute fatal diseases. Developing strategies for the antiviral drugs are focused on two different approaches: Targeting the viruses themselves or the host cell factors. Antiviral drugs that directly target the viruses include the inhibitors of virus attachment, inhibitors of virus entry, uncoating inhibitors, polymerase inhibitors, protease inhibitors, inhibitors of nucleoside and nucleotide reverse transcriptase and the inhibitors of integrase. The inhibitors of protease (ritonavir, atazanavir and darunavir), viral DNA polymerase (acyclovir, tenofovir, valganciclovir and valacyclovir) and of integrase (raltegravir) are listed among the Top 200 Drugs by sales during 2010s. Still no effective antiviral drugs are available for many viral infections. Though, there are a couple of drugs for herpesviruses, many for influenza and some new antiviral drugs for treating hepatitis C infection and HIV. Action mechanism of antiviral drugs consists of its transformation to triphosphate following the viral DNA synthesis inhibition. An analysis of the action mechanism of known antiviral drugs concluded that they can increase the cell's resistance to a virus (interferons), suppress the virus adsorption in the cell or its diffusion into the cell and its deproteinisation process in the cell (amantadine) along with antimetabolites that causes the inhibition of nucleic acids synthesis. This review will address currently used antiviral drugs, mechanism of action and antiviral agents reported against COVID-19.


Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation.
Chromosome 16 open reading frame 74 (C16orf74) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in cancer cell proliferation and invasion through binding to calcineurin (CN). Therefore, C16orf74 is a good target for the development of a PDAC treatment. A cell-permeable dominant-negative (DN) peptide that can inhibit the C16orf74/CN interaction was designed to examine whether this peptide can inhibit PDAC cell proliferation in vitro and in vivo. TheDN-C16orf74 peptide, which corresponds to the portion of C16orf74 that interacts with CN, was synthesized, and we assessed its anti-tumor activity in proliferation assays with human PDAC cells and the underlying molecular signaling pathway. Using an orthotopic xenograft model of PDAC, we treated mice intraperitoneally with phosphate-buffered saline (PBS), control peptide, or DN-C16orf74 and analyzed the tumor-suppressive effects. DN-C16orf74 inhibited the binding of C16orf74 to CN in an immunoprecipitation assay. DN-C16orf74 suppressed PDAC cell proliferation, and the level of suppression depended on the expression levels of C16orf74 in vitro. DN-C16orf74 also exhibited anti-tumor effects in orthotopic xenograft model. Furthermore, the tumor-suppressive effect was associated with inhibition of the phosphorylation of Akt and mTOR. The cell-permeable peptide DN-C16orf74 has a strong anti-tumor effect against PDAC in vitro and in vivo.


Expression profiling suggests a regulatory role of gallbladder in lipid homeostasis.
To examine expression profile of gallbladder using microarray and to investigate the role of gallbladder in lipid homeostasis. 33P-labelled cDNA derived from total RNA of gallbladder tissue was hybridized to a cDNA array representing 17,000 cDNA clusters. Genes with intensities > or =2 and variation <0.33 between two samples were considered as positive signals with subtraction of background chosen from an area where no cDNA was spotted. The average gray level of two gallbladders was adopted to analyze its bioinformatics. Identified target genes were confirmed by touch-down polymerase chain reaction and sequencing. A total of 11 047 genes expressed in normal gallbladder, which was more than that predicted by another author, and the first 10 genes highly expressed (high gray level in hybridization image), e.g. ARPC5 (2 225.88+/-90.46), LOC55972 (2 220.32+/-446.51) and SLC20A2 (1 865.21+/-98.02), were related to the function of smooth muscle contraction and material transport. Meanwhile, 149 lipid-related genes were expressed in the gallbladder, 89 of which were first identified (with gray level in hybridization image), e.g. FASN (11.42+/-2.62), APOD (92.61+/-8.90) and CYP21A2 (246.11+/-42.36), and they were involved in each step of lipid metabolism pathway. In addition, 19 of those 149 genes were gallstone candidate susceptibility genes (with gray level in hybridization image), e.g. HMGCR (10.98+/-0.31), NPC1 (34.88+/-12.12) and NR1H4 (16.8+/-0.65), which were previously thought to be expressed in the liver and/or intestine tissue only. Gallbladder expresses 11 047 genes and takes part in lipid homeostasis.


Are more environmentally sustainable diets with less meat and dairy nutritionally adequate?
Our current food consumption patterns, and in particular our meat and dairy intakes, cause high environmental pressure. The present modelling study investigates the impact of diets with less or no meat and dairy foods on nutrient intakes and assesses nutritional adequacy by comparing these diets with dietary reference intakes. Environmental impact and nutrient intakes were assessed for the observed consumption pattern (reference) and two replacement scenarios. For the replacement scenarios, 30 % or 100 % of meat and dairy consumption (in grams) was replaced with plant-based alternatives and nutrient intakes, greenhouse gas emissions and land use were calculated. The Netherlands. Dutch adults (n 2102) aged 19-69 years. Replacing 30 % of meat and dairy with plant-based alternatives did not substantially alter percentages below the Estimated Average Requirement (EAR) for all studied nutrients. In the 100 % replacement scenario, SFA intake decreased on average by ~35 % and Na intake by ~8 %. Median Ca intakes were below the Adequate Intake. Estimated habitual fibre, Fe and vitamin D intakes were higher; however, non-haem Fe had lower bioavailability. For Zn, thiamin and vitamin B12, 10-31 % and for vitamin A, 60 % of adults had intakes below the EAR. Diets with all meat and dairy replaced with plant-based foods lowered environmental impacts by >40 %. Estimated intakes of Zn, thiamin, vitamins A and B12, and probably Ca, were below recommendations. Replacing 30 % was beneficial for SFA, Na, fibre and vitamin D intakes, neutral for other nutrients, while reducing environmental impacts by 14 %.


Levorphanol for Treatment of Intractable Neuropathic Pain in Cancer Patients.
Neuropathic pain in cancer patients is often difficult to treat, requiring a combination of several different pharmacological therapies. We describe two patients with complex neuropathic pain syndromes in the form of phantom limb pain and Brown-Sequard syndrome who did not respond to conventional treatments but responded dramatically to the addition of levorphanol. Levorphanol is a synthetic strong opioid that is a potent N-methyl-d-aspartate receptor antagonist, mu, kappa, and delta opioid receptor agonist, and reuptake inhibitor of serotonin and norepinephrine. It bypasses hepatic first-pass metabolism and thereby not subjected to numerous drug interactions. Levorphanol's unique profile makes it a potentially attractive opioid in cancer pain management.


A multispectral-sensor-based colorimetric reader for biological assays.
Tests that depend on changes in color are commonly used in biosensing. Here, we report on a colorimetric reader for such applications. The device is simple to construct and operate, making it ideal for research laboratories with limited resources or skilled personnel. It consists of a commercial multispectral sensor interfaced with a Raspberry Pi and a touchscreen. Unlike camera-based readers, this instrument requires no calibration of wavelengths by the user or extensive image processing to obtain results. We demonstrate its potential for colorimetric biosensing by applying it to the birefringent enzyme-linked immunosorbent assay. It was able to prevent certain false positives that the assay is susceptible to and lowered its limit of detection for glucose by an order of magnitude.


A well known and important adverse effect of phenytoin in a neurosurgical patient.
Gum hypertrophy is a well-known and important adverse effect of phenytoin therapy in a neurosurgical patient. We present an interesting case of a 21-year-old man who, following head injury after a road traffic accident, developed status epilepticus diagnosed with gum hypertrophy in the jaws, with ongoing antiepileptics. He was managed conservatively as per hospital protocol.


Minimally Invasive Approaches for Anterior Skull Base Meningiomas: Supraorbital Eyebrow, Endoscopic Endonasal, or a Combination of Both? Anatomic Study, Limitations, and Surgical Application.
Minimally invasive accesses to the anterior skull base include the endoscopic endonasal approach (EEA) and the supraorbital eyebrow approach. These 2 are often seen as competing approaches, not alternative or combinatory approaches. In this study, we evaluated the anatomic limitations of each approach and the combined approach for accessing the anterior skull base. Ten neurovascular injected cadaver heads were used for the study. The supraorbital approach to the anterior skull base was performed on 5 heads, and EEA was done on the other 5 heads. Then, the supraorbital approach was added to the 5 heads receiving EEA. Visualization and surgical limitations were recorded by the ability to perform resection of the crista galli, anterior clinoid, cribriform plate, and planum sellae. The maximal lateral extension of EEA for anterior skull base was the midorbit line anteriorly but narrowing down toward the orbital apex. The limitation of the supraorbital approach was found mostly medial and anterior. Drilling of anterior skull base was impossible medially between the sphenoethmoidal suture and the posterior aspect of the crista galli. The combined approach showed complementary areas of visualization and surgical maneuverability. Three clinical cases were presented to illustrate the indications for the stand-alone supraorbital approach, EEA, and combined approach. The limitations of the EEA when dealing with lateral extension of anterior skull base meningiomas, and the limitations of the supraorbital eyebrow approach for medial skull base drilling and reconstruction, can be overcome by a judicious, anatomically based combination of both approaches.


