Glass-ceramic resin-bonded fixed partial dentures for replacing a single premolar tooth: A prospective investigation with a 4-year follow-up.
Resin-bonded fixed partial dentures (RBFPDs) are a reliable treatment option for the replacement of a single missing tooth. Glass-ceramic may be a promising material for the fabrication of RBFPDs, but clinical verification has been lacking. The purpose of this prospective clinical study was to evaluate the outcomes of glass-ceramic RBFPDs on participants with a single missing premolar. Twenty participants (6 men, 14 women; age range: 20 to 54 years) were treated with 2-retainer RBFPDs. These RBFPDs were made of lithium disilicate glass-ceramic (IPS e.max Press; Ivoclar Vivadent AG) and designed with improved C-shaped retention. These prostheses were evaluated at 6 months, 12 months, and annually thereafter and were classified as survival or failure. Analysis was performed with the Kaplan-Meier analysis (95% confidence interval). Modified United States Public Health Service (USPHS) criteria were used to rate the clinical performance. Parameters assessed were fracture, marginal integrity, marginal discoloration, color of restoration, secondary caries, and abutment mobility. Twenty RBFPDs were provided, 9 in the maxilla and 11 in the mandible. The mean observation time was 49.2 months (minimum 9 months, maximum 53 months). Nineteen RBFPDs were evaluated as having survived during the observation period with some acceptable marginal discoloration, 1 RBFPD had to be replaced because of fracture and secondary caries and was evaluated as a failure. The Kaplan-Meier analysis revealed a survival rate of 95% after a 4-year observation. The glass-ceramic RBFPDs in this study displayed a good survival rate and clinical performance, indicating that glass-ceramic RBFPDs might be a promising approach for the short-term replacement of a single premolar. However, further investigations are needed to determine the long-term outcome.


Home mechanical ventilation: quality of life patterns after six months of treatment.
It has been shown that home mechanical ventilation improves quality of life, but it has not been widely studied which particular patient groups benefit the most from starting this type of therapy. The purpose of this prospective observational study was to evaluate quality of life change patterns 6 months after initiation of home mechanical ventilation in patients suffering from chronic respiratory failure using patient reported outcomes. We enrolled 74 chronic respiratory failure patients starting invasive or noninvasive home mechanical ventilation through the Semmelweis University Home Mechanical Ventilation Program. Quality of life was evaluated at baseline and at 6 months after initiation of home mechanical ventilation using the Severe Respiratory Insufficiency Questionnaire. Overall quality of life showed 10.5% improvement 6 months after initiation of home mechanical ventilation (p < 0.001). The greatest improvement was observed in Respiratory complaint (20.4%, p = 0.015), Sleep and attendant symptoms (19.3%, p < 0.001), and Anxiety related subscales (14.4%, p < 0.001). Interface (invasive versus noninvasive ventilation) was not associated with improvement in quality of life (p = 0.660). Severely impaired patients showed the greatest improvement (CC = -0.328, p < 0.001). Initial diagnosis contributed to the observed change (p = 0.025), with chronic obstructive pulmonary disease and obesity hypoventilation syndrome patients showing the greatest improvement, while amyotrophic lateral sclerosis patients showed no improvement in quality of life. We found that patients who were started on long term ventilation in an acute setting, required oxygen supplementation and had low baseline quality of life, showed the most improvement during the six-month study period. Our study highlights the profound effect of home mechanical ventilation on quality of life in chronic respiratory failure patients that is indifferent of ventilation interface but is dependent on initial diagnosis and some baseline characteristics, like acute initiation, oxygen supplementation need and baseline quality of life. This study was approved by and registered at the ethics committee of Semmelweis University (SE TUKEB 251/2017; 20th of December, 2017).


Toxicological Impacts of TiO2 Nanoparticles on Growth, Photosynthesis Pigments, and Protein and Lipid Content of the Marine Microalga Tetraselmis Suecica.
Regarding the widespread use of titanium dioxide nanoparticles (TiO2NPs) in industry, many concerns have been raised about the risks of their potential release into aquatic ecosystems. Among the marine primary producers, Tetraselmis suecica is an ecologically important microalgae species used also as live feed in the shrimp culture industry. In the present study, the impacts of TiO2NPs on growth performance, photosynthetic pigments, lipid and protein content and its interaction with the cells of T. suecica were assessed. Based on the preliminary tests and OECD suggestion, concentrations of 5, 10, 50, 100, 200 and 400 mg/L TiO2NPs were applied to algal cells for 10 days. With increasing concentration, a decrease in T. suecica cell density was observed each day. TiO2NPs induced a half-maximal inhibitory concentration (IC50) of 106.26 mg/L on algal cells on the 3rd day. Chlorophyll a and b contents of the microalga decreased up to 56.08% and 52.74%, respectively following the exposure to TiO2NPs at 400 mg/L. TiO2NPs also decreased the algal contents of protein and lipid up to 7.21% and 50.64%, respectively at the highest concentration. Based on FTIR, FESEM with EDS and mapping analyses, the interaction of TiO2NPs with the T. suecica cells was revealed. The stocks of T. suecica could be damaged by the toxic effects of the released TiO2NPs affecting their application as live feed in mariculture.


Patient Characteristics Associated with Hospital Admission or Antiarrhythmic Medication Changes After Emergency Department Evaluation of Supraventricular Tachycardia.
Supraventricular tachycardia (SVT) is a relatively frequent diagnosis in the pediatric emergency department (ED). However, there are no consensus guidelines for ED disposition, and there are limited data on ED outcomes. Better understanding of those who are admitted or have antiarrhythmic medication changes may avoid potentially unnecessary transfers or admissions. Our objective was to identify patient factors associated with discharge from the emergency department without medication initiation or modification after management of SVT in the pediatric ED. A retrospective review of children aged 0-18 years seen in the emergency department for SVT was conducted using electronic medical record data over a ten-year period at a single academic tertiary children's hospital. Patients with congenital cardiac disease or prior cardiac surgeries were excluded. Multivariable logistic regression analysis was used to determine association between patient factors of interest and the primary outcome of admission and secondary outcome of change to antiarrhythmic medications. We analyzed 197 patients encounters. The mean age was 7 years. Of these 104 (52.8%) were admitted to the hospital or discharged with antiarrhythmic medication changes. This primary outcome was associated with younger age (aOR 0.77, 95% CI 0.67-0.86), history of pre-excitation (aOR 5.82, 95% CI 2.01-18.8), intercurrent illness (aOR 3.75, 95% CI 1.27-12.1), number of adenosine doses prior to arrival (aOR 5.45, 95% CI 1.55-22.3), and in-person cardiology consultation (aOR 6.42, 95% CI 2.43-19.4). Nearly half of children treated in a pediatric ED for SVT are discharged without changes in medications. We identified patient factors associated with hospital admission or antiarrhythmic medication changes. These factors represent high value care and can be assessed when considering transfer from a referring facility. Risk stratification using these patient characteristics may reduce potentially avoidable transfers and admissions.


Evaluation of the intranasal route for porcine reproductive and respiratory disease modified-live virus vaccination.
In pigs, modified live virus (MLV) vaccines against porcine reproductive and respiratory syndrome virus (PRRSV) are commonly used and administered by intramuscular (IM) injection. In contrast, PRRSV, as a primary respiratory pathogen, is mainly transmitted via the intranasal (IN) route. The objective of this study was to evaluate the efficacy of a commonly used commercial PRRSV MLV delivered IN compared to the IM route. Fifty-four pigs were divided into five treatment groups. All vaccinated groups received the same MLV vaccine but administered via different routes. Group IN-JET-VAC was vaccinated with an automated high pressure prototype nasal jet device (IN-JET-VAC, n = 12), group IN-MAD-VAC was vaccinated with a mucosal atomization device (IN-MAD-VAC, n = 12), group IM-VAC was vaccinated intramuscularly (IM-VAC; n = 12) according to label instructions, while the NEG-CONTROL (n = 6) and the POS-CONTROL (n = 12) groups were both unvaccinated. At 28 days post vaccination all vaccinated groups and the POS-CONTROL pigs were challenged with a pathogenic US PRRSV isolate. Blood and nasal swabs were collected at regular intervals, and all pigs were necropsied at day 10 post challenge (dpc) when gross and microscopic lung lesions were assessed. Prior to challenge most vaccinated pigs had seroconverted to PRRSV. Clinical signs (fever, inappetence) were most obvious in the POS-CONTROL group from dpc 7 onwards. The vaccinated groups were not different for PRRSV viremia, seroconversion, or average daily weight gain. However, IN-JET-VAC and IN-MAD-VAC had significantly higher neutralizing antibody levels against the vaccine virus at challenge. Comparable vaccine responses were obtained in IN and IM vaccinated pigs, suggesting the intranasal administration route as an alternative option for PRRSV vaccination.


Gain-of-function TLR7 and loss-of-function A20 gene variants identify a novel pathway for Mendelian lupus and lupus nephritis.
Systemic lupus erythematosus (SLE) is a chronic and inflammatory autoimmune disease of unknown origin that may cause kidney disease, i.e. lupus nephritis (LN). Within a wider trend towards an expanding field of genetic causes of kidney disease, two recent reports have emphasized the role of Mendelian autoimmune disorders in causing LN both in children and in young adults. Loss-of-function (LOF) variants of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and gain of function (GOF) variants of Toll-like receptor 7 (TLR7) cause SLE and LN, respectively. Interestingly, both genes regulate the same signaling route, as A20, the protein encoded by TNFAIP3, inhibits nuclear factor ĸB (NF-ĸB) activation while TLR7 promoted NF-ĸB activation. Moreover, TNFAIP3 and TLR7 variants are relatively frequent, potentially contributing to polygenic risk for LN. Finally, they both may be expressed by kidney cells, potentially contributing to the severity of kidney injury in persons who have already developed autoimmunity. The fact that both genes regulate the same pathway may lead to novel therapeutic approaches targeting the shared molecular pathway.


Endoderm Jagged induces liver and pancreas duct lineage in zebrafish.
Liver duct paucity is characteristic of children born with Alagille Syndrome (ALGS), a disease associated with JAGGED1 mutations. Here, we report that zebrafish embryos with compound homozygous mutations in two Notch ligand genes, jagged1b (jag1b) and jagged2b (jag2b) exhibit a complete loss of canonical Notch activity and duct cells within the liver and exocrine pancreas, whereas hepatocyte and acinar pancreas development is not affected. Further, animal chimera studies demonstrate that wild-type endoderm cells within the liver and pancreas can rescue Notch activity and duct lineage specification in adjacent cells lacking jag1b and jag2b expression. We conclude that these two Notch ligands are directly and solely responsible for all duct lineage specification in these organs in zebrafish. Our study uncovers genes required for lineage specification of the intrahepatopancreatic duct cells, challenges the role of duct cells as progenitors, and suggests a genetic mechanism for ALGS ductal paucity.The hepatopancreatic duct cells connect liver hepatocytes and pancreatic acinar cells to the intestine, but the mechanism for their lineage specification is unclear. Here, the authors reveal that Notch ligands Jagged1b and Jagged2b induce duct cell lineage in the liver and pancreas of the zebrafish.


