Optimizing labelling conditions of 213Bi-DOTATATE for preclinical applications of peptide receptor targeted alpha therapy.
213Bismuth (213Bi, T1/2 = 45.6 min) is one of the most frequently used α-emitters in cancer research. High specific activity radioligands are required for peptide receptor radionuclide therapy. The use of generators containing less than 222 MBq 225Ac (actinium), due to limited availability and the high cost to produce large-scale 225Ac/213Bi generators, might complicate in vitro and in vivo applications though.Here we present optimized labelling conditions of a DOTA-peptide with an 225Ac/213Bi generator (< 222 MBq) for preclinical applications using DOTA-Tyr3-octreotate (DOTATATE), a somatostatin analogue. The following labelling conditions of DOTATATE with 213Bi were investigated; peptide mass was varied from 1.7 to 7.0 nmol, concentration of TRIS buffer from 0.15 mol.L-1 to 0.34 mol.L-1, and ascorbic acid from 0 to 71 mmol.L-1 in 800 μL. All reactions were performed at 95 °C for 5 min. After incubation, DTPA (50 nmol) was added to stop the labelling reaction. Besides optimizing the labelling conditions, incorporation yield was determined by ITLC-SG and radiochemical purity (RCP) was monitored by RP-HPLC up to 120 min after labelling. Dosimetry studies in the reaction vial were performed using Monte Carlo and in vitro clonogenic assay was performed with a rat pancreatic tumour cell line, CA20948. At least 3.5 nmol DOTATATE was required to obtain incorporation ≥ 99 % with 100 MBq 213Bi (at optimized pH conditions, pH 8.3 with 0.15 mol.L-1 TRIS) in a reaction volume of 800 μL. The cumulative absorbed dose in the reaction vial was 230 Gy/100 MBq in 30 min. A minimal final concentration of 0.9 mmol.L-1 ascorbic acid was required for ~100 MBq (t = 0) to minimize radiation damage of DOTATATE. The osmolarity was decreased to 0.45 Osmol/L.Under optimized labelling conditions, 213Bi-DOTATATE remained stable up to 2 h after labelling, RCP was ≥ 85 %. In vitro showed a negative correlation between ascorbic acid concentration and cell survival. 213Bismuth-DOTA-peptide labelling conditions including peptide amount, quencher and pH were optimized to meet the requirements needed for preclinical applications in peptide receptor radionuclide therapy.


[A large aneurysm of the inferior mesenteric artery. Apropos of a case. Review of the literature].
The prevalence of inferior mesenteric aneurysms is difficult to evaluate in the literature, only four cases having been published up to the present. The case described here was a large aneurysm of the inferior mesenteric artery measuring 10 cm by 8 cm of atheromatous origin, discovered echotomographic investigation of an abdominal mass and confirmed by aortography. Operation consisted in endoaneurysmorrhaphy with reimplantation of the main branch supplying the sigmoid arteries into the aorta combined with reimplantation of the right common iliac eroded by the aneurysm into the right side of the aorta. This type of lesion raises two problems: diagnostic: echotomography and digitalised angiography will certainly facilitate the detection of such lesions, the risk of rupture of which is considerable; therapeutic: distal reimplantation of the inferior mesenteric artery which is decided on the basis of its anatomical state and above all the superior mesenteric and coeliac collateral circulation in order to avoid any risk of ischaemia of the descending colon.


Mechanism that regulates nitric oxide production by lipopolysaccharide-stimulated rat Kupffer cells.
Mechanism that regulates nitric oxide (NO) production by stimulated Kupffer cells was studied. Lipopolysaccharide (LPS) stimulated NO production by primary-cultured Kupffer cells in a time- and dose-dependent manner. Twenty-four h after incubation with 1 microgram/ml of LPS, the nitrite concentration in the culture medium increased from 2.87 +/- 1.4 to 73.6 +/- 6.9 nmol/ml. NO production started to increase around 6 h after adding LPS and reached a maximum within 24 h. NO production was inhibited by 0.3 mM of NG-monomethyl-L-arginine and was reversed by adding 3 mM of L-arginine. When incubated with 1 microgram/ml of LPS for 24 h, NO synthase activity in Kupffer cells increased from 0.164 +/- 0.035 to 3.16 +/- 0.11 nmol/min/mg protein. Dexamethasone and prednisolone significantly inhibited the induction of NO synthase and NO production in Kupffer cells. Expression of mRNA for inducible type of NO synthase (iNOS) started to increase around 4 h after adding LPS (1 microgram/ml) and reached a maximum by about 20 h. The enhanced expression of iNOS mRNA was also suppressed by 1 microM dexamethasone. On the other hand, calcium ionophore A23187 significantly enhanced the induction of NO synthase and iNOS mRNA expression in LPS-stimulated Kupffer cells. In addition, a tyrosine kinase inhibitor, genistein (100 microM), significantly inhibited NO production by LPS-stimulated Kupffer cells. Neither phorbol 12-myristate 13-acetate, dibutyryl cAMP, indomethacin nor a protein kinase C inhibitor H-7 affected NO production by Kupffer cells. These results suggested that iNOS mRNA expression, NO synthase activity and NO production increased in LPS-stimulated Kupffer cells by a glucocorticoid-inhibitable mechanism and that Ca2+ and tyrosine phosphorylation might play important roles in LPS-dependent induction of NO synthase.


Meta-Analysis of Mechano-Sensitive Ion Channels in Human Hearts: Chamber- and Disease-Preferential mRNA Expression.
The cardiac cell mechanical environment changes on a beat-by-beat basis as well as in the course of various cardiac diseases. Cells sense and respond to mechanical cues via specialized mechano-sensors initiating adaptive signaling cascades. With the aim of revealing new candidates underlying mechano-transduction relevant to cardiac diseases, we investigated mechano-sensitive ion channels (MSC) in human hearts for their chamber- and disease-preferential mRNA expression. Based on a meta-analysis of RNA sequencing studies, we compared the mRNA expression levels of MSC in human atrial and ventricular tissue samples from transplant donor hearts (no cardiac disease), and from patients in sinus rhythm (underlying diseases: heart failure, coronary artery disease, heart valve disease) or with atrial fibrillation. Our results suggest that a number of MSC genes are expressed chamber preferentially, e.g., CHRNE in the atria (compared to the ventricles), TRPV4 in the right atrium (compared to the left atrium), CACNA1B and KCNMB1 in the left atrium (compared to the right atrium), as well as KCNK2 and KCNJ2 in ventricles (compared to the atria). Furthermore, 15 MSC genes are differentially expressed in cardiac disease, out of which SCN9A (lower expressed in heart failure compared to donor tissue) and KCNQ5 (lower expressed in atrial fibrillation compared to sinus rhythm) show a more than twofold difference, indicative of possible functional relevance. Thus, we provide an overview of cardiac MSC mRNA expression in the four cardiac chambers from patients with different cardiac diseases. We suggest that the observed differences in MSC mRNA expression may identify candidates involved in altered mechano-transduction in the respective diseases.


Sebaceous lymphadenoma of the parotid gland.
Sebaceous differentiation in salivary gland tissue is common. However, sebaceous neoplasms within the salivary glands are rare. We present the case of a sebaceous lymphadenoma with unusual features, arising in the parotid gland of a 60-year-old male. To the best of our knowledge, this is the first report of the ultrasound and MRI characteristics of this rare tumour. The difficulties encountered in reaching a definitive diagnosis both radiologically and histologically are described.


The delta agent: HBsAg particles with delta antigen and RNA in the serum of an HBV carrier.
The hepatitis B virus-associated delta antigen was detected in the serum of a young female drug addict with acute hepatitis and a previous history of hepatitis B surface antigen carrier. Delta antigen was associated with a 35- to 37-nm subpopulation of hepatitis B surface antigen particles which banded at a density of 1.25 gm per cm3 of CsCl and contained a small RNA of approximately 5.5 X 10(5) molecular weight. This report demonstrates that delta antigen is associated with a unique subpopulation of hepatitis B surface antigen particles and small RNA in human serum.


Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the "twitcher" mouse model of globoid cell leukodystrophy.
The twitcher mouse is well known as a naturally occurring authentic mouse model of human globoid cell leukodystrophy (GLD; Krabbe disease) due to genetic deficiency of lysosomal galactosylceramidase. The twitcher mice used most commonly are on the C57BL/6J background. We generated twitcher mice that were on the mixed background of C57BL/6J and 129SvEv, the standard strain for production of targeted mutations. Twitcher mice on the mixed background were smaller and had a shorter lifespan than were those on the C57BL/6J background. Many twitcher mice on the mixed background developed generalized seizures around 30 days that were never seen in twitcher mice on the C57BL/6J background. Neuropathologically, although the degree of the typical demyelination with infiltration of macrophages was similar in the central and peripheral nervous systems, in both strains, marked neuronal cell death was observed only in twitcher mice on the mixed background. In the hippocampus, the neuronal cell death occurred prominently in the CA3 region in contrast to the relatively well-preserved CA1 and CA2 areas. This neuropathology has never been seen in twitcher mice on the C57BL/6J background. Biochemically, the brain of twitcher mice on the mixed background showed much greater accumulation of lactosylceramide. Genetic background must be carefully taken into consideration when phenotype of mutant mice is evaluated, particularly because most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. These findings also suggest an intriguing possibility of important function of some sphingolipids in the hippocampal neuronal organization and maintenance.


Clinical nurse specialist outcomes: vision, voice, and value.
In keeping with the conference theme, this presentation will challenge nurses to envision clinical nurse specialist (CNS) influence. Opportunities for future CNS roles will be considered. CNSs will be encouraged to articulate their roles and their influence using a powerful collective voice. Practical strategies for capturing CNS outcomes and impact will be presented.


