Quantitative contribution of factors regulating rat colonic crypt epithelium: role of parenteral and enteral feeding, caloric intake, dietary cellulose level and the colon carcinogen DMH.
To elucidate the role and quantitative contribution of several exogenous factors which may regulate colon crypt mitotic activity, proliferative zone height (PZH) and crypt height, groups of rats were subjected to various feeding regimens both with and without treatment with the colon carcinogen, 1,2-dimethylhydrazine (DMH). The rats were divided into two major groups and one group was given eight weekly injections of DMH base at 9.5 mg kg-1 body weight. Throughout this period and for two additional weeks the rats were isocalorically fed either a defined nutritionally complete diet with different levels of dietary cellulose or they were parenterally (i.v.) fed a nutritionally complete liquid formula with different caloric levels. The rats were then injected with colchicine 3 h prior to sacrifice to arrest and to collect dividing cells at metaphase. The results of multiple regression analysis of all data were interpreted to indicate that parenteral feeding caused dramatic suppression of the colon crypt height (CH) and of the number of metaphase figures per crypt (MC). Increased cellulose intake stimulated CH but suppressed MC. The CH was also stimulated by DMH. CH was positively correlated to PZH and MC. The MC was suppressed by cellulose intake and negatively correlated to PZH but was positively correlated to CH. The PZH was positively correlated to CH. These findings were related to the role of luminal food, functional workload, kcal intake and treatment with DMH on the measured colon crypt parameters. A quantitative assessment of factors that regulate the measured colonic crypt parameters was accomplished.


Flavone mutagenicity in Salmonella typhimurium: dependence on the pKM101 plasmid and excision-repair deficiency.
Flavones mutagenic in Salmonella typhimurium fall into two distinct classes, characterized by different structural and metabolic activation requirements and by different strain responses. The mutagenic potencies of a prototype agent of each class, quercetin (3,3',4',5,7-hydroxyflavone) and norwogonin (5,7,8-hydroxyflavone), were determined in tester strains differing in excision-repair capability and in the presence or absence of plasmid pKM101. Two series of strains were used, one with the hisD3052 frameshift mutation and one with the hisG46 missense mutation. With both agents and for both series of strains, the mutagenic response was markedly dependent on the absence of excision repair and the presence of the pKM101 plasmid.


Diatom adhesive trail proteins acquired by horizontal gene transfer from bacteria serve as primers for marine biofilm formation.
Biofilm-forming benthic diatoms are key primary producers in coastal habitats, where they frequently dominate sunlit intertidal substrata. The development of gliding motility in raphid diatoms was a key molecular adaptation that contributed to their evolutionary success. However, the structure-function correlation between diatom adhesives utilized for gliding and their relationship to the extracellular matrix that constitutes the diatom biofilm is unknown. Here, we have used proteomics, immunolocalization, comparative genomics, phylogenetics and structural homology analysis to investigate the evolutionary history and function of diatom adhesive proteins. Our study identified eight proteins from the adhesive trails of Craspedostauros australis, of which four form a new protein family called Trailins that contain an enigmatic Choice-of-Anchor A (CAA) domain, which was acquired through horizontal gene transfer from bacteria. Notably, the CAA-domain shares a striking structural similarity with one of the most widespread domains found in ice-binding proteins (IPR021884). Our work offers new insights into the molecular basis for diatom biofilm formation, shedding light on the function and evolution of diatom adhesive proteins. This discovery suggests that there is a transition in the composition of biomolecules required for initial surface colonization and those utilized for 3D biofilm matrix formation.


Timing for removal of tympanic ventilation tube in children.
The medical records of 220 ears of 137 pediatric patients (85 male and 52 female) in which three kinds of ventilation tubes were inserted for treating otitis media with effusion (OME) were reviewed. The tubes selected were the Shepard grommet (75 ears), Goode-T (39 ears), and Paparella type II tube (106 ears). The criteria for tube placement were as follows: (1) continuous conductive hearing loss with over 25 dB air-bone gap, (2) resistance to conservative therapy for over 6 months, and (3) retracted and glue-colored tympanic membrane with type B tympanogram. The tubes that remained in place for over 18-24 months were removed intentionally in combination with a freshening of the perforation edge and tape-patch technique using Steri-Strip tape (3M) for preventing permanent eardrum perforation, because the incidence of persistent perforation became higher after long-term intubation. Shepard grommets tended to be extruded earlier, while Paparella type II tubes tended to stay longer. The OME recurrence rate decreased 12 months or more after tubal insertion. There was a tendency for the recurrence rate to decrease the longer the tube stayed in the eardrum. The number of recurrences decreased when the patient's age at the tube removal or extrusion was 7-8 years old. Adenoidectomy did not influence the recurrence rate of OME. Although the Goode-T and Paparella tube II tubes showed high perforation rates, the perforation rate after extrusion or removal of the tube was decreased by the use of the tape patch technique in combination with a freshening of the perforation edge. From these findings, it was concluded that the appropriate intubation period for the treatment of OME in children is over 12 months with the use of a long-term tube, and that if the patient's age at the time of tube insertion was below 6 years, it might be better that the removal of the tube is postponed until the patient is 8 years of age.


Reimbursement of analgesics for chronic pain.
The prevalence of chronic non-malignant pain in Norway is between 24% and 30%. The proportion of the population using opioids for non-malignant pain on a long-term basis is around 1%. The purpose of our study was to investigate how many were prescribed analgesics on reimbursable prescription under reimbursement code -71 (chronic non-malignant pain) in 2009 and 2010, which analgesics were prescribed and whether prescribing practices were in accordance with national guidelines. We retrieved pseudonymised data from the National Prescription Database on all those who received drugs with reimbursement code -71 in 2009 and 2010. The data contain information on drug, dosage, formulation, reimbursement code and date of issue. 90,731 patients received reimbursement for drugs indicated for chronic non-malignant pain in 2010. Of these, 6,875 were given opioids, 33,242 received paracetamol, 25,865 non-steroid inflammatory drugs (NSAIDs), 20,654 amitryptiline and 16,507 gabapentin. Oxycodone was the most frequently prescribed opioid, followed by buprenorphine, tramadol and codeine/paracetamol. Of those who were prescribed opioids, 4,047 (59%) received mainly slow-release opioids, 2,631 (38%) also received benzodiazepines and 2,418 (35%) received benzodiazepine-like sleep medications. The number of patients who received analgesics and opioids on reimbursable prescriptions was low compared to the proportion of the population with chronic pain and the proportion using opioids long-term. 38% of those reimbursed for opioids also used benzodiazepines, which is contrary to official Norwegian guidelines.


Antifungal activity of the local complement system in cerebral aspergillosis.
Dissemination of aspergillosis into the central nervous system is associated with nearly 100% mortality. To study the reasons for the antifungal immune failure we analyzed the efficacy of cerebral complement to combat the fungus Aspergillus. Incubation of Aspergillus in non-inflammatory cerebrospinal fluid (CSF) revealed that complement levels were sufficient to obtain a deposition on the surface, but opsonization was much weaker than in serum. Consequently complement deposition from normal CSF on fungal surface stimulated a very low phagocytic activity of microglia, granulocytes, monocytes and macrophages compared to stimulation by conidia opsonized in serum. Similarly, opsonization of Aspergillus by CSF was not sufficient to induce an oxidative burst in infiltrating granulocytes, whereas conidia opsonized in serum induced a clear respiratory signal. Thus, granulocytes were capable of considerably reducing the viability of serum-opsonized Aspergillus conidia, but not of conidia opsonized in CSF. The limited efficacy of antifungal attack by cerebral complement can be partly compensated by enhanced synthesis, leading to elevated complement concentrations in CSF derived from a patient with cerebral aspergillosis. This inflammatory CSF was able to induce (i) a higher complement deposition on the Aspergillus surface than non-inflammatory CSF, (ii) an accumulation of complement activation products and (iii) an increase in phagocytic and killing activity of infiltrating granulocytes. However, levels and efficacy of the serum-derived complement were not reached. These data indicate that low local complement synthesis and activation may represent a central reason for the insufficient antifungal defense in the brain and the high mortality rate of cerebral aspergillosis.


Serum Shiga toxin 2 values in patients during acute phase of diarrhoea-associated haemolytic uraemic syndrome.
Shiga toxins are delivered via systemic circulation and are considered to be the cause of diarrhoea-associated haemolytic uraemic syndrome (HUS), as they injure endothelial cells, particularly in the glomeruli. This study measured Shiga toxin 2 (Stx2) in the serum of children affected in by HUS due to Stx2 producing Escherichia coli. The concentration of free Stx2 was measured in the serum of 16 children, collected immediately after admission to the clinic in the acute phase of HUS, using a sandwich enzyme-linked immunosorbent assay. The family members of two children were also investigated, with the relative toxicity of Stx2 assessed by a Vero cell-based fluorescent assay. Stx2 was found in the serum of eight of the 16 children who were investigated. It was also detected in four of the six family members not showing symptomatic HUS, with an extremely high level in two. An absent or rather low concentration of Stx2 was found in the serum of children admitted to the clinic with diarrhoea-associated HUS. The high concentration of Stx2 in family members without HUS, but mostly with watery diarrhoea and raised functional activity, was in line with the concept of early injury by Stx2.