Interleukin 11 blockade during mid to late gestation does not affect maternal blood pressure, pregnancy viability or subsequent fertility in mice.
Interleukin (IL)11 is a crucial regulator during the initiation of pregnancy in humans and mice. Elevated levels are detected in serum, placenta and decidua of women with pre-eclampsia. Elevated IL11 during placentation recapitulates pre-eclampsia in mice, although withdrawal rescues pre-eclampsia features, suggesting that IL11 could provide a novel therapeutic target. The aim of this study was to determine the safety profile of an IL11 antagonist ligated to polyethylene glycol (PEGIL11A) during pregnancy in mice. Blocking IL11 signalling during mid to late gestation pregnancy in mice did not affect pregnancy viability, or alter placental or fetal weight, or morphology. Importantly, decidual area remained unchanged. PEGIL11A did not affect maternal blood pressure, urinary protein or term pup weight. PEGIL11A administration to non-pregnant mice did not affect subsequent fertility; there was no difference in number of implantation sites, or placental or fetal weight between PEGIL11A and PEG-treated mice. These data show that blocking IL11Rα during placentation does not alter the placenta, decidua, fetus, maternal blood pressure or kidneys. These findings highlight the potential of IL11 signalling inhibition as a safe therapy to alleviate pre-eclampsia symptoms and demonstrate the potential for IL11 inhibition as a novel fertility-preserving therapy for women with cancer.


Management of the Positive Axilla in 2017.
The role of surgery in breast cancer treatment and axillary staging is changing. It is not very far from today, when axillary dissection was the standard treatment and staging procedure for all stages of breast cancer. Today, we are on the edge of omitting axillary dissection even in patients with the axillary disease. In this review, we walked through the changes in axillary management throughout the past hundred years.


Extracellular signal-regulated kinases 2 (Erk2) and Erk5 in the central nervous system differentially contribute to central sensitization in male mice.
Nervous systems are designed to become extra sensitive to afferent nociceptive stimuli under certain circumstances such as inflammation and nerve injury. How pain hypersensitivity comes about is key issue in the field since it ultimately results in chronic pain. Central sensitization represents enhanced pain sensitivity due to increased neural signaling within the central nervous system (CNS). Particularly, much evidence indicates that underlying mechanism of central sensitization is associated with the change of spinal neurons. Extracellular signal-regulated kinases have received attention as key molecules in central sensitization. Previously, we revealed the isoform-specific function of extracellular signal-regulated kinase 2 (Erk2) in spinal neurons for central sensitization using mice with Cre-loxP-mediated deletion of Erk2 in the CNS. Still, how extracellular signal-regulated kinase 5 (Erk5) in spinal neurons contributes to central sensitization has not been directly tested, nor is the functional relevance of Erk5 and Erk2 known. Here, we show that Erk5 and Erk2 in the CNS play redundant and/or distinct roles in central sensitization, depending on the plasticity context (cell types, pain types, time, etc.). We used male mice with Erk5 deletion specifically in the CNS and found that Erk5 plays important roles in central sensitization in a formalin-induced inflammatory pain model. Deletion of both Erk2 and Erk5 leads to greater attenuation of central sensitization in this model, compared to deletion of either isoform alone. Conversely, Erk2 but not Erk5 plays important roles in central sensitization in neuropathic pain, a type of chronic pain caused by nerve damage. Our results suggest the elaborate mechanisms of Erk signaling in central sensitization.


Redox regulation of protein kinases.
Reactive oxygen species (ROS) have been long regarded as by-products of a cascade of reactions stemming from cellular oxygen metabolism, which, if they accumulate to toxic levels, can have detrimental effects on cellular biomolecules. However, more recently, the recognition of ROS as mediators of cellular communications has led to their classification as signalling mediators in their own right. The prototypic redox-regulated targets downstream of ROS are the protein tyrosine phosphatases, and the wealth of research that has focused on this area has come to shape our understanding of how redox-signalling contributes to and facilitates protein tyrosine phosphorylation signalling cascades. However, it is becoming increasingly apparent that there is more to this system than simply the negative regulation of protein tyrosine phosphatases. Identification of redox-sensitive kinases such as Src led to the slow emergence of a role for redox regulation of tyrosine kinases. A flow of evidence, which has increased exponentially in recent times as a result of the development of new methods for the detection of oxidative modifications, demonstrates that, by concurrent oxidative activation of tyrosine kinases, ROS fine tune the duration and amplification of the phosphorylation signal. A more thorough understanding of the complex regulatory mechanism of redox-modification will allow targeting of both the production of ROS and their downstream effectors for therapeutic purposes. The present review assesses the most relevant recent literature that demonstrates a role for kinase regulation by oxidation, highlights the most significant findings and proposes future directions for this crucial area of redox biology.


[Laryngeal cancer risk factors].
Laryngeal cancer is the most common of head and neck cancers. Neoplasm used to develop basing on DNA mutation which leads to uncontrolled growth and cells' division. It is due to spontaneous mutations or influence of chemical, biological and physical factors. Laryngeal cancer generation is conditioned by many synergic factors. Some of them certainly participate in cancer genesis and this thesis is accepted by medical environment and other of them have been discussed giving different information. Definition of the risk factors role in laryngeal cancer etiology is very difficult especially regarding their contemporary occurrence in one person. Most common risk factors are environmental factors, gastroesophageal reflux, viral infections, diet, radiation, individual predisposition. Some of them, such as cigarette smoking and abuse alcohol are significantly oftener confirmed in patients with neoplasm diagnosis and others' role in developing of illness has been still researched. Thus the purpose of the study was to present so far achievements in laryngeal cancer etiology and to emphasize controversies relating to some factors' role in cancer genesis.


The impact of preoperative thrombolysis on long-term survival after coronary artery bypass grafting.
Coronary artery bypass grafting (CABG) is frequently used after thrombolytic therapy. However, there is little information regarding long-term survival in this setting. The purpose of the present study was to compare the long-term survival of patients subjected to CABG after thrombolysis to those without thrombolysis. We studied 3760 consecutive patients with isolated CABG between 1992 and 2002. CABG patients without thrombolysis were compared with those who were treated with thrombolysis within 7 days before CABG. Groups were compared by Cox proportional hazard models and Kaplan-Meier survival plots. The propensity for thrombolysis was determined by logistic regression analysis, and each patient with thrombolysis was then matched to 5 patients without thrombolysis. One hundred ninety-six patients (5.2%) were treated with thrombolysis. Patients with thrombolysis were more likely to be male, younger, and with higher rates of unstable angina, emergency operation, recent or transmural myocardial infarction, preoperative intraaortic balloon pump, hemodynamic instability, shock, intravenous nitroglycerine, left-ventricular hypertrophy, sustained ventricular arrhythmia, and higher EuroSCORE. There were no differences in early outcome between matched groups, but the 5-year actuarial survival was higher in patients with thrombolysis (90.3+/-2.2% versus 78.5+/-1.6%; P=0.0007). After adjustment for all factors, the hazard ratio of long-term mortality for patients with thrombolysis was 0.54 (95% CI, 0.36 to 0.81; P=0.003) and, if deaths during the first 12 months were excluded, 0.46 (95% CI, 0.27 to 0.76; P=0.003). Patients subjected to CABG within 7 days after thrombolysis demonstrated increased long-term survival.


Reactivation of hepatitis B virus in hematopoietic stem cell transplant recipients in Japan: efficacy of nucleos(t)ide analogues for prevention and treatment.
We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV.


Assessment of the humoral and cell-mediated immunity against the Plasmodium falciparum vaccine candidates circumsporozoite protein and SPf66 in adults living in highly endemic malarious areas of Papua New Guinea.
To assess natural immunity against the circumsporozoite (CS) protein and the synthetic vaccine SPf66, immunologic studies were carried out in a highly endemic malarious area of Papua New Guinea. Antibody prevalence, antibody titers, and T cell proliferation against both antigens were measured in 214 adults. Immunologic data were analyzed with respect to longitudinal malariologic and morbidity data. Evidence of genetic traits such as glucose-6-phosphate dehydrogenase deficiency and ovalocytosis was analyzed. Antibody prevalence was high, with 79% and 84% for CS protein and SPf66, respectively, while T cell proliferation was infrequent and low, with 14% and 12% responders, respectively. Anti-CS protein antibodies increased with age but showed no association to malaria indices or morbidity. No protective value was observed with T cell responses or with humoral response to SPf66. These results provide a first description of naturally developed immunity against SPf66 and suggest further studies in to fully understand the mechanism of immunity against this antigen.


Heterogeneous One-Pot Carbonylation and Mizoroki-Heck Reaction in a Parallel Manner Following the Cleavage of Cinnamaldehyde Derivatives.
Carbon monoxide (CO) and styrene derivatives that can be both generated by a palladium on carbon (Pd/C)-catalyzed carbon-carbon (C-C) bond cleavage reaction of cinnamaldehyde derivatives were effectively utilized in further palladium-catalyzed C-C bond forming reactions in a direct and practical way. CO derived from simple and affordable CO carriers such as cinnamaldehyde or terephthalaldehyde was efficiently employed in the in situ CO fixation with various aromatic iodides through a palladium-catalyzed carbonylation followed by an inter- or intramolecular coupling reaction with alcohols to afford the corresponding esters or lactones, respectively. Styrene derivatives were also efficient substrates in an in situ Mizoroki-Heck-type cross-coupling reaction with aryl iodides, leading to the effective formation of asymmetric stilbenes. The decarbonylation of cinnamaldehyde derivatives and the subsequent independent syntheses of both esters/lactones and 1,2-diarylethenes could be achieved in a virtual one-pot and in situ reaction using a H-shaped pressure-tight glass-sealed tube consisting of two independent but laterally connected reaction tubes in the gas space.