A Single-Center Pilot Prospective Study of Topical Application of Platelet-Derived Eye Drops for Patients with Ocular Chronic Graft-versus-Host Disease.
Ocular involvement of chronic graft-versus-host disease (cGVHD) is a complication that occurs in up to 60% of patients after allogeneic hematopoietic stem cell transplantation. Conventional therapeutic options include medical and surgical procedures that are administered depending on the severity of the condition, but most of them have provided unsatisfactory results and, to date, there is no consensus about treatment. We considered that topical application of a platelet lysate, administered as eye drops, might be considered an alternative worthwhile of investigation to treat ocular surface disorders in patients suffering from cGVHD. Therefore, we conducted a single-center prospective pilot study to assess the efficacy and safety of using eye drops made from reconstituted lysed platelet concentrate. Twenty-six patients with ocular cGVHD were eligible for the study; all but 2 completed their scheduled 1-year treatment and complied with the hematologic and ophthalmic regimen. At their first assessment interviews, after 30 days of treatment, 91% of patients reported an improvement in their symptoms and for 32%, substantive objective differences were measured. Remission of corneal damage was seen for 86% of our cohort, and improved National Institutes of Health scores for 73%, of whom 8% achieved the best score of 0 (ie, non-dry eye). Similar results were seen at later time points. Comparing outcomes for our patient cohort to those determined retrospectively for patients in our institutional database revealed a 5-year overall survival (OS) of 65%. This OS is comparable to patients with limited cGVHD (75%) and is superior to that of patients with nonocular extensive cGVHD or without cGVHD (30% and 59%, respectively) (P = .013). Our results suggest that platelet-derived eye drops are a safe, practical, and well-tolerated therapeutic option that offers substantial benefits for most patients affected by ocular cGVHD at onset. The favorable OS of our patient cohort suggests that this topical therapy, rather than systemic immunosuppression, may be the treatment of choice.


Comparing the outcomes of gold-standard dental examinations with photographic screening by mid-level dental providers.
To determine the detectability of the intra-oral photographic method in comparison to the baseline, comprehensive dental examination (CDE), in children when performed by different levels of dental practitioners. As part of a quality assurance program, intra-oral photographs were obtained from 77 patients (2-18 years) as part of a CDE before undertaking dental treatment under general anaesthesia. A DSLR camera was utilised to acquire images which were subsequently uploaded to a cloud-based server. The baseline for each participant was established during the CDE, utilising both visual and radiographic examination, which was then compared to the assessment made by a mid-level dental practitioners (MLDP). The evaluation was based on utilising an odontogram where the teeth were charted either as decayed or filled. Specificity (95%) was higher than sensitivity (61.5%) when comparing the photographic assessment with the benchmark CDE assessment. The inter-rater reliability between the two methods of assessment was substantial, with a kappa score of 0.62. The photographic assessment method underestimated the decayed and filled teeth, as observed by the caries experience (dft/DFT scores) (CDE = 7.01 vs. photographic assessment = 5.22). There were lower levels of diagnostic detection in the posterior teeth as compared to the anterior teeth assessments. Although the CDE is still considered to be the gold-standard, this study found that the photographic caries assessment by MLDP produced an acceptable diagnostic level of detection particularly for the anterior teeth. The photographic method could offer a potential cost-saving and user-friendly screening.


Effects of anesthetic and sedative agents on sympathetic nerve activity.
The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood. The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans. We implanted radiotransmitters in 6 dogs to record stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (ScNA), and blood pressure (BP). After recovery, we injected dexmedetomidine (3 μg/kg), morphine (0.1 mg/kg), hydromorphone (0.05 mg/kg), and midazolam (0.1 mg/kg) on different days. We also studied 12 human patients (10 male; age 68.0 ± 9.1 years old) undergoing cardioversion for atrial fibrillation with propofol (0.77 ± 0.18 mg/kg) or methohexital (0.65 mg/kg) anesthesia. Skin sympathetic nerve activity (SKNA) and electrocardiogram were recorded during the study. SGNA and ScNA were significantly suppressed immediately after administration of dexmedetomidine (P = .000 and P = .000, respectively), morphine (P = .011 and P = .014, respectively), and hydromorphone (P = .000 and P = .012, respectively), along with decreased BP and heart rate (HR) (P <.001 for each). Midazolam had no significant effect on SGNA and ScNA (P = .248 and P = .149, respectively) but increased HR (P = .015) and decreased BP (P = .004) in ambulatory dogs. In patients undergoing cardioversion, bolus propofol administration significantly suppressed SKNA (from 1.11 ± 0.25 μV to 0.77 ± 0.15 μV; P = .001), and the effects lasted for at least 10 minutes after the final cardioversion shock. Methohexital decreased chest SKNA from 1.59 ± 0.45 μV to 1.22 ± 0.58 μV (P = .000) and arm SKNA from 0.76 ± 0.43 μV to 0.55 ± 0.07 μV (P = .001). The effects lasted for at least 10 minutes after the cardioversion shock. Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.


Induction of neovascularization by mitogen-activated spleen cells and their supernatants.
The first objective of the experiment was to demonstrate that murine spleen cells treated with the T cell mitogen phytohemagglutinin induced neovascularization when adoptively transferred to the chorioallantoic membrane of chicken eggs. The second objective was to show that neovascularization could be induced by the supernatants from these cultures. The assay for neovascularization was based on the well established observation that angiogenesis can be induced on the chorioallantoic membrane by tumors and other substances. The supernatants were incorporated into a slow release polymer of hydroxyethylmethacrylate so as to produce a sustained release of the angiogenic material. The results showed that phytohemagglutinin activated spleen cells and their culture supernatants induced neovascularization on the chorioallantoic membrane. The significance of these observations are discussed as they relate to the hypothesis of lymphoid-induced neovascularization during tumor growth and other types of immunological inflammatory reactions.


Mechanistic Studies on a Cooperative NHC Organocatalysis/Palladium Catalysis System: Uncovering Significant Lessons for Mixed Chiral Pd(NHC)(PR3) Catalyst Design.
A comprehensive investigation of the mechanism of the highly enantioselective Pd(PPh3)4/NHC-catalyzed annulation of vinyl benzoxazinanones and enals has been conducted. A study of reaction orders supports the postulated cooperative catalysis. Interestingly, a detailed investigation of the catalytically active palladium species pointed toward a dual role of the NHC acting as an organocatalyst and forming a novel mixed ligand Pd/NHC/phosphine complex. The catalytically active Pd/NHC/phosphine complex represents a new class of chiral palladium catalyst. Remarkably, phosphine plays a crucial role in this transformation. These complexes could be characterized by X-ray crystallographic analysis and employed as catalysts for the enantioselective [4 + 1] annulation reaction of vinyl benzoxazinones and sulfur ylides in good yields and good enantioselectivities.


Heart Rate Variability Analysis: A Useful Tool to Assess Poststroke Cardiac Dysautonomia.
Neurogenic heart syndrome represents a phenomenon often encountered in clinical practice after ischemic stroke. Further poststroke cardiovascular complications are possibly related to cardiac autonomic dysregulation. Multiple Trigonometric Regressive Spectral (MTRS) analysis of the heart rate variability (HRV) allows a precise evaluation of cardiovascular modulation under different conditions. This research aims to evaluate the impact of the middle cerebral artery (MCA) ischemic stroke on cardiac autonomic function, using the MTRS analysis of HRV, during sympathetic and parasympathetic activation tests. The authors analyzed HRV parameters in 20 patients who had a right and 20 who had a left MCA ischemic stroke, under rest condition and during autonomic activation tests (deep breathing and standing tests). Data were compared with 20 age-matched and sex-matched healthy controls. Patients who had a right MCA ischemic stroke presented a decreased vagal modulation of the heart rate compared with healthy controls and patients who had a left MCA ischemic stroke, in resting state and during autonomic activation tests. Decreased root mean square of the successive differences, pNN50, high frequency, and high-frequency normalized units values (P<0.05) and increased low frequency/high frequency ratio (P<0.05) in resting state and during autonomic activation tests in patients who had a right MCA stroke indicate a sympathetic predominance in the control of the heart rate. The parasympathetic activation test did not change the sympathovagal balance in this group of patients. The autonomic nervous system represents an attractive target for the therapeutic approach. As MCA ischemic stroke, especially in the right hemisphere, seems to cause significant long-lasting autonomic dysregulation, implementing early pharmacological or nonpharmacological intervention for autonomic restoration may improve the outcome of patients who had an ischemic stroke.


[Xinfeng Capsule improves lung function by regulating Notch/Jagged-HES axis of type II alveolar epithelial cells in adjuvant arthritis rats].
Objective To observe the effect of Xinfeng Capsule (XFC) on Notch/Jagged-HES of type II alveolar epithelial cells (AECII). Methods Rats were divided for four groups: normal control (NC) group, model control (MC) group, leflunomide (LEF) group, XFC group, with 10 rats in each group. Complete Freund's adjuvant (CFA) was injected in the right foot plantar skin of each rat except for the NC group. After adjuvant arthritis was successfully induced, LEF group was given LEF (0.5 mg/100 g), and XFC group was treated with XFC (0.034 g/100 g), once a day from the 13th day to the 42th day. The NC and MC groups were given normal saline instead. Swelling degree (SD), arthritis index (AI) and pulmonary function were observed. AECII was observed by transmission electron microscopy (TEM). The expressions of transforming growth factor β1 (TGF-β1), Notch1, Notch3, Jagged1 and HES1 proteins in AECII were detected by Western blotting. Results The pulmonary function parameters such as forced expiratory volume in 1 second (FEV1), maximum expiratory flow rate at 50% FVC (FEF50), instantaneous flow at 75% of expired volume (FEF75), peak expiratory flow (PEF) in the MC group were significantly lower than those in the NC group, and the expressions of TGF-β1, Notch1, Notch3, Jagged1 and HES1 in AECII increased. The ultrastructure of AECII was damaged. Compared with the MC group, FEV1, FEF50, FEF75 and PEF increased, and TGF-β1, Notch1, Notch3, Jagged1 and HES1 decreased in the XFC group. Compared with LEF group, the lung function was better in XFC group. Conclusion XFC can inhibit pulmonary fibrosis and improve pulmonary function by down-regulating TGF-β1, Notch1, Notch3, Jagged1 and HES1 in rats with adjuvant arthritis.