Failure of propagation of human norovirus in intestinal epithelial cells with microvilli grown in three-dimensional cultures.
Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis. Establishment of a cell culture system for in vitro HuNoV growth remains challenging. Replication of HuNoVs in human intestinal cell lines (INT-407 and Caco-2) that differentiate to produce microvilli in rotation wall vessel (RWV) three-dimensional cultures has been reported (Straub et al. in Emerg Infect Dis 13:396-403, 2007; J Water Health 9:225-240, 2011, and Water Sci Technol 67:863-868, 2013). We used a similar RWV system, intestinal cell lines, and the same (Genogroup [G] I.1) plus additional (GII.4 and GII.12) HuNoV strains to test the system's reproducibility and to expand the earlier findings. Apical microvilli were observed on the surface of both cell lines by light and electron microscopy. However, none of the cell types tested resulted in productive viral replication of any of the HuNoV strains, as confirmed by plateau or declining viral RNA titers in the supernatants and cell lysates of HuNoV-infected cells, determined by real-time reverse transcription PCR. These trends were the same when culture supplements were added that have been reported to be effective for replication of other fastidious enteric viruses in vitro. Additionally, by confocal microscopy and orthoslice analysis, viral capsid proteins were mainly observed above the actin filament signals, which suggested that the majority of viral antigens were on the cell surface. We conclude that even intestinal cells displaying microvilli were not sufficient to support HuNoV replication under the conditions tested.


Management of Motor Features in Advanced Parkinson Disease.
Advanced Parkinson disease (PD) is characterized by the presence of motor fluctuations becoming the focus of treatment, prominent postural instability, significant disability despite levodopa therapy, and the presence of symptoms refractory to levodopa therapy. In this article, the authors review the motor manifestations of patients with advanced PD, as well as the most common pharmacologic and nonpharmacologic available therapies.


Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630.
IRL 3630 (3), a single enantiomer of IRL 3461 with more potency was identified. Coupling reaction of the racemic fragment (1) with the chiral (L)-valinesulfonamide (2) under a biphasic solvent system (CH2Cl2-H2O) successfully led to the predominant formation of the desired isomer (3) with concomitant isomerization of 1. IRL 3630, N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-+ ++isoxazolyl) -phenyl]-(D)-alanyl]-(L)-valineamide, is a highly potent and bifunctional (ETA + ETB) antagonist [Ki(ETA) = 1.5 nM, Ki(ETB) = 1.2 nM].


Tasquinimod: a novel angiogenesis inhibitor-development in prostate cancer.
Castration resistant prostate cancer (CRPC) treatment has been revolutionized over the past few years by the approval of novel therapies including cabazitaxel, sipuleucel-T, abiraterone and enzalutamide. Though androgen deprivation and chemotherapy remain the main therapeutic approaches for this disease, a series of targeted agents is also in development for the treatment of CRPC. Tasquinimod is a quinolone-3-carboxamide with antiangiogenic and antitumor activity in preclinical models of prostate cancer. A recent Phase II trial with this agent has demonstrated a significant clinical activity in asymptomatic or minimally symptomatic, chemotherapy-naïve, CRPC patients. A confirmatory Phase III trial of tasquinimod in prostate cancer is underway. Because of its antiangiogenic and immunomodulatory properties tasquinimod represents a novel targeted therapy with a unique mechanism of action.


Electromagnetic scattering and absorption by randomly oriented fibers.
In this paper, we numerically calculate the extinction, scattering, absorption, and radar cross sections for a randomly oriented finite conducting fiber. Calculations in the long (centimeter) and short (infrared) wavelengths are presented and compared with the fixed orientation value when the incident electric field is aligned along the fiber length. The calculations presented in this paper are necessary for the parametrization of fibers to play the role of efficient obscurant and anti-radio frequency interference.


Isolation of coumarins with anti-Trichophyton rubrum activity from Heracleum vicinum Boiss.
Heracleum vicinum Boiss., a perennial plant of Angelica in Umbelliferae, is mainly distributed in Sichuan and Hunan of China. Trichophyton rubrum is a common skin fungus causing dermatophyte. The previous experimental study found that the ethanol extract from Heracleum vicinum Boiss. had excellent anti-Trichophyton rubrum activity, especially the ethanol extract further extracted with petroleum ether and dichloromethane has the best antibacterial effect and has good potential for treating dermatophytes. In this study, Heracleum vicinum Boiss. was extracted with ethanol by microwave-assisted ultrasonic extraction method and isolated with silica gel column to obtain a coumarin compound M1-1 by the guidance of anti-Trichophyton rubrum activity, which was characterized by nuclear magnetic resonance spectroscopy(13C-NMR), hydrogen nuclear magnetic resonance (1H-NMR), Fourier transform infrared spectroscopy (FTIR), high-resolution mass spectrometry (HR-ESI-MS), and ultraviolet (UV) and identified as imperatorin and belonged to coumarins, with the minimum inhibitory concentration (MIC) against Trichophyton rubrum of 12.5 μg/mL. According to the discussion on the inhibitory mechanism of the compound, we found that the compound may exert its inhibitory effect by destroying the mycelial membrane and inhibiting the mycelial growth of Trichophyton rubrum. In a word, imperatorin isolated from Heracleum vicinum Boiss. is expected to be used as an antibacterial agent to treat dermatophytes a potential natural compound against Trichophyton rubrum, and a template for drug development of dermatophytes the future.


The EnPlace® sacrospinous ligament fixation-A novel minimally invasive transvaginal procedure for apical pelvic organ prolapse repair: Safety and short-term outcome results.
The EnPlace® device is a novel minimally invasive tool allowing transvaginal sacrospinous ligament (SSL) fixation of apical pelvic organ prolapse (POP). The study aimed to investigate the safety and short-term efficacy of the EnPlace® SSL fixation for significant apical POP repair. A retrospective cohort study of 123 consecutive patients (mean age 64.4 ± 11.1 years) with stage III or IV apical POP who underwent SSL fixation by the EnPlace® device. Safety and 6-month outcome results were analyzed and compared between 91 (74%) patients with uterine prolapse versus 32 (26%) patients with vaginal vault prolapse. There were no intraoperative or early postoperative complications. The mean (± standard deviation) duration of surgery was 30 ± 6.9 min and mean blood loss was 30.5 ± 18.5 mL. The average position of point C by POP-Quantification measurements before surgery and at 6 months postoperatively was 4.5 ± 2.8 cm and -3.1 ± 3.3 cm, respectively. Of 91 patients with preoperative uterine prolapse, eight (8.8%) patients developed a recurrent uterine prolapse within 6 months postoperatively. Of 32 patients with preoperative vault prolapse, two patients (6.3%) had recurrent vault prolapse. Short-term outcome results of EnPlace® SSL fixation suggest that it is a safe and effective minimally invasive transvaginal procedure for significant apical POP repair.


Inorganic pyrophosphatase 1 activates the phosphatidylinositol 3-kinase/Akt signaling to promote tumorigenicity and stemness properties in colorectal cancer.
Colorectal cancer (CRC) is a common malignant tumor of the human digestive tract. Inorganic pyrophosphatase 1 (PPA1) plays an imperative role in the advancement of malignant tumors, but its function in CRC is ill-defined. In this study, we inspected the functions of PPA1 in CRC. The abundance of PPA1 in CRC tissues was analyzed by utilizing publicly available data from the The Cancer Genome Atlas and Human Protein Atlas project. Cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay were used to evaluate the viability and proliferation of CRC cells. Bioinformatics analysis was used to forecast the PPA1 related genes and signal pathways in CRC. The protein expression was examined by western blot. The xenograft model was implemented to determine the influence of PPA1 in CRC in vivo. Proliferating cell nuclear antigen, CD133, and CD44 contents in xenograft tumors were evaluated by immunohistochemistry. In the present study, we found that the PPA1 content was heightened in CRC, and the diagnostic value of PPA1 in CRC was enormous. Overexpression of PPA1 enhanced cell proliferation and stemness properties in CRC cells, while downregulation of PPA1 had the opposite effects. PPA1 promoted the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Activation of the PI3K/Akt signaling reversed the effect of PPA1 silencing on cell proliferation and stemness properties in CRC cells. Silencing of PPA1 reduced xenograft tumor growth via modulating the PI3K/Akt signaling pathway in vivo. In conclusion, PPA1 promoted cell proliferation and stemness properties in CRC by activating the PI3K/Akt signaling pathway.


Molecular investigations of Mycobacterium tuberculosis genotypes among baseline and follow-up strains circulating in four regions of Eswatini.
The tuberculosis (TB) epidemic remains a major global health problem and Eswatini is not excluded. Our study investigated the circulating genotypes in Eswatini and compared them at baseline (start of treatment) and follow-up during TB treatment. Three hundred and ninety (n = 390) participants were prospectively enrolled from referral clinics and patients who met the inclusion criteria, were included in the study. A total of 103 participants provided specimens at baseline and follow-up within six months. Mycobacterium tuberculosis (M.tb) strains were detected by GeneXpert® MTB/RIF assay (Cephied, USA) and Ziehl -Neelsen (ZN) microscopy respectively at baseline and follow-up time-points respectively. The 206 collected specimens were decontaminated and cultured on BACTEC™ MGIT™ 960 Mycobacteria Culture System (Becton Dickinson, USA). Drug sensitivity testing was performed at both baseline and follow-up time points. Spoligotyping was performed on both baseline and follow-up strains after DNA extraction. Resistance to at least one first line drug was detected higher at baseline compared to follow-up specimens with most of them developing into multidrug-resistant (MDR)-TB. A total of four lineages and twenty genotypes were detected. The distribution of the lineages varied among the different regions in Eswatini. The Euro-American lineage was the most prevalent with 46.12% (95/206) followed by the East Asian with 24.27% (50/206); Indo-Oceanic at 9.71% (20/206) and Central Asian at 1.94% (4/206). Furthermore, a high proportion of the Beijing genotype at 24.27% (50/206) and S genotype at 16.50% (34/206) were detected. The Beijing genotype was predominant in follow-up specimens collected from the Manzini region with 48.9% (23/47) (p = 0.001). A significant proportion of follow-up specimens developed MDR-TB (p = 0.001) with Beijing being the major genotype in most follow-up specimens (p < 0.000). Eswatini has a high M.tb genotypic diversity. A significant proportion of the TB infected participants had the Beijing genotype associated with MDR-TB in follow-up specimens and thus indicate community wide transmission.