Response to Anthracnose in a Tarwi (Lupinus mutabilis) Collection Is Influenced by Anthocyanin Pigmentation.
Anthracnose, caused by Colletotrichum lupini, is a major limiting factor for lupin production. Tarwi or Andean Lupin (Lupinus mutabilis) is generally regarded as susceptible to anthracnose, but the high protein and oil content of its seeds raise interest in promoting its cultivation in Europe. In this study we evaluated the response to anthracnose of 10 tarwi accessions contrasting in anthocyanin pigmentation, by comparison to white lupin (Lupinus albus), using a contemporary Portuguese fungal isolate. A severity rating scale was optimized, including weighted parameters considering the type of symptoms and organs affected. All tarwi accessions were classified as susceptible, exhibiting sporulating necroses on the main stem from seven days after inoculation. Anthracnose severity was lower on anthocyanin-rich tarwi plants, with accession LM34/LIB209 standing out as the less susceptible. Accession I82/LIB201 better combines anthracnose response and yield. In global terms, disease severity was lower on white lupin than on tarwi. Although based on a limited collection, the results of the study show the existence of genetic variability among L. mutabilis towards anthracnose response relatable with anthocyanin pigmentation, providing insights for more detailed and thorough characterization of tarwi resistance to anthracnose.


MMPI-2 characteristics of transsexuals requesting sex reassignment: comparison of patients in prehormonal and presurgical phases.
To assess psychopathology in transsexuals at different phases of sex reassignment, we administered the Spanish adaptation of the MMPI-2 (Avila-Espada & Jiménez-Gómez, 1999) to 107 male-to-female and 56 female-to-male transsexuals. Except for the Mf scale, mean T scores from the Clinical scales were within the normal range and did not differ between sexes. Male-to-female transsexuals seeking sex-reassignment hormonal therapy, but not female-to-male patients, scored significantly higher on the Depression, Hysteria, Psychopathic Deviate, Schizophrenia, and Social Introversion scales than patients seeking sex-reassignment surgery. The results show that the majority of patients were free of psychopathology. Transsexuals in the initial phases of sex reassignment may experience more distress than in later phases; however, these results are unlikely to reflect clinically relevant differences.


Barker Hypothesis and Hypertension.
Early onset hypertension is one of many major medical disorders that have evolved over the current millennium across both the developing as well as the developed world. Though various mechanisms have been postulated for the evolution of hypertension in these individuals, one of the most relevant ones is that of low birth weight and its association with hypertension. Barker from historical evidence has postulated the foetal onset adult disease (FOAD) or Thrifty phenotype on Low Birth Weight (LBW) associated hypertension. Later, Brenner highlighted the importance of low nephron mass and future implications. In this review we elaborate the mechanisms that were postulated for LBW-related hypertension as well the potential antihypertensive therapy that may be used in these individuals.


Induction of biologically active antineutrophil cytoplasmic antibodies by immunization with human apoptotic polymorphonuclear leukocytes.
Translocation of intracellular components to the cell surface during the priming or apoptosis of polymorphonuclear leukocytes (PMN) is an important mechanism for interaction of antineutrophil cytoplasmic antibodies (ANCA) with these antigens. To test the capacity of apoptotic PMN to trigger production of ANCA, six groups of mice were immunized with either live or apoptotic lymphocytes, or with live, apoptotic, formalin-fixed, or lysed PMN. Mice immunized with both live and apoptotic neutrophils developed high titers of antibodies which gave a granular cytoplasmic immunofluorescent pattern. These antibodies were specific for lactoferrin and myeloperoxidase. Following a second intravenous infusion of apoptotic PMNs, mice developed anti-PR3 antibodies. Vasculitis lesions were not found in mice which developed ANCA. The ANCA-containing IgG fraction induced superoxide production by human PMNs. These results support the hypothesis that neutrophil-specific antigens presented on the cell membranes of apoptotic PMN may induce ANCA in the proper conditions.


Clinical Application of Anlotinib Combined with Docetaxel: Safe and Effective Treatment for Lung Carcinoma.
To compare the clinical efficacy and long-term survival between anlotinib monotherapy and anlotinib plus docetaxel in patients with lung carcinoma. Between October 2019 and December 2021, 84 patients with lung cancer diagnosed and treated at our hospital were enrolled and randomly allocated to the control (n = 42) and experimental (n = 42) groups. Patients in the control group only received anlotinib, whereas those in the experimental group were administered both anlotinib and docetaxel. The clinical effectiveness, long-term survival, and other associated variables of the two groups were compared. There were no CR cases, 7 PR cases, 22 SD cases, and 13 PD cases in the control group. In the experimental group, there were 4 cases of CR, 20 cases of CR, 11 cases of SD, and 7 cases of PD. The overall clinical effectiveness of the experimental group was much higher than that of the control group. There were 3 cases of anemia, 5 cases of pyrexia, 6 cases of proteinuria, 9 cases of nausea and vomiting, and 4 cases of abnormal liver and renal function in the control group. (P < 0.05). In the experimental group, there were 2 cases of anemia, 3 cases of pyrexia, 1 case of proteinuria, 5 cases of nausea and vomiting, and 1 case of abnormal liver and kidney function. The incidence of adverse reactions in the experimental group was significantly lower than in the control group (64.29%) (P < 0.05). According to the two-year follow-up results, the survival rate was 19.05% in the control group and 54.76% in the experimental group, and the mortality rate was 80.95% in the control group and 45.24% in the experimental group. The experimental group had a significantly higher survival rate than the control group (P < 0.05). Anlotinib combined with docetaxel is a safe and effective treatment for lung carcinoma to reduce the incidence of adverse reactions and improve the long-term survival rate. These benefits make it worthy of a broader clinical application. Although pharmacological treatment was applied in this study based on the mechanism, specific bioeffective markers are yet to be identified, presenting a direction for future research.


Impact of the ESR gene on litter size and production traits in Czech Large White pigs.
To evaluate the effect of the PvuII polymorphism of the oestrogen receptor gene on litter size and production traits in Czech Large White swine, data from 1250 sows and 3600 litters were analysed with two four-trait animal models. The traits in the first model were number of piglets born alive in a sow's first litter, number of piglets born alive in second and subsequent litters, lifetime daily gain and lean meat percentage. The second model included number of piglets born, number of piglets born alive, number of piglets weaned and litter weight at weaning from first and subsequent litters. The oestrogen receptor (ESR) locus significantly affected prolicacy in the first parity and averaged over all parities (P < 0.05), with allele A superior to allele B. In the first parity, AA sows produced approximately 0.5 more live piglets per litter than BB sows. Averaged over all parities, this difference was c. 0.25 piglets. Results for total number of piglets born and number of piglets weaned were similar to results for numbers born alive. No significant dominance effect was found for prolificacy traits. For litter weight at weaning, no significant additive effect was observed at the ESR locus, but a significant negative dominance effect (-1.5 kg) was estimated averaged across parities (litters of AB sows were similar to litters of BB sows for this trait). No pleiotropic effect of the ESR polymorphism on average daily gain or lean meat percentage was found.


A Pak-regulated cell intercalation event leading to a novel radial cell polarity is involved in positioning of the follicle stem cell niche in the Drosophila ovary.
In the germarium of the Drosophila ovary, germline cysts are encapsulated one at a time by a follicular epithelium derived from two follicle stem cells (FSCs). Ovaries in flies mutant for the serine/threonine kinase Pak exhibit a novel phenotype, in which two side-by-side cysts are encapsulated at a time, generating paired egg chambers. This striking phenotype originates in the pupal ovary, where the developing germarium is shaped by the basal stalk, a stack of cells formed by cell intercalation. The process of basal stalk formation is not well understood, and we provide evidence that the cell intercalation is driven by actomyosin contractility of DE-Cadherin-adhered cells, leading to a column of disk-shaped cells exhibiting a novel radial cell polarity. Cell intercalation fails in Pak mutant ovaries, leading to abnormally wide basal stalks and consequently wide germaria with side-by-side cysts. We present evidence that Pak mutant germaria have extra FSCs, and we propose that contact of a germline cyst with the basal stalk in the pupal ovary contributes to FSC niche formation. The wide basal stalk in Pak mutants enables the formation of extra FSC niches which are mispositioned and yet functional, indicating that the FSC niche can be established in diverse locations.


Intramedullary fibular allograft and nail for treatment of femoral shaft nonunion.
We present a difficult case of hypertrophic nonunion associated with a large cavity in the lower third of the femur. The cavity had been created by a windshield-wiper effect after failure of fixation with a Schneider intramedullary rod in a patient weighing 450 pounds. Treatment consisted of exchanging the Schneider nail with a larger-diame-ter interlocking nail and using the intramedullary fibular allograft to fill the cavity. The fracture healed 4 months after the procedure. At 5-year follow-up, the patient had no complaint, and plain radiographs showed obliteration of the large cavity in the distal femur. Intramedullary fibular graft technique can be used as an adjunct to use of an intramedullary nail when the distal femur contains a large cavity or when the intramedullary rod does not provide adequate fixation stability.


Exploring the Role of Phytochemicals as Potent Natural Photosensitizers in Photodynamic Therapy.
Cancer is still considered a deadly disease worldwide due to difficulties in diagnosis, painful treatment procedures, costly therapies, side effects, and cancer relapse. Cancer treatments using conventional methods like chemotherapy and radiotherapy were not convincing due to its post-treatment toxicity in the host. In Photodynamic Therapy (PDT), three individual non-toxic components including a photosensitizer, light source and oxygen cause damage to the cells and tissues when they are combined. In recent years, phytochemicals are being increasingly recognized as potent complementary drugs for cancer because of its natural availability, less toxicity and therapeutic efficiency in par with commercial drugs. Hence, the idea of using phytochemicals as natural photosensitizers in PDT resulted in a multiple pool of research studies with promising results in preclinical and clinical investigations. In this review, the potential of phytochemicals to act as natural photosensitizers for PDT, their mode of action, drawbacks, challenges and possible solutions are discussed in detail. In PDT, natural photosensitizers, when used alone or in combination with other photosensitizers, induced cell death by apoptosis and necrosis, increased oxidative stress, altered cancer cell death signaling pathways, increased cytotoxicity and DNA damage in cancer cells. The pro-oxidant nature of certain antioxidant polyphenols, hormesis phenomenon, Warburg effect and DNA damaging potential plays a significant role in the photosensitizing mechanism of phytochemicals in PDT. This review explores the role of phytochemicals that can act as photosensitizers alone or in combination with PDT and its mechanism of action on different cancers.