Parechovirus infection in infants: Evidence-based parental counselling for paediatricians.
Human parechovirus (HPeV) is an increasingly recognised cause of severe illness and central nervous system infection in infants. Medium- to long-term neurodevelopmental outcomes post-HPeV infection remain unknown. This study aims to assess neurodevelopmental outcomes for children hospitalised as infants with HPeV infection in their second and third years of life. This prospective cohort study followed children hospitalised with HPeV in Brisbane, Queensland during the 2017/2018 outbreak. Serial application of Ages and Stages Questionnaire (ASQ) was used to assess developmental progress in the second and third years of life. Data from clinical follow-up, audiology and neuroradiology were included. In the second year of life, 63% (n = 29) of children showed some or significant concerns for developmental delay. This had largely been ameliorated by the third year of life when only 30% (n = 14) reported developmental concerns. Prematurity and apnoeas were associated with developmental concerns at 27-36 months of age. Communication was the most common domain of concern. The majority of infants hospitalised with HPeV infection in 2017-2018 showed normalisation of developmental progress by 27-36 months of age. Further investigation into more subtle neurological impairments in later childhood is required. These results can help guide clinicians in counselling parents during the acute illness and in planning appropriate follow-up.


Cancer gene analysis of liquid-based cytology specimens using next-generation sequencing: A technical report of bimodal DNA- and RNA-based panel application.
As liquid-based cytology (LBC) specimens harbor high-quality DNA, genomic analysis using LBC specimens is beneficial for integrative diagnosis. This study aimed to clarify the feasibility of LBC specimens for a bimodal application of DNA- and RNA-based next-generation sequencing (NGS) panels. LBC specimens were prepared from cultured human cancer HEC59 cells using commercially available fixatives (Cellprep, CytoRich Red, and SurePath solutions), and were subjected to NGS for a feasibility study. Clinical LBC specimens of thyroid and salivary gland tumors were prepared using CytoRich Red solution. After DNA and RNA extraction, NGS analyses were performed in a single run using combined DNA- and RNA-based custom-made cancer panels for the detection of gene mutations and fusions. High-quality DNA and RNA were obtained, and the expected gene mutations and fusions were detected in HEC59 cells using all types of LBC fixatives. Most available clinical cases (18 out of 20) exhibited pathogenic gene mutations (15 cases) and fusion genes (3 cases) using the bimodal DNA- and RNA-based panels. Overall, 18 cases (90%) showed oncogenic mutations or fusion genes of diagnostic values. Simultaneous application of bimodal DNA- and RNA-based gene panels was useful in NGS analysis using residual LBC specimens for integrative diagnosis. Residual LBC specimens for genomic analysis, including fusion gene analysis, are particularly useful for obtaining genomic information before surgical resection.


[Surgical treatment of epispadias].
To analyse the surgical treatment of 124 cases of epispadias (incomplete 27 cases, complete 21 and complex 76). Leadbetter's operation was used for anti-incontinence. Urethral tightening was used in 4 cases of complete female epispadias. Penile straightening was adopted for incomplete epispadias and penile lengthening for complete and complex male epispadias. In 97 cases of urinary incontinence, complete continence was achieved in 73. The orthopedic effects of external genitals were satisfactory.


Vitalism, Holism, and Metaphorical Dynamics of Hans Spemann's "Organizer" in the Interwar Period.
This paper aims to provide a fresh historical perspective on the debates on vitalism and holism in Germany by analyzing the work of the zoologist Hans Spemann (1869-1941) in the interwar period. Following up previous historical studies, it takes the controversial question about Spemann's affinity to vitalistic approaches as a starting point. The focus is on Spemann's holistic research style, and on the shifting meanings of Spemann's concept of an organizer. It is argued that the organizer concept unfolded multiple layers of meanings (biological, philosophical, and popular) during the 1920s and early 1930s. A detailed analysis of the metaphorical dynamics in Spemann's writings sheds light on the subtle vitalistic connotations of his experimental work. How Spemann's work was received by contemporary scientists and philosophers is analyzed briefly, and Spemann's holism is explored in the broader historical context of the various issues about reductionism and holism and related methodological questions that were so prominently discussed not only in Germany in the 1920s.


In-vivo measurement of spin lattice relaxation time (T1) of liver in healthy volunteers: the effects of age, sex and oral contraceptive usage.
Magnetic resonance imaging of 81 healthy adult volunteers has been undertaken to establish the normal range of liver spin lattice relaxation time (T1) at 0.08 tesla. The influence of age, sex and oral contraceptive usage has been assessed. Liver T1 decreased with age. The mean liver T1 of subjects under 40 years of age was significantly longer than that of older subjects. A wider range of T1 values was observed in the younger age group. No difference in T1 was found between males and females who were not oral contraceptive users. The mean liver T1 of females who were taking the pill was significantly longer than that of females of similar age who were not oral contraceptive users. Serial examinations of eight oral contraceptive users showed that mean liver T1 values were significantly longer in the 3 weeks during which they were taking the pill than during the week off the pill.


Dietary similarity and foraging range of two seed-harvester ants during resource fluctuations.
Diets of desert seed-harvester ants Veromessor pergandei and Pogonomyrmex rugosus were studied for 3 years at two habitats where they are common and sympatric. Diets of the two species were similar, consisting mainly (87% of 23,913 seeds) of three annual plant species (Schismus arabicus, Plantago insularis, and Pectocarya recurvata). Diets converged following a drought in Winter/Spring 1984 which reduced seed production during this time. Foraging range of P. rugosus almost doubled following the drought while foraging range of V. pergandei remained constant. Neither ant species move their nests once established rendering them effectively sessile granivores. This limits the dietary options of a given colony and may explain interspecific dietary convergence.


Spinal cord necrosis after intrathecal injection of methylene blue.
A 59 year old man had 6 ml of unbuffered methylene blue injected into the lumbar theca in an attempt to localise the source of cerebrospinal fluid rhinorrhoea. After injection of the dye he became shocked, and within the next few days he developed a mild paraparesis which subsequently progressed to a total paraplegia. The distribution of the spinal cord damage found at necropsy, eight and a half years after injection of the dye, is described and its relationship to the clinical picture discussed.


Role of excitation-contraction coupling in muscle fatigue.
The force produced by muscles declines during prolonged activity and this decline arises largely from processes within the muscle. At a cellular level the reduced force could be caused by: (a) reduced intracellular calcium release during activity; (b) reduced sensitivity of the myofilaments to calcium; or (c) reduced maximal force development. Experiments involving intracellular calcium measurements in isolated single fibres show that all 3 of the above contribute to the decline of force during fatigue. Metabolic changes associated with fatigue are probably involved in each of the 3 factors. Thus the accumulation of phosphate and protons which occur during fatigue cause a reduction in calcium sensitivity and a decline in maximal force. The cause of the reduced intracellular calcium during contractions in fatigue is less clear. During prolonged tetani the conduction of the action potential in the T-tubules appears to fail leading to reduced intracellular calcium in the central part of the muscle fibre. However, during repeated tetani there is a uniform decline of intracellular calcium across the fibre and this remains one of the least understood processes which contribute to fatigue.


Spinal cord injury--a systems approach: prevention, emergency medical services, and emergency room management.
Spinal cord injury is considered a catastrophic disease because of the significant morbidity, mortality, and costs not only in fiscal terms but in social terms. There are approximately ten thousand new spinal cord injuries per year with the national prevalence estimated at between three and five hundred thousand Americans. These authors advocate a systems approach for the comprehensive management of these devastating injuries. In all phases of care for the spinal-cord-injured person, the key is a team approach and a commitment to an optimal patient care program that can result in minimizing patient morbidity, mortality, and the cost of care as well as making neurologic function maximal.


Differential kinase systems are involved in the rapidly turning over phosphorylation of prominent nuclear proteins.
The activity of endogenous nuclear protein kinases has been probed in an vitro assay system of isolated nuclei from Chironomus salivary gland cells. The phosphorylation of a set of seven prominent rapidly phosphorylated non-histone proteins and of histones H3, H2A and H4 was analyzed using ATP or GTP as phosphoryl donor and heparin as protein kinase effector. The core histones H2A and H3 both incorporate 32P from [gamma-32P]ATP as well as from [gamma-32P]GTP but their phosphorylation is differentially affected by heparin. The phosphorylation of H2A is blocked by heparin while that of H3 is even stimulated in the presence of heparin when ATP is used as phosphate donor. H4 is unable to incorporate phosphate groups from GTP but its ATP-based phosphorylation is heparin sensitive. Of the non-histone protein kinase substrates, we could only detect two, the 44-kDa and 115-kDa proteins, which are heparin sensitive with either ATP or GTP and, thus, strictly meet the criteria for casein kinase type II-specific phosphorylation. The investigated histones and non-histone proteins can be grouped into three broad categories on the basis of their phosphorylation properties. (A) Proteins very likely affected by casein kinase NII. (B) Proteins phosphorylated by strictly ATP-specific protein kinases. (C) Proteins phosphorylated by ATP as well as GTP utilizing protein kinase(s) other than casein NII. Category B proteins can be subdivided into proteins phosphorylated in a heparin-resistant (B1) and heparin-sensitive (B2) manner. The phosphorylation of category C proteins may be heparin sensitive with ATP only (C1), heparin sensitive with GTP only (C2), heparin insensitive with both ATP and GTP (C3) or stimulated by heparin (C4).


Using forest health monitoring data to integrate above and below ground carbon information.
The national Forest Health Monitoring (FHM) program conducted a remeasurement study in 1999 to evaluate the usefulness and feasibility of collecting data needed for investigating carbon budgets in forests. This study indicated that FHM data are adequate for detecting a 20% change over 10 years (2% change per year) in percent total carbon and carbon content (MgC/ha) when sampling by horizon, with greater than 80% probability that a change in carbon content will be determined when a change has truly occurred (P < or = 0.33). The data were also useful in producing estimates of forest floor and soil carbon stocks by depth that were somewhat lower than literature values used for comparison. The scale at which the data were collected lends itself to producing standing stock estimates needed for carbon budget development and carbon cycle modeling. The availability of site-specific forest mensuration data enables the exploration of above ground and below ground linkages.