[Cost effectiveness and budget impact analysis of inhaled nitric oxide in a neonatal unit from the perspective of the public health system].
Inhaled nitric oxide (iNO) is currently the first-line therapy in severe hypoxaemic respiratory failure of the newborn. Most of regional neonatal centres in Chile do not have this therapeutic alternative. To determine the cost effectiveness of inhaled nitric oxide in the treatment of respiratory failure associated with pulmonary hypertension of the newborn compared to the usual care, including the transfer to a more complex unit. A clinical decision tree was designed from the perspective of Chilean Public Health Service. Incremental cost effectiveness rates (ICER) were calculated, deterministic sensitivity analysis was performed, and probabilistic budget impact was estimated using: TreeAge Pro Healthcare 2014 software. The iNO option leads to an increase in mean cost of $ 11.7 million Chilean pesos (€15,000) per patient treated, with an ICER compared with the usual care of $23 million pesos (€30,000) in case of death or ECMO avoided. By sensitising the results by incidence, it was found that from 7 cases and upwards treated annually, inhaled nitric oxide is less costly than the transfer to a more complex unit. From the perspective of a Chilean regional hospital, incorporating inhaled nitric oxide into the management of neonatal respiratory failure is the optimal alternative in most scenarios.


[Ambulatory combination therapy with cisplatin, bleomycin (DDP-BLM) in recurrence and metastasis of malignant tumors of the head and neck].
16 patients with recurrent or metastatic carcinomas of the upper respiratory and digestive tract underwent a total of 55 courses of chemotherapy with Cisplatin and Bleomycin. The cytostatic treatment was performed under outpatient conditions. 0.75 mg./kg. Cisplatin was administered at intervals of 5-8 weeks. In addition, 15 mg. Bleomycin was administered weekly. Hydratation and diuresis were forced by 1000 ml. 0,9% NaCl solution and 1000 ml. levulose 5% with potassium substitution and 250 ml. mannitol 10% after an initial injection of 2 ml. Furosemid. The treatment was generally well tolerated. A nausea lasting 1-3 days was observed after Cisplatin application. Remission of tumours, stopping of tumour progression and a reduction of pain was achieved. The "performance status" was maintained. In 6 cases there was no effect.


Clinical Significance of Nasal Pathologies in Transnasal Transsphenoidal Pituitary Surgery.
We evaluated the frequency of nasal pathologies and the significance of surgical access to the sellar region in patients who underwent an operation for sellar mass using the endonasal and microscopic transsphenoidal approaches. We retrospectively evaluated all patients who underwent surgery for pituitary macroadenoma using microscopic (n = 78) and endonasal (n = 20) transsphenoidal approaches. Patients' epicrisis, preoperative, and postoperative imaging as well as their operative notes were reviewed. Nasal pathologies and surgeries performed before or during the pituitary surgery were also documented. All endonasal surgeries were binostril and performed jointly by an ear, nose, and throat specialist and neurosurgeon. To determine the feasibility of endonasal and microscopic approaches, we developed an algorithm using the septum deviation classifications to determine the need for septoplasty. The most common nasal pathology was septum deviation (n = 17; 17.3%). Of the other nasal pathologies, 6 cases (6%) were chronic sinusitis and 2 were (2.1%) middle turbinate bullosa. The preoperative evaluation of patients undergoing endonasal transsphenoidal surgery by an ear, nose, and throat surgeon allows for the detection and treatment of nasal pathologies that may lead to serious perioperative and postoperative complications. Evaluating patients with septum deviation using our classification will help determine the necessity of preoperative or perioperative septum surgery, depending on the preferred pituitary surgical method.


Subscapularis tears: arthroscopic repair techniques.
The subscapularis is an essential component of normal shoulder function. An intact subscapularis muscle provides the anterior moment for the transverse plane force couple. Any disruption of the subscapularis disrupts normal glenohumeral biomechanics. If this occurs the shoulder functions abnormally, leading to pain and disability. A thorough history and physical examination lead the surgeon to the diagnosis of a torn subscapularis. Radiographs and MRI are helpful in delineating the rotator cuff tear pattern and other intra-articular lesions and in determining subcoracoid stenosis. Advancements with arthroscopic techniques have enabled surgeons to deal with subscapularis tears arthroscopically. There are seven key points to arthroscopic subscapularis repair: (1) portal placement (posterior portal, anterior portal, anterolateral portal, and accessory anterolateral portal), (2) visualization of the pathology by using a 30 degree and a 70 degree arthroscope, (3) manipulating the arm into maximal internal rotation to assist in assessing the tendon's relationship to its footprint, (4) appropriate anchor placement, (5) suture passage through the tendon, (6) tying secure arthroscopic knots, and (7) appropriate rehabilitation that minimizes stress on the repair. With these principles in mind, the shoulder surgeon can address disruptions of the anterior rotator cuff by repairing the subscapularis, thus alleviating the disability associated with this overlooked and under-appreciated pathology.


Double Head: Giant Solitary Occipital Scalp Plexiform Neurofibroma Without Neurofibromatosis.
A 16-year-old male presented with solitary occipital plexiform neurofibroma, which had grown slowly over several years to reach giant size, thereby mimicking a "double head." There were no features of neurofibromatosis type 1. Total excision of the neurofibroma was done by infiltrating adrenaline circumferentially around the tumor before scalp incision. The feeding arteries were identified in the dense connective tissue above the aponeurosis and ligated or cauterized. Dissection was then carried out in the loose areolar tissue preserving the periosteal layer. There was no evidence of malignant transformation on histopathology, and 5-year follow-up showed no tumor recurrence.


Computationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation.
The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design. Here, multiple data-driven computational approaches are systematically integrated to perform a virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the list of prioritized drugs, a subset of representative candidates to test in human cells is selected. Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs.


Disorders of the External Ear-A Historical Perspective.
This article provides a historical overview of disorders of the external ear, focusing on advances in technology, pharmacology, and education that have been beneficial. While the diagnosis and treatment of various conditions involving the external ear canal and auricle continue to evolve, it remains to be seen how the latest challenges will be met.


Development of the maternal anal canal during pregnancy and the postpartum period: a longitudinal and functional ultrasound study.
Normal anatomical and physiological development of the maternal anal canal during and after pregnancy has been documented scarcely. We aimed to study the position and volume of the anal canal, during and after pregnancy, in women without previous delivery. This was a longitudinal study in which transvaginal three-dimensional ultrasound was used to measure anatomical structures in the anal canal during rest and squeeze in 23 nulliparous women. The total anal canal volume (ACV), anorectal curvature (ARC), anovaginal angle (AVA) and anal canal length were determined at 18, 28 and 36 weeks of pregnancy and at 3 months postpartum. Total ACV at rest increased from a mean of 10.17 cm(3) at 18 weeks to 12.37 cm(3) and 12.21 cm(3) at 28 and 36 weeks, respectively (P = 0.001 and P = 0.010 vs. first measurement). For anal canal length, the corresponding mean measurements were 3.91 cm, 4.07 cm (P = 0.13) and 4.21 cm (P = 0.017). Postpartum, the mean total ACV was 10.86 cm(3) and length was 3.90 cm (P = 0.10 and P = 0.70 vs. first measurement). No significant changes were observed in ARC and AVA during or after pregnancy. Compared to at-rest status, the anal length significantly increased on voluntary squeeze (P = 0.007, 0.007, 0.022 and 0.004 at the four time points), while no differences in total ACV were observed. In mid-pregnancy AVA significantly increased during squeeze (P = 0.006 and 0.002 at weeks 18 and 28, respectively). Anal canal length and total ACV increase during pregnancy in women without previous delivery. Voluntary squeezing elongates the anal canal and increases the angle formed with respect to the direction of the vagina. During postpartum involution, the characteristics of the anal canal revert to those observed at 18 weeks of pregnancy.


Quantitative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 1,4-dihydropyridines and pyridines as multidrug resistance modulators.
The aim of this study was to develop quantitative structure-activity/pharmacokinetic relationships (QSAR/QSPKR) for a series of synthesized 1,4-dihydropyridines (DHPs) and pyridines as P-glycoprotein (P-gp) inhibitors. Molecular descriptors of test compounds were generated by 3D molecular modeling using SYBYL and KowWin programs. Forward inclusion coupled with multiple linear regression (MLR) was used to derive a QSAR equation for Ca2+ channel binding. A multivariate statistical technique, partial least square (PLS) regression, was applied to derive a QSAR model for P-gp inhibition and QSPKR models. Cross-validation using the "leave-one-out" method was performed to evaluate the predictive performance of models. For Ca2+ channel binding, the MLR equation indicated a good correlation between observed and predicted values (R2 = 0.90), and cross-validation confirmed the predictive ability of the model (Q2 = 0.67). For P-gp reversal, the model obtained by PLS could account for most of the variation in P-gp inhibition (R2 = 0.76) with fair predictive performance (Q2 = 0.62). Nine structurally related 1,4-DHP drugs were used for QSPKR analysis. The models could explain the majority of the variation in clearance (R2 = 0.90), and cross-validation confirmed the prediction ability (Q2 = 0.69). QSAR/QSPKR models were developed, and the QSAR models were capable of identifying synthesized 1,4-DHPs and pyridines with potent P-gp inhibition and reduced Ca2+ channel binding. The QSPKR models provide insight into the contribution of electronic, steric, and lipophilic factors to the clearance of DHPs.


Radiologic impact on operative access to a retrorectal cyst.
Diverse incisions have been used to excise retrorectal lesions. Operative access must be planned with regard to level and type of lesion, and prevention of postoperative complications. In this case, pelvic contrast CT scan conclusively showed communication between the rectum and a retrorectal cyst-hamartoma. A potential rectocutaneous fistula through the previously planned parasacrococcygeal incision was avoided by this preoperative documentation.


Complete genome sequence of Streptomyces fulvissimus.
The complete genome sequence of Streptomyces fulvissimus (DSM 40593), consisting of a linear chromosome with a size of 7.9Mbp, is reported. Preliminary data indicates that the chromosome of S. fulvissimus contains 32 putative gene clusters involved in the biosynthesis of secondary metabolites, two of them showing very high similarity to the valinomycin and nonactin biosynthetic clusters. The availability of genome sequence of S. fulvissimus will contribute to the evaluation of the full biosynthetical potential of streptomycetes.