Does HNO3 dissociate on gas-phase ice nanoparticles?
We investigated the dissociation of nitric acid on large water clusters (H2O)N, N̄ ≈ 30-500, i.e., ice nanoparticles with diameters of 1-3 nm, in a molecular beam. The (H2O)N clusters were doped with single HNO3 molecules in a pickup cell and probed by mass spectrometry after a low-energy (1.5-15 eV) electron attachment. The negative ion mass spectra provided direct evidence for HNO3 dissociation with the formation of NO3-⋯H3O+ ion pairs, but over half of the observed cluster ions originated from non-dissociated HNO3 molecules. This behavior is in contrast with the complete dissociation of nitric acid on amorphous ice surfaces above 100 K. Thus, the proton transfer is significantly suppressed on nanometer-sized particles compared to macroscopic ice surfaces. This can have considerable implications for heterogeneous processes on atmospheric ice particles.


Oral health condition and occurrence of depression in the elderly.
Depression is a common disorder among the elderly; however, it is not a standard element of the ageing process. Depression can affect oral health as a result of neglecting oral hygiene procedures, cariogenic nutrition, avoidance of necessary dental care which leads to an increased risk of dental caries and periodontal disease.Assessment of the relationship of oral health parameters with depression.500 subjects aged ≥65 (mean 74.4 ± 7.4) were involved in the study. Dental condition (decay-missing-filled index [DMFT], number of missing teeth [MT], removable denture wearing, teeth mobility), periodontal condition (bleeding on probing [BoP], pocket depth [PD], loss of attachment), oral dryness (the Challacombe Scale) and depression according to the Patient Health Questionnaire-9 (PHQ-9) scale were assessed.Depression on a minimal level was detected in 60.2% of the subjects, mild-in 22.2%, moderate-in 6.0% and moderately-in 2.6%. The mean of the PHQ-9 scale was 3.56 ± 4.07. Regression analysis showed a positive relationship of the PHQ-9 value with DMFT, the number of MT, oral dryness and with age. No correlation was observed between other examined oral health indicators, such as periodontal condition (BoP, PD, clinical attachment level), periodontitis, removable denture wearing a PHQ-9.The results of our study have shown that among people aged 65 and over, the severity of depression increases with a higher number of MT, the number of decayed teeth, as well as prevalence of oral dryness.


Dolichoectatic arterial compression of the chiasm and optic nerve: a case report.
Dolichoectatic arterial compression of the anterior visual pathway is a rare but recognized condition. The functional impact, however, is still less clear. We describe a case of a 56-year-old male with diminished visual acuity in the left eye and incongruent inferior visual defect in both eyes caused by dolichoectasia due to a congenital hypoplasia of one horizontal segment of the circle of Willis and subsequent arterial compression of the chiasm and left optic nerve.


Congenital amegakaryocytic thrombocytopenia with multiple physical anomalies in a female neonate.
Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare disorder of infancy characterized by isolated thrombocytopenia along with hypoplasia or aplasia of megakaryocytes in the bone marrow. It is caused by c-mpl mutation which disrupts the function of thrombopoietin (TPO) receptor. CAMT in association with physical anomalies is a rare entity with only limited data from single case reports being available. Here we present a case of 35 days neonate who had CAMT together with facial malformations and cardiac defects.


Infection in orthopedic implant surgery, its risk factors and outcome.
Infection in orthopedic surgery is a disaster both for the patient and surgeon. Although its incidence has been reduced due to modern theatre facilities and aseptic measures but in developing countries its prevalence is still high. It is better to prevent infection rather than to treat it. The objective of this study is to know the frequency of infection in orthopedic implant surgery in a public hospital and to evaluate the risk factors, causative organism, complications and treatment. This prospective study was conducted in orthopedic unit-B Ayub Teaching Hospital, Abbottabad, from 1st April 2007 to 30th October 2007. Close fracture cases admitted for internal fixation devices were included. The exclusion criteria were soft tissue surgery, wounds and open fractures needing external fixation devices. The follow up was done for six months. Infection developed in 6 patients (5.76%), out of which superficial and deep infections were 2 (1.92%) and 4 (3.84%) respectively. There were 2 infection cases in each stage of the infection i.e. early, delayed and late. The staphylococcus aureus was the commonest organism, i.e., 3 (50%) out of 6. The age of the patients was more than 60 years in 3 (2.88%) patients, 30 to 60 years in 2 (1.92%) patients and below 30 year in 1 (0.96%) patient. The smoking history was in 2 (1.92%) patients. Infection rate in our study was quite high and needs proper measures to control it because it had great financial burden on patient and on hospital resources and could lead to morbidity and mortality in patients. We could not find significant risk factors in our small sample size study although the infection was relatively more common in patients with advanced age, prolonged surgery time, smoking and skin abrasion at fracture site. Commonest organism was Staphylococcus aureus.


Structural and Mechanistic Basis of the Inhibitory Potency of Selected 2-Aminothiazole Compounds on Protein Kinase CK2.
Selective inhibitors of protein kinase CK2 with significant cytotoxicity on tumor cells based on a 2-aminothiazole scaffold were described recently. Here, these studies are supplemented with representative CK2α/CK2α' complex structures. They reveal that the 2-aminothiazole-based inhibitors occupy the ATP cavity, whereas preliminary data had indicated an allosteric binding site. The crystal structure findings are corroborated by subsequent enzyme kinetic studies; their atomic-resolution quality provides the basis for future optimization of these promising CK2 inhibitors.


Reducing medication errors involving antiretroviral therapy with targeted electronic medical record modifications.
Medication errors are common among HIV-infected patients on anti-retroviral therapy (ART), especially when transitioning to the inpatient setting. In previous studies, medication error rates among hospitalized patients on ART have been reported to exceed 50%. When patients receiving ART are admitted to the hospital, medication errors can be prevented through optimization of administration instructions and dosing defaults in order-entry screens in the electronic medical record (EMR). We sought to evaluate the impact of EMR modifications (defaulted doses, frequencies, and administration instructions) implemented to improve the order-entry process and reduce errors. All adult patients admitted between 10/1/2010-3/31/2012 (pre-EMR modification) and 10/1/2013-3/31/2014 (post-EMR modification) that continued on ART upon admission were included. The primary outcome was the overall rate of medication errors identified through review by the antimicrobial stewardship program (ASP). We also characterized the types of medication errors identified during the two time periods. Following EMR modifications, the medication error rate identified through ASP review was reduced from 50.2% to 28.2% (P < 0.01). The number of medication related errors relating to dosage (regimens requiring dose optimization, renal dose adjustment, and dose timing) were reduced by 22% (P < 0.01). Modifications at the anti-retroviral medication order-entry screens in the EMR significantly reduced medication errors, particularly with respect to dosing and dose timing.


Multiple and multidrug resistance in Botrytis cinerea: molecular mechanisms of MLR/MDR strains in Greece and effects of co-existence of different resistance mechanisms on fungicide sensitivity.
Botrytis cinerea is a high-risk pathogen for fungicide resistance development. Within the fungal populations, strains have developed multiple mutations in different target genes leading to multiple resistance (MLR) or mutations associated with overexpression of efflux transporters leading to multidrug resistance (MDR). These types of resistance are a major threat, and their successful management is a major challenge. The current study was initiated to a) determine frequencies of MLR/MDR strains in populations originating from several crops, b) identify the types of MDR that occur in Greece, and c) determine interactions between MLR and MDR at the level of sensitivity to botryticides. The frequencies of MLR/MDR phenotypes were determined in 515 isolates subjected to bioassays using discriminatory concentrations of thiophanate-methyl, iprodione, cyprodinil, fenhexamid, boscalid, fluopyram, fludioxonil, pyraclostrobin, and tolnaftate. Interestingly, 7.8% and 31.3% of isolates from strawberry and rootstock seedlings were resistant to every single fungicide class, while MDR phenotypes from strawberries, rootstocks, and tomatoes accounted for 26%, 87%, and 13.4%, respectively. The MLR and MDR isolates were further molecularly analyzed regarding genes erg27, sdhB, Bcpos5, and Mrr1, responsible for resistance to fenhexamid, boscalid and fluopyram, cyprodinil, and MDR, respectively. The different mutations' presence was determined along with a new mutation in Mrr1 leading to MDR. MDR isolates were characterized as MDR1 or MDR1h based on the presence of a 3-bp deletion in Mrr1. MDR1h was predominant in isolates from rootstocks and MDR1 from tomatoes and strawberries, whereas the most frequent target-site mutations were F412S (erg27), H272R (sdhB), and L412F (Bcpos5). To determine whether the accumulation of target-site mutations along with MDR mutations exhibits an additive effect concerning fungicide resistance, the sensitivity of isolates possessing the predominant target-site mutations was calculated in both the presence and the absence of MDR-associated mutations. EC50 in cyprodinil and boscalid increased to about twofold in the presence of MDR mutations, while there was no difference for fenhexamid. In conclusion, MLR/MDR frequencies are notably high in heavily treated crops in Greece, and the combination of MLR and MDR mutations leads to even higher fungicide resistance levels, highlighting the importance of resistance management.