Beautiful Claws of a Tiny Water Bear: a Review and Proposal for Claw Configuration.
Tardigrades in the genus Milnesium have complex double claws on each leg, which consist of two slender primary branches and two basal secondary branches. The latter usually have two or three hooks. For more than a century, taxonomists have had great difficulties evaluating the claw variation in species identification in Milnesium. This review explains the complicated story and proposes a new notation system for Milnesium claw configuration with a discussion about anterior-posterior axes on tardigrade legs.


Mini-Review of Published Reports on Coccidioidomycosis in China.
Coccidioidomycosis is a deep mycotic infection endemic to Americas. Although it has also been reported to occur in non-endemic areas, it has rarely been reported in China. We reviewed the literature on case reports of coccidioidomycosis in China from 1958 to 2015. A total of 30 cases were reported from 11 provinces in China, and 23 (76.7%) cases were men, and 23 (76.7%) were in 30-60 years old. Twenty-seven (90.0%) cases were reported from southern China. Twenty-four (80.0%) cases had no history of exposure in endemic areas. Three cases were immunosuppressed, four cases had chronic disease, and 23 cases (76.7 %) were otherwise healthy. Twenty cases (66.6%) had related lung infection, six had skin infection, three cases were in lymph node, and one in the cornea, one in the bone and joint, and three had systemic disseminated infection. All of the 30 cases were diagnosis upon finding spherules in histological examination. Interestingly, 12 (40.0%) patients underwent surgery and removed the focus of infection because they were misdiagnosed or suspected of tumor or cancer previously. Fifteen cases (50.0%) were treated with amphotericin B, fluconazole, clotrimazole or ketoconazole. Diagnosis of coccidioidomycosis is complex, and misdiagnosis can occur easily in non-epidemic areas such as China.


Definition of a third VLR gene in hagfish.
Jawless vertebrates (cyclostomes) have an alternative adaptive immune system in which lymphocytes somatically diversify their variable lymphocyte receptors (VLR) through recombinatorial use of leucine-rich repeat cassettes during VLR gene assembly. Three types of these anticipatory receptors in lampreys (VLRA, VLRB, and VLRC) are expressed by separate lymphocyte lineages. However, only two VLR genes (VLRA and VLRB) have been found in hagfish. Here we have identified a third hagfish VLR, which undergoes somatic assembly to generate sufficient diversity to encode a large repertoire of anticipatory receptors. Sequence analysis, structural comparison, and phylogenetic analysis indicate that the unique hagfish VLR is the counterpart of lamprey VLRA and the previously identified hagfish "VLRA" is the lamprey VLRC counterpart. The demonstration of three orthologous VLR genes in both lampreys and hagfish suggests that this anticipatory receptor system evolved in a common ancestor of the two cyclostome lineages around 480 Mya.


Amyloid-like (Congophilic) neurofibrillary tangles do not react with neurofilament antisera in Alzheimer's cerebral cortex.
The immunohistological properties of Alzheimer's neurofibrillary tangles (NFT) were studied by immunofluorescence with neurofilament (NF) antisera and with antiserum raised to paired helical filaments (PHF) in NFT preparations, brain smears, and cryostat sections. NFT decorated by NF antisera were Congo red-negative. Conversely, PHF antisera stained Congo red-positive NFT but failed to decorate NF-positive NFT. It is concluded that NF do not cross react with typical NFT, i.e., NFT displaying amyloid-like birefringence, under the conditions reported in this study.


Toll-like receptor signalling and their therapeutic targeting in colorectal cancer.
Intestinal homeostasis is dependent on the proper host/microbiota interaction via pattern recognition receptors. Toll-like receptors are a specialised group of membrane receptors which detect pathogen-associated conserved structures. They are present in the intestinal tract and are required for intestinal homeostasis. Dysregulation in the Toll-like receptor signalling can conceivably result in a dysregulated immune response which could contribute to major intestinal pathologies including colorectal cancer. Evidence for the role of microbiota and toll-like receptors in colorectal cancer is emerging. In this report the evidence for the contribution of toll-like receptors to the pathogenesis of colorectal cancer; potential mechanisms affecting toll-like receptor signalling; and their therapeutic targeting in colorectal cancer are reviewed.


[A study of Chlamydia trachomatis infection in gynecological outpatients--direct specimen test and chlamydial IgG antibodies].
Among 226 outpatients, 30(13.3%) harboured Chlamydia trachomatis in the cervix. C. trachomatis was found in 15.1% of the patients with lower genital tract infection, 8.0% of pregnant women, 0.0% of sterile women, 14.3% of patients with pelvic inflammation and 88.9% of sexual partners respectively. The frequency of C.trachomatis infection in those 50 years old or more was 0.0%. One hundred and sixty-six women were also found to have titers of serum antibody to C.trachomatis. Serum IgG antibodies were found in 64 of 166(38.6%). Serum IgG antibodies were positive in 66.7% of the Chlamydia-positive women (20/30 subjects), whereas the positive rate was 31.0% in the Chlamydia-negative women (39/126 cases). In 40.0% of chlamydia positive patients, there was seen a significant rise in the number of paired sera. For C. trachomatis infection treatment with minocycline 100mg p.o. twice a day was effective (100%).


The Role of Neonatal Gr-1+ Myeloid Cells in a Murine Model of Rhesus-Rotavirus-Induced Biliary Atresia.
Activation of innate immunity together with cholangiocyte damage occurs in biliary atresia (BA). However, detailed information on the inflammatory cells involved is lacking. This study investigates both the pathophysiology of CD11b+Gr-1+ cells in a mouse model of BA and their presence in BA patients. CD11b+Gr-1+ cells were targeted by an anti-Ly6G antibody in murine BA induced by inoculation with rhesus rotavirus. Expression of the Ly6G homolog CD177+ was examined in biopsies from BA patients. The symptoms of BA were ameliorated, and survival was prolonged in those mice receiving 5 to 10 μg of antibody per mouse every 3 days for four times compared with the mice treated with virus alone. However, the mice later developed chronic BA with persistent low body weight and jaundice. Hepatic inflammatory cells were reduced compared with acute BA. Blockade of extrahepatic bile ducts occurred, whereas intrahepatic ductules were partially preserved, and a progressive increase in liver fibrosis was observed. High levels of CD11b+Gr-1+ cells were present in these mice. The administration of an anti-Ly6G antibody again in those chronic BA mice reduced jaundice and restored body weight. In BA patients CD177+ cells were highly expressed in the liver. Our data suggest that the chronic mouse BA model shares key characteristics with clinical BA and indicates the importance of CD11b+Gr-1+ cells in the initiation and progression of BA.


Bilateral eyelid swelling attributable to lymphosarcoma in a horse.
Bilateral swelling of upper and lower eyelids was caused by lymphocytic infiltration in an 8-year-old Thoroughbred mare. The condition worsened with pregnancy and became associated with subcutaneous dissemination of lymphosarcoma at distant sites.


Complications related to bone augmentation procedures of localized defects in the alveolar ridge. A retrospective clinical study.
This retrospective clinical study aims to evaluate complications after augmentation of localized bone defects of the alveolar ridge. From standardized registrations, the following complications related to bone augmentation procedures were recorded: soft tissue dehiscence, infection, sensory disturbance, additional augmentation procedures needed, and early implant failure. A total of 223 patients (132 women, 91 men; mean age 23.5 years; range 17-65 years) with 331 bone defects had bone augmentation performed into which 350 implants were placed. Soft tissue dehiscence occurred in 1.7 % after GBR procedures, 25.9 % after staged horizontal ridge augmentation, and 18.2 % after staged vertical ridge augmentation. Infections were diagnosed in 2 % after GBR procedures, 12.5 % after sinus floor elevation (SFE) (transcrestal technique), 5 % after staged SFE, 11 % after staged horizontal ridge augmentation, and 9 % after staged vertical ridge augmentation. Additional augmentation procedures were needed in 2 % after GBR procedures, 37 % after staged horizontal ridge augmentation, and 9 % after staged vertical ridge augmentation. A total of six early implant failures occurred (1.7 %), four after GBR procedures (1.6 %), and two (12 %) after staged vertical ridge augmentation. Predictable methods exist to augment localized defects in the alveolar ridge, as documented by low complication rates and high early implant survival rates.


TET2 promotes IL-1β expression in J774.1 cell through TLR4/MAPK signaling pathway with demethylation of TAB2 promoter.
Interleukin (IL)-1β produced by macrophages plays an important role in inflammation development. However, the underlying mechanism in epigenetic regulation of IL-1β production is not fully addressed. Though DNA methylcytosine dioxygenase ten-eleven translocation 2 (TET2) is known to be involved in the regulation of inflammatory factors by oxidizing 5-methylcytosine (5mC), the underlying molecular mechanism is largely unknown. In this study, we found that the expression of both IL-1β and TET2 is upregulated by lipopolysaccharide (LPS)-stimulated mononuclear macrophage. We then knocked down TET2 in mouse macrophagelike cell line (J774.1) and found that LPS-induced IL-1β is also downregulated. In addition, LPS-stimulated phosphorylation of the mitogen-activated protein kinase (MAPK) signaling pathway and intracellular effectors of the toll-like receptor 4 (TLR4) signaling pathway were also suppressed in TET2-knockdown cells. The methylation status in the promoter regions of myeloid differentiation primary response gene (MyD)88 and TAK1 binding protein 2 (TAB2) were estimated by bisulfite polymerase chain reaction. Compared with that of the control, the 5mC level on the TAB2 promoter is downregulated in the LPS-stimulated cells which can be reversed by TET2-knockdown. These findings altogether suggest that LPS-upregulated TET2 enhances IL-1β expression through demethylating the promoter region of TAB2, the key member of the TLR4/MAPK signaling pathway, a previously unreported molecular mechanism in TET2-regulated expression of inflammatory factors.


Perception of three-dimensional structure from motion in monkey and man.
Information on motion is important for the determination of the three-dimensional (3-D) structure of the environment for both human and non-human primates. For example, if a person were to close one eye and look at an evenly illuminated, irregularly shaped object, he would be unlikely to guess its shape correctly. But if the object is moved about, the correct shape immediately becomes apparent. Little is known about how the primate visual system actually does this, although various theories have been proposed. We have developed novel, highly controlled motion stimuli to use with psychophysical and physiological techniques to study how 3-D structure is obtained from motion. We show that the Rhesus monkey can detect 3-D structure from motion in the same way as human subjects. Furthermore, the dependence of both species on certain parameters of the display shows that information is integrated both spatially and temporally for this higher visual function.