Statistical tests of models of DNA substitution.
Penny et al. have written that "The most fundamental criterion for a scientific method is that the data must, in principle, be able to reject the model. Hardly any [phylogenetic] tree-reconstruction methods meet this simple requirement." The ability to reject models is of such great importance because the results of all phylogenetic analyses depend on their underlying models--to have confidence in the inferences, it is necessary to have confidence in the models. In this paper, a test statistic suggested by Cox is employed to test the adequacy of some statistical models of DNA sequence evolution used in the phylogenetic inference method introduced by Felsenstein. Monte Carlo simulations are used to assess significance levels. The resulting statistical tests provide an objective and very general assessment of all the components of a DNA substitution model; more specific versions of the test are devised to test individual components of a model. In all cases, the new analyses have the additional advantage that values of phylogenetic parameters do not have to be assumed in order to perform the tests.


Differential diagnosis: a reasonable clinical approach.
The reasonable clinical approach to the patient who has low back pain includes a search for any of the red flags that would prompt consideration of additional diagnostic testing for serious underlying disease. The common patterns of back pain would be explored in an effort to categorize the patient's symptoms and to begin formulation of a diagnostic impression. Re-evaluation of the patient in light of his response (or lack of response) to these measures is an essential component of the clinical assessment. Finally, some consideration must be given to the various biopsychosocial factors that may affect prognosis, particularly in patients who have more chronic pain and disability-related issues.


[Progressive respiratory failure and weakness in a 61-year-old woman].
A 61-year-old woman was admitted with a suspected diagnosis of atypical pneumonia. Extended diagnostic measures revealed interstitial lung disease (ILD), polyserositis, polyarthritis and myopathy. With detection of an antibody against PL-7 (anti-threonyl-transfer-RNA synthetase) the diagnosis of anti-synthetase syndrome (ASS) was established. ASS are rare inflammatory myopathies which frequently present as multisystemic diseases with severe organ involvement. An immunosuppressive regimen with steroids and cyclophosphamide led to successful induction of disease remission. Maintenance therapy will be conducted with azathioprine. ASS should always be considered in the differential diagnosis of myopathies and ILDs.


Molecular epidemiology of KPC-2-producing Enterobacteriaceae (non-Klebsiella pneumoniae) isolated from Brazil.
In Brazil, since 2009, there has been an ever increasing widespread of the bla(KPC-2) gene, mainly in Klebsiella pneumoniae. This study aims to assess the molecular epidemiology and genetic background of this gene in Enterobacteriaceae (non-K. pneumoniae) species from 9 Brazilian states between 2009 and 2011. Three hundred eighty-seven isolates were analyzed exhibiting nonsusceptibility to carbapenems, in which the bla(KPC-2) gene was detected in 21.4%. By disk diffusion and E-test, these isolates exhibited high rates of resistance to most of the antimicrobials tested, including tigecycline (45.6% nonsusceptible) and polymyxin B (16.5%), the most resistant species being Enterobacter aerogenes and Enterobacter cloacae. We found great clonal diversity and a variety of bla(KPC-2)-carrying plasmids, all of them exhibiting a partial Tn4401 structure. Therefore, this study demonstrates the dissemination of KPC-2 in 9 Enterobacteriaceae species, including species that were not previously described such as Pantoea agglomerans and Providencia stuartii.


Comparison of plasma steroid and gonadotrophin profiles in spontaneous cycles in which conception did and did not occur.
Luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and progesterone were measured in plasma from blood samples obtained daily throughout 23 menstrual cycles in a total of 18 normal women. Eight of these women were trying to conceive at the time of investigation and five succeeded. The subjects were divided into those who were not exposed to pregnancy (Group I), those who became pregnant (Group II) and those who were trying to become pregnant but failed to do so (Group III). The mean profiles of each of the four hormones were similar for the three groups studied. Statistical comparisons (using 't' tests) between Groups II and III showed that FSH concentrations were significantly lower (P less than 0.01) in the late follicular phase (Days -7 to -3 before the LH peak) in Group III. Similarly, progresterone concentrations were significantly lower (P less than 0.05) during the early luteal phase (Days +3 to +7 after the LH peak) in Group III.


Contact allergens for armpits--allergenic fragrances specified on deodorants.
According to the so-called "26 allergens rule" 26 supposedly allergenic fragrances must be specified on the containers of cosmetic products if they are present above 0.001% in leave-on products and, 0.01% in rinse-off products. This declaration is meant to inform the consumers of potential risks of skin sensitizers in the products. As many consumers of deodorants suffer from allergic or irritant contact dermatitis in the axillae, the presence of allergens in deodorants deserves special attention. The objective of this study was to find answers to the following questions: Does compulsory labeling lead to omission of strong allergenic fragrances in deodorants? Is there a difference in the use patterns of strong and weak allergens? What is the quantitative exposure to fragrances by deodorants? Is the situation in Germany different from other European countries? Is there a difference between deodorants for men and for women? I tested the implementation of the "26 allergens rule" and compiled which allergenic fragrances are specified on the containers of deodorants. Three market studies were conducted in Germany in 2008, 2010 and 2011. The labels of a total number of 374 deodorants were analyzed as to whether any of the "26 allergens" were listed. The frequency of each allergen in the deodorants was compared with results from previous studies by other authors. It was found that up to 83% of the deodorants contain at least one of the "26 allergens" and that up to 30% of all products contain strong allergens above the threshold for labeling (0.001% in the product). The most frequently listed allergens are medium or weak allergens. In comparison with other authors, the frequency of the "26 allergens" in products is slightly smaller in these recent studies for the German market. There is no significant difference between deodorants for men and women, as far as the labeling of the "26 allergens" is concerned. The results show that the mandatory labeling procedure as designed in the "26 allergen rule" is not suitable to guarantee consumer safety for deodorants. As long as consumers are not informed about allergens in products in an easy to understand and transparent way, a compulsory pictogram on the container should inform them about possible risks.


Spatial pain propagation over time following painful glutamate activation of latent myofascial trigger points in humans.
The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation.


Stimulatory effect of tumor necrosis factor-alpha on the growth of CMK, a human megakaryoblastic leukemia cell line.
Recombinant human tumor necrosis factor-alpha (TNF-alpha) was found to stimulate the growth of CMK, a human megakaryoblastic leukemia cell line. This stimulatory effect of TNF-alpha was blocked by anti-TNF-alpha antibody, but antibodies to recombinant human interleukin 3, granulocyte-macrophage colony-stimulating factor and interleukin 6 (all growth factors for CMK cells) did not reduce the stimulatory effect of TNF-alpha. Scatchard analysis showed that CMK cells expressed TNF-alpha receptors on the cell surface. The growth of CMK cells was also stimulated by lymphotoxin, which shares the same receptor as TNF-alpha. These results suggest that TNF-alpha stimulated the growth of CMK cells directly via its specific receptor.


Mycobacterium Tuberculosis Infection, Immigration Status, and Diagnostic Discordance: A Comparison of Tuberculin Skin Test and QuantiFERON-TB Gold In-Tube Test Among Immigrants to the U.S.
We used a recent source of nationally representative population data on tuberculosis (TB) infection to characterize concordance between the tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) blood test for immigrants in the United States. We used TB screening data from the 2011-2012 National Health and Nutrition Examination Survey to examine concordance between the TST and QFT-GIT--an interferon-gamma release assay (IGRA) blood test--for 7,097 U.S. natives, naturalized citizens, and noncitizens. Consistent with prior findings, one in five immigrants in the survey was identified with latent TB infection (LTBI), a rate 14 times higher than for U.S. natives. We also found higher rates of discordant TST/IGRA results among immigrants than among U.S. natives. Unadjusted discordance between TST and IGRA was 3% among U.S. natives (weighted N=5,684,274 of 191,179,213) but ranged up to 19% for noncitizens (weighted N=3,722,960 of 19,377,147). Adjusting for age, sex, and race/ethnicity, noncitizens had more than nine times the odds of having a positive TST result but negative QFT-GIT result compared with U.S. natives. Our findings suggest that whether and how either of these tests should be deployed is highly context sensitive. Significant discordance in test results when used among immigrants raises the possibility of missed opportunities for harm reduction in this already at-risk population. However, we found little distinction between the tests in terms of diagnostic outcome when used in a U.S. native population, suggesting little benefit to the adoption and use of the QFT-GIT test in place of TST on the basis of test performance alone for this population.


[Simultaneous micro-transplantation of fetal mesencephalic cells to the striate and substantia nigra pars reticulata in hemi-parkinsonian rats. A study of behavior].
Microtransplantation of fetal dopaminergic cells has been used over the past ten years with good results in models of Parkinson's disease. To evaluate the effect of microtransplantation of fetal dopaminergic cells 'seeded' in the substantia nigra pars reticulata (SNpr) and striate (St) simultaneously. The animals received a transplant or microtransplant of cells into the St and SNpr ipsilateral to the lesion in the substantia nigra pars compacta or to both regions. Depending on the site and technique used the following experimental groups were considered: I. Macrotransplantation to the St (n = 20); II. Microtransplant to the St (n = 20); III. Microtransplant to St + SNpr (n = 20); IV. Microtransplant to St + SNpr (n = 20); V. Macrotransplantation to SNpr (n = 20); VI. Microtransplantation to SNpr (n = 20); and VII. Control (lesion only) (n = 20). The rotations induced by D-amphetamine (5 mg/kg i.p.) and by apomorphine were studied 1, 2, 3 and 6 months and 3 and 6 months respectively after transplantation. Three months after transplantation we studied the motor asymmetry shown by the animals by means of the ladder test. The rotations were reduced in the groups with intrastriate transplantation. Comparison between the surgical techniques showed nonsignificant differences between them. The ladder test showed significant differences in use of the limbs in all experimental groups. Use of the left limb was significantly reduced in all groups. Modification of the rotations seems more sensitive to the site of transplant than to the technique used. It seems that the skills studied using the ladder test are not altered by the microtransplant technique.