Immunomodulation for type 1 diabetes mellitus.
Type 1 diabetes (T1D) is characterised by immune-mediated pancreatic islet beta-cell destruction. The initial immune response engenders secondary and tertiary responses which collectively result in impairment of beta-cell function, progressive destruction of beta-cells and consequent development of T1D. The process is insidious and may evolve over many years, with the overt expression of clinical symptoms becoming apparent only when most beta-cells have been destroyed. Over the last quarter century much investigation has been directed at interdicting the T1D disease process, both during the stage of evolution of the disease and at the time of disease onset. This chapter of the Yearbook of Advanced Technology and Treatments in Diabetes reviews the key articles that have appeared in this field between January 2008 and June 2009.


Infections of Ligula intestinalis on Freshwater Fish in Kars Plateau of North-Eastern Anatolia, Turkey.
This study was conducted to determine the prevalence of Ligula intestinalis and infections caused by these on freshwater fish in rivers and streams in the Kars plateau of north-eastern Anatolia, Turkey. This research was conducted between April and July 2011. Fish samples were caught via a casting net and an electro-shocker. The samples were immediately examined to determine the prevalence of L. intestinalis plerocercoids. In this research, 310 stream fishes were studied to determine the prevalence of L. intestinalis plerocercoids. Detected fishes included 55.8% Capoeta capoeta, 24.2% Squalius cephalus, 11.0% Alburnus filippii, 5.8% Barbus plebejus lacerta, and 3.2% Alburnoides bipunctatus. L. intestinalis plerocercoids were found in 2.6% (8/310) of the examined fishes. The percentage of this parasite was found to be 38.9% (7/18) on B. plebejus lacerta and 0.6% (1/173) on C. capoeta. L. intestinalis plerocercoids were not observed on the other three fish species (S. cephalus, A. filippii, and Al. bipunctatus). In this study, L. intestinalis plerocercoids were reported for the first time in the Kars stream and its distributaries on the Kars plateau in north-eastern Anatolia, Turkey.


Assessing Potato Cultivar Sensitivity to Tuber Necrosis Caused by Potato mop-top virus.
Potato mop-top virus (PMTV) causes mop top disease in potato. This disease can result in a decline in tuber quality causing economic losses to growers due to the production of necrotic lesions and discolored tissue in infected tubers. Due to the soilborne nature of PMTV, identifying and developing host resistance against the virus is considered the best disease management option. Very little is known about the sensitivity of U.S. potato cultivars to PMTV-induced tuber necrosis. The current study is aimed at investigating the sensitivity of a large number of potato cultivars to PMTV-induced tuber necrosis. Sixty-three cultivars representing all market-types were evaluated in North Dakota over a 2-year period for virus-induced tuber necrosis incidence and severity. PMTV-induced tuber necrosis (P < 0.0001) and severity (P < 0.0001) were significantly different among cultivars. Cultivars were categorized into sensitive, insensitive, and moderately sensitive/insensitive groups based on the virus-tuber induced necrosis data from both years. Based on data from ND trials, six cultivars (Red Endeavor, Viking, Dakota Jewel, Dark Red Norland, Nicolet, and Modoc) were rated as sensitive and 43 were rated as insensitive to PMTV-induced tuber necrosis. Four cultivars, including Bannock Russet, Gemstar Russet, Lelah, and Waneta showed zero PMTV incidence over 2 years. These results will help growers in making individual or coordinated decisions for the management of PMTV-induced tuber necrosis under field and storage conditions.


Modulation of the rat micturition reflex with transcutaneous ultrasound.
Low intensity focused ultrasound has recently been identified as a novel method of stimulating targeted neurons. We hypothesized that ultrasound stimulation of the posterior tibial nerve would inhibit bladder contractions in an established rat model of rhythmic bladder contractions. Cyclical detrusor contractions were initiated by placing a transurethral catheter in female rats and infusing saline into the bladder. Transcutaneous ultrasound pulses were then delivered to the lower extremity of a rat (overlying the posterior tibial nerve) using a single element spherically focused 250 kHz transducer. Sixty-three cycles were repeated at 2 kHz for 300 ms at peak negative pressure of 900 kPa pulsed at 0.5 Hz. We report successful suppression of bladder contractions using ultrasound stimulation in 10 animals. The average latency between the initiation of ultrasound and suppression of bladder contractions was 3 min 23 s (±51 s), the average time of contraction suppression was 13 min and 50 s (±2 min 25 s) and the average time from the end of ultrasound to return of contractions was 9 min 37 s (±2 min and 30 s). In this work, we demonstrate the ability of targeted transcutaneous ultrasound to inhibit rhythmic bladder contractions in anesthetized rats. Due to its non-invasive nature and ease of application, we believe ultrasound mediated suppression of the micturition reflex is potentially an ideal outpatient treatment of overactive bladder and dysfunctional elimination.


Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies.
The age-related decline in serum dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) has suggested that a relative deficiency of these steroids may be causally related to the development of chronic diseases generally associated with aging, including insulin resistance, obesity, cardiovascular disease, cancer, reductions of the immune defense, depression and a general deterioration in the sensation of well-being. The numerous studies which have focused on the link between DHEA and cardiovascular disease have generally been inconsistent, generating much debate and controversy on this issue. The present article is an analysis of studies on the relationship between endogenous DHEA or DHEA-S, obesity and cardiovascular disease risk, as well as DHEA treatment studies. Elevated plasma levels of free DHEA are associated with reduced obesity in both men and women, and with smaller abdominal body fat accumulations in men. However, contradictory results have been reported regarding the relationships between the sulfate ester DHEA-S and adiposity. Age differences in the populations studied may have been a confounding factor in these associations. On the other hand, DHEA-S level is not a predictor of cardiovascular disease endpoints in women, and appears to be a relatively weak one in men. DHEA intervention studies suggest that the effects of DHEA on serum lipids are, at best, modest or non-significant. The uncertainty as to whether endogenous and exogenous DHEA should be considered cardioprotective is related to discrepancies in the literature on this topic. Several studies may have been plagued by methodological problems such as low power, unreliable analytical methods, confounding factors or other differences in the populations studied. As a consequence, the original reports demonstrating dramatic effects of either endogenous or exogenous DHEA on cardiovascular disease risk have never been replicated. We propose that the effects of DHEA on cardiovascular disease risk (either favorable or unfavorable) should be considered to be much more modest than previously believed.


Impact of human immunodeficiency virus type 1 gp41 amino acid substitutions selected during enfuvirtide treatment on gp41 binding and antiviral potency of enfuvirtide in vitro.
Enfuvirtide (ENF), a novel human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, has potent antiviral activity against HIV-1 both in vitro and in vivo. Resistance to ENF observed after in vitro passaging was associated with changes in a three-amino-acid (aa) motif, GIV, at positions 36 to 38 of gp41. Patients with ongoing viral replication while receiving ENF during clinical trials acquired substitutions within gp41 aa 36 to 45 in the first heptad repeat (HR-1) of gp41 in both population-based plasma virus sequences and proviral DNA sequences from isolates showing reduced susceptibilities to ENF. To investigate their impact on ENF susceptibility, substitutions were introduced into a modified pNL4-3 strain by site-directed mutagenesis, and the susceptibilities of mutant viruses and patient-derived isolates to ENF were tested. In general, susceptibility decreases for single substitutions were lower than those for double substitutions, and the levels of ENF resistance seen for clinical isolates were higher than those observed for the site-directed mutant viruses. The mechanism of ENF resistance was explored for a subset of the substitutions by expressing them in the context of a maltose binding protein chimera containing a portion of the gp41 ectodomain and measuring their binding affinity to fluorescein-labeled ENF. Changes in binding affinity for the mutant gp41 fusion proteins correlated with the ENF susceptibilities of viruses containing the same substitutions. The combined results support the key role of gp41 aa 36 to 45 in the development of resistance to ENF and illustrate that additional envelope regions contribute to the ENF susceptibility of fusion inhibitor-naïve viruses and resistance to ENF.


Modified technique of laparoscopy-assisted surgeries (transportal).
We present the role of the transportal technique of laparoscopy-assisted surgeries.This report highlights the advantages of transportal technique over pure laparoscopic surgeries and laparoscopy-assisted surgeries. In the last 3 years, we have adopted this approach for six patients during various procedures. This report highlights modified extracorporeal (transportal) technique, namely, ileal isolation, restoration of ileal continuity in ileal conduit and ileal ureter; ileal isolation, restoration of ileal continuity detubularization of the loop in ileocystoplasty; and ureteral tailoring in the megaureter before ureteral reimplantation. This technique was performed by transportal exteriorization of the bowel through the 12- or 15- or 20-mm port followed by the conventional technique of hand-sewn anastomosis. The bowel and ureter are restored to the abdominal cavity through the same port once the extracorporeal part is completed. There was no significant intraoperative or postoperative morbidity or mortality. The transportal technique without a formal incision reduces operative time; is less demanding; and avoids an abdominal incision,as in the laparoscopy-assisted technique. The transportal technique of laparoscopy-assisted surgery achieves all the advantages of pure laparoscopic surgery without a formal incision, as in laparoscopy-assisted surgery. Hence, it is a less morbid, quicker, and cost-effective method.


Synthesis and diverse biological activity profile of triethylammonium isatin-3-hydrazones.
A series of biorelevant triethylammonium isatin hydrazones containing various substituents in the aromatic fragment have been synthesized. Their structure and composition were confirmed by NMR- and IR-spectroscopies, mass-spectrometry and elemental analysis. It was found that some representatives show activity against Staphylococcus aureus and Bacillus cereus higher or at the level of norfloxacin, including methicillin-resistant Staphylococcus aureus strains. The study also showed low hemo- and cytotoxicity (Chang Liver) and high antiaggregatory and anticoagulant activity of these compounds. The high potential of new ammonium isatin-3-acylhydrazones in the search for antimicrobial activity against phytopathogens of bacterial and fungal nature has been shown for the first time.