Evaluation of onsite sewage treatment and disposal systems in shallow karst terrain.
Two conventional onsite sewage treatment and disposal systems (OSTDSs) at Manatee Springs State Park, Florida, USA, were studied to assess their impact on groundwater quality in a shallow karst environment. Sulfur hexafluoride (SF6) and fluorescein were used as tracers to establish connections between the drainfields and monitoring wells. Elevated nutrients were found in all wells where significant concentrations of both tracers were observed, with the mean of the highest nitrate (NO3) concentration observed at each well being 47.8+/-14.9 (n=11) mg/L NO3-N. The most elevated nutrient concentrations were found directly in the flow path of the effluent. Fecal coliform densities above 10 colony-forming units (cfu)/100 mL were observed in wells with the most rapid connection to the drainfield. The proximity and connectivity of the 0.4-4m thick sandy surficial soils and the underlying karst aquifer allow rapid contaminant transport and limit the ability of conventional OSTDSs to attenuate NO3.


Vitamin D status is inversely associated with anemia and serum erythropoietin during pregnancy.
Vitamin D and iron deficiencies frequently co-exist. It is now appreciated that mechanistic interactions between iron and vitamin D metabolism may underlie these associations. We examined interrelations between iron and vitamin D status and their regulatory hormones in pregnant adolescents, who are a group at risk of both suboptimal vitamin D and suboptimal iron status. The trial was a prospective longitudinal study of 158 pregnant adolescents (aged ≤18 y). Maternal circulating biomarkers of vitamin D and iron were determined at midgestation (∼25 wk) and delivery (∼40 wk). Linear regression was used to assess associations between vitamin D and iron status indicators. Bivariate and multivariate logistic regressions were used to generate the OR of anemia as a function of vitamin D status. A mediation analysis was performed to examine direct and indirect relations between vitamin D status, hemoglobin, and erythropoietin in maternal serum. Maternal 25-hydroxyvitamin D [25(OH)D] was positively associated with maternal hemoglobin at both midgestation and at delivery (P < 0.01 for both). After adjustment for age at enrollment and race, the odds of anemia at delivery was 8 times greater in adolescents with delivery 25(OH)D concentrations <50 nmol/L than in those with 25(OH)D concentrations ≥50 nmol/L (P <0.001). Maternal 25(OH)D was inversely associated with erythropoietin at both midgestation (P <0.05) and delivery (P <0.001). The significant relation observed between 25(OH)D and hemoglobin could be explained by a direct relation between 25(OH)D and hemoglobin and an indirect relation that was mediated by erythropoietin. In this group of pregnant adolescents, suboptimal vitamin D status was associated with increased risk of iron insufficiency and vice versa. These findings emphasize the need for screening for multiple nutrient deficiencies during pregnancy and greater attention to overlapping metabolic pathways when selecting prenatal supplementation regimens.


Cutaneous toxicities of antiretroviral therapy for HIV: part I. Lipodystrophy syndrome, nucleoside reverse transcriptase inhibitors, and protease inhibitors.
Antiretroviral medications for the treatment of HIV are common drugs with diverse and frequent skin manifestations. Multiple new cutaneous effects have been recognized in the past decade. Dermatologists play an important role in accurately diagnosing and managing the cutaneous toxicities of these medications, thereby ensuring that a patient has as many therapeutic options as possible for life-long viral suppression. Part I of this two-part series on the cutaneous adverse effects of antiretroviral medications will discuss HIV-associated lipodystrophy syndrome, which can be seen as a result of many antiretroviral medications for HIV, and the specific cutaneous effects of the nucleoside reverse transcriptase inhibitors and protease inhibitors.


Edema associated with long-term valproate therapy.
Scattered reports of facial and limb edema have been reported, predominantly in the context of valproate (VPA)-induced hepatic injury. We report seven patients with edema associated with long-term VPA therapy in the absence of hepatic disease.


A case study of a real-time internet of things system for site-specific potato crop management in El-Salhia Area-Egypt.
The site-specific management is the technology that considers the natural variability within the same field of factors related to crop growth to improve its management practices such that the agricultural treatments are varied for field's small production zones saving resources and environment, and improving crop quality and size. Since site-specific decisions are not far from the Fourth Industrial Revolution and the concept of processes automation, this work addresses improving the process of spatial variability analysis and thus supporting management decisions by developing a system-entitled EGYPADS-based on the Internet of Things and its enabling technologies. EGYPADS automates data collection, zones delineation according to their land suitability evaluation, and maps generation. The paper addresses a case study of potato crop in a specific area in Egypt, El-Salhia, in which eighty-five sites were chosen as main dataset for the modeling process during different stages of crop growth. Three management zones were recognized of the selected field based on the differentiation in their land suitability characteristics, representing about 5%, 65%, and 30% of the total area, respectively. The structure, screens, and services of EGYPADS are described in this paper. EGYPADS offered services include: management zones delineation using absolute and virtual coordinates, Land Suitability Assessment (LSA), data entry from field in real-time as well as from excel sheets, saving maps in suitable format for variable rate application, real-time and historical data processing, centralized management, and flexible formulation of events and related actions. The implementation of EGYPADS was verified. The system dynamically produces non-contiguous isobands, each representing a specific range of parameter values, and can be properly exported for use by other programs or smart machinery. It was proven that EGYPADS supports more than one land with different geometry, area, location, and number of nodes. EGYPADS was compared with the traditional LSA method, and was found to produce similar management zones.


Effect of diethylnitrosamine on prostaglandin E and lipid peroxidation levels in rat's liver, lung and renal tissue.
We have investigated the generation of a prooxidant state and effect on prostaglandin E (PGE) levels after administration of diethylnitrosamine (DENA) to rats. Lipid peroxides were assayed by monitoring thiobarbituric acid (TBA) a reactive material. PGE--like activity was assayed by using bioassay procedure. Our results demonstrate that increased lipid peroxide and decreased PGE levels were found in a dose dependent manner in DENA injected groups when compared to control groups. According to these findings, it is suggested that there is a negative correlation between carcinogenic DENA induced lipid peroxidation and PGE in rat's liver, lung, and renal tissue.


Increased interleukin-2 receptor affinity in normal HLA A1 B8 DR3 subjects.
Twenty-two subjects (11 HLA A1 B8 DR3, 11 non-A1 B8 DR3) were tested for the capacity of their lymphocytes to express Tac molecules and interleukin-2 (IL-2) receptors (quantified using radiolabelled IL-2) after mitogen stimulation. Ten of these subjects (five A1 B8 DR3 and five non-A1 B8 DR3) were also tested for the ability of their lymphocytes to proliferate under IL-2 stimulation. A1 B8 DR3 subjects express a normal number of high-affinity IL-2 receptor sites, but the affinity of these receptors sites is significantly increased. Unexpectedly, A1 B8 DR3 lymphoblasts show a lower response to IL-2 than non-A1 B8 DR3 for high doses of recombinant IL-2.


Nonlinear SSVEP responses are sensitive to the perceptual binding of visual hemifields during conventional 'eye' rivalry and interocular 'percept' rivalry.
We conducted behavioral and EEG experiments to identify physiological correlates of perceptual binding during two types of binocular rivalry: (1) conventional 'eye' rivalry where perception alternates between the two monocular images presented one to each eye and (2) interocular 'percept' rivalry, where perception alternates between percepts formed by grouping complementary hemifields one from each eye. We employed 'frequency-tagging' by flickering a grating in each hemifield of each eye at different frequencies to elicit SSVEP responses specific to each hemifield of each eye. When the gratings in complementary visual fields of the two eyes were congruent in color and orientation, robust interocular 'percept' rivalry was observed with roughly equal probability to conventional 'eye' rivalry. The SSVEPs evoked by the flickering gratings were enhanced by conscious perception at both posterior and frontal electrodes only during conventional 'eye' rivalry and not during interocular 'percept' rivalry, suggesting that dominance of one eye is the basis of most previous reports of SSVEP modulation by conscious perception. We also observed nonlinear SSVEP responses at the sums of our four fundamental frequencies. These combination responses were only produced by flicker in complementary visual hemifields--in the same eye or across eyes, but never by incongruent flickering gratings that occupy the same visual field across eyes, suggesting that they are related to the binding of the visual hemifields (monocular or interocular) into a coherent percept. These combination responses were modulated by the type of rivalry experienced by the observer, but not by the specific conscious perception. Neural processes related to perceptual binding of both rival percepts take place during binocular rivalry even when only one percept is consciously perceived. This suggests that conventional 'eye' and interocular 'percept' rivalry both involve competition between percepts.


Alteration in the disposition and metabolism of S(-)-propranolol in rats with active respiratory viral infection.
Viral illness elicited marked changes in the disposition and metabolism of S(-)-propranolol in rats during the course of a recent viral outbreak in our rodent colony. A slower rate of gastrointestinal absorption and a much higher clearance of orally-administered S(-)-propranolol were observed. The apparent increase in metabolic clearance is partly attributed to a decrease in the serum protein binding of S(-)-propranolol. A direct stimulation of microsomal oxidative metabolism was also suggested by an increase in urinary recovery of the monohydroxyl metabolites of S(-)-propranolol. In addition, a greater portion of the phenolic metabolites were present in urine as the glucuronic acid conjugates, which may be explained by a concomitant stimulation in conjugative reaction. These observations are unusual in that existing reports indicate that viral illness in man and animals generally leads to an inhibition of oxidative drug metabolism.


Antisense oligonucleotide against 47-kDa heat shock protein (Hsp47) inhibits wound-induced enhancement of collagen production.
It is well known that excessive collagen synthesis during the wound-healing process causes scar formation. Our recent in-vivo study indicates that antisense treatment against 47-kDa heat shock protein (Hsp47), a collagen-specific molecular chaperone, relieves scar formation following skin wounds in rats [Wang et al., Plast. Reconstr. Surg., in press]. In order to understand the mechanism of this phenomenon, we examined the effects of antisense treatment on the expression of mRNAs and proteins of Hsp47 and collagens in fibroblasts derived from wounded rat tongues. Hsp47 and procollagen alpha1(I) and alpha1(III) mRNAs were consistently increased after wounding and were maximal at day 5 post-injury. Treatment with antisense oligonucleotide against Hsp47 efficiently blocked the production of procollagen alpha2(I) and alpha1(III) proteins, but had little effect on their mRNA levels. Therefore, we conclude that antisense oligonucleotide against Hsp47 inhibits the production of procollagen type I and III proteins in fibroblasts derived from wounded tongues, overcoming the increase in their mRNAs.


Francisella tularensis subsp. holarctica bacteraemia in an immunocompetent male.
Tularemia is a rare zoonotic disease caused by the two predominant subspecies of Francisella tularensis, namely subspecies tularensis and subspecies holarctica. The latter is less virulent than the former, is endemic in Europe, and usually has a mild disease course, although respiratory involvement and bacteraemia can occur. Tularemia in Belgium is rare, but the incidence seems to be increasing. It therefore seems prudent to raise awareness among clinicians for this potentially severe disease. We report the first case of pneumonic tularemia with bacteraemia from Belgium, and want to recommend including Francisella tularensis in the differential diagnosis of pneumonia when an unfavorable evolution is seen with standard treatment.