Comparison of routine health management information system versus enhanced inpatient malaria surveillance for estimating the burden of malaria among children admitted to four hospitals in Uganda.
The primary source of malaria surveillance data in Uganda is the Health Management Information System (HMIS), which does not require laboratory confirmation of reported malaria cases. To improve data quality, an enhanced inpatient malaria surveillance system (EIMSS) was implemented with emphasis on malaria testing of all children admitted in select hospitals. Data were compared between the HMIS and the EIMSS at four hospitals over a period of 12 months. After the implementation of the EIMSS, over 96% of admitted children under 5 years of age underwent laboratory testing for malaria. The HMIS significantly overreported the proportion of children under 5 years of age admitted with malaria (average absolute difference = 19%, range = 8-27% across the four hospitals) compared with the EIMSS. To improve the quality of the HMIS data for malaria surveillance, the National Malaria Control Program should, in addition to increasing malaria testing rates, focus on linking laboratory test results to reported malaria cases.


[Alcohol and drugs in Central Europe--problems and possible solutions].
The high alcohol consumption and increasing abuse of other addictive inducing substances in Central Europe calls for broadley conceived preventive programmes and cheap and widely applicable therapeutic strategies (early treatment at the first contact level, self-help manuals, self-aid organizations). Social instability along with greater availability of alcohol and drugs create a dangerous combination. In addition to strategies of stress prevention at the societal level also strategy at the individual level is important (e.g. relaxation training, yoga, psychotherapy). It is also important to change the "image" of western society and commercial interests of those who make profits on alcohol and drugs should be under control and advertising should be greatly restricted if not prohibited. Prevention of problems caused by alcohol and drugs in particular in youths must be combined and really effective strategies should be used such as peer programmes. The authors mention also their own preventive programme FIT IN and print materials oriented specifically on certain population groups.


Kinetic Monte Carlo simulation of faceted islands in heteroepitaxy using a multistate lattice model.
A solid-on-solid model is generalized to study the formation of Ge pyramid islands bounded by (105) facets on Si(100) substrates in two dimensions. Each atomic column is not only characterized by the local surface height but also by two deformation state variables dictating the local surface tilt and vertical extension. These local deformations phenomenologically model surface reconstructions in (105) facets and enable the formation of islands which better resemble faceted pyramids. We apply the model to study a kinetic limited growth regime. Transitions from stepped mounds into faceted islands under deposition conditions are demonstrated. It is shown that a significantly reduced growth rate after faceting leads to a continuous nucleation of new islands until overcrowding occurs. The island size distribution is now dominated by fluctuations in the initial island size during faceting and the increased diversity in the ages of the islands. This multistate model may find applications in kinetic simulations of other nanostructures or nanoclusters involving arbitrary high-index surfaces.


Varied patterns of postoperative course of disappearance of hemifacial spasm after microvascular decompression.
The precise course of resolution of postoperative residual HFS after a single MVD has not been well categorised quantitatively in the literature. Not all patients with HFS were cured immediately after a single MVD; some of them exhibited a gradual disappearance of the HFS over a period of time. The time course of the gradual resolution of HFS is categorised and the situation of re-exploration in a few patients whose HFS persisted or recurred is determined. The results of 547 MVDs in 545 Chinese patients were reviewed using the database from the author's personal records between January 1992 and December 2002. Different outcomes were observed and divided into four categories according to the variable convalescent period: type 1, spasm cured immediately; type 2, spasm persisted with milder severity and faded away gradually from 7 days to as long as 2 years; type 3, spasm ceased immediately but recurred after 3 days and ran the same course as in type 2; type 4, failed. Four hundred and seventy-nine patients followed a type 1 course, which constituted an 87.9% immediate success rate. Forty-one patients (7.5%) followed a type 2 course, including three whose spasm persisted for more than 2 years. Twenty-three patients (4.2%), including one with venous compression, followed a type 3 course with their spasm ceased within three months. All of them had typical vascular loop compression. Another patient with a venous contact failed to respond positively to the first MVD underwent re-operation within 2 months. Re-operation was also performed in one patient four days after the first MVD due to persisting and even more severe spasm. These two patients were categorized type 4 as they failed the first MVD (0.4%). Late recurrence was noted in five patients from 1 to 2 years after the first MVD, only one of whom underwent re-exploration and was then cured again. Approximately 80% of the patients with HFS achieved immediate excellent results after a single MVD, the rest of the patients exhibited residual but usually milder spasms, which resolved gradually over a period of time. According to the patterns of the residual or persisting spasms, the situation and timing of re-exploration can be determined without difficulty. The surgeon should be concerned about missing the responsible vessels in patients with typical HFS who completely failed the first MVD.


Helicase primase: targeting the Achilles heel of herpes simplex viruses.
The majority of the population is infected by several herpesviruses. Once these infections are established the viruses persist for life. Therefore, current therapy may at best reduce symptoms but does not cure the infection. Moreover, the only classes of compounds licensed for systemic treatment of disease are nucleoside, nucleotide and pyrophosphate analogues; all of these ultimately target the herpesvirus DNA polymerase. A vaccine against varicella zoster virus (VZV) is available, but so far no effective vaccines against other human herpesviruses have been launched. At the same time, rising resistance to current medication, especially in the immunocompromised patient population, is a concern. For these reasons, there is an urgent need for new treatment options. Recently, some promising new drugs have been discovered; one of these compounds, developed at Bayer HealthCare under the name BAY 57-1293, is a potent HSV helicase primase inhibitor.


Acquired dyslexia after stroke in the prereading stage: a single case treatment study with f MRI.
The authors report a treatment study of a child (CK) who suffered a left-hemisphere stroke at age 6.3 years, a few months before beginning school. Despite complete recovery of spoken language abilities, CK failed to acquire written language abilities. Neurolinguistic assessment 2 years after the stroke revealed marked impairments in working memory, deficits in acquiring a sublexical reading strategy, and a very rudimentary orthographic network. Functional imaging demonstrated activation in posterior language areas during reading of familiar words while the attempt to read unfamiliar words activated peri- and contralesional structures of the anterior language areas. It was assumed that despite sufficient neural plasticity, the acquisition of a sublexical reading strategy was prevented by severe working memory deficits. Therefore, a specific treatment intervention was developed, choosing a compensatory strategy for reading remediation. Reading development was monitored over three months before and three months after an intensive training was conducted. Data showed significant gains in reading performance only after the specific intervention. These gains remained stable in a catamnesis 2 years later.


Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas.
Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood-brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene. We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case-control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy. i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood-brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found. This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.


Blue rubber bleb nevus syndrome and pulmonary hypertension: an unusual association.
Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital systemic angiodysplasia with multiple vascular malformations in the skin, gastrointestinal tract and, less often, in other internal organs and the brain. A 36-year-old man with past history of BRBNS was admitted to our hospital for progressive dyspnea and fatigue. Primary pulmonary hypertension (PPH) was diagnosed. He then developed acute abdominal pain and dyspnea, dying in a few hours due to sudden cardiac arrest. Postmortem examination demonstrated angiomatous lesions located in the skin, small bowel, heart, lungs, liver and thyroid. The lesions were slightly raised, soft and compressible and microscopically consisted of dilated vascular channels lined by a flattened endothelium. The vascular wall was formed by several layers of smooth muscle cells, intermixed with abundant aggregates of elastic lamellae and thin collagen fibers. Luminal thrombi were a frequent finding. In the small bowel, we identified the presence of an abnormally large artery directly opening into a thin-walled venous channel. The most striking finding in the lungs was the presence of thrombi of varying age in the lumen of segmental and elastic arteries, as well as muscular arteries and arterioles. Severe medial hypertrophy of muscular arteries and muscolarization of arterioles were also present. Intimal proliferative lesions and plexiform lesions were never observed. The pulmonary findings are consistent with recurrent thromboembolic events from shunts in the visceral lesions. To our knowledge, this is the first report of BRBNS with visceral arterovenous (AV) fistulae complicated by thromboembolic pulmonary hypertension (PH).


The National Diabetes Education Program at 20 Years: Lessons Learned and Plans for the Future.
The National Diabetes Education Program (NDEP) was established to translate findings from diabetes research studies into clinical and public health practice. Over 20 years, NDEP has built a program with partnership engagement that includes science-based resources for multiple population and stakeholder audiences. Throughout its history, NDEP has developed strategies and messages based on communication research and relied on established behavior change models from health education, communication, and social marketing. The program's success in continuing to engage diverse partners after 20 years has led to time-proven and high-quality resources that have been sustained. Today, NDEP maintains a national repository of diabetes education tools and resources that are high quality, science- and audience-based, culturally and linguistically appropriate, and available free of charge to a wide variety of audiences. This review looks back and describes NDEP's evolution in transforming and communicating diabetes management and type 2 diabetes prevention strategies through partnerships, campaigns, educational resources, and tools and identifies future opportunities and plans.