The breast radiation injury litigation and the clinical oncologist.
A number of women with breast cancer believed they were suffering injury because radiotherapy had been given negligently. In March 1995, their solicitors were permitted by the High Court, to select 10 cases in order to further a group action. In the legal exchanges which followed, the principal issues put forward by the plaintiffs went through a number of modifications until finally, in December 1997, they were abandoned. Two cases came to trial and after a hearing of 21 days, the Judge found no negligence. Clinical oncologists should be aware of the course of the litigation and consider the lessons to be learned.


Continuous renal replacement therapy combined with extracorporeal membrane oxygenation in advanced cardiac failure patients.
Acute renal failure during extracorporeal membrane oxygenation (ECMO) support is associated with extremely high mortality. This report describes treatment of myocardial dysfunction in one 48-year-old and one 11-year-old patient. Venoarterial ECMO was required to support myocardial dysfunction. Continuous venovenous hemodialysis was performed for acute renal failure with pulmonary edema and oliguria. Both patients survived following treatment with venoarterial ECMO combined with continuous venovenous hemodialysis.


Protective effects of a compound isolated from Alnus japonica on oxidative stress-induced death in transformed retinal ganglion cells.
Here, we investigated whether hirsutenone, a compound isolated from Alnus japonica, was able to attenuate oxidative stress-induced death in transformed retinal ganglion (RGC-5) cells. Hirsutenone effectively protected RGC-5 cells from oxidative insult induced by, l-buthionine-(S,R)-sulfoximine (BSO) plus glutamate in a concentration-dependent manner, as demonstrated by propidium iodide (PI)/Hoechst 33342 double staining, flow cytometry, and MTT assays. Moreover, hirsutenone inhibited the increase in apoptotic protein expression resulting from BSO plus glutamate. Hirsutenone also effectively inhibited sodium nitroprusside (SNP)-induced lipid peroxidation in rat brain homogenates. To investigate the effects of hirsutenone in vivo, we used N-methyl-d-aspartate (NMDA) as a negative insult on the retinas of rats. NMDA affects the thinning of the inner plexiform layer (IPL) and causes an increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive ganglion cells in the ganglion cell layer (GCL). Hirsutenone treatment led to a reduction in NMDA-induced IPL and TUNEL staining of the GCL. In conclusion, hirsutenone isolated from A. japonica may act as neuroprotective agent for conditions such as glaucoma.


Misperception of sleep in bipolar disorder: an exploratory study using questionnaire versus actigraphy.
The concept of misperception of sleep refers to the estimated discrepancy between subjective and objective measures of sleep. This has been assessed only in a few prior studies in individuals with Bipolar Disorder (BD) as compared to Healthy Controls (HC) and with mixed results. We assessed a sample of 133 euthymic individuals with BD and 63 HC for retrospective subjective (Pittsburgh Sleep Quality Index) and objective (21 days of actigraphy recording) measures of total sleep time, sleep latency and sleep efficiency. We first investigated the correlations between these subjective and objective measures in the two groups. We then compared individuals with BD and HC for the absolute values of the differences between subjective and objective sleep parameters, used as a proxy of the magnitude of misperception of sleep. Finally, we undertook regression analyses to assess associations between clinical groups, core demographics, clinical factors and misperception of sleep. The correlation coefficients between subjective and objective measures of sleep did not differ between groups (total sleep time: rho = .539 in BD and rho = .584 in HC; sleep latency: rho = .190 in BD and rho = .125 in HC; sleep efficiency: rho = .166 in BD and rho = .222 in HC). Individuals with BD did not differ from HC in the magnitude of misperception of total sleep time, sleep latency nor sleep efficiency. Individuals with BD type 1 misperceived their sleep efficiency significantly more than individuals with BD type 2, with no further difference between BD type 1 and BD type 2 regarding sleep latency and sleep duration misperceptions. Three factors (age, symptoms of obstructive sleep apnea, and mild depressive symptoms), were the main contributors to the magnitude of misperception of sleep. Misperception of sleep was not associated with a diagnosis of BD. In this sample, mild depressive symptoms, older age, or symptoms of obstructive sleep apnea may be related to greater sleep misperception. In that case, the reliability of subjective measures may decrease as the misperception of sleep increases. This study may help guide clinicians in selecting the best approach for assessing sleep (objective versus subjective measures) in individuals with BD.


Pituitary leptin gene expression is reduced by neonatal androgenization of female rats.
We have previously reported evidence of leptin gene expression (ob mRNA) in adult rat brain and pituitary gland. We have also shown that ob mRNA levels in female rat brain and pituitary are regulated in an age- and tissue-dependent fashion. In view of the known sexual dimorphism in adipose tissue leptin expression, we have extended our original work to include an assessment of ob mRNA levels in brain, pituitary and fat of developing male and female rats. In addition we determined the effects of neonatal androgenization of female rat pups with testosterone propionate. Leptin (ob) mRNA expression was evaluated using semi-quantitative RT-PCR analysis. Leptin mRNA levels were developmentally regulated in the pituitary and cortex of male rats, paralleling the changes previously observed in female rats. In the pituitary, leptin expression was significantly higher during the early postnatal period and dropped abruptly by postnatal day (PD) 22. In the cortex, leptin expression was lowest at PD 4 and rose significantly by PD 14. In addition gender differences, most notably in the pituitary, were also observed. In pituitary gland, ob mRNA was significantly higher in female rats than in males at PD 14 (+60%; p < 0.05) but there were no sex differences at PD 4 and PD 22. Testosterone treatment of neonatal female rats profoundly reduced ob mRNA at PD 14 (3.5-fold; p < 0.01) and PD 22 (3-fold; p = 0.05). In subcutaneous adipose tissue and hypothalamus we observed no sex difference in ob mRNA levels nor an effect of testosterone. We conclude that leptin gene expression in rat pituitary gland is sexually dimorphic and sensitive to neonatal manipulation of sex steroid levels.


Stem cell therapy for central nervous system disorders: Metabolic interactions between transplanted cells and local microenvironments.
Stem cell therapy is a promising and rapidly advancing treatment strategy for a multitude of neurologic disorders. Yet, while early phase clinical trials are being pursued in many disorders, the mechanism of action often remains unclear. One important potential mechanism by which stem cells provide neuroprotection is through metabolic signaling with diseased neurons, glia, and other cell types in the nervous system microenvironment. Early studies exploring such interactions report normalization of glucose metabolism, induction of protective mitochondrial genes, and even interactions with supportive neurovasculature. Local metabolic conditions also impact stem cell biology, which can have a large impact on transplant viability and efficacy. Epigenetic changes that occur in the donor prior to collection of stem cells, and even during in vitro culture conditions, may have effects on stem cell biology that are carried into the host upon stem cell transplantation. Transplanted stem cells also face potentially toxic metabolic microenvironments at the targeted transplant site. Novel approaches for metabolically "preconditioning" stem cells prior to transplant harness metabolic machinery to optimize stem cell survival upon transplant. Ultimately, an improved understanding of the metabolic cross-talk between implanted stem cells and the local nervous system environment, in both disease and injury states, will increase the likelihood of success in translating stem cell therapy to early trials in neurological disease.


Evaluation of producer and consumer benefits resulting from eradication of bovine viral diarrhoea (BVD) in Scotland, United Kingdom.
In this paper we evaluated the distributional effects on actors in the milk market of a hypothetical programme to eradicate bovine viral diarrhoea (BVD) from the Scottish dairy herd. With this in mind, we applied an economic welfare methodology which utilizes data on price, on output quantity, on elasticities of supply and demand and on simulated cost and yield effects of an eradication programme. Our analysis is based on Markov-chain Monte Carlo simulation of BVD spread in the dairy herd. We found that consequent upon the eradication of the disease milk yield per cow increased for all herd sizes in Scotland whereas milk price received by farmers fell. Consequently, milk consumers gained around pound11 million in discounted economic surplus and producers with infected herds gained around pound39 million whereas producers with un-infected herds lost around pound2 million in discounted surplus. On balance, however, the eradication programme generated around pound 47 million in discounted economic gain for Scotland. We found that the results are sensitive to changes in yield gains made by owners of the infected herd.


Dietary fat, sedentary behaviors and the prevalence of the metabolic syndrome among Qingdao adults.
Currently, more than 30% of energy comes from fat, and 2.3h/day on average are spent watching television and 0.9h/day using a computer during non-working hours among adults in China. Moreover, one-fifth of Chinese adults have the metabolic syndrome. Recent reports showed that dietary fat and sedentary behaviors were two potential determinants of the metabolic syndrome frequency. To examine the association of dietary fat and sedentary behaviors with the metabolic syndrome among Qingdao's adults. A total of 1460 adults aged 25 year and over, from the first city-wide Nutrition and Health Survey in Qingdao, were evaluated. The nutrient intake of the participates was assessed using three consecutive days of dietary recollection. The metabolic syndrome was defined according to the National Cholesterol Education Program and introduced Asia-Pacific criteria for abdominal obesity recommended by the World Health Organization (WHO). In unadjusted analysis, participants having >or=44.4%of energy from fat had twice the odds of having the metabolic syndrome [odds ratio (ORs), 2.00; 95% confidence interval (CI), 1.37-2.91] as those having <28.9%. And in unadjusted model, adults engaged >or=4 h/day in watching television or reading or using a computer had ORs 1.44 (95% CI 0.97-2.14) times more than those spent <2h/day for having the syndrome. Adjustment for other covariates led to slight or few attenuation of the above associations. The joint association of the two factors with the syndrome was not detected. Dietary fat and sedentary behaviors were independently associated with the metabolic syndrome among adults aged 25 and over in Qingdao.