Bivalirudin: a direct thrombin inhibitor.
Studies of the anticoagulant effects of hirudin, which is derived from the saliva of the leech Hirudo medicinalis, led to the development of compounds that can directly inhibit thrombin activity without the need for additional cofactors. One of these is the direct thrombin inhibitor bivalirudin, which has recently been approved by the US Food and Drug Administration for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. This is a review of the pharmacologic properties, efficacy, tolerability, and potential cost-effectiveness of bivalirudin in the treatment of ischemic coronary syndromes. Articles were identified by searches of MEDLINE (1966-September 2001), International Pharmaceutical Abstracts (1970-September 2001), and the Iowa Drug Information Service (1966-September 2001) using the terms bivalirudin and Hirulog. The reference lists of retrieved articles were also reviewed for relevant articles. Bivalirudin is a synthetic polypeptide that directly inhibits thrombin by binding simultaneously to its active catalytic site and its substrate recognition site. After intravenous administration, peak plasma concentrations occur in 2 minutes. In patients given a 1.0-mg/kg bolus followed by a 2.5-mg/kg per hour infusion, a median activated clotting time of 346 seconds is achieved with little interpatient or intrapatient variability. Clearance of bivalirudin occurs through a combination of renal elimination and proteolytic cleavage, and doses may need to be decreased in the presence of renal dysfunction. In patients undergoing percutaneous coronary interventions, bivalirudin has been associated with equivalent efficacy but lower bleeding rates (P < 0.001) than unfractionated heparin (UFH). Data from the Hirulog Early Reperfusion/Occlusion-2 study suggest no reduction in mortality with bivalirudin compared with heparin when either is added to aspirin and streptokinase in patients with acute myocardial infarction, despite a lower reinfarction rate (P < 0.001). Experience with bivalirudin in patients with unstable angina and heparin-induced thrombocytopenia (HIT), as well as in patients receiving glycoprotein IIb/IIIla inhibitors, is limited. The differences in bleeding rates between bivalirudin and heparin in published clinical trials probably reflect differences in levels of anticoagulation achieved in comparator groups. Given its high cost, bivalirudin should be reserved for use as an alternative to UFH, primarily in patients with HIT, until clinical trials have more clearly demonstrated its benefits in terms of efficacy or safety.


Doppler identification of in situ vein graft arteriovenous fistulas.
Accurate identification of vein graft fistulas was confirmed by correlation of Doppler findings with intraoperative arteriograms in 25 consecutive instances. We recommend use of this simple method to all those performing in situ bypass procedures.


Touch and tactile neuropathic pain sensitivity are set by corticospinal projections.
Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain1-4. Mental influence on perception is largely assumed to occur locally within the brain. Here we investigate whether sensory inflow through the spinal cord undergoes direct top-down control by the cortex. Although the corticospinal tract (CST) is traditionally viewed as a primary motor pathway5, a subset of corticospinal neurons (CSNs) originating in the primary and secondary somatosensory cortex directly innervate the spinal dorsal horn via CST axons. Either reduction in somatosensory CSN activity or transection of the CST in mice selectively impairs behavioural responses to light touch without altering responses to noxious stimuli. Moreover, such CSN manipulation greatly attenuates tactile allodynia in a model of peripheral neuropathic pain. Tactile stimulation activates somatosensory CSNs, and their corticospinal projections facilitate light-touch-evoked activity of cholecystokinin interneurons in the deep dorsal horn. This touch-driven feed-forward spinal-cortical-spinal sensitization loop is important for the recruitment of spinal nociceptive neurons under tactile allodynia. These results reveal direct cortical modulation of normal and pathological tactile sensory processing in the spinal cord and open up opportunities for new treatments for neuropathic pain.


Association of Rho-kinase Gene Polymorphisms with Respiratory Distress Syndrome in Preterm Neonates.
Respiratory distress syndrome (RDS) of the newborn is one of the most common causes of morbidity and mortality in preterm infants. Our objective was to determine the association between Rho-kinase (ROCK1 and ROCK2) gene polymorphisms and RDS in preterm neonates. A total of 193 preterm infants with RDS and 186 preterm infants without respiratory problems were included in this study. Polymorphisms were analyzed in genomic DNA using a BioMark 96.96 dynamic array system. We observed that ROCK1 gene rs2271255 (Lys222Glu) and rs35996865 polymorphisms, and ROCK2 gene rs726843, rs2290156, rs10178332, and rs35768389 (Asp601Val) polymorphisms were associated with RDS. However, no associations were found with rs73963110, rs1515219, rs965665, rs2230774 (Thr431Asn), rs6755196, and rs10929732 polymorphisms. Additionally, 12 haplotypes (6 in ROCK1 and 6 in ROCK2) were found to be markedly associated with RDS. This is the first study to examine the involvement of ROCK gene variation in the risk of incident RDS. The results strongly suggest that ROCK gene polymorphisms may modify individual susceptibility to RDS in the Turkish population.


Intracellular calcium levels are differentially regulated in T lymphocytes triggered by anti-CD2 and anti-CD3 monoclonal antibodies.
Antigen and/or mitogen-driven T-cell activation is mediated by a rise in intracellular free Ca2+, as second messenger. A regulatory key role for this process is represented by membrane-associated [Ca2+/Mg2+] ATP-ase that is mainly devoted to extrusion of intracellular ion excess. In the present study we have investigated the kinetics of CA2+ fluxes in both resting and already activated (Jurkat T-cell line) T lymphocytes after CD3 and CD2 (T11(2) and T11(3)) triggering and focused our attention on plasma membrane [Ca2+/Mg2+] ATP-ase activity. In both resting T cells and Jurkat cell line, the CD2 stimulation was able to determine a rise in intracellular free Ca2+ higher than that observed after CD3 triggering. In addition, this calcium signal was independent of negative feedback control exerted by [Ca2+/Mg2+] ATP-ase, as well as of IP3 generation. Thus the CD2 molecular system may, together with cell-adhesion properties, act as an amplifier of Ca2+ signals that, if delivered in the context of other molecular systems, such as CD3 or MHC class II antigens, are essentially devoted to the polyclonal co-stimulatory recruitment of a larger cellular repertoire.


Survivorship care planning in gynecologic oncology-perspectives from patients, caregivers, and health care providers.
This qualitative study sought to describe the challenges following treatment and the preferences regarding survivorship care among patients treated for gynecological cancer, their caregivers, and health care providers. Between July and August 2017, in-depth semi-structured interviews regarding survivorship were conducted at a large academic hospital in the USA among patients who recently completed treatment (< 12 months) for a gynecological cancer (ovarian, endometrial, cervical, and vulvar) and their primary caregivers. A focus group was conducted among health care providers (oncologists, nurses, and fellows). Main themes were identified using descriptive content analysis. A total of 30 individuals participated in this study (13 patients, 9 caregivers, 8 health care providers). Almost all participants reported a desire for more information on how to address survivorship needs, specifically as they related to side effects, follow-up schedule, and psychological assistance. Despite this uniformly identified need for more information, preferences for survivorship care planning differed across cancer types and individuals, with respect to content, timing, and mode of delivery. Health care providers expressed challenges in communicating with patients about survivorship, a desire to shift post-treatment conversations to the goal of improving quality of life as opposed to focusing on disease recurrence, and an unmet need for disease specific and individualized survivorship care planning. Patients, caregivers, and health care providers each expressed a need for gynecologic cancer-tailored survivorship care resources. The variation of disease types and patient and caregiver needs may require multi-faceted, individualized survivorship care planning.


Acute and subacute effects of neuroleptics dopamine synthesis and release in the rat striatum.
The effects of acute and subacute treatments with moderate doses of thioproperazine and haloperidol on dopamine synthesis and release have been examined in rat striatal slices. Synthesis and release of dopamine were determined by measuring the rate of formation of 3H-H2O during the conversion of L3,5-3H-tyrosine into 3H-Dopa and the accumulation of newly synthesized 3H-dopamine in striatal slices and their incubating medium. Possible effects of the treatments on tyrosine striatal levels or tyrosine specific activity were also investigated. Dopamine synthesis rate was markedly accelerated 2.5 hrs after the acute injection of thioproperazine, but was equal to control levels 24 hrs later. The effects of thioproperazine and haloperidol were thus determined 2.5 and 24 hrs after an acute injection and following the last injection of a repeated daily treatment of 11 days. Dopamine synthesis and release were still markedly increased 2.5 hrs after the last injection of the subacute neuroleptic treatments when compared to controls, but these effects were less pronounced than those observed 2.5 hrs after an acute injection of either drug. Conversely, dopamine synthesis and release were significantly decreased 24 hrs after the last injection of the subacute neuroleptic treatments when compared to controls. Two hypotheses are proposed to explain the changes in dopamine synthesis induced by repeated treatments with neurolptics.


The Interplay Between Systemic Inflammatory Factors and MicroRNAs in Age-Related Macular Degeneration.
We aimed to explore the expression of systemic inflammatory factors and selected intracellular miRNAs that regulate inflammatory signaling pathways potentially involved in age-related macular degeneration (AMD) pathogenesis. A total of 179 patients with wet AMD, 175 with dry AMD and 121 controls were enrolled in the study. Soluble inflammatory factors were analyzed in plasma samples using Luminex technology. Expression of selected miRNAs was analyzed in isolated nucleated peripheral blood cells (PBNCs) using real-time qPCR. Wet AMD was an independent factor associated with higher concentrations of IL-6 (β = +0.24, p = 0.0004), GM-CSF (β = +0.31, p < 0.001), IFN-γ (β = +0.58, p < 0.001), higher expression of miRNA-23a-3p (β = +0.60, p < 0.0001), miRNA-30b (β = +0.32, p < 0.0001), miRNA-191-5p (β = +0.28, p < 0.0001) and lower concentration of IL-1β (β = -0.25, p = 0.0003), IL-5 (β = -0.45, p < 0.001), IL-10 (β = -0.45, p < 0.001), IL-12 (β = -0.35, p < 0.001), lower expression of miRNA-16-5p (β = -0.31, p < 0.0001), miRNA-17-3p (β = -0.18, p = 0.01), miRNA-150-5p (β = -0.18, p = 0.01) and miRNA-155-5p (β = -0.47, p < 0.0001). Multivariate analysis revealed that dry AMD was an independent factor associated with higher concentration of GM-CSF (β = +0.34, p < 0.001), IL-6 (β = +0.13, p = 0.05), higher expression of miRNA-23a-3p (β = +0.60, p < 0.0001), miRNA-126-3p (β = +0.23, p = 0.0005), miRNA-126-5p (β = +0.16, p = 0.01), miRNA 146a (β = +0.14, p = 0.03), and mRNA191-5p (β = +0.15, p = 0.03) and lower concentrations of TNF-α (β = +0.24, p = 0.0004), IL-1β (β = -0.39, p < 0.001), IL-2 (β = -0.20, p = 0.003), IL-5 (β = -0.54, p < 0.001), IL-10 (β = -0.56, p < 0.001), IL-12 (β = -0.51, p < 0.001), lower expression of miRNA-16-5p (β = -0.23, p = 0.0004), miRNA-17-3p (β = -0.20, p = 0.003) and miRNA-17-5p (β = -0.19, p = 0.004). Negative correlations between visual acuity and WBC, lymphocyte count, TNF-α, IL-1 β, IL-2, IL-4, IL-6, IL-10 concentrations and miRNA-191-5p, as well as positive correlations between visual acuity and miRNA-126-3p, -126-5p, and -155-5p PBNCs expression were found in AMD patients. No such correlations were found in the control group. Our results may suggest the role of both intra- and extracellular mechanisms implicated in inflammatory response regulation in multifactorial AMD pathogenesis.