The Significance of the Sulfatase Pathway for Local Estrogen Formation in Endometrial Cancer.
Endometrial cancer (EC) is the most common estrogen-dependent gynecological malignancy in the developed World. To investigate the local formation of estradiol (E2), we first measured the concentrations of the steroid precursor androstenedione (A-dione) and the most potent estrogen, E2, and we evaluated the metabolism of A-dione, estrone-sulfate (E1-S), and estrone (E1) in cancerous and adjacent control endometrium. Furthermore, we studied expression of the key genes for estradiol formation via the aromatase and sulfatase pathways. A-dione and E2 were detected in cancerous and adjacent control endometrium. In cancerous endometrium, A-dione was metabolized to testosterone, and no E2 was formed. Both, E1-S and E1 were metabolized to E2, with increased levels of E2 seen in cancerous tissue. There was no significant difference in expression of the key genes of the aromatase (CYP19A1) and the sulfatase (STS, HSD17B1, HSD17B2) pathways in cancerous endometrium compared to adjacent control tissue. The mRNA levels of CYP19A1 and HSD17B1 were low, and HSD17B14, which promotes inactivation of E2, was significantly down-regulated in cancerous endometrium, especially in patients with lymphovascular invasion. At the protein level, there were no differences in the levels of STS and HSD17B2 between cancerous and adjacent control tissue by Western blotting, and immunohistochemistry revealed intense staining for STS and HSD17B2, and weak staining for SULT1E1 and HSD17B1 in cancerous tissue. Our data demonstrate that in cancerous endometrium, E2 is formed from E1-S via the sulfatase pathway, and not from A-dione via the aromatase pathway.


The rhetoric and reality of youth mentoring.
Enduring and supportive mentoring relationships can powerfully influence the course and quality of adolescent lives. As mentoring continues to expand, community agencies are implementing alternatives to the traditional one-on-one mentoring mode. Such efforts may help to reach youth who might otherwise fall through the cracks.


Microdomains bounded by endoplasmic reticulum segregate cell cycle calcium transients in syncytial Drosophila embryos.
Cell cycle calcium signals are generated by the inositol trisphosphate (InsP3)-mediated release of calcium from internal stores (Ciapa, B., D. Pesando, M. Wilding, and M. Whitaker. 1994. Nature. 368:875-878; Groigno, L., and M. Whitaker. 1998. Cell. 92:193-204). The major internal calcium store is the endoplasmic reticulum (ER); thus, the spatial organization of the ER during mitosis may be important in shaping and defining calcium signals. In early Drosophila melanogaster embryos, ER surrounds the nucleus and mitotic spindle during mitosis, offering an opportunity to determine whether perinuclear localization of ER conditions calcium signaling during mitosis. We establish that the nuclear divisions in syncytial Drosophila embryos are accompanied by both cortical and nuclear localized calcium transients. Constructs that chelate InsP3 also prevent nuclear division. An analysis of nuclear calcium concentrations demonstrates that they are differentially regulated. These observations demonstrate that mitotic calcium signals in Drosophila embryos are confined to mitotic microdomains and offer an explanation for the apparent absence of detectable global calcium signals during mitosis in some cell types.


Molecular alterations of coexisting thyroid papillary carcinoma and anaplastic carcinoma: identification of TERT mutation as an independent risk factor for transformation.
Thyroid papillary carcinoma is the most common endocrine neoplasm and generally carries a favorable prognosis. However, a small subset of papillary carcinomas transforms into anaplastic carcinoma, an undifferentiated cancer with a dismal prognosis. Recent studies using next-generation sequencing revealed the genomic landscape of papillary carcinoma and anaplastic carcinoma. However, risk factors for anaplastic transformation in papillary carcinoma remain obscure. In the present study, we investigated molecular alterations of papillary carcinoma and anaplastic carcinoma components in 27 tumors in which anaplastic carcinoma coexisted with antecedent papillary carcinoma. We conducted direct sequencing for BRAF, TERT promoter and PIK3CA, and immunohistochemistry for p53, TTF-1 and subunits of the SWI/SNF complex (ARID1A, ARID1B, ATRX, SMARCA2, SMARCA4, SMARCB1, and PBRM1). BRAFV600E and TERT promoter mutated at the rate of 90% and 95%, respectively, and these mutational statuses were almost identical between the papillary carcinoma and anaplastic carcinoma components. PIK3CA mutation was positive in 33% of our samples with a heterogeneous mutation pattern of the papillary carcinoma and anaplastic carcinoma components. Aberrant expression of p53 and loss of TTF-1 were present in 63 and 59%, respectively, and these two alterations were confined to the anaplastic carcinoma components. There was a loss of the SWI/SNF complex in a subset of the tumors with a heterogeneous pattern of the papillary carcinoma and anaplastic carcinoma components: SMARCA4 in 4% and PBRM1 in 4%. In a multivariate comparison between the antecedent papillary carcinoma components and control papillary carcinomas without anaplastic transformation, TERT promoter mutation was independently associated with anaplastic transformation. Collectively, papillary carcinoma-derived anaplastic carcinomas are characterized by BRAF and TERT promoter mutations, and these mutations occur prior to anaplastic transformation. Alterations of PIK3CA and the SWI/SNF complex are relatively rare and temporally heterogeneous. Of note, a papillary carcinoma harboring TERT promoter mutation is at higher risk for anaplastic transformation.


Foreign Body in Jugal Mucosa.
Introduction Foreign body in the oral cavity may be asymptomatic for long time and only sometimes it can lead to a typical granulomatous foreign body reaction. Some patients may complain of oral pain and present signs of inflammation with purulent discharge. A granuloma is a distinct, compact microscopic structure composed of epithelioid-shaped macrophages typically surrounded by a rim of lymphocytes and filled with fibroblasts and collagen. Nowadays, the increase of cosmetic invasive procedures such as injection of prosthetic materials in lips and cheeks may lead to unusual forms of inflammatory granulomas. Objectives Describe an unusual presentation of a foreign body reaction in the buccal mucosa due to previous injection of cosmetic agent. Resumed Report A 74-year-old woman was referred to the Department of Otorhinolaryngology, Head and Neck Surgery to investigate the presence of multiple painless, bilateral nodules in the buccal mucosa, with progressive growth observed during the previous 2 months. The histologic results showed a foreign body inflammatory reaction. Conclusion Oral granulomatosis lesions represent a challenging diagnosis for clinicians and a biopsy may be necessary. Patients may feel ashamed to report previous aesthetic procedures, and the clinicians must have a proactive approach.


Asthma in patients with attention-deficit/hyperactivity disorder: a nationwide population-based study.
Asthma symptoms can interrupt daily activities, disturb sleep, and increase the risk of a child having an attention deficit or irritability, which also are symptoms of attention-deficit/hyperactivity disorder (ADHD). Previous studies have shown conflicting results regarding the association between ADHD and asthma. This study investigates the possible correlation between asthma and ADHD. We retrieved data on 221,068 pediatric patients from Taiwan's National Health Insurance Research Database in 2005, and calculated the prevalence and risk factors of allergic diseases among ADHD patients. The prevalence of asthma in the ADHD group, compared with the control group, was 4.3 fold higher in the age 12 to 17 subgroup (95% CI, 1.71 to 10.6), 1.5-fold higher in males (95% CI, 1.05 to 2.03), and 1.6-fold higher for children living in urban areas (95% CI, 1.12 to 2.28). Multivariate logistic regression models showed the odds ratio of asthma for children with ADHD was 1.43 (95% CI, 1.05 to 1.95) as compared with children without ADHD. Pediatric ADHD was associated positively with asthma, but the underlying mechanisms require further clarification.


An in vitro evaluation of leakage of two etch and rinse and two self-etch adhesives after thermocycling.
Our experiment evaluated the microleakage in resin composite restorations bonded to dental tissues with different adhesive systems. 40 class V cavities were prepared on the facial and lingual surfaces of each tooth with coronal margins in enamel and apical margins in cementum (root dentin). The teeth were restored with Z100 resin composite bonded with different adhesive systems: Scotchbond Multipurpose (SBMP), a 3-step Etch and Rinse adhesive, Adper Scotchbond 1 XT (SB1), a 2-step Etch and Rinse adhesive, AdheSE One (ADSE-1), a 1-step Self-Etch adhesive, and AdheSE (ADSE), a 2-step Self-Etch adhesive. Teeth were thermocycled and immersed in 50% silver nitrate solution. When both interfaces were considered, SBMP has exhibited significantly less microleakage than other adhesive systems (resp., for SB1, ADSE-1 and ADSE, P = 0.0007, P < 0.0001 and P < 0.0001). When enamel and dentin interfaces were evaluated separately, (1) for the Self-Etch adhesives, microleakage was found greater at enamel than at dentin interfaces (for ADSE, P = 0.024 and for ADSE-1, P < 0.0001); (2) for the Etch and Rinse adhesive systems, there was no significant difference between enamel and dentin interfaces; (3) SBMP was found significantly better than other adhesives both at enamel and dentin interfaces. In our experiment Etch and Rinse adhesives remain better than Self-Etch adhesives at enamel interface. In addition, there was no statistical difference between 1-step (ADSE-1) and 2-step (ADSE) Self-Etch adhesives.


[Analysis of heart rhythm variability by linear and non-linear dynamics methods].
Spectral analysis of heart rhythm variability is a noninvasive method to study cardiovascular autonomic control. Nonlinear methods of analysis of heart rhythm variability may provide an additional information on properties of RR interval dynamics, which cannot be revealed by linear methods. The aim of this study was to investigate and to compare some parameters of deterministic chaos, tractal and spectral properties of heart rhythm variability in healthy subjects. Sixty healthy subjects, who participated in this study, were divided in four different age groups: children (< 15 years old), young (15-24 years), adults (25-39 years) and middle-aged (40-61 years). We analyzed the heart period variability extracted from a 5-minute electrocardiograms recordings in supine rest. Short-term fractal scaling exponent, sample entropy, minimum embedding dimension and the largest Lyapunov exponent along with the spectral measures (low-frequency and high-frequency power) were determined. Heart frequency, short-term fractal scaling exponent, and the largest Lyapunov exponent did not differ between the tested groups (p > 0.05). Middle-aged subjects had the lower low-frequency power as compared to the children (p < 0.001) and the young (p < 0.05), and the lower high-frequency power as compared to the other three groups (p < 0.001). Middle-aged also had a significantly lower power of high frequency and sample entropy as compared to the other three groups (p < 0.001). Children had lower values of minimum embedding dimension compared to the middle aged (p < 0.001). Significant negative correlation between the age of the tested subjects, and the low-and, high-frequency power and sample entropy was found. The obtained results suggested that healthy aging was associated with significant alteration in heart rhythm dynamics reflected on a higher regularity and lower variability of heart rhythm time-series. Significant decrease in a high-frequency power with aging suggested that reduction in parasympathetic activity was the basic cause of these changes.