New evidence of a mitochondrial genetic background paradox: impact of the J haplogroup on the A3243G mutation.
The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients - diagnosed as carriers of the A3243G mutation - by control-region sequencing and RFLP survey of their mtDNAs. The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08-0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages. Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts.


Crystal structure of apatite type Ca2.49Nd7.51(SiO4)6O1.75.
The title compound, Ca2+x Nd8-x (SiO4)6O2-0.5x (x = 0.49), was synthesized at 1873 K and rapidly quenched to room temperature. Its structure has been determined using single-crystal X-ray diffraction and compared with results reported using neutron and X-ray powder diffraction from samples prepared by slow cooling. The single-crystal structure from room temperature data was found to belong to the space group P63/m and has the composition Ca2.49Nd7.51(SiO4)6O1.75 [dicalcium octa-neodymium hexa-kis-(ortho-silicate) dioxide], being isotypic with natural apatite and the previously reported Ca2Nd8(SiO4)6O2 and Ca2.2Nd7.8(SiO4)6O1.9. The solubility limit of calcium in the equilibrium state at 1873 K was found to occur at a composition of Ca2+x Nd8-x (SiO4)6O2-0.5x , where x = 0.49.


Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety.
The anxious phenotype of the 5-HT1A receptor knockout mouse and the anxiolytic properties of 5-HT1A agonists suggest that the 5-HT1A receptor modulates anxiety. We investigated the relationship of anxiety expressed in major depressive disorder (MDD) to regional 5-HT1A binding. Positron emission tomography with [carbonyl-11C]WAY-100635 was used to estimate regional 5-HT1A binding potential (BP) in 28 medication-free MDD subjects. Stepwise linear regression assessed the predictive capacity of three anxiety components, derived from a larger MDD sample and termed psychic, somatic, and motoric anxiety, on regional 5-HT1A BP. Higher psychic (beta >or= .63) and lower somatic (beta <or= -.70) anxiety predicted over 50% of the variance in 5-HT1A BP in multiple cortical regions, but not in amygdala, hippocampus, or autoreceptors of the raphe nuclei. The psychic and somatic anxiety components were not related to depression severity. Comorbid panic disorder was associated with lower cortical and subcortical 5-HT1A BP. The 5-HT1A receptor in the same brain regions has different relationships to psychic anxiety versus somatic anxiety. Lower 5-HT1A BP in panic disorder may be accounted for by higher somatic and lower psychic anxiety. Further study of the pathobiology of these anxiety components may identify distinct therapeutic targets or mechanisms.


Editorial for "Materials Chemistry" Section, in Journal Molecules.
Dear colleagues and friends, it is a great pleasure to summarize the most significant successes achieved during 2019 in the "Materials Chemistry" Section (https://www [...].


Efficacy of budesonide-loaded mesoporous silica microparticles capped with a bulky azo derivative in rats with TNBS-induced colitis.
A colon targeted drug delivery system for inflammatory bowel diseases (IBD), consisting in budesonide loaded mesoporous silica microparticles functionalized with a selective azo-molecular gate (M-Bud), has been evaluated for in vivo efficacy. Experimental colitis in male Wistar rats was induced by rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). M-Bud was orally administered to the rats as a suspension in water. Colon/body weight ratio, clinical activity score, and histological evaluation were used as inflammatory indices to measure the performance of the microparticles. The formulation was compared with a suspension prepared from the commercial drug Entocord®. Statistical analyses of all scores indicate that the controlled release of budesonide in colon from M-Bud showed efficacy similar to that of Entocord in the healing of induced colitis in rats.


Simultaneous determination of azathioprine and 6-mercaptopurine in serum by reversed-phase high-performance liquid chromatography.
The simultaneous determination of azathioprine and its metabolite 6-mercaptopurine in serum by reversed-phase high-performance liquid chromatography is described. 6-Mercaptopurine was converted to a derivative, 6-mercaptopurine-N-ethylmaleimide, which is stable against autoxidation, on reaction with N-ethylmaleimide. Since the N-ethylmaleimide derivative was more hydrophobic than the parent compound, it could be extracted into ethyl acetate together with azathioprine and the derivative was retained on the reversed-phase column better than 6-mercaptopurine. In addition, 6-mercaptopurine-N-ethylmaleimide absorbed at the same wavelength (280 nm) as azathioprine. Consequently, this derivatization procedure enabled the simultaneous extraction, separation, and detection of these compounds.


Structural changes in the oligosaccharide moiety of human IgG with aging.
In order to elucidate the relationship between glycosylation of IgG and aging, oligosaccharide structures of human IgG purified from sera of men and women aged 18 to 73 years were investigated. Oligosaccharides were liberated quantitatively from IgG by hydrazinolysis followed by N-acetylation and were tagged with p-aminobenzoic acid ethyl ester. The oligosaccharide structures were then analyzed by HPLC in conjunction with sequential exoglycosidase digestion. All IgG samples were shown to contain a series of biantennary complex type oligosaccharides which consisted of +/-Galbeta1-4GlcNAcbeta1-2Manalpha1-6(+/-GlcNAcbeta 1-4)(+/-Galbeta1-4GlcNAcbeta1-2Man(alpha)1-3)Man(beta)1-+ ++4GlcNAcbeta1-4(+/- Fucalpha1-6)GlcNAc and their mono- and disialo glycoforms in different ratios. In female IgG samples only, the incidence of non-galactosylated oligosaccharides with non-reducing terminal GlcNAc residues increased with aging (r>0.8), whereas that of digalactosylated oligosaccharides decreased (r<-0.8). A weaker correlation was observed between aging and the incidence of neutral and monosialo oligosaccharides in female IgG (r=0.461 and r= -0.538, respectively) and between aging and the incidence of oligosaccharides with a bisecting GlcNAc in both male and female IgG samples (r=0.566 and r=0.440, respectively). In addition, a significant change with aging in the galactosylation of IgG oligosaccharides was observed in females in their thirties, fifties, and sixties (p<0.02, p<0.01, and p<0.04, respectively). These findings may contribute to our understanding of autoimmune diseases such as rheumatoid arthritis in which glycosylation is involved.


Assessing the effect of patient navigator assistance for psychosocial support services on health-related quality of life in a randomized clinical trial in Latino breast, prostate, and colorectal cancer survivors.
After a diagnosis of prostate, breast, or colorectal cancer, Latinos experience higher mortality rates and lower health-related quality of life (HRQOL) in comparison with other ethnic/racial groups. Patient navigation (PN) and lay community health workers or promotores are effective in increasing cancer screening and early-stage diagnosis among Latinos. However, little is known about the effect of PN on HRQOL among Latino cancer survivors. Latinos previously diagnosed with breast, prostate, or colorectal cancer (n = 288) were randomized to 1 of 2 conditions: 1) the Patient Navigator LIVESTRONG Cancer Navigation Services (PN-LCNS) survivor care program or 2) PN only. HRQOL was measured with the Functional Assessment of Cancer Therapy-General, and cancer-specific HRQOL was measured with the Functional Assessment of Cancer Therapy-Breast, the Functional Assessment of Cancer Therapy-Prostate, and the Functional Assessment of Cancer Therapy-Colorectal for breast, prostate, and colorectal cancer survivors, respectively, at the baseline and at 3 follow-up time points. Generalized estimating equation analyses were conducted to estimate the effect of condition on HRQOL with adjustments for covariates and baseline HRQOL. PN-LCNS demonstrated a significant improvement in HRQOL in comparison with PN only for colorectal cancer survivors but not for breast and prostate cancer survivors. Enhanced PN improves HRQOL among Latino colorectal cancer survivors. Future research should identify the best strategies for engaging Latino survivors in PN programs. PN programs should also be adapted to address HRQOL concerns among Latina breast cancer survivors.


[Bone abnormalities and fetal cytomegalovirus infection].
Viruses, such as those of congenital rubella and cytomegalovirus infection, have been associated with bone lesions of rarefaction. A full-term neonate was admitted at bith (birth weight: 1,630 mg; head circumference: 29 cm) for hypotrophy. A severe growth retardation had been diagnosed at 32 weeks of gestation. The fetal karyotype was normal. Search for maternal toxoplasmosis, syphilis and rubella was negative. The neonate had a complex heart defect; skeletal X-ray films showed metaphyseal transverse bands of rarefaction of the long bones and longitudinally streaked band of sclerosis and rarefaction at the ends of the femora. Urine culture was highly positive for CMV while CMV IgM were negative and CMV IgG highly positive in serum. Neonatal bone changes usually seen in congenital rubella infection may also be observed in CMV infection.


Purification of chemically synthesised dinucleoside(5',5') polyphosphates by displacement chromatography.
Dinucleoside(5',5') polyphosphates (ApnA, ApnG, GpnG, n=3-6) are new group of hormones controlling important biological processes. Because some of the dinucleoside(5',5') polyphosphates are commercially not available purification of chemical synthesised dinucleoside(5',5') polyphosphates became necessary in order to test their physiological and pharmacological properties. It was the aim of this study to find a method which allows purification of 0.1-0.2 g quantities of dinucleoside polyphosphates by analytical HPLC columns yielding products with impurities lower than 1.0%. Adenosine(5')-polyphospho-(5')guanosines were synthesised by mixing the corresponding mononucleotides. The reaction results in a complex mixture of ApnA, ApnG and GpnG (with n=3-6 in all cases). The reaction mixture was concentrated on a preparative C18 reversed-phase column. The concentrate was displaced on a reversed-phase stationary. As a result of displacement chromatography, anion-exchange chromatography in gradient modus yielded baseline separated dinucleoside polyphosphates (homogeneity of the fractions>99%). The identity of the substances were determined by matrix assisted laser desorption ionisation mass spectrometry.