Tracing of labile zinc in live fish hepatocytes using FluoZin-3.
Intracellular zinc levels are homeostatically regulated and although most is bound, a pool of labile Zn(II) is present in cells. We show here that the zinc probe FluoZin-3 is useful to monitor zinc fluxes during fluorescent imaging of the trout hepatic cell line D11. Nuclei and bulk cytosol appeared to lack detectable labile zinc, while the punctuate staining pattern colocalized with a lysosome-specific probe. Applying extracellular zinc alone resulted in vesicular sequestration of the metal ion. Together with Na-pyrithione a delayed and toxic rise in cellular fluorescence was triggered. When using another ionophore, 4-Br A23187, a zinc buffering effect of the vesicular pools was evident. Secondly, N-ethylmaleimide induced a homogeneous fluorescence rise, which was strongly enhanced by addition of Zn-pyrithione and disappeared after TPEN washing. This suggests the involvement of thiol residues in controlling available cytosolic zinc. Our observations have implications for the interpretation of calculated intracellular Zn2+ concentrations.


Incidence and predictors of delirium on the intensive care unit after acute myocardial infarction, insight from a retrospective registry.
This study aimed to identify the incidence and potential risk factors for delirium after myocardial infarction (MI). Delirium is a common complication on intensive care units. Data on incidence and especially on predictors of delirium in patients after acute MI are rare. In this retrospective study, all patients hospitalized for MI treated with coronary angiography in an university hospital in 2018 were included and analyzed. Onset of delirium within the first 5 days after MI was attributed to the MI and was defined by a Nursing Delirium screening scale (NuDesc) ≥2. This score is taken as part of daily care in every patient on intensive care unit three times a day by especially trained nurses. A total of 624 patients with MI (age 68.5 ± 13.2 years, ST-elevation MI 41.6%, hospital mortality 3.2%) were included in the study. Delirium was detected in 10.9% of all patients. In the subgroup of patients with a stay on the intensive care unit (ICU) for more than 24 hr (n = 229), delirium was detected in 29.7%. Hospital and ICU stay were significantly longer in patients with delirium (p < .001). Delirium was an independent predictor of prolonged ICU-stay. Independent predictors of delirium were age, dementia, alcohol abuse, cardiac arrest, hypotension, and leucocytosis. Infarct size or presentation with ST-elevation were not associated with incidence of delirium. Development of delirium is frequent after acute MI and prolongs hospitalization. Incidence of delirium is associated with clinical instability, preexisting comorbidity, and age rather than MI type or size.


Contribution of ATM and ATR to the resistance of glioblastoma and malignant melanoma cells to the methylating anticancer drug temozolomide.
The major cytotoxic DNA adduct induced by temozolomide and other methylating agents used in malignant glioma and metastasized melanoma therapy is O(6)-methylguanine (O(6)-MeG). This primary DNA damage is converted by mismatch repair into secondary lesions, which block replication and in turn induce DNA double-strand breaks that trigger the DNA damage response (DDR). Key upstream players in the DDR are the phosphoinositide 3-kinases ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR). Here, we addressed the question of the importance of ATM and ATR in the cell death response following temozolomide. We show that (i) ATM- and ATR-mutated cells are hypersensitive to temozolomide, (ii) O(6)-MeG triggers ATM and ATR activation, (iii) knockdown of ATM and ATR enhances cell kill in gliobalstoma and malignant melanoma cells with a stronger and significant effect in ATR knockdown cells, (iv) ATR, but not ATM, knockdown abolished phosphorylation of H2AX, CHK1, and CHK2 in glioma cells, and (v) temozolomide-induced cell death was more prominently enhanced by pharmacologic inhibition of CHK1 compared with CHK2. The data suggest that ATM and, even better, ATR inhibition is a useful strategy in sensitizing cancer cells to temozolomide and presumably also other anticancer drugs.


cAMP-dependent protein kinase and anoxia survival in turtles: purification and properties of liver PKA.
The catalytic subunit of turtle (Trachemys scripta elegans) liver cyclic AMP-dependent protein kinase (PKAc) was purified to homogeneity with a final specific activity of 65,783 pmol phosphate transferred.min-1.mg protein-1. Subunit molecular weight was 42-43 kDa as determined by SDS-PAGE and Sephacryl S-300 chromatography. The isolectric point was pH 6.41 +/- 0.02. Turtle liver PKAc showed highest activity with kemptide as its substrate; activity with other artificial substrates, histone IIA and protamine, was only 21 and 11%, respectively, of the activity with kemptide. Km values were 83 +/- 6.5 microM for Mg.ATP and 11.7 +/- 0.5 microM for kemptide and enzyme activity was strongly reduced by inhibitors of mammalian PKA (H-89, PKA-1) but not by inhibitors of other protein kinases. The enzyme was also inhibited by salts, especially fluoride salts (I50 about 30 mM), and showed a sharp break in the Arrhenius plot (0-45 degrees C) with activation energy increasing by 4-fold from 27.9 +/- 1.85 to 115 +/- 2.5 kJ/mol for temperatures above versus below 15 degrees C. Temperature effects may be important in suppressing PKA function, and therefore PKA-mediated responses, in vivo to enhance anoxic survival time during winter hibernation under water. Analysis of the effects of in vivo anoxia exposure at 7 degrees C on PKA in turtle organs showed a rapid 2.3-fold increase in the amount of active enzyme in liver within 1 h of anoxic submergence accompanied by a 60% increase cAMP levels; with longer anoxia (5 or 20 h) the percentage of active PKA was suppressed to 2.1-3.7% of the total.(ABSTRACT TRUNCATED AT 250 WORDS)


Volumetric structural magnetic resonance imaging (MRI) of the rat hippocampus following kainic acid (KA) treatment.
An in vivo MRI study employing a high field (7T) magnet and a T1- and T2-weighted imaging sequence with subsequent histopathological evaluations was undertaken to develop and evaluate MRI-based volumetric measurements in the rat. The brain structures considered were the hippocampus, the cingulate cortex, the retrosplenial granular cortex and the ventricles. Control (n=3) and kainic acid (KA; n=4) treated rats were scanned 10 days following the manifestation of stage four seizures. The MRI images exhibited anatomical details (125 microm in-plane resolution) that enabled volumetric analysis with high intra-rater reliability. Volumetric analysis revealed that KA-treated rats had significantly smaller hippocampi, and a significant increase in ventricular size. The cingulate cortex and the retrosplenial granular cortex did not differ in volume between the two groups. The histological observations supported the MRI data showing neuronal loss and neuronal degeneration in CA1 and CA3 of the hippocampus, which was accompanied by strong microglia activation. These data demonstrate a reliable and valid method for the measurement of the rat hippocampus in vivo using MRI with a high field magnet, thereby providing a useful tool for future studies of rodent models of neuro-degenerative diseases.


Characterization and mapping of the human SOX4 gene.
The SOX genes comprise a large family related by homology to the HMG-box region of the testis-determining gene SRY. We have cloned and sequenced the human SOX4 gene. The open reading frame encodes a 474 amino acid protein, which includes an HMG-box. The non-box sequence is particularly rich in serine residues and has several polyglycine and polyalanine stretches. With somatic cell hybrids, human SOX4 has been mapped to Chromosome (Chr) 6p distal to the MHC region. There is no evidence for clustering of other members of the SOX1, -2, and -3 or SOX4 gene families around the SOX4 locus.


Computer-based testing: initial report of extensive use in a medical school curriculum.
Computer-based digital technology offers many opportunities in medical education. One type of digital technology, computer-based testing (CBT), has potentially wide application in undergraduate, graduate, and continuing medical education. This articles describes the development of CBT in an undergraduate medical curriculum. An early step in evaluating CBT is to be sure that the exam format is measuring the examinees' knowledge and not their comfort level or confidence with the technology. It is, therefore, important that the CBT reproduce or accommodate traditional test-taking behavior. CBT also provides for a number of enhancements not easily achieved with traditional paper-and-pencil exams. These include easier control and editing of exam items, better incorporation of testing into the learning environment using specific feedback, and enhancing the questions by incorporating multimedia. CBT does present some unique challenges in testing security, and this article discusses the approach to the security issues. In addition, before initiating CBT into a medical curriculum, the institution must understand the technical and infrastructure requirements for CBT. By providing a 5-year experience with CBT in the medical curriculum, this article hopes to facilitate discussions among medical educators in its appropriate application and evaluation.


Densitometric measurement of increased endothelial permeability in arteriosclerotic plaques and inhibition of permeability under the influence of two calcium antagonists.
A densitometric technique was established to investigate quantitative changes in endothelial permeability for horseradish peroxidase (HRP), mol. wt. 40,000 daltons, in rabbit carotid artery. Repeated weak electrical stimulations of rabbit carotid arterial walls with implanted electrodes lead to fibromuscular plaques mainly beneath the anode. It could be demonstrated that there exists a typical growth curve of the plaques dependent on the number of days of electrostimulation, with a fast proliferation rate of smooth muscle cells in the first 2 weeks of electrostimulation, and an increasing retardation of proliferation during the next 4 weeks. Endothelial permeability for HRP increases in close relation to the plaque development. Intravenous applications of single doses of the calcium entry blockers flunarizine or nimodipine are able to inhibit the increased permeability of the endothelial lining covering arteriosclerotic plaques. The intensity of the inhibitory action of these calcium antagonists correlates with the size of the arteriosclerotic plaques in inverse proportion, but nevertheless in large plaques an inhibitory effect is seen.


Aspiration of high-density barium contrast medium causing acute pulmonary inflammation--report of two fatal cases in elderly women with disordered swallowing.
Two cases are reported in which accidental inhalation of barium contrast medium occurred owing to disordered swallowing in elderly women. In each case there was a pulmonary inflammatory reaction followed within a few hours by death. Experimental and clinical reports of barium inhalation are reviewed and the hazard of aspiration of high density barium preparations in elderly and debilitated patients with dysphagia is emphasised. It is concluded that particular care should be taken in the radiological examination of such patients, and a suggested method for performing a contrast swallow in those who are liable to aspirate is described.