Epidemiology of systemic lupus erythematosus.
A major international study, properly designed and executed, could establish whether the population differences that seem to exist in prevalences of SLE are real and whether these differences, eg, in black and Chinese groups residing in different parts of the world, depend upon varied genetic constitution or whether they reflect environmental influences. The noninfectious environmental influences that should be considered are toxic and dietary ones.


The Estimation of Physiologic Ability and Surgical Stress (E-PASS) model as a predictor of postoperative complications and mortality after digestive surgeries: a meta-analysis and systematic review.
Conflicting results exist about the usefulness of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) model in patients undergoing digestive surgeries. Thus, this study aims to analyze and evaluate the E-PASS model for predicting postoperative complications and mortality. A literature search strategy for "E-PASS" was carried out in PubMed, Embase, Google Scholar, Ovid, and Cochrane databases for studies published before November 2020. "E-PASS" or "Estimation of Physiologic Ability and Surgical Stress" were used as the search terms in all databases, and a total of 20 published English language studies with available data relating to digestive surgery were selected for this study. Clinical data and indices including preoperative risk score (PRS), surgical stress score (SSS), comprehensive risk score (CRS), postoperative complications, mortality, and overall survival (OS) were collected. Meta-analyses of heterogeneity were performed using Review Manager version 5.3 and STATA 14.0. Twenty studies with 9,136 patients were included in our meta-analysis. Using a random-effects model, the indices of the E-PASS model in patients with postoperative complications were significantly greater than those in patients without complications [PRS: 95% confidence interval (CI): 0.14-1.50; SSS: 95% CI: 0.28-1.06; CRS: 95% CI: 048-1.49]. Moreover, patient morbidity and mortality were associated with a higher CRS (morbidity: 95% CI: 2.17-6.29; mortality: 95% CI: 1.57-4.78), while subgroup analyses showed that a high CRS in the elderly was related to increased morbidity (95% CI: 1.57-4.78) without heterogeneity. In addition, we found that a high E-PASS CRS was significantly associated with shorter OS after digestive surgery (95% CI: 1.24-5.41). The higher CRS score in the E-PASS model accompanies with many postoperative complications, increased mortality and shorter OS. Collectively, the E-PASS model is a convenient and effective risk assessment for patients undergoing digestive surgeries. More stringently designed studies are expected to develop better estimates of the application value of this model in digestive surgeries.


[Effects of Peritrophe roxburghiana on blood pressure in renal hypertensive and hyperlipidemic rats].
To observe the effects of Peristrophe roxburghiana (HSX) on the blood pressure in renal hypertensive and hyperlipidemic rats (RHHR), and investigate the possible mechanisms of its pharmacological effects. The two-kidney, two-clip method was used to produce the renovascular hypertensive rats, then high lipid emulsion was administered to produce the model of hyperlipidemic rats. Drugs were administered for 5 weeks. Blood pressure was measured weekly before and after administration. After rats were killed at the end of the 5th week,blood was sampled to measure plasma angiotensin IT and serum NO. Angiotensin II in the thoratic aorta was measured too. The BP decreased significantly to the end of 5th week (P < 0.05) after treatment of 1-2 weeks with HSX. HSX (H or L dosage) increased the level of serum NO evidently at the end of the experiment. No significant statistical difference was found in the level of plasma angiotensin, but HSX(H) and captopril decreased the value of angiotensin II in blood vessel (P < 0.01). HSX decreased the blood pressure significantly for RHHR and the mechanism of its antihypertensive effect was possibly related to the increasing of serum NO and the decreasing of angiotensin II1 in the thoratic aorta.


Determining the impact of Walk Kansas: applying a team-building approach to community physical activity promotion.
Research and practice partnerships have the potential to enhance the translation of research findings into practice. This paper describes such a partnership in the development of Walk Kansas (WK) and highlights individual and organizational level outcomes. Phase 1 examined: (a) the reach of WK, (b) physical activity changes, and (c) maintenance of physical activity changes 6 months after the program was completed. Phase 2 explored WK adoption and sustainability over 5 years. WK attracted a large number of participants who were more likely to be female, more active, and older than the adult population within the counties where they resided. Inactive or insufficiently active participants at baseline experienced significant increases in both moderate (p < 0.001) and vigorous (p < 0.001) physical activity. A random selection of participants who were assessed 6 months post-program did not demonstrate a significant decrease in moderate or vigorous activity between program completion and 6-month follow-up. The number of counties adopting the program increased across years, peaking at 97 in 2006 and demonstrated the sustainability of the WK over 5 years. WK is effective, has a broad reach, and enables participants to maintain increased activity. It also shows promise for broad adoption and sustainability.


The Cardiotoxic Mechanism of Doxorubicin (DOX) and Pegylated Liposomal DOX in Mice Bearing C-26 Colon Carcinoma: a Study Focused on microRNA Role for Toxicity Assessment of New Formulations.
MicroRNAs (miRs) are a group of small non-coding RNAs that regulate transcriptional or post-transcriptional gene expression. The aim of the present study was to investigate the role of miR -1, -21 and -145 and their targets in cardiotoxicity-induced by DOX and pegylated liposomal DOX. BALB/c mice subjected to subcutaneous injection of C-26 tumor cells. Eight days after tumor inoculation, animals were divided into 6 groups: control, liposome, DOX (6 and 9 mg/kg) and PL-DOX (6 and 9 mg/kg). The formulations were administered one time per week for four weeks. 24 h after the last injection, mice were sacrificed; blood and heart samples were taken. Western blot analysis was done on protein extracts to investigate the expression of cardiac caspase-3, -8, Bax, Bcl2, Programmed cell death 4 (PDCD4) and BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 (BNIP3). The expression levels of miR -1, -21 and -145 were also evaluated by quantitative real-time PCR. Mice treated with both DOX formulations showed a marked inhibition in tumor growth. Western blot analysis indicated that the expression level of cardiac caspase-3, caspase-8, Bax and BNIP3 were up-regulated due to DOX injection (9 mg/kg). Exposure of mice with DOX resulted in a significant increase in cardiac miR-1 and miR-21 expression level. PL-DOX treatment did not change the proteins and miRs expression. The results suggest that miR -1, -21 and -145 may involve in cardiotoxicity induced by DOX. Evaluation of miRs signaling pathways might be of potential value for toxicity assessment of new formulations. Graphical Abstract The cardiotoxic mechanism of doxorubicin (DOX) and pegylated liposomal DOX (PL-DOX).


Psyche and human thought from the anatomies of the past.
De Blasio's research focuses on the anthropology of the late 19th and early 20th centuries. His investigations extend from criminalistics to ancient mummies, driven by his passion for archaeology and human history. He delves into the intricate relationship between anatomy and the human psyche, intertwining disciplines like archaeology, anthropology, and history. His examination of ancient human remains, though lacking modern tools, reveals insights into embalming practices and cultural beliefs. De Blasio's interest in craniology leads to the exploration of cranial deformations, considering as cultural factors. By connecting anthropology with psychology, he questions the cognitive effects of cranial deformations and even associates certain traits with skull morphology. This interplay showcases his ability to merge natural and cultural sciences, offering unique perspectives on human development and cultural practices.


The Foundry: the DNA synthesis and construction Foundry at Imperial College.
The establishment of a DNA synthesis and construction foundry at Imperial College in London heralds a new chapter in the development of synthetic biology to meet new global challenges. The Foundry employs the latest technology to make the process of engineering biology easier, faster and scalable. The integration of advanced software, automation and analytics allows the rapid design, build and testing of engineered organisms.


Regulatory delays in a multinational clinical stroke trial.
The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586-1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93-293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = -0.002; p = 0.02). In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.


Resolution of an absolute scotoma and improvement of relative scotomata after successful macular hole surgery.
Visual loss in eyes with full-thickness macular holes is thought to be caused by the absence of retinal function in the area of the neurosensory defect as well as reduction in retinal function in the surrounding area of neurosensory retinal detachment. To improve characterization of the visual function of eyes after successful macular hole surgery, we studied six eyes preoperatively and postoperatively with macular microperimetry using the scanning laser ophthalmoscope. Best-corrected visual acuity was improved postoperatively in all eyes. Microperimetry performed preoperatively demonstrated an absolute scotoma that corresponded to the neurosensory defect in all eyes, with surrounding concentric isopters of relative scotomata. No detectable absolute scotoma was found in any eye postoperatively. All eyes showed partial or complete resolution of the surrounding relative scotomata. Improvements in visual acuity after successful macular hole surgery may be related to disappearance of a detectable absolute scotoma as well as improvement in the surrounding retinal function.