Profilin1 activity in cerebellar granule neurons is required for radial migration in vivo.
Neuron migration defects are an important aspect of human neuropathies. The underlying molecular mechanisms of such migration defects are largely unknown. Actin dynamics has been recognized as an important determinant of neuronal migration, and we recently found that the actin-binding protein profilin1 is relevant for radial migration of cerebellar granule neurons (CGN). As the exploited brain-specific mutants lacked profilin1 in both neurons and glial cells, it remained unknown whether profilin1 activity in CGN is relevant for CGN migration in vivo. To test this, we capitalized on a transgenic mouse line that expresses a tamoxifen-inducible Cre variant in CGN, but no other cerebellar cell type. In these profilin1 mutants, the cell density was elevated in the molecular layer, and ectopic CGN occurred. Moreover, 5-bromo-2'-deoxyuridine tracing experiments revealed impaired CGN radial migration. Hence, our data demonstrate the cell autonomous role of profilin1 activity in CGN for radial migration.


Allogeneic bone marrow transplantation for patients with acute nonlymphocytic leukemia.
Seventy patients with acute nonlymphocytic leukemia (ANLL) underwent allogeneic bone marrow transplantation following cytoreduction with total body irradiation and cyclophosphamide. Thirty patients underwent transplantation in first remission, 11 in second remission, 3 in third remission, and 26 in relapse. At a median follow-up of 30 mo, 17 of those in first remission and 7 of those in second remission survive in continuous remission, compared to 1 in third remission and 3 in relapse. The 3-yr Kaplan-Meier probability of disease-free survival among the various groups was 55% (+/- 9.2%) for the first remission transplants, 64% (+/- 14.5%) for second remission, 33% (+/- 20%) in third remission, and 10.3% (+/- 6.3%) in the relapse group. Statistical analysis showed a similar survival in the first and second remission groups that was significantly better than that seen in the third remission and relapse groups (p less than 0.01). The improved survival seen in the early remission groups was due to a significant decrease in the incidence of relapse posttransplant (p less than 0.01). These results confirm observations that a significant number of patients transplanted in first remission may achieve extended disease-free survival and document similar results for patients transplanted in second remission.


Mitoproteome: human heart mitochondrial protein sequence database.
The human mitochondrial proteome database has been developed by deriving data from a combination of public repositories and experimental and computational prediction methods. The experimental data is derived from highly purified mitochondria from human heart tissue, whereas predictions have been performed by MITOPRED, a genome-scale method for the prediction of nucleus-encoded mitochondrial proteins. Mitochondrial protein sequences from different sources have been clustered to generate a nonredundant dataset. Annotations related to the protein function, structure, disease association, pathways, and so on are collected from a number of public databases using commonly used UNIX and Perl scripts. This chapter provides a detailed description of various data sources and methods used to download, curate, parse, and generate meaningful annotations from primary as well as derived databases.


Tooth fairy update.
Early in 1980, we published a series of articles about the Tooth Fairy in cal. We discovered that the author's interest was shared by may other individuals. As a result, he fame... and that of cal ...has spread to the far corners of the Earth.


The impact of structured laboratory routines in computerized medical records in a primary care service setting.
Inappropriate laboratory ordering is a problem affecting medical systems worldwide. An intervention was called for as a result of increasing laboratory costs. Thus, we aimed to assess the impact of introducing computerized laboratory routines to a computerized primary care setting. The study included 380 primary care physician practices of Clalit Health Service (HMO) southern district (CHS-SD) in Israel, caring for 470,000 members. Consensus laboratory routines order sets were electronically introduced into all physicians' computerized medical record (CMR) software, after consensus and internal marketing process. The primary findings were that a previously observed annual increase in laboratory test utilization was stopped, a 2% reduction in total number of tests and a 4 % reduction in the total number of tests per age adjusted person was observed. In conclusion the wide use of CMRs and communication technology combined with an appropriate organizational process can be used to increase appropriate utilization of laboratory tests.


Barriers in access to dementia care in minority ethnic groups in Denmark: a qualitative study.
To explore barriers in access to dementia care in Turkish, Pakistani and Arabic speaking minority ethnic groups in Denmark. Semi-structured qualitative individual- and group interviews with minority ethnic family carers, primary care dementia coordinators, staff in elderly daycare, and multicultural link workers. Hermeneutic phenomenology was used as theoretical framework. A total of 21 individual- and 6 group interviews were conducted, including a total of 35 participants. On the service user side, barriers in access to dementia care were related to lacking language proficiency and strong cultural norms, including familial responsibility for the care of older family members and stigma associated with mental illness and dementia. On the care provider side, the available formal services were rarely tailored to the specific needs of minority ethnic service users and were often considered inadequate or unacceptable. Care practices and perceived consequences of dementia in minority ethnic communities were heavily influenced by cultural factors leading to a number of persisting barriers to accessing dementia care services. There is a simultaneous need to raise awareness about dementia and the existence of dementia care services in minority ethnic groups, to reduce stigma, and to develop culturally appropriate dementia care options.


Monoclonal antibody RG1 against rat Müller cells recognizes optic nerve and cerebral cortex glia in culture.
A monoclonal antibody designated as RG1 was produced by the fusion of mouse myeloma cells with spleen cells from mice immunized with rat retinas. The monoclonal antibody was shown to bind to Müller cells of the rat retina by the avidin-biotin peroxidase complex method. The screening of antibody-producing hybridomas and the analysis of the monoclonal antibody obtained were performed by enzyme-linked immunosorbent assay. The optic nerve, cerebral cortex and dorsal root ganglia were cultured from 17-day embryonic rats and maintained for 17-20 days. Expressions of the RG1 antigen were examined by indirect immunofluorescence in the cultured glial cells. In both the optic nerve and the cerebral cortex glial cells the RG1 antigen was expressed; however, the RG1 antigen was not expressed in cultured Schwann cells throughout the whole culture period. Our results suggest that the RG1 antigen is a common antigen in the supporting neuroectodermal glial cells in the central nervous system.


A rare tumor with unusual clinical presentation detected by positron emission tomography-computed tomography.
Primary hepatic lymphoma represents <1% of extranodal lymphoma and predominantly seen in men older than 50 years of age. Exact etiology for these tumors is not certain yet, but presumed to be caused by certain viruses like Epstein-Barr virus and hepatitis C virus due to the frequent association of these viruses with disease. Most of these tumors are diffuse large B cell non-Hodgkin lymphoma. Direct tissue histopathology with immunochemistry may give clues about diagnosis and prognosis up to certain extent. The rituximab-based chemotherapy is the mainstay of therapy for these tumors; the role of radiotherapy is still not clear but used for management for bulky tumors.


Comparison of outcomes between off-pump versus on-pump coronary artery bypass surgery in elderly patients: a meta-analysis.
The aim of this study was to analyze if off-pump coronary artery bypass surgery (CABG) is associated with better treatment outcomes in elderly patients (>70 years of age) than on-pump CABG, using meta-analysis. Medline, PubMed, Cochrane and Google Scholar databases were searched until September 13, 2016. Sensitivity and quality assessment were performed. Twenty-two studies, three randomized control trials (RCTs) and 20 non-RCTs were included with 24,127 patients. The risk of death associated with on-pump or off-pump CABG in the RCTs were similar (pooled OR=0.945, 95%CI=0.652 to 1.371, P=0.766). However, in the non-RCTs, mortality risk was lower in patients treated with off-pump CABG than on-pump CABG (pooled OR=0.631, 95%CI=0.587 to 0.944, P=0.003). No differences were observed between the two treatment groups in terms of the occurrence of 30-day post-operative stroke or myocardial infarction (P≥0.147). In the non-RCTs, off-pump CABG treatment was associated with a shorter length of hospital stay (pooled standardized difference in means=-0.401, 95%CI=-0.621 to -0.181, P≤0.001). The meta-analysis with pooled data from non-RCTs, but not RCTs, found that mortality was lower with off-pump compared with on-pump CABG, and suggested that there may be some benefit of off-pump CABG compared with on-pump CABG in the risk of mortality and length of hospital stay.


Pulmonary effects of chronic exposure to airborne cadmium.
Workers chronically exposed to high concentrations of airborne cadmium showed a significantly decreased forced vital capacity relative to a low-exposure group and had Po2 values in the normal range, but at the extreme low end. They had no significant decrease in 1-sec forced expiratory volume or maximal mid-expiratory flow. Chest roentgenograms showed mild or moderate interstitial fibrosis in 29 per cent of the group exposed to cadmium. Collectively, these results suggest a mild fibrotic reaction associated with exposure to cadmium. A dose-response association was observed between forced vital capacity, expressed as per cent predicted, and both average urinary cadmium concentration (P less than 0.003; r=-0.53) and maximal urinary cadmium concentration (P less than 0.005; r=-0.51). Further, a dose-response relationship was found between the forced vital capacity and months of work in cadmium fume areas, but not for months of exposure to cadmium sulfate aerosol.


Neuroprotective Activity of Enantiomers of Salsolinol and N-Methyl-(R)-salsolinol: In Vitro and In Silico Studies.
Salsolinol (1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol) is a close structural analogue of dopamine with an asymmetric center at the C1 position, and its presence in vivo, both in humans and rodents, has already been proven. Yet, given the fact that salsolinol colocalizes with dopamine-rich regions and was first detected in the urine of Parkinson's disease patients, its direct role in the process of neurodegeneration has been proposed. Here, we report that R and S enantiomers of salsolinol, which we purified from commercially available racemic mixture by means of high-performance liquid chromatography, exhibited neuroprotective properties (at the concentration of 50 μM) toward the human dopaminergic SH-SY5Y neuroblastoma cell line. Furthermore, within the study, we observed no toxic effect of N-methyl-(R)-salsolinol on SH-SY5Y neuroblastoma cells up to the concentration of 750 μM, either. Additionally, our molecular docking analysis showed that enantiomers of salsolinol should exhibit a distinct ability to interact with dopamine D2 receptors. Thus, we postulate that our results highlight the need to acknowledge salsolinol as an active dopamine metabolite and to further explore the neuroregulatory role of enantiomers of salsolinol.