Mitochondrial contributions to tissue damage in stroke.
Tissue infarction, involving death of essentially all cells within a part of the brain, is a common pathology resulting from stroke and an important determinant of the long-term consequences of this disorder. The cell death that leads to infarct formation is likely to be the result of multiple interacting pathological processes. A range of factors, including the severity of the ischemic insult and whether this is permanent or reversed, determine which mechanisms predominate. Although evaluating mitochondrial properties in intact brain is difficult, evidence for several potentially deleterious responses to cerebral ischemia or post-ischemic reperfusion have been obtained from investigations using animal models of stroke. Marked changes in ATP and related energy metabolites develop quickly in response to occlusion of a cerebral artery, as expected from limitations in the delivery of oxygen and glucose. However, these alterations are often only partially reversed on reperfusion despite improved substrate delivery. Ischemia-induced decreases in the mitochondrial capacity for respiratory activity probably contribute to the ongoing impairment of energy metabolism during reperfusion and possibly also to the magnitude of changes seen during ischemia. Conditions during reperfusion are likely to be conducive to the induction of the permeability transition in mitochondria. There are as yet no well-characterized techniques to identify this change in the intact brain. However, the protective effects of some agents that block formation of the transition pore are consistent with both the induction of the permeability transition during early recirculation and a role for this in the development of tissue damage. Release of cytochrome c into the cytoplasm of cells has been observed with both permanent and reversed ischemia and could trigger the death of some cells by apoptosis, a process which probably contributes to the expansion of the ischemic lesion. Mitochondria are also likely to contribute to the widely-accepted role of nitric oxide in the development of ischemic damage. These organelles are a probable target for the deleterious effects of this substance and can also act as a source of superoxide for reaction with the nitric oxide to produce the damaging species, peroxynitrite. Further characterization of these mitochondrial responses should help to elucidate the mechanisms of cell death due to cerebral ischemia and possibly point to novel sites for therapeutic interventions in stroke.


A Three-Dimensional Bioabsorbable Tissue Marker for Volume Replacement and Radiation Planning: A Multicenter Study of Surgical and Patient-Reported Outcomes for 818 Patients with Breast Cancer.
Accurate identification of the tumor bed after breast-conserving surgery (BCS) ensures appropriate radiation to the tumor bed while minimizing normal tissue exposure. The BioZorb® three-dimensional (3D) bioabsorbable tissue marker provides a reliable target for radiation therapy (RT) planning and follow-up evaluation while serving as a scaffold to maintain breast contour. After informed consent, 818 patients (826 breasts) implanted with the BioZorb® at 14 U.S. sites were enrolled in a national registry. All the patients were prospectively followed with the BioZorb® implant after BCS. The data collected at 3, 6, 12, and 24 months included all demographics, treatment parameters, and provider/patient-assessed cosmesis. The median follow-up period was 18.2 months (range, 0.2-53.4 months). The 30-day breast infection rate was 0.5 % of the patients (n = 4), and re-excision was performed for 8.1 % of the patients (n = 66), whereas 2.6 % of the patients (n = 21) underwent mastectomy. Two patients (0.2 %) had local recurrence. The patient-reported cosmetic outcomes at 6, 12, and 24 months were rated as good-to-excellent by 92.4 %, 90.6 %, and 87.3 % of the patients, respectively and similarly by the surgeons. The radiation oncologists reported planning of target volume (PTV) reduction for 46.2 % of the patients receiving radiation boost, with PTV reduction most commonly estimated at 30 %. This report describes the first large multicenter study of 818 patients implanted with the BioZorb® tissue marker during BCS. Radiation oncologists found that the device yielded reduced PTVs and that both the patients and the surgeons reported good-to-excellent long-term cosmetic outcomes, with low adverse effects. The BioZorb® 3D tissue marker is a safe adjunct to BCS and may add benefits for both surgeons and radiation oncologists.


Contrast sensitivity and spatial frequency response of primate cortical neurons in and around the cytochrome oxidase blobs.
The striate cortex of macaque monkeys contains an array of patches which stain heavily for the enzyme cytochrome oxidase (CO blobs). Cells inside and outside these blobs are often described as belonging to two distinct populations or streams. In order to better understand the function of the CO blobs, we measured the contrast sensitivity and spatial frequency response of single neurons in and around the CO blobs. Density profiles of each blob were assessed using a new quantitative method, and correlations of local CO density with the physiology were noted. We found that the CO density dropped off gradually with distance from blob centers: in a typical blob the CO density dropped from 75% to 25% over 100 microns. Recordings were confined to cortical layers 2/3. Most neurons in these layers have poor contrast sensitivity, similar to that of the parvocellular neurons in the lateral geniculate nucleus. However, in a small proportion of layers 2/3 neurons we found higher contrast sensitivity, similar to that of the magnocellular neurons. These neurons were found to cluster near blob centers. This finding is consistent with (indirect) parvocellular input spread uniformly throughout layers 2/3, and (indirect) magnocellular input focused on CO blobs. We also measured spatial tuning curves for both single units and multiple unit activity. In agreement with other workers we found that the optimal spatial frequencies of cells near blob centers were low (median 2.8 c/deg), while the optimal frequencies of cells in the interblob regions were spread over a wide range of spatial frequencies. The high cut-off spatial frequency of multi-unit activity increased with distance from blob centers. We found no correlation between spatial bandwidth and distance from blob centers. All measured physiological properties varied gradually with distance from CO blob centers. This suggests that the view of blob cells subserving visual functions which are entirely distinct from non-blob cells may have to be reevaluated.


High prevalence of pharmacologically induced platelet dysfunction in the acute setting of brain injury.
The management of patients with traumatic brain injury (TBI), primary intracerebral hemorrhage (pICH) and primary subarachnoid hemorrhage (pSAH) remains a highly demanding challenge in critical care medicine. Antithrombotic agents are one of the most relevant risk factors for poor outcome. However, in the acute setting of brain injury, information on preexisting medication might not be available. This group of patients is insufficiently characterized regarding pharmacologically induced platelet impairment. We retrospectively analyzed consecutive patients with TBI, pICH and pSAH admitted to our department with unknown preexisting medication. The impact of acetylsalicylic acid and ADP-receptor antagonists on platelet function was tested via the Multiplate analyzer. Patients' characteristics, management and the influence of platelet impairment on outcome were evaluated. Within 25 months 103 patients with TBI (61), pICH (32) or pSAH (10) and unknown antithrombotic medication were admitted to our department. In 54 (52.4 %) of the patients reduced platelet function was detected, mainly caused by acetylsalicylic acid. In the TBI group, 30 patients (49.2 %) were identified, while Multiplate analysis detected platelet dysfunction in 19 (59.4 %) subjects in the pICH group and 5 in the pSAH group (50 %). In multivariable analysis the pathological Multiplate result was not associated with worse outcome; however, in our cohort 47 (87 %) patients received hemostatic therapy following detection of impaired platelet function. Our results demonstrate the high frequency of pharmacologically impaired platelet function in patients with unknown preexisting medication. Early assessment of platelet function is an important tool to allow optimized treatment in these patients.


Histamine release from rat mast cells induced by the lectin from the snail, Cepaea nemoralis L. - a counterpart to the triggering action of polycations?
One of the two lectins, occurring in the albumen gland of the snail, Cepaea nemoralis L., is shown to be a histamine releaser from isolated rat mast cells as well as in vivo. The release reaction is induced in the same dosage range as the agglutination of human red blood cells occurs. Both the reactions are inhibitable by the addition of N-acetyl-neuraminic acid. The releasing activity of the lectin seems to be a counterpart to the triggering action of polycations, because its specificity is directed against this sugar.


Effect of interferon on encephalomyocarditis virus infection of cultured mouse pancreatic B cells.
The M variant of encephalomyocarditis virus (EMC) produces a disease similar to human insulin-dependent diabetes mellitus in some but not all strains of mice. This diabetogenic M variant was found to induce fivefold more interferon than non-diabetogenic strains of EMC in cultures of mouse L 929 fibroblasts. When interferon induced by the M variant was added to monolayers of B cells from both diabetes-'susceptible' CD-1 mice and 'resistant' C57 bl/6 mice before EMC infection, B cell damage and virus replication were delayed. In addition, viral production in B cell cultures from C57 bl/6 mice was reduced five- to tenfold. A similar effect was not found when cultures from CD-1 mice were treated with interferon. Thus, interferon might play an important role in modulating the severity of the initial infection of B cells.


[Ecological adaptation of the lizzardCryptoblepharus boutoni cognatus (boettger) for life in the interditel zone (reptilia, skinkidae)].
The lizardCryptoblepharus boutoni cognatus was observed in Madagaskar. The animals descended daily into the intertidal zone to feed there on insects, crustaceans and fish (juvenilePeriophthalmus kohlreuteri). The pattern of activity of the animals is related to the movements of the tides.The lizards have a definite home range and migrate between intertidal feeding area and resting place on land along pathways established by experience. They return to their home even if released at about 200 m from their home range because they seem to acquire a knowledge of the surrounding by occasional exploratory visits. The tendency to establish a home range and homing behaviour are considered as adaptations for life in the intertidal zone, but the lizard remains a purely terrestial animal.


17beta-estradiol increases rat cerebrovascular prostacyclin synthesis by elevating cyclooxygenase-1 and prostacyclin synthase.
It has been reported that estrogens modulate peripheral vascular synthesis of vasodilatory hormones, including prostacyclin. If this occurs in the cerebral circulation, it could have important consequences in the modulation of cerebral hemodynamic function and improvement of stroke outcome. We investigated the hypothesis that in vivo 17beta-estradiol treatment of ovariectomized rats increases cerebrovascular prostacyclin production via elevation of the enzymes responsible for prostacyclin synthesis. Cerebral blood vessels from 17beta-estradiol-treated and nontreated ovariectomized rats were isolated and examined for prostacyclin synthesis by enzyme-linked immunosorbent assay or for protein levels of cyclooxygenase-1, prostacyclin-synthase, and cytosolic phospholipase A2 by immunoblot analysis. We report that chronic in vivo 17beta-estradiol treatment significantly enhanced basal prostacyclin synthesis in rat cerebral blood vessels by 2.6-fold over control. 17beta-estradiol treatment also resulted in a 5.1-fold increase of cyclooxygenase-1 protein and a 6.7-fold increase of prostacyclin-synthase protein in the cerebral vasculature. There was no effect of estrogen on levels of cytosolic phospholipase A2. Our findings suggest that estrogen influences the biosynthesis of prostacyclin, which may be important in the regulation of cerebral blood flow and thrombosis. This finding may shed light on the mechanisms that govern sex-based differences in cerebrovascular disease.