Percutaneous Mitral Valve Repair With the MitraClip in Primary Compared With Secondary Mitral Valve Regurgitation Using the Mitral Valve Academic Research Consortium Criteria.
To compare early device success, procedural success, and 30-day safety endpoint according to the new Mitral Valve Academic Research Consortium criteria (MVARC) in severe primary and secondary mitral regurgitation (MR) patients. A total of 210 patients were enrolled; 105 patients with primary MR were compared with 105 patients with secondary MR. All patients were highly symptomatic (New York Heart Association III/IV 79.0% vs 87.6%). Decision for MitraClip therapy was done by the heart team. Patients were on optimal medical heart failure therapy. Preprocedural MR grade was 3.4 ± 0.5 in secondary MR vs 3.7 ± 0.4 in primary MR (P<.001). Device success according to MVARC was high in both groups (93.3% in secondary MR vs 94.3% in primary MR), treated with 1.4 ± 0.6 vs 1.3 ± 0.5 MitraClips (P=.14). Reduction of New York Heart Association class from baseline to 30-day follow-up was 1.7 ± 1.1 in secondary MR vs 2.2 ± 1.2 in primary MR (P<.01). Rate of MVARC minor vascular complications was low. Thirty-day safety endpoint according to MVARC criteria was low in both groups (4.8% in secondary MR vs 5.7% in primary MR (P=non-significant). Percutaneous mitral valve repair using the MitraClip device is safe and effective in patients with primary and secondary MR, with a high early device success rate and low 30-day safety endpoint according to the MVARC criteria.


Going Your Own Way: A Cross-Cultural Validation of the Motivational Demands at Work Scale (Mind@Work).
In modern jobs, performing well at work requires to an increasing degree that workers manage and motivate themselves for their tasks. Rather than to rely on a supervisor, they must set their own goals, decide how hard they work to achieve that goal, and decide when the task is completed. This manuscript describes the validation of an instrument that measures the extent to which workers must deal with such "motivational job demands"; the Motivational Demands at Work Scale (Mind@Work). Using data from a Dutch (N = 308) and a Chinese (N = 681) sample of working adults, confirmatory factor analysis showed that this instrument was reliable and robust in both samples, and that the factor structures obtained in both samples were highly comparable. Subsequent analyses demonstrated that high scores on the dimensions of the Mind@Work were associated with higher levels of engagement, work passion, job crafting and innovation behavior, even after controlling for job control, and job demands. These findings suggest that motivational job demands can be measured in a reliable and valid way. Thus, more research that examines the potential of this new concept for well-being and performance of employees seems warranted.


Effect of lipid peroxide loading on lipid peroxidation and on the glutathione and cytochrome systems in rabbits.
New Zealand White rabbits (6 males and 6 females) were fed a diet of high lipid peroxide content (peroxide value: 249.05 meq/kg fat) for 21 days. Twelve rabbits served as controls (peroxide value: 40.3 meq/kg fat). The lipid peroxide loading did not cause clinical signs. The rate of lipid peroxidation, as measured on the basis of thiobarbituric acid reactive substances (TBARS), was significantly (P < 0.05) higher in all of the investigated tissues, in the following order: liver > red blood cells (RBC) > blood plasma. Reduced and oxidised glutathione content was higher in the blood plasma (P < 0.01) and liver (P < 0.001) of rabbits exposed to the peroxide load. Lipid peroxide loading decreased the activity of glutathione peroxidase in the blood plasma, RBC haemolysate and liver and that of glutathione reductase in the liver. The amount of cytochrome P450 (both CO- and metyrapone-reduced) and the activity of cytochrome c (P450) oxidoreductase in the microsomal fraction of the liver homogenate were also lower in the group exposed to lipid peroxide load. Subchronic alimentary lipid peroxide loading in the presence of sufficiently high levels of antioxidants in the complete feed was found to increase the rate of lipid peroxidation and markedly lower the activities of both the glutathione and xenobiotic transforming enzyme systems without causing any clinical signs of toxicity.


Molecular biomarkers for facilitating genome‑directed precision medicine in gynecological cancer (Review).
Prominent recent advancements in cancer treatment include the development and clinical application of next-generation sequencing (NGS) technologies, alongside a diverse array of novel molecular targeting therapeutics. NGS has enabled the high-speed and low-cost sequencing of whole genomes in individual patients, which has opened the era of genome-based precision medicine. The development of numerous molecular targeting agents, including anti-VEGF antibodies, poly (ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors, have all improved the efficacy of systemic cancer therapy. Accumulating bench and translational research evidence has led to identification of various cancer-related biomarker profiles. In particular, companion diagnostics have been developed for some of these biomarkers, which can be clinically applied and are now widely used for guiding cancer therapies. Selecting biomarkers accurately will improve therapeutic efficacy, avoid overtreatment, enable earlier diagnosis and reduce the cost of preventing and treating gynecological cancer. Therefore, biomarkers are fast becoming indispensable tools in the practice of genome-directed precision medicine. In the present review, the current evidence of cancer-related biomarkers in the field of gynecological oncology, their molecular interpretations and future perspectives are outlined. The aim of the present review is to provide potentially useful information for the formulation of clinical trials.


BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining.
Tumor microenvironment (TME) plays a crucial role in the initiation and progression of lung adenocarcinoma (LUAD); however, there is still a challenge in understanding the dynamic modulation of the immune and stromal components in TME. In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cell (TIC) and the amount of immune and stromal components in 551 LUAD cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein-protein interaction (PPI) network construction. Then, Bruton tyrosine kinase (BTK) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that BTK expression was negatively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and positively correlated with the survival of LUAD patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression BTK group were mainly enriched in immune-related activities. In the low-expression BTK group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that B-cell memory and CD8+ T cells were positively correlated with BTK expression, suggesting that BTK might be responsible for the preservation of immune-dominant status for TME. Thus, the levels of BTK might be useful for outlining the prognosis of LUAD patients and especially be a clue that the status of TME transition from immune-dominant to metabolic activity, which offered an extra insight for therapeutics of LUAD.


Association of high-risk scores for obstructive sleep apnea with symptomatic bradyarrhythmias.
Obstructive sleep apnea (OSA) may have an association with bradyarrhythmias but often remains undiagnosed. Our aim was to determine if patients with a high risk of OSA attending our cardiology clinics had an association with symptomatic bradyarrhythmias, as this information might lead to changes in management strategy. The Berlin questionnaire was used to assess risk of OSA in 190 patients, and they were divided into high-risk or low-risk groups. Demographic data and medical histories were recorded and patients groups were compared with t-tests and chi-square tests. A multivariate regression analysis was done to correct for confounding variables. The mean age of our sample population was 63.0 ± 14.7 years with a mean BMI of 29.5 ± 7.8 kg/m2. Using the Berlin questionnaire, 41.3% of the patients were classified as high risk; 15.7% of the patients had a known diagnosis of OSA. Between high-risk and low-risk groups, there was no significant difference in the prevalence of bradyarrhythmias (22.5 vs. 15.2% P = 0.21), symptomatic sinus node dysfunction (14.4 vs. 11.4% P = 0.66) or atrioventricular block (10.8 vs. 6.3% P = 0.33). A multivariable logistic regression analysis demonstrated that dyslipidemia had the strongest association with a high risk for OSA, but not bradyarrhythmias. Based on the Berlin questionnaire, patients at a high risk for OSA did not have an increased prevalence of bradyarrhythmias. More studies are needed to assess the utility of evaluating patients with bradyarrhythmias for OSA prior to implanting permanent pacing devices.


Cytidine deaminase motifs within the DYW domain of two pentatricopeptide repeat-containing proteins are required for site-specific chloroplast RNA editing.
In angiosperm organelles, cytidines are converted to uridines by a deamination reaction in the process termed RNA editing. The C targets of editing are recognized by members of the pentatricopeptide repeat (PPR) protein family. Although other members of the editosome have begun to be identified, the enzyme that catalyzes the C-U conversion is still unknown. The DYW motif at the C terminus of many PPR editing factors contains residues conserved with known cytidine deaminase active sites; however, some PPR editing factors lack a DYW motif. Furthermore, in many PPR-DYW editing factors, the truncation of the DYW motif does not affect editing efficiency, so the role of the DYW motif in RNA editing is unclear. Here, a chloroplast PPR-DYW editing factor, quintuple editing factor 1 (QED1), was shown to affect five different plastid editing sites, the greatest number of chloroplast C targets known to be affected by a single PPR protein. Loss of editing at the five sites resulted in stunted growth and accumulation of apparent photodamage. Adding a C-terminal protein tag to QED1 was found to severely inhibit editing function. QED1 and RARE1, another plastid PPR-DYW editing factor, were discovered to require their DYW motifs for efficient editing. To identify specific residues critical for editing, conserved deaminase residues in each PPR protein were mutagenized. The mutant PPR proteins, when expressed in qed1 or rare1 mutant protoplasts, could not complement the editing defect. Therefore, the DYW motif, and specifically, the deaminase residues, of QED1 and RARE1 are required for editing efficiency.


Variation in enamel development of South African fossil hominids.
Dental tissues provide important insights into aspects of hominid palaeobiology that are otherwise difficult to obtain from studies of the bony skeleton. Tooth enamel is formed by ameloblasts, which demonstrate daily secretory rhythms developing tissue-specific structures known as cross striations, and longer period markings called striae of Retzius. These enamel features were studied in the molars of two well known South African hominid species, Australopithecus africanus and Paranthropus robustus. Using newly developed portable confocal microscopy, we have obtained cross striation periodicities (number of cross striations between adjacent striae) for the largest sample of hominid teeth reported to date. These data indicate a mean periodicity of seven days in these small-bodied hominids. Important differences were observed in the inferred mechanisms of enamel development between these taxa. Ameloblasts maintain high rates of differentiation throughout cervical enamel development in P. robustus but not in A. africanus. In our sample, there were fewer lateral striae of Retzius in P. robustus than in A. africanus. In a molar of P. robustus, lateral enamel formed in a much shorter time than cuspal enamel, and the opposite was observed in two molars of A. africanus. In spite of the greater occlusal area and enamel thickness of the molars of both fossil species compared with modern humans, the total crown formation time of these three fossil molars was shorter than the corresponding tooth type in modern humans. Our results provide support for previous conclusions that molar crown formation time was short in Plio-Pleistocene hominids, and strongly suggest the presence of different mechanisms of amelogenesis, and thus tooth development, in these taxa.