Agenesis of the corpus callosum, developmental delay, autism spectrum disorder, facial dysmorphism, and posterior polymorphous corneal dystrophy associated with ZEB1 gene deletion.
We report on a girl diagnosed prenatally with agenesis of the corpus callosum (ACC) on fetal ultrasound and MRI. On postnatal follow-up she was noted to have developmental delay, facial dysmorphism, autism spectrum disorder, and posterior polymorphous corneal dystrophy (PPD). Array-comparative genomic hybridization analysis (Array-CGH) showed a 2.05 Mb de novo interstitial deletion at 10p11.23p11.22. The deleted region overlaps 1 OMIM Morbid Map gene, ZEB1 (the zinc finger E-box binding homeobox transcription factor 1), previously associated with posterior polymorphous corneal dystrophy type 3 (PPCD3). To our best knowledge this is the first reported case with a deletion of the ZEB1 gene in an individual with ACC and PPD, showing that the haploinsufficiency of the ZEB1 is likely the cause of our patient's phenotype.


Error reduction in retrievals of atmospheric species from symmetrically measured lidar sounding absorption spectra.
We report new methods for retrieving atmospheric constituents from symmetrically-measured lidar-sounding absorption spectra. The forward model accounts for laser line-center frequency noise and broadened line-shape, and is essentially linearized by linking estimated optical-depths to the mixing ratios. Errors from the spectral distortion and laser frequency drift are substantially reduced by averaging optical-depths at each pair of symmetric wavelength channels. Retrieval errors from measurement noise and model bias are analyzed parametrically and numerically for multiple atmospheric layers, to provide deeper insight. Errors from surface height and reflectance variations are reduced to tolerable levels by "averaging before log" with pulse-by-pulse ranging knowledge incorporated.


Screening for tylosin and other antimicrobial residues in fresh and fermented (nono) cow milk in Delta state, South-South, Nigeria.
Milk is a food that contains almost all the essential nutrients needed for growth and maintenance for both young and old animals and man. Since quite nutritious and in high demand, dairy products should be free of both chemical and biological contaminants. Unfortunately, antibiotics used in the treatment of infectious diseases in dairy cattle are often seen in their products if withdrawal periods of those drugs are not observed before milking. This study aimed to detect the presence of antibiotics and the level of tylosin in fresh and fermented (nono) milk from cows in Delta state, Nigeria. Two hundred and five samples comprising 126 fresh milk and 79 fermented milk (nono) were sampled from Kwale, Ozoro, and Oleh representing one senatorial district of Delta state, South-South Nigeria. They were screened for the presence of tylosin and other antimicrobial residues using four-plate test and tylosin was confirmed with high-performance liquid chromatography. Antibiotic residues were obtained in 76% and 85% of fresh milk and nono, respectively. Tylosin residue was also detected in 24% fresh milk and 11% nono samples at mean concentrations of 14.64±0.69 µg/l and 7.97±0.23 µg/l, respectively. The mean concentrations of tylosin from both milk types were below the recommended maximum residue limit (MRL) of 50 µg/l in dairy. High prevalence of antimicrobial residues in fresh milk and nono shows that consumers in the study area are predisposed to health hazards due to the presence of residues of different antibiotics in fresh milk and nono. Although tylosin was confirmed in both milk products, the mean concentrations were below the MRL. However, it is still very vital to resort to the observance of withdrawal periods and avoid gross misuse of antimicrobials. It is also necessary to emphasize the need for effective prevention of infectious diseases and most importantly create awareness and establish a national antibiotic residue monitoring program in Nigeria.


Cordyceps militaris Modulates Intestinal Barrier Function and Gut Microbiota in a Pig Model.
This study investigated the effects of Cordyceps militaris (CM) on intestinal barrier function and gut microbiota in a pig model. A total of 160 pigs were randomly allocated to either a control group (fed the basal diet) or a CM group (fed the basal diet supplemented with 300 mg/kg CM). CM improved intestinal morphology and increased the numbers of goblet cells and intraepithelial lymphocytes. CM also elevated the expression of zona occluden-1, claudin-1, mucin-2 and secretory immunoglobulin A. Furthermore, the mucosal levels of pro-inflammatory cytokines were downregulated while the levels of anti-inflammatory cytokines were upregulated in the CM group. Mechanistically, CM downregulated the expression of key proteins of the TLR4/MyD88/NF-κB signaling pathway. Moreover, CM altered the colonic microbial composition and increased the concentrations of acetate and butyrate. In conclusion, CM can modulate the intestinal barrier function and gut microbiota, which may provide a new strategy for improving intestinal health.


Soluble amyloid beta-peptide and myelin basic protein strongly stimulate, alone and in synergism with combined proinflammatory cytokines, the expression of functional nitric oxide synthase-2 in normal adult human astrocytes.
The accumulation of amyloid beta (Abeta)-peptides and their collection in fibrillar plaques in the human brain are believed to be responsible for Alzheimer's disease. The major neuron killers in the Alzheimer brain include proinflammatory cytokines and NO made by NOS-2 (inducible nitric oxide synthase-2). We have determined the effect of a soluble Abeta peptide, Abeta(1-40), on the expression of NOS-2 in astrocytes using a novel model system consisting of pure cultures of cells from adult human brains that, after the first three passages in vitro, become stably locked into the normal astrocytic phenotype like their counterparts in the adult human brain. Abeta(1-40) alone stimulated quiescent astrocytes to start expressing functional NOS-2 and dumping NO into the culture medium during the next 4 days. But adding three of the proinflammatory cytokines commonly produced in the Alzheimer brain--IFN-gamma, IL-1beta, and TNF-alpha--along with Abeta(1-40) more than trebled NOS-2 expression and doubled NO production. In view of the possibility of myelin breakdown in the Alzheimer brain, we also tested the capability of myelin basic protein (MBP) to stimulate NO production using human astrocytes. We found that MBP mimicked the ability of Abeta(1-40) to induce cells to release NO and adding the cytokine triad along with MBP more than doubled NO production and release. Thus, it appears that Abeta peptides and MBP can join forces with proinflammatory cytokines to enhance the NO-mediated killing of neurons in the Alzheimer brain.


The progressive tactile hyperalgesia induced by peripheral inflammation is nerve growth factor dependent.
Experimental peripheral inflammation results in cutaneous mechanical hypersensitivity, and repeated low intensity mechanical stimulation of the inflamed skin induces a progressively incrementing hyperalgesia. We have now examined whether the elevation in nerve growth factor (NGF) induced by the inflammation contributes to this progressive hyperalgesia. An i.p. injection of anti-NGF antiserum (5 microliters g-1) 1 h before induction of inflammation by intraplantar complete Freund's adjuvant (CFA) injection and 24 h after, both reduced the basal inflammatory hypersensitivity and significantly attenuated the progressive increase of spontaneous activity, touch-, pinch- and A beta-afferent-evoked responses, and the progressive reduction of the mechanical threshold of biceps femoris/semitendinosus alpha motoneurones normally evoked by repeated (every 5 min) tactile stimulation of the inflamed hindpaw, in decerebrate-spinal rats. NGF contributes, therefore, to the progressive tactile hyperalgesia elicited by repeated touch stimulation of inflamed tissue.


Rejuvenation of aged pig facial skin by transplanting allogeneic granulocyte colony-stimulating factor-induced peripheral blood stem cells from a young pig.
Following a stroke, the administration of stem cells that have been treated with granulocyte colony-stimulating factor (GCSF) can ameliorate functional deficits in both rats and humans. It is not known, however, whether the application of GCSF-mobilized peripheral blood stem cells (PBSCs) to human skin can function as an antiaging treatment. We used a Lanyu pig (Sus scrofa) model, since compared with rodents, the structure of a pig's skin is very similar to human skin, to provide preliminary data on whether these cells can exert antiaging effects over a short time frame. GCSF-mobilized PBSCs from a young male Lanyu pig (5 months) were injected intradermally into the cheek skin of aged female Lanyu pigs, and tissues before and after the cell injections were compared to determine whether this treatment caused skin rejuvenation. Increased levels of collagen, elastin, hyaluronic acid, and the hyaluronic acid receptor CD44 were observed in both dermal and subcutaneous layers following the injection of PBSCs. In addition, the treated skin tissue was tighter and more elastic than adjacent control regions of aged skin tissue. In the epidermal layer, PBSC injection altered the levels of both involucrin and integrin, indicating an increased rate of epidermal cell renewal as evidenced by reductions in both cornified cells and cells of the spinous layers and increases in the number of dividing cells within the basal layer. We found that the exogenous PBSCs, visualized using fluorescence in situ hybridization, were located primarily in hair follicles and adjacent tissues. In summary, PBSC injection restored young skin properties in the skin of aged (90 months) pigs. On the basis of our preliminary data, we conclude that intradermal injection of GCSF-mobilized PBSCs from a young pig can rejuvenate the skin in aged pigs.