Missed Opportunities for Repeat HIV Testing in Pregnancy: Implications for Elimination of Mother-to-Child Transmission in the United States.
HIV testing is an effective intervention that is used for reducing perinatal HIV transmission. Centers for Disease Control and Prevention recommends a second HIV test during the third trimester of pregnancy for women in settings with an elevated HIV incidence (≥17 cases per 100,000 person-years). We conducted a retrospective cohort study at a single hospital in Baltimore, Maryland, to determine whether a second HIV test was done and to compare HIV retesting with mandated syphilis retesting. Of women who delivered at this hospital, 98.8% received prenatal care. Descriptive, bivariate, and multivariable analyses were performed. Among 1632 women, mean age was 27.6 years (standard deviation: 6.3), 59.6% were black, and 55.5% were single. HIV retesting was done in 28.4% of women, which was significantly less often compared with the state-mandated syphilis retesting (78.7%, p < 0.001). The odds of having an HIV retest were 15 times higher among women who received prenatal care at a teaching clinic [adjusted odds ratio (aOR): 15.58; 95% confidence interval (CI): 11.12-21.81], and they were lower among women with private insurance (aOR: 0.54, 95% CI: 0.34-0.86). The odds of having a syphilis retest were twice as high among women who received prenatal care at a faculty practice (aOR: 2.17; 95% CI: 1.53-3.09), and they were lower among women with private insurance (aOR: 0.61, 95% CI: 0.43-0.88). Emphasizing an "opt-out" HIV retesting approach through state laws may minimize risk perception, and this is one strategy that can be considered in areas of high HIV incidence to reach the goal of eliminating perinatal HIV transmission in the United States.


High-speed and high-performance size-exclusion chromatography of proteins on a new hydrophilic polystyrene-based resin.
High-performance size-exclusion chromatography of some standard proteins, peptides and amino acids on a new hydrophilic packing material obtained by chemical transformation of a cross-linked polystyrene-divinylbenzene copolymer was studied. Columns filled with 4 and 7 micron particles were compared. The influence of the concentration of acetonitrile, isopropanol and trifluoroacetic acid in the mobile phase on the chromatographic performance was investigated. A good linear calibration graph covering the molecular weight range from 200 to 700,000, was obtained under the optimal conditions. The packing material can be used for separations, for molecular weight determinations and for the pre-fractionation of proteins. The high rigidity of the packing material allows relatively high pressures to be used and therefore fast separations to be achieved. The packing material was applied to the chromatography of proteins from beer, bones and milk.


Shifts in carbon isotope ratios of two C3 halophytes under natural and artificial conditions.
The total carbon δ13C values of two C3 halophytes,Salicornia europaea L. ssp.rubra (Nels.) Breitung andPuccinellia muttalliana (Schultes) Hitch., native to inland saline areas of Alberta, Canada, were determined for plants grown under controlled conditions of supplied NaCl in the nutrient solution, and for plants found growing in the field. Field specimens were collected along line transects which ran from areas of high salinity to areas of low salinity across the pattern of species zonation. The δ13C value of the two species seemed to reflect the water potential of the soil (ψ wsoil ) as measured arbitrarily at a depth of 10 cm, becoming less negative as the ψ wsoil decreased. Over a linear distance of 5.55 m,S. europaea spp.rubra showed a shift of +5.3‰ as the ψ wsoil went from-25x102 kPa to a minimum of-73x102 kPa. ForP. nuttalliana, the δ13C values differed by 3.4‰ over a distance of 7.45 m where the maximum difference in ψ wsoil was 12.7x102 kPa. However, δ13C values ofP. nuttalliana only roughly reflected the spatial trends in ψ wsoil at the time of collection. In the growth chamber, the δ13C value ofS. europaea ssp.rubra changed by a maximum of +8.0‰ when the solute potential of the nutrient solution (ψ wsoil ) was dropped from-0.25x102 kPa to-64.25x102 kPa; while the δ13C value ofP. nuttalliana changed by a maximum of +10.8‰ when the ψ wsoil was dropped from-0.25x102 kPa to-40.25x102 kPa. Linear regression analyses indicated that the δ13C values of both species were strongly correlated (P<0.2%) with ψ wsoil . The observed shifts in δ12C may represent changes in the mode of photosynthetic CO2 fixation. However, a number of other explanations, some of which are discussed in the text, are also possible. A proper ecophysiological interpretation of such shifts in δ13C values of C3 plants awaits a better understanding of the isotope fractionation mechanisms involved.


Pyrazoles, 1,2,4-triazoles, and tetrazoles as surrogates for cis-amide bonds in boronate ester thrombin inhibitors.
Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.


Ichthyosis-cheek-eyebrow (ICE) syndrome: a new autosomal dominant disorder.
A family presenting with ichthyosis vulgaris, prominent full cheeks, sparse lateral eyebrows and other craniofacial and musculoskeletal defects is described in detail. This constellation of physical findings represents a new syndrome, transmitted in an autosomal dominant fashion. For reasons of simplicity it has been termed the I (ichthyosis), C (cheek), E (eyebrow) syndrome.


All trans retinoic acid in combination with intermediate-dose cytarabine and idarubicin in patients with relapsed or refractory non promyelocytic acute myeloid leukemia: a phase II randomized trial.
All trans retinoic acid has shown a remarkable effectiveness in acute promyelocytic leukemia. These results have encouraged studies of treatment with ATRA in other acute myeloid leukemia subtypes. In order to evaluate toxicity and antileukemic efficacy of all ATRA in patients with relapsed or refractory non promyelocytic AML, 95 patients (median age, 58 years; range, 20 to 80 years), with unclassified AML according to the FAB classification or secondary AML at diagnosis, or refractory or relapsing AML, received induction therapy with Idarubicin, 10 mg/m(2)/day, for 3 days and cytarabine, 1000 mg/m(2)/12 h, for 6 days, alone or combined, on a randomized basis, with ATRA, 45 mg/m(2)/day, from day 1 to complete remission. Patients in CR received maintenance therapy with 6 monthly courses combining Ida, 10 mg/m(2)/day, intravenously, on day 1 with Ara-C100 mg/m(2)/day, subcutaneously, from day 1 to day 5. Results were evaluated after one induction course. Overall 54 patients (57%, 26 with ATRA and 28 without ATRA) achieved CR including five patients treated at time of initial diagnosis, seven previously resistant, 38 in first relapse and four in further relapse. Thirty patients (31%) had resistant disease and 11 (12%) died from toxicity. Median time for neutrophil recovery to 0.5 x 10(9)/l and platelets to 20 x 10(9)/l was 31 and 21 days respectively. Severe toxicity (WHO grade >or=3) included infections (37%), diarrhea (9%), bleeding (3%), vomiting (16%), hyperbilirubinemia (5%), mucositis (6%) and hypercreatininemia (2%). No ATRA syndrome was noted in the ATRA arm. Median overall survival for the entire cohort was 6.3 months and median disease-free survival was 4.7 months. There were no statistical differences in terms of CR, DFS, and OS between the two arms. We conclude that ATRA in combination with Ida and Ara-C can be administered safely to high-risk AML patients. However, in this setting, ATRA did not offer any advantage when compared to chemotherapy alone.


Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial.
Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m2, nab-paclitaxel 150 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 and oral capecitabine 1250 mg/m2 on days 1-28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. Celgene.


Enhancement of the antibody-dependent tumoricidal activity of human monocytes by human monocytic colony-stimulating factor.
Human monocytic colony-stimulating factor (hM-CSF) stimulates mature cells as well as progenitor cells of human monocyte lineage. In the present study, we investigated the effect of completely purified native hM-CSF on the tumoricidal activity of human monocytes against Raji (Burkitt lymphoma-derived cell line) using a chromium release assay. Preincubation of human peripheral blood monocytes with hM-CSF for 48 h markedly enhanced their antibody-dependent cellular cytotoxicity (ADCC). This enhancing effect was dependent on the concentration of hM-CSF, and maximal enhancement was achieved at the concentration of 66 ng/ml. The number of receptor sites on monocytes against the Fc portion of immunoglobulin G increased 2- to 4-fold during 48 h incubation with hM-CSF. These results suggest that hM-CSF stimulates monocyte-ADCC by increasing the number of Fc receptor sites on human monocytes.


Astatination of nanoparticles containing silver as possible carriers of 211At.
The alpha emitter 211At is a prospective radionuclide for the therapy of smaller tumours and metastases. However, the chemical properties of 211At together with the fact that it is available only in trace amounts, makes the labelling of prospective astatine carriers rather complicated. In this context we have studied a new class of possible astatine carriers--nanoparticle systems, which tend to concentrate themselves in some types of tumours by means of the EPR effect. Additionally, such nanoparticles have the advantage that they may be chemically modified by the attachment of a tumour-seeking agent, and also directly applied to the target site. In order to reach high labelling yields, and in order to protect the nanoparticles from rapid degradation by the immune system, silver-containing particles covalently coated by poly(ethylene oxide) were developed and tested. The effect of the different reducing and oxidizing agents on the labelling yield was also determined. It was found that labelling yields were almost quantitative and well reproducible under reducing conditions, while under oxidizing conditions they dropped to ca. 50%. In the absence of any reducing or oxidizing agent, the labelling yields were randomly distributed between a range of 50% and 97%. The labelled nanoparticles were stable even in a large surplus of competing chloride ions.