Ecotoxicology and macroecology--time for integration.
Despite considerable progress in ecotoxicology, it has become clear that this discipline cannot answer its central questions, such as, "What are the effects of toxicants on biodiversity?" and "How the ecosystem functions and services are affected by the toxicants?". We argue that if such questions are to be answered, a paradigm shift is needed. The current bottom-up approach of ecotoxicology that implies the use of small-scale experiments to predict effects on the entire ecosystems and landscapes should be merged with a top-down macroecological approach that is directly focused on ecological effects at large spatial scales and consider ecological systems as integral entities. Analysis of the existing methods in ecotoxicology, ecology, and environmental chemistry shows that such integration is currently possible. Therefore, we conclude that to tackle the current pressing challenges, ecotoxicology has to progress using both the bottom-up and top-down approaches, similar to digging a tunnel from both ends at once.


Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma.
The overexpression of receptor tyrosine kinase EphA2 has been reported in various cancers. In non-small cell lung cancer (NSCLC), a positive correlation has been reported between high EphA2 immunohistochemical staining level and poor prognosis. However, its ligand, ephrin-A1, is supposed to act as a tumor suppressor via the kinase activity of EphA2. Thus, the biphasic roles of this system are not fully elucidated. We retrospectively evaluated the expression levels of EphA2 and ephrin-A1 in surgically treated pathological (p-) stage I NSCLC tumor samples, and their relation to clinicopathologic features or postoperative prognoses. The levels of EphA2 and ephrin-A1 mRNA expression were quantified by real-time reverse-transcription polymerase chain reaction in tissue samples from p-stage I NSCLC patients who had undergone complete resection in our facility (n=195). They were divided into two (EphA2/ephrin-A1-Low and -High) groups based on the median expression level, and their respective clinicopathologic features and prognoses were analyzed. Furthermore, samples were stained immunohistochemically and classified into four groups according to their staining levels, and their prognoses analyzed. Marked demographic differences were found between EphA2/ephrin-A1-Low and -High groups. Both EphA2-High and ephrin-A1-High groups had more females, no smoking history, adenocarcinoma histology, well-differentiated carcinomas, p-stage IA patients, and patients with EGFR gene mutations. Five-year overall survival rates of the EphA2-Low and the EphA2-High patient groups were 68.9% and 86.1%, respectively (P=0.017), and five-year disease-free survival rates were 69.9% and 83.2%, respectively (P=0.035). There were no statistical differences between ephrin-A1-Low and ephrin-A1-High groups concerning postoperative survival. Although showing smaller differences, the findings from the immunohistochemical analyses supported the above results. Higher expression of EphA2 and ephrin-A1 was more related to the female sex, reduced smoking status, adenocarcinoma, well differentiated carcinomas, p-stage IA, and EGFR gene mutations. Higher EphA2 mRNA expression in p-stage I NSCLC patients was positively related to improved prognoses. These results may reflect a tumor suppressive role for the EphA2/ephrin-A1 system in a population of patients restricted to p-stage I NSCLC.


Endoscopic third ventriculostomy and posterior fossa tumors.
The management of hydrocephalus associated with a posterior fossa tumor is debated. Some authors emphasize the advantages of an immediate tumor removal that may normalize the cerebrospinal fluid (CSF) dynamics. However, in clinical practice, the mere excision of the lesion has been demonstrated to be accompanied by a persisting hydrocephalus in about one third of the cases. Preoperative endoscopic third ventriculostomy (ETV) offers several advantages. It may control the intracranial pressure (ICP), avoid the necessity of an emergency procedure, allow appropriate scheduling of the operation for tumor removal, and eliminate the risks related to the presence of an external drainage. The procedure also reduces the incidence of postoperative hydrocephalus. A final advantage, more difficult to weight, but obvious to the neurosurgeon, is the possibility to remove the lesion with a relaxed brain and normal ICP. In the postoperative phase, ETV can be used in case of persisting hydrocephalus, both in patients who underwent only the excision of the tumor and in those whose preoperative ETV failed as a consequence of intraventricular bleeding with secondary closure of the stoma (redoETV). The main advantage of postoperative ETV is that the procedure is carried out only in case of persisting hydrocephalus; its use is consequently more selective than preoperative ETV. The disadvantage consists in the common use of an external CSF drainage in the first few postoperative days, which is necessary to control the pressure and for ruling out those cases that reach a spontaneous cure of the hydrocephalus. The authors review the criteria for patient selection and the results of ETV performed in case of hydrocephalus secondary to a posterior fossa tumor. Preoperative ETV constitutes an effective procedure for controlling the hydrocephalus associated with posterior fossa tumors. It might lower the rate of persistent postoperative hydrocephalus and result in a short hospital stay. Low rates of patients requiring an extrathecal-CSF shunt device are also reported by authors who utilize ETV postoperatively. As, however, the assessment of the persistent hydrocephalus in these children is based on prolonged ICP monitoring through an external CSF drainage, their results are weighted by a major risk of infective complications and longer hospital stay.


Long-term anaerobic digestion of food waste stabilized by trace elements.
The purpose of this study was to examine if long-term anaerobic digestion of food waste in a semi-continuous single-stage reactor could be stabilized by supplementing trace elements. Contrary to the failure of anaerobic digestion of food waste alone, stable anaerobic digestion of food waste was achieved for 368 days by supplementing trace elements. Under the conditions of OLR (organic loading rates) of 2.19-6.64 g VS (volatile solid)/L day and 20-30 days of HRT (hydraulic retention time), a high methane yield (352-450 mL CH(4)/g VS(added)) was obtained, and no significant accumulation of volatile fatty acids was observed. The subsequent investigation on effects of individual trace elements (Co, Fe, Mo and Ni) showed that iron was essential for maintaining stable methane production. These results proved that the food waste used in this study was deficient in trace elements.


Time-resolved resonant soft X-ray scattering combined with MHz synchrotron X-ray and laser pulses at the Photon Factory.
A picosecond pump-probe resonant soft X-ray scattering measurement system has been developed at the Photon Factory storage ring for highly efficient data collection. A high-repetition-rate high-power compact laser system has been installed to improve efficiency via flexible data acquisition to a sub-MHz frequency in time-resolved experiments. Data are acquired by gating the signal of a channel electron multiplier with a pulse-counting mode capable of discriminating single-bunch soft X-ray pulses in the dark gap of the hybrid operation mode in the storage ring. The photoinduced dynamics of magnetic order for multiferroic manganite SmMn2O5 are clearly demonstrated by the detection of transient changes in the resonant soft X-ray scattering intensity around the Mn LIII- and O K-edges.


Immobilization of β-d-galactosidase from Kluyveromyces lactis on functionalized silicon dioxide nanoparticles: characterization and lactose hydrolysis.
β-D-Galactosidase (BGAL) from Kluyveromyces lactis was covalently immobilized to functionalized silicon dioxide nanoparticles (10-20 nm). The binding of the enzyme to the nanoparticles was confirmed by Fourier transform-infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Functionalized nanoparticles showed 87% immobilization yield. Soluble and immobilized enzyme preparation exhibited pH-optima at pH 6.5 and 7.0, respectively, with temperature optima at 35 and 40°C, respectively. Michaelis constant (K(m)) was 4.77 and 8.4mM for free and immobilized BGAL, respectively. V(max) for the soluble and immobilized enzyme was 12.25 and 13.51 U/ml, respectively. Nanoparticle immobilized BGAL demonstrated improved stability after favoring multipoint covalent attachment. Thermal stability of the immobilized enzyme was enhanced at 40, 50 and 65°C. Immobilized nanoparticle-enzyme conjugate retained more than 50% enzyme activity up to the eleventh cycle. Maximum lactose hydrolysis by immobilized BGAL was achieved at 8h.


Ammonia-induced alterations in the activities of synaptosomal cholinesterases of rat brain under in vitro and in vivo conditions.
Effects of in vivo and in vitro pathophysiological concentrations of ammonium acetate were studied on the activities of acetyl and pseudocholinesterases in the synaptosomes isolated from cerebral cortex, cerebellum and brain stem of rat brain. Administration of subacute and acute doses of ammonium acetate elevated the activities of both the cholinesterases in synaptosomes of all the above three regions. A linear relationship (r = 0.98) was observed between brain-ammonia levels and magnitude of elevation in the activities of cerebral cholinesterases. Kinetic analysis revealed that this elevation was due to a change in the Vm but not in the Km of the enzymes. Incubation of synaptosomes isolated from normal animals with 1, 5 and 10 mM ammonium acetate marginally elevated the activities of these enzymes and had no effects on purified enzyme. It is suggested that the changes in the activities might be due to altered architecture of the membranes which exposes more number of catalytic sites.


A method for detecting protein-DNA interactions at sites of chromatin replication.
Two versions of an approach to identify DNA-protein interactions at sites of DNA replication in HeLa cell nuclei are described. In this procedure, newly replicated DNA chains are first labeled and photosensitized in vitro by the incorporation of [alpha-32P] dCTP and bromodeoxyuridine triphosphate, respectively. Irradiation with ultraviolet light is then used to covalently crosslink the proteins that are adjacent to the photosensitized and isotopically labeled strands of newly replicated DNA. After the bulk of the DNA is digested with nucleases, the crosslinked proteins--marked by short covalently linked radioactive DNA tags--are fractionated by electrophoresis in sodium dodecyl sulfate-polyacrylamide gels and detected by autoradiography. With this technology, certain proteins have been shown to associate selectively with newly replicated DNA. The method appears adaptable for application to a variety of problems involving DNA-protein association.


The burden of road traffic injuries in developing countries: the 1st national injury survey of Pakistan.
To assess the burden of road traffic injuries in Pakistan-a developing country in South Asia. A nationally representative household interview survey, to measure the burden of all injuries for all ages and in both genders using a three-month recall period. The overall incidence of injury events was 41 (CI: 39.2-43.8) per 1000 per year and for road traffic injuries 15 (CI: 13.7-16.5) per 1000 per year. The relative risk for road traffic injuries was found to be higher in males, those 16-45 years old, and those in the professional category of laborers and vendors. This first national survey reflects the growing impact of injuries, especially road traffic injuries in Pakistan and portends a challenge for the national health system.