Cytokines in the Pathogenesis of Large Granular Lymphocytic Leukemia.
Large granular lymphocytic leukemia (LGLL) is a lymphoproliferative disorder of older adults characterized by the clonal expansion of cytotoxic T/natural killer cells due to constitutive pro-survival signaling. In recent years, it has become clear that cytokines and their receptors are aberrantly expressed in LGLL cells. The exact initiation process of LGLL is unknown, although several cytokine-driven mechanisms have emerged. Elevated levels of several cytokines, including interleukin-15 (IL-15) and platelet-derived growth factor (PDGF), have been described in LGLL patients. Evidence from humans and animal models has shown that cytokines may also contribute to the co-occurrence of a wide range of autoimmune diseases seen in patients with LGLL. The goal of this review is to provide a comprehensive analysis of the link between cytokines and pro-survival signaling in LGLL and to discuss the various strategies and research approaches that are being utilized to study this link. This review will also highlight the importance of cytokine-targeted therapeutics in the treatment of LGLL.


High-throughput metabolic engineering: advances in small-molecule screening and selection.
Metabolic engineering for the overproduction of high-value small molecules is dependent upon techniques in directed evolution to improve production titers. The majority of small molecules targeted for overproduction are inconspicuous and cannot be readily obtained by screening. We provide a review on the development of high-throughput colorimetric, fluorescent, and growth-coupled screening techniques, enabling inconspicuous small-molecule detection. We first outline constraints on throughput imposed during the standard directed evolution workflow (library construction, transformation, and screening) and establish a screening and selection ladder on the basis of small-molecule assay throughput and sensitivity. An in-depth analysis of demonstrated screening and selection approaches for small-molecule detection is provided. Particular focus is placed on in vivo biosensor-based detection methods that reduce or eliminate in vitro assay manipulations and increase throughput. We conclude by providing our prospectus for the future, focusing on transcription factor-based detection systems as a natural microbial mode of small-molecule detection.


The Effect of Antiviral Therapy on the Incidence of Bacterial Aggravations and Administration of Systemic Antibiotics in Patients with Acute Respiratory Viral Infections and Influenza (Results of International Cohort Observational Study).
to evaluate the incidence of bacterial aggravations and antibiotics administration with analysis of effectiveness of antiviral therapy in ambulatory patients with acute viral respiratory infection (ARVI) and influenza. International cohort open non-interventional .study <<Treatment of ARVI and influenza in routine clinical practice? was conducted. The data analysis covers treatment results of 18946 ambulatory patients aged 18-93 years with clinical diagnosis of ARVI or influenza in 262 centers in Russia, Moldova, Armenia and Georgia. One group of patients received treatment in accordance with approved and applicable in their country schemes of complex treatment of ARVI and influenza; other group included patients treated with the complex treatment including antiviral drug Kagocel@ (Russia). On each of 3 visits were evaluated clinical symptoms (in scores), the presence of bacterial aggravations, and the effectiveness of drug treatment including antibacterial therapy. Bacterial aggravations were recorded in 8.3% cases, and-systemic antibiotics were prescribed by doctors in 9.3% cases. The incidence of bacterial aggravations and administration of systemic antibiotics increased proportionally to the age of patients, severity of disease, times of first visit to the doctor and the start of treatment. Prescription of Kagocel@ in the complex treatment of ARVI and influenza contributes to reduction of number of bacterial aggravations in 1.65 times (p<0.01) and decreases necessity of systemic antibiotic therapy in 1.51 times (p<0.01), which leads to better disease outcome at various therapy start times. Maximum efficiency and fewer treatment aggravations were recorded for working age patients. Antiviral therapy has shown its effectiveness in the treatment of ARVI and influenza, its implementation leads to decrease of bacterial aggravations incidence.


Metabolic Dynamics and Prediction of Gestational Age and Time to Delivery in Pregnant Women.
Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities.


Advanced Oxidative Protein Products Drive Trophoblast Cells Into Senescence by Inhibiting the Autophagy: The Potential Implication of Preeclampsia.
Introduction: Advanced oxidation protein products (AOPPs), the novel marker of oxidative stress, have been found to be elevated in preeclampsia (PE). To date, the effect of AOPPs on the senescence of trophoblast cells is still unclear. In this study, we investigated whether AOPPs promoted the senescence of trophoblast cells and explored the underlying mechanisms of AOPPs-induced aging process which may facilitate the progression of PE. Methods: The trophoblast cell line HTR-8/SV neo cells were cultured in the presence of PBS, AOPPs, AOPPs plus an anti-oxidant N-acetyl-L-cysteine (NAC). In some experiments, cells were pre-treated with rapamycin (an activator of autophagy), 3-MA (an inhibitor of autophagy), or cyclic pifithrin-α (PFT-α, an antagonist of p53), and then treated with AOPPs. Cellular senescence was analyzed by measuring the levels of senescence-associated β-galactosidase (SA β-Gal), senescence-associated heterochromatin foci (SAHF), mitochondrial membrane potential (ΔΨm), and cell cycle. Cell autophagic flux was analyzed by measuring tandem fluorescence-tagged LC3 reporter (mCherry-EGFP-LC3). Levels of p53, phosphorylated p53 (p-p53), p21, BECN1, p62, p-mTOR and p-p70S6K were measured by western blot. Results: Treatment with AOPPs significantly increased the levels of SA β-Gal and SAHF, the percentage of cells in the G0/G1 phase, and decreased cell ΔΨm compared with the control group. Co-treatment with NAC and AOPPs significantly reversed AOPPs-induced senescence. Pre-treatment with rapamycin or 3-MA significantly inhibited or promoted AOPPs-induced senescence, respectively. In addition, administration of AOPPs significantly decreased the numbers of mCherry+EGFP+ autophagosomes and mCherry+EGFP- autolysosomes in cells compared with cells treated with PBS. Furthermore, AOPPs significantly increased the levels of proteins p-p53, p21, p-mTOR and p-p70S6K compared with the control group. Pre-treatment with rapamycin or PFT-α significantly down-regulated the levels of SA β-Gal, SAHF, p-p53, p21, autophagy related protein p62, the percentage of cells in the G0/G1 phase, and significantly up-regulated ΔΨm, autophagy related protein BECN1, autophagosomes and autolysosomes compared with cells only treated with AOPPs. Conclusion: AOPPs may induce trophoblast cell senescence by inhibiting the autophagy process in a p53/mTOR/p70S6K-dependent pathway.


Antifungal agents and liver toxicity: a complex interaction.
The number of antifungal agents has sharply increased in recent decades. Antifungals differ in their spectrum of activity, pharmacokinetic/pharmacodynamic properties, dosing, safety-profiles and costs. Risk of developing antifungal associated hepatotoxicity is multifactorial and is influenced by pre-existing liver disease, chemical properties of the drug, patient demographics, comorbidities, drug-drug interactions, environmental and genetic factors. Antifungal related liver injury typically manifests as elevations in serum aminotransferase levels, although the clinical significance of these biochemical alterations is not always clear. Incidence rates of hepatotoxicity induced by antifungal therapy range widely, occurring most frequently in patients treated with azole antifungals for documented fungal infections. This review provides an update regarding the hepatotoxicity profiles of the modern systemic antifungals used in treatment of invasive fungal infections. Expert commentary: Understanding the likelihood and pattern of hepatotoxicity for all suspected drugs can aid the clinician in early detection of liver injury allowing for intervention and potential mitigation of liver damage. Therapeutic drug monitoring is emerging as a potential tool to assess risk for hepatotoxicity.


Evaluation of the toxicity of Adonis aestivalis in calves.
Toxicosis of Adonis aestivalis is well documented in horses, but little is known of its toxicity in cattle. A. aestivalis (summer pheasant's eye) was collected over multiple years, under different growing conditions, and at various stages of maturity, dried, and administered to calves to evaluate the toxicity of A. aestivalis in cattle. Four 300-lb Holstein, and 2 90-lb, preruminating Jersey calves were administered 1% body weight of ground A. aestivalis via a stomach tube and monitored for clinical signs for 2 weeks and 1 week, respectively. The Holstein calves were then fed 0.2 to 1% body weight A. aestivalis daily for 4 to 5 weeks. The Holstein calves had transient, mild cardiac abnormalities during the feeding trial. Mild, transient gastrointestinal and cardiac signs were noted in the preruminating calves. No gross or microscopic lesions were seen on necropsies performed at the end of the study. Based on the results of this study, cattle do not appear to be as susceptible to toxicosis from A. aestivalis as other species, such as horses and pigs.


Comparison of the ex vivo receptor occupancy profile of ketamine to several NMDA receptor antagonists in mouse hippocampus.
NMDA receptor antagonists, particularly these targeting the GluN2B subunit are of therapeutic interest for the treatment of severe mood disorders. The receptor occupancy profiles of several NMDA receptor antagonists (30 mg/kg, s.c.) were compared in mouse hippocampus by ex vivo autoradiography using [(3)H]MK-801, a non-selective NMDA channel blocker, and [(3)H]ifenprodil a selective GluN2B antagonist. Subcutaneous administration of ketamine ((RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone) and memantine (3,5-dimethyladamantan-1-amine) inhibited [(3)H]MK-801 but not [(3)H]ifenprodil binding in mouse hippocampus. Ketamine reached maximal occupancy of [(3)H]MK-801 binding sites after 15 min and rapidly cleared from the brain with no significant level of occupancy measured at the 1h time point. Memantine significantly occupied [(3)H]MK-801 binding sites throughout the 6h time course. The selective GluN2B antagonist CP101,606 ((1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol) and Ro 25-6981 ((αR,βS)-α-(4-Hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate) inhibited [(3)H]ifenprodil but not [(3)H]MK-801 binding and significant levels of occupancy (above 50%) were measured throughout the 6h time course. These data highlight the unique quick pulse target engagement profile of ketamine compared to other NMDA receptor antagonists.