Bulk tank milk somatic cell count as an indicator of the hygiene status of primary milk production.
The objective was to clarify the association between bulk tank milk somatic cell count (BTSCC) and total bacterial count (BTTBC) and coliform bacteria count (BTCBC) in a large set of data based on the currently accepted legal limit of BTSCC=400,000/ml. We analysed the database obtained from one of four laboratories offering routine estimation of microbiological indicators and counts of somatic cells in bulk tank milk samples in the Czech Republic during the year 2003 (74,174; 73,921 and 33,020 records of BTSCC, BTTBC and BTCBC estimations, respectively, in milk from 2,769 suppliers). Raw data of BTSCC (with arithmetic mean 220,000/ml; 95th percentile=502,000/ml; 99th percentile=784,000/ml) indicated that the BTSCC limit was exceeded in 12% of samples. BTSCC did not sufficiently reflect the hygiene status of particular producing herds because correlation coefficients between bulk tank milk somatic cell score (BTSCS) and log BTTBC or log BTCBC were low. Categorization of herds according to the percentage of records exceeding the BTSCC limit gave significantly higher correlation coefficients for the association between this characteristic and log BTTBC or log BTCBC (r=0.84 and r=0.68, respectively). The percentage of records exceeding the BTSCC limit was a useful tool to highlight problem herds kept in inadequate hygienic conditions in primary milk production. Likewise, the value of BTSCS>5 seemed to be a useful tool for the discrimination of problem herds.


Bundled-Care Program for the Prevention of Surgical-Site Infections Following Lower Extremity Total Joint Arthroplasty.
Surgical-site infections (SSIs) are among the most difficult-to-manage complications after lower extremity total joint arthroplasty (TJA). While the rates of most implant-related complications have decreased over time due to improvements in prosthetic materials and surgical techniques, the incidence of periprosthetic joint infections (PJIs) continues to increase. They place a tremendous economic burden on healthcare systems that is projected to reach $1.8 billion by the year 2030. A number of perioperative infection mitigation strategies exist that are often implemented concurrently to minimize the risk of these complications. A multicenter randomized controlled trial is underway to evaluate the efficacy of a bundled care program for the prevention of PJIs in lower extremity TJA. This bundle includes five infection-reduction strategies that are used pre-, peri-, and postoperatively, including: (1) povidone-iodine skin preparation and nasal decolonization; (2) iodine-alcohol surgical prepping solution; (3) iodophor-impregnated incise drapes; (4) forced-air warming blankets; and (5) negative pressure wound therapy for select patients. The aim of this review is to describe these products and their appropriate usage, review the available literature evaluating their use, and compare them with other commercially available products. Based on the available literature, each of these strategies appear to be important components for SSI-prevention protocols. We believe that implementing all five of these mitigation strategies concurrently will lead to a synergistic effect for infection control following lower extremity TJA.


Terahertz beam steering and frequency tuning by using the spatial dispersion of ultrafast laser pulses.
We demonstrate a terahertz (THz) beam steering method using difference frequency generation that is based on the principle of phased array antennas. A strip-line photoconductive antenna was illuminated by two spatially dispersed beams produced from an ultrafast laser. THz radiation with a bandwidth of 65 GHz was generated from the overlapping area of the two beams, between which the frequency difference was approximately constant. We confirmed that the THz beam can be steered by tilting one of the incident pump beams so as to change their relative phase relation. The steering range of the THz beam was 29 degrees when the angle between the incident pump beams was only varied within a range of 0.155 degrees, that is, 187 times less. In addition, by laterally shifting one of the pump beams, the frequency of the THz radiation could be tuned from 0.3 to 1.7 THz. This technique can be applied to high-speed terahertz imaging and spectroscopy systems.


Four Human Cases of Diphyllobothrium nihonkaiense (Eucestoda: Diphyllobothriidae) in China with a Brief Review of Chinese Cases.
We described 4 human infection cases of zoonotic fish-tapeworm, Diphyllobothrium nihonkaiense, identified with morphological and molecular characters and briefly reviewed Chinese cases in consideration of it as an emerging parasitic disease in China. The scolex and mature and gravid proglottids of some cases were seen, a rosette-shaped uterus was observed in the middle of the mature and gravid proglottids, and the diphyllobothriid eggs were yellowish-brown in color and displayed a small knob or abopercular protuberance on the opposite end of a lid-like opening. The average size of the eggs was recorded as 62-67×42-45 μm. The parasitic materials gathered from 4 human cases were morphologically identified as belonging to the genera Diphyllobothrium and Adenocephalus. The phylogenetic analysis based on the nucleotide sequences of cytochrome c oxidase subunit 1 gene of the etiologic agents confirmed that the 4 cases were D. nihonkaiense infection. The finding of 4 additional D. nihonkaiense cases suggests that D. nihonkaiense might be a major causative species of human diphyllobothriasis in China. A combined morphological and molecular analysis is the main method to confirm D. nihonkaiense infection.


[Prevention of venous thrombosis in surgery].
Efficacy and safety of low-molecular weight heparins in preventing postoperative thromboembolism are sustained by randomized trials versus low-doses subcutaneous heparin. There are many discussions about their optimal regimen. Near this effective method of prophylaxis, the very significant role of venous stasis justifies all attempts for increase venous return.


Relative weighting of acoustic information during mating decisions in grasshoppers indicates signatures of sexual selection.
The decision with whom to mate is crucial in determining an individual's fitness and is often based on the evaluation of visual or acoustic displays produced during courtship. Accordingly, the algorithms for evaluating such courtship signals are shaped by sexual selection and should reflect the expected benefits and costs of mating: signals bearing heterospecific features should be rapidly rejected, since mating would produce no fertile offspring, while signals resembling conspecific ones should be weighted proportional to mate quality. We test these hypotheses in females of the grasshopper Chorthippus biguttulus who assess males by their song, which is produced as a sequence of subunits with species and individual specific signatures. We present mixed sequences of subunits with conflicting cues and use a computational model of decision-making to infer how sensory information is weighted and integrated over the song. Consistent with our hypothesis, females do weight sensory cues according to the expected fitness benefits/costs: heterospecific subunits are weighted particularly negatively and lead to a rejection of the male early in the song. Conspecific subunits are weighted moderately, permitting a more complete evaluation of the full song. However, there exists an overall negative bias against mating, possible causes of which are discussed.


Intermittent Capture of the Left Bundle With Permanent His Bundle Pacing: Mechanistic Insights and Implications for an Emerging Field.
We present a case of a patient with elevated His lead capture thresholds and intermittent recruitment of the left bundle. The patient underwent a noninvasive electrophysiology study and was determined to have a left bundle branch block due to postrepolarization refractoriness. The nature of bundle branch block can have important implications for optimal patient selection and device programming in the emerging field of His bundle pacing.


A diagnostic HIV-1 tropism system based on sequence relatedness.
Key clinical studies for HIV coreceptor antagonists have used the phenotyping-based Trofile test. Meanwhile various simpler-to-do genotypic tests have become available that are compatible with standard laboratory equipment and Web-based interpretation tools. However, these systems typically analyze only the most prominent virus sequence in a specimen. We present a new diagnostic HIV tropism test not needing DNA sequencing. The system, XTrack, uses physical properties of DNA duplexes after hybridization of single-stranded HIV-1 env V3 loop probes to the clinical specimen. Resulting "heteroduplexes" possess unique properties driven by sequence relatedness to the reference and resulting in a discrete electrophoretic mobility. A detailed optimization process identified diagnostic probe candidates relating best to a large number of HIV-1 sequences with known tropism. From over 500 V3 sequences representing all main HIV-1 subtypes (Los Alamos database), we obtained a small set of probes to determine the tropism in clinical samples. We found a high concordance with the commercial TrofileES test (84.9%) and the Web-based tool Geno2Pheno (83.0%). Moreover, the new system reveals mixed virus populations, and it was successful on specimens with low virus loads or on provirus from leukocytes. A replicative phenotyping system was used for validation. Our data show that the XTrack test is favorably suitable for routine diagnostics. It detects and dissects mixed virus populations and viral minorities; samples with viral loads (VL) of <200 copies/ml are successfully analyzed. We further expect that the principles of the platform can be adapted also to other sequence-divergent pathogens, such as hepatitis B and C viruses.


Electrochemical current-sensing atomic force microscopy in conductive solutions.
Insulated atomic force microscopy probes carrying gold conductive tips were fabricated and employed as bifunctional force and current sensors in electrolyte solutions under electrochemical potential control. The application of the probes for current-sensing imaging, force and current-distance spectroscopy as well as scanning electrochemical microscopy experiments was demonstrated.


Prognostic significance of constitutive phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase phosphorylation in acute myeloid leukemia.
Acute myeloid leukemia (AML) is a malignant hematopoietic disease with poor clinical course and outcome. There is a constant need for new prognostic factors that could facilitate patient risk stratification. The aim of our research was to determine the phosphorylation levels of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways in leukemic cells, their relation to P-glycoprotein (P-gp) expression/activity and their prognostic significance in adult de novo AML. A total of 118 patients with AML were enrolled in the study. In a multivariate Cox regression analysis we found that P-gp activity and Akt phosphorylation were independent poor prognostic factors of overall survival (OS). In contrast, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) represented a favorable prognostic factor of OS and relapse-free survival (RFS). A negative correlation between P-gp activity and p38 phosphorylation level was found, implying a possible role of this MAPK pathway in P-gp regulation. In addition, we found correlation between Akt and p38 phosphorylation levels, indicative of co-activation of two signaling cascades in AML.