Medical care and biomarker-based assessment of mortality in two cohorts of patients with chronic coronary syndrome 10 years apart.
This study aimed to describe the characteristics and mortality of two cohorts of patients with chronic coronary syndrome (CCS) recruited with identical study designs in the same rehabilitation clinics but approximately 10 years apart. The KAROLA cohorts included patients with CCS participating in an inpatient cardiac rehabilitation programme in Germany (KAROLA-I: years 1999/2000, KAROLA-II: 2009-2011). Blood samples and information on sociodemographic factors, lifestyle, and medical treatment were collected at baseline, at the end of rehabilitation, and after one year of follow-up. A biomarker-based risk model (ABC-CHD model) and Cox regression analysis were used to evaluate cardiovascular (CV) and non-CV mortality risk. We included 1130 patients from KAROLA-I (mean age 58.7 years, 84.4% men) and 860 from KAROLA-II (mean age 60.4 years, 83.4% men). Patients in the KAROLA-I cohort had significantly higher concentrations of CV biomarkers and fewer patients were taking CV medications, except for statins. The biomarker-based ABC-CHD model provided a higher estimate of CV death risk for patients in the KAROLA-I cohort (median 3-year risk, 3.8%) than for patients in the KAROLA-II cohort (median 3-year risk, 2.7%, p-value for difference < 0.001). After 10 years of follow-up, 91 (8.1%) patients in KAROLA-I and 45 (5.2%) in KAROLA-II had died from a CV event. Advances in disease management over the past 20 years may have led to modest improvements in pharmacological treatment during cardiac rehabilitation and long-term outpatient care for patients with CCS. However, modifiable risk factors such as obesity have increased in the more recent cohort and should be targeted to further improve the prognosis of these patients.


Inheritable CRISPR based epigenetic modification in a fungus.
The CRISPRoff system was recently introduced as a programmable epigenetic memory writer that can be used to silence genes in human cells. The system makes use of a dead Cas9 protein (dCas9) that is fused with the ZNF10 KRAB, Dnmt3A, and Dnmt3L protein domains. The DNA methylation resulting from the CRISPRoff system can be removed by the CRISPRon system that consists of dCas9 fused to the catalytic domain of Tet1. Here, the CRISPRoff and CRISPRon systems were applied for the first time in a fungus. The CRISPRoff system resulted in an inactivation up to 100 % of the target genes flbA and GFP in Aspergillus niger. Phenotypes correlated with the degree of gene silencing in the transformants and were stable when going through a conidiation cycle, even when the CRISPRoff plasmid was removed from the flbA silenced strain. Introducing the CRISPRon system in a strain in which the CRISPRoff plasmid was removed fully reactivated flbA showing a phenotype similar to that of the wildtype. Together, the CRISPRoff and CRISPRon systems can be used to study gene function in A. niger.


Menopause, wellbeing and health: A care pathway from the European Menopause and Andropause Society.
This care pathway from the European Menopause and Andropause Society (EMAS) provides an updated pathway for monitoring and guidance of women at midlife, focusing on those approaching the end of the reproductive life-cycle, going through the menopausal transition and beyond. The care pathway is written by professionals involved in women's health and provides a stepwise individualized approach, stratified according to needs, symptoms and reproductive stage. Furthermore, the pathway provides details on screening for chronic diseases related to menopause and ageing. Treatment options for climacteric symptoms range from menopausal hormone therapy to non-hormonal alternatives and lifestyle modifications. Therapy should be tailored to personal needs and wishes. The pathway aims to offer a holistic, balanced approach for monitoring middle-aged women, aiming to control health problems effectively and ensure healthy ageing.


Stress-induced physiologic changes as a basis for the biopsychosocial model of chronic musculoskeletal pain: a new theory?
(1) To integrate the scientific literatures of the biopsychosocial model of chronic musculoskeletal pain and of stress-induced physiologic wound and muscle changes, and (2) to propose a clinical assessment and treatment model that incorporates this dual literature into the management of chronic musculoskeletal pain. English language literature search from January 1990 to February 2008 using the MEDLINE and PsycINFO databases and the keywords "wound healing," "musculoskeletal injury," "skeletal muscle injury," "psychological," "social," "stress," "anxiety," and "pain." An illustrative case report is introduced. Review of the scientific literature revealed that psychologic stress is associated with slower or delayed wound healing in stressed older adults, restrained mice, socially isolated hamsters, adults with leg wounds, and surgical patients. One study showed that expressive writing positively affected the healing of a small skin puncture. Psychosocial stress affected aspects of muscle activity and spinal loading. Slaughter studies demonstrated that high preslaughter stress in pigs negatively affected postslaughter meat quality. A clinical model for the treatment of selected patients with painful musculoskeletal symptoms is offered. Important links exist between psychologic and social factors and recovery from insults to the "soft tissues." Identifiable biochemical and physiologic processes mediate this relationship. It is time to rethink and refine views of the role of psychologic and social factors in musculoskeletal illness, chronicity, and pain.


Comparison of the effect of two systems for the promotion of exclusive breastfeeding.
Promotion of breastfeeding is an important child-survival intervention, yet little is known about which promotional strategies are the most effective. We aimed to compare the effects on rates of breastfeeding of two systems for promotion of breastfeeding in Brazil--a hospital-based system and the same system combined with a programme of home visits. In February, 2001, maternity staff from two hospitals in Pernambuco, Brazil, were trained according to the Baby-Friendly Hospital Initiative (BFHI). In a randomised trial between March and August, 2001, 350 mothers giving birth at these hospitals were assigned ten postnatal home visits to promote and support breastfeeding (n=175) or no home visits (n=175). Breastfeeding practices were studied on days 1, 10, 30, 60, 90, 120, 150, and 180 by researchers unaware of group allocation. The primary outcome measure was the rate of exclusive breastfeeding from birth to 6 months. Analyses were by intention to treat. The hospital-training intervention achieved a high rate (70%) of exclusive breastfeeding in the hospitals, but this rate was not sustained at home and at 10 days of age only 30% of infants were exclusively breastfed The patterns of exclusive breastfeeding in the two trial groups for days 10-180 differed significantly (p<0.0001), with a mean aggregated prevalence of 45% among the group assigned home visits compared with 13% for the group assigned none. The BFHI achieves high rates of exclusive breastfeeding in hospital; however, in Brazil at least, the rates fall rapidly thereafter. Reliance on the BFHI as a strategy for breastfeeding promotion should be reassessed. A combination of promotional systems (hospital-based and in the community) is needed.


Postnatal growth curves for extremely low birth weight infants with early enteral nutrition.
Early enteral nutrition improves growth of extremely low birth weight infants, but growth curves beyond 30 days of life are lacking for such infants receiving early enteral nutrition. Based on the data of all infants born in a 4-year interval with a birth weight <1000 g and surviving for >56 days, we calculated growth rates and weight gain over 120 postnatal days. Infants with major congenital anomalies or necrotising enterocolitis were excluded. Daily weight, weekly length, head circumference and nutritional data were collected until discharge or for maximal 120 days. Curves were calculated in 100 g birth weight intervals, and separately for appropriate for gestational age (AGA) and small for gestational age (SGA) infants. Data were available from 163 infants (birth weight 768 g +/- 153 g; gestational age 26.8+/-1.8 weeks; mean +/- SD) including 55 SGA infants (33.7%). Full enteral feeding was achieved at day 21.7 (+/-10.4). After 12.8% (+/-6.6%) maximal postnatal weight loss at day 7.5 (+/-3.0), birth weight was regained at 14.6 (+/-6.0) days. Mean overall weight gain was 15 g/kg per day with a significantly higher weight gain for SGA than for AGA infants (P <0.05). Our early fed infants achieved better weight gain than those recently published receiving late enteral nutrition, but nevertheless fell below the 10th percentile of intrauterine curves. Which postnatal growth is ideal for extremely low birth weight infants infants is unclear. Our growth curves should not be taken as reference curves of a "normal population" but may help to identify infants with growth failure.


Aortic regurgitation caused by fibrous strand rupture in a fenestrated aortic valve.
Fibrous strand rupture in a fenestrated aortic valve can cause acute severe aortic regurgitation. We report the case of a 56-year-old woman with severe aortic regurgitation. Transesophageal echocardiography showed an abnormal fibrous strand echo on the prolapsed left coronary cusp (LCC). The operative finding revealed one ruptured fibrous strand attached to the LCC at the commissure between the left and noncoronary cusps. Pathologic examination of the aortic valve revealed myxomatous degeneration.


Surgical education: Lessons from parenthood.
Although one might think surgery and parenting have little in common, there are clear parallels. Historically there has been little formal education for either role. Educators and parents relied on modelling the behavior of others, or trial and error techniques. Mentorship and role models have played a critical role in professional development and continue to have a profound impact. Over the past two decades there has been a marked increase in the resources that are available. Coaching, debriefing, deliberate practice, and formal training are now incorporated in residency programs. Specific lessons from parenthood that can be applied to surgical education include: providing a framework, learning through graduated responsibility, communicating expectations, creating a culture, setting the example, encouraging resilience, promoting autonomy, providing feedback, and navigating failure. The final lesson from parenthood: trust that you have taught them well. And you have to let them go.


Methoxy-stilbenes downregulate the transcription of Wnt/β-catenin-dependent genes and lead to cell cycle arrest and apoptosis in human T98G glioblastoma cells.
Glioblastoma is the most common and the deadliest brain cancer. The aim of this study was to analyze the impact of resveratrol and its five analogs: 3,4,4'-trimethoxy, 3,4,2'-trimethoxy, 3,4,2',4'-tetramethoxy, 3,4,2',6'-tetramethoxy and 3,4,2',4',6'-pentamethoxy-trans-stilbenes (MS) on human glioblastoma T98G cells. The Parallel Artificial Membrane Permeation Assay (PAMPA) was used for the prediction of blood-brain barrier penetration ability of the tested stilbenes (PAMPA-BBB). MTT test was applied to analyze the cytotoxicity of the compounds, whereas their ability to inhibit Wnt/β-catenin target genes expression was verified using qPCR. The potential DNA demethylating properties of the analyzed compounds were tested by Methylation-Sensitive High Resolution Melting (MS-HRM). Cell cycle distribution was tested using Fluorescence-Activated Cell Sorting (FACS), whereas apoptosis was analyzed using FITC Annexin V/propidium iodide double staining assay and Western blot. High blood-brain barrier permeability coefficient was obtained for both resveratrol as well as methoxy-stilbenes. Their ability to downregulate the expression of Wnt/β-catenin pathway-related genes was confirmed. The 4'-methoxy substituted derivatives showed higher activity, whereas 3,4,4'-tri-MS was the most potent Wnt/β-catenin pathway inhibitor. None of the compounds affected DNA methylation level of MGMT, SFRP1, or RUNX3, despite inducing moderate changes in the level of expression of epigenetic modifiers DNMT3B and TET1-3. Importantly, treatment with 3,4,4'-tri-MS and 3,4,2',4'-tetra-MS led to cycle arrest in the S phase and induced apoptosis. Both, resveratrol, as well as its synthetic methoxy-derivatives, should be further studied as promising adjuvants in glioblastoma treatment.