Animal models to investigate the pathogenesis of rheumatic heart disease.
Rheumatic fever (RF) and rheumatic heart disease (RHD) are sequelae of group A streptococcal (GAS) infection. Although an autoimmune process has long been considered to be responsible for the initiation of RF/RHD, it is only in the last few decades that the mechanisms involved in the pathogenesis of the inflammatory condition have been unraveled partly due to experimentation on animal models. RF/RHD is a uniquely human condition and modeling this disease in animals is challenging. Antibody and T cell responses to recombinant GAS M protein (rM) and the subsequent interactions with cardiac tissue have been predominantly investigated using a rat autoimmune valvulitis model. In Lewis rats immunized with rM, the development of hallmark histological features akin to RF/RHD, both in the myocardial and in valvular tissue have been reported, with the generation of heart tissue cross-reactive antibodies and T cells. Recently, a Lewis rat model of Sydenham's chorea and related neuropsychiatric disorders has also been described. Rodent models are very useful for assessing disease mechanisms due to the availability of reagents to precisely determine sequential events following infection with GAS or post-challenge with specific proteins and or carbohydrate preparations from GAS. However, studies of cardiac function are more problematic in such models. In this review, a historical overview of animal models previously used and those that are currently available will be discussed in terms of their usefulness in modeling different aspects of the disease process. Ultimately, cardiologists, microbiologists, immunologists, and physiologists may have to resort to diverse models to investigate different aspects of RF/RHD.


Expression of the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator during chick cardiogenesis is consistent with 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced heart defects.
We examined cardiotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the chick embryo and the cardiac expression of transcription factors, the aryl hydrocarbon receptor (AhR) which binds TCDD, and its dimer partner, the AhR nuclear translocator (Arnt). Chicken eggs were injected with control (triolein) or 1.0 pmol TCDD/g egg prior to incubation and collected on Day 10 when cardiomorphogenesis is complete. Relative to controls, TCDD increased heart wet weight (27.2 +/- 0.5 versus 36.6 +/- 1.3 mg, p < 0.001) and dry weight (2.7 +/- 0.1 versus 3.1 +/- 0.1 mg, p < 0.01), and tended to increase heart myosin content (3.5 +/- 0.6 versus 6.3 +/- 2.5 microg, p < 0.07), suggesting an increase in cardiac muscle mass and edema. Histologic and morphometric analyses revealed that 10/13 TCDD-exposed hearts exhibited enlarged right and left ventricles, thickened ventricular septum, and a thinner left ventricular wall with increased trabeculation, and 4/13 exhibited ventricular septal defects compared to controls (0/23). To evaluate AhR and Arnt expression, untreated chick embryos were collected on Days 2.2, 3, 4, 5, and 8 of incubation, preserved in Bouin's fixative, sectioned, and stained with AhR and Arnt antibodies. The AhR was expressed ubiquitously in cardiac myocytes, while Arnt expression was restricted to myocytes overlying developing septa: atrioventricular canal, outflow tract, and atrial and ventricular septa. Both proteins were absent from endocardium and endocardial-derived mesenchyme. In addition, cardiac expression of an AhR/Arnt target, cytochrome P4501A1, was restricted to myocardium coexpressing AhR and Arnt. Thus, the spatial and temporal expression of AhR and Arnt suggests that the developing myocardium and cardiac septa are potential targets of TCDD-induced teratogenicity, and such targets are also consistent with cardiac hypertrophy and septal defects observed following TCDD exposure.


Early municipal bacteriology in Brighton, Aberdeen and Bristol: blessing or burden?
In contrast to the idea that bacteriology was introduced as a tool for the diagnosis and management of the individual patient, this review highlights the work of the municipal bacteriological laboratory in the United Kingdom to illustrate how bacteriological laboratories were introduced as means to control community epidemic disease. Using the examples of municipal laboratories in Brighton, Bristol and Aberdeen, it shows how public health considerations of community infectious diseases such as diphtheria and typhoid dominated the early development and workload of the municipal laboratory, rather than examination of patients with pathological states of uncertain aetiology. It argues that this public health focus of the Medical Officer of Health limited the range of diagnostic tests carried out in such laboratories for over two decades. The growing number of pathogenic microbes being discovered in the late 19th century appears to have had little impact on the tests being carried out in the municipal laboratory. Municipal bacteriological facilities in three towns, a central municipal laboratory (in Brighton), a central university pathological department (Aberdeen) or a combination of both (Bristol) all provided the same limited set of tests. This restricted set of bacteriological examinations is likely to have diminished the value and status of bacteriology in what should have been a period of increasing scope.


Congenital anomaly of combined tracheal and accessory cardiac bronchus.
The presence of congenital tracheobronchial abnormalities remain rare and have been reported to range from 0.1% to 2% in the literature. The most commonly described abnormalities are the tracheal bronchus and the accessory cardiac bronchus. We present the case of a 67-year-old man presenting for evaluation of interstitial lung disease, on computed tomography found to have presence of both the anomalies; the findings later confirmed on bronchoscopy. We believe this report is important as it adds more descriptive information regarding this unusual presentation, including bronchoscopic and computed tomographic images. We believe that it is imperative that bronchoscopists are cognizant of these congenital abnormalities and their combinations. Inability to properly characterize these abnormalities has a potential leading to unnecessary investigations of these relatively benign entities.


Group size and density effects on physical indices and cell-mediated immunity in two genetic lines of white leghorn layers.
Social stress resulting from varied group sizes with density in caging systems is a common problem that affects bird welfare in the poultry industry in the United States. To examine whether there is a genetic basis for variations in response to group size and density, 2 genetic strains of White Leghorn hens were used in this study: HGPS, a line selected for high group productivity and survivability in multiple-bird cages and DXL (Dekalb XL), a commercial line individually selected for production. Birds from each line were housed in either 4-bird cages (542 cm(2)/bird) or 10-bird cages (434 cm(2)/bird) from 17 to 60 wk of age. Blood samples, BW, and adrenal weight were collected from the birds at 30, 45, and 60 wk of age (n = 12, respectively) after euthanasia. Subsets of T cells (CD4(+) and CD8(+)) were measured by flow cytometry. Hematological parameters were collected from blood smears. Results showed that there were no significant differences for BW, the relative adrenal glands, and the heterophil:lymphocyte ratio between and across lines after the treatments (P > 0.05, respectively). Compared with DXL birds, the HGPS birds had a greater ratio of CD4(+):CD8(+) at 30 and 45 wk of age. There was an age-associated decrease in CD4(+) cells in all groups from 45 to 60 wk of age. However, an age-related decrease in CD8(+) cells from 45 to 60 wk was found in the DXL birds only. The unique changes in T-cell subpopulations and the ratio of CD4(+):CD8(+) may suggest that HGPS birds had a greater cell-mediated immunity than DXL birds. The genetic basis of variations in immunity may correlate with the line-unique ability of birds to cope in social environments and their survivability.


Controlling financial variables--changing prescribing patterns.
Techniques of formulary management, pharmacy and therapeutics committee intervention, and the use of clinical pharmacy services to change prescribing patterns and contain costs in hospital pharmacy departments are reviewed. Methods of using the formulary to contain costs include deletion of generic and therapeutic equivalents, inclusion of therapeutic categories and cost codes, and regular reviews and updates of its contents. Drug monographs for formulary evaluation prepared for the P & T committee should include a comparative review of other drugs in the therapeutic category and a cost impact statement. The P & T committee can help contain costs by developing policies for automatic stop orders and restricted drug use. Clinical pharmacy activities that can result in cost savings include physician education (focused on prescribing), target drug programs, target disease programs, pharmacist participation on TPN and i.v. therapy teams, and patient training programs for home care. A matrix for evaluating cost-containment activities is presented. By tailoring the described methods to departmental personnel resources and hospital needs, the pharmacy can be effective in controlling costs.


[The effect of FII c.1787G>A (prothrombin Belgrade) mutation on prothrombin gene expression in vitro].
The FII c.1787G>A (prothrombin Belgrade) is a novel prothrombotic mutation which leads to impaired inhibition of thrombin by antithrombin (antithrombin resistance). So far, the mechanism of this variant has not been fully elucidated. To investigate the effect of FII c.1787G>A mutation on the prothrombin gene expression, its functional analysis was performed in vitro. By Real-Time PCR, expression levels of FII gene variants were evaluated in Cos-7 cells transiently transfected with c.1787G (wild-type) and c.1787A prothrombin expression vectors, with no differences observed. The relative quantification of prothrombin protein amounts was accomplished by Western blot analysis, also with no differences observed. Therefore, the mechanism of FII c.1787G>A mutation does not alter prothrombin expression profile.


[Monotherapy using gabapentin in epilepsy].
We report a study of 62 patients with partial seizures treated with gabapentin as monotherapy for two years. After two years 78% of the patients were still on the same treatment. In 67.7% of the patients there was more than 50% reduction in major seizures and 11.1% were free of seizures. There was little difference in efficacy and tolerance when the first and second years were compared. We reviewed the data published in the literature, both in clinical trials and open studies. Gabapentin is an effective, well tolerated drug used as monotherapy in newly diagnosed epilepsy.


PhagePhisher: a pipeline for the discovery of covert viral sequences in complex genomic datasets.
Obtaining meaningful viral information from large sequencing datasets presents unique challenges distinct from prokaryotic and eukaryotic sequencing efforts. The difficulties surrounding this issue can be ascribed in part to the genomic plasticity of viruses themselves as well as the scarcity of existing information in genomic databases. The open-source software PhagePhisher (http://www.putonti-lab.com/phagephisher) has been designed as a simple pipeline to extract relevant information from complex and mixed datasets, and will improve the examination of bacteriophages, viruses, and virally related sequences, in a range of environments. Key aspects of the software include speed and ease of use; PhagePhisher can be used with limited operator knowledge of bioinformatics on a standard workstation. As a proof-of-concept, PhagePhisher was successfully implemented with bacteria-virus mixed samples of varying complexity. Furthermore, viral signals within microbial metagenomic datasets were easily and quickly identified by PhagePhisher, including those from prophages as well as lysogenic phages, an important and often neglected aspect of examining phage populations in the environment. PhagePhisher resolves viral-related sequences which may be obscured by or imbedded in bacterial genomes.