Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro.
Hypoxia leads to the upregulation of a variety of genes mediated largely via the hypoxia inducible transcription factor (HIF). Prominent HIF-regulated target genes such as the vascular endothelial growth factor (VEGF), the glucose transporter 1 (Glut-1), or erythropoietin (EPO) help to assure survival of cells and organisms in a low oxygenated environment. Here, we are the first to report the hypoxic regulation of the sperm associated antigen 4 (SPAG4). SPAG4 is a member of the cancer testis (CT) gene family and to date little is known about its physiological function or its involvement in tumor biology. A number of CT family candidate genes are therefore currently being investigated as potential cancer markers, due to their predominant testicular expression pattern. We analyzed RNA and protein expression by RNAse protection assay, immunofluorescent as well as immunohistological stainings. To evaluate the influence of SPAG4 on migration and invasion capabilities, siRNA knockdown as well as transient overexpression was performed prior to scratch or invasion assay analysis. The hypoxic regulation of SPAG4 is clearly mediated in a HIF-1 and VHL dependent manner. We furthermore show upregulation of SPAG4 expression in human renal clear cell carcinoma (RCC) and co-localization within the nucleolus in physiological human testis tissue. SPAG4 knockdown reduces the invasion capability of RCC cells in vitro and overexpression leads to enhancement of tumor cell migration. Together, SPAG4 could possibly play a role in the invasion capability and growth of renal tumors and could represent an interesting target for clinical intervention.


Development and Validation of the Revised Multicultural Ideology Scale in Germany and Luxembourg.
A revised version of the Multicultural Ideology Scale (rMCI) is currently being developed to measure endorsement of multiculturalism in different cultural contexts. This study, which is part of a wider cross-cultural research project, presents the first assessment of the rMCI scale in the German language. The measure aims to cover several attitudinal dimensions of multiculturalism, relevant to the integration of different ethnocultural groups: Cultural Maintenance, Equity/Inclusion, Social interaction, Essentialistic Boundaries, Extent of Differences, and Consequences of Diversity. Two independent datasets were acquired from Germany (N = 382) and Luxembourg (N = 148) to estimate the factor structure of the rMCI using different confirmatory factor analysis techniques. The findings suggest that a four-factor solution, including Cultural Maintenance, Equity/Inclusion, Social interaction, and Consequences of Diversity, was the best fit for the data. Most of these subscales demonstrated adequate psychometric properties (internal consistency, convergent, and discriminant validity). The four-factor model of the rMCI was partially invariant across the two ethnic groups and full measurement invariance was established across gender.


Influence of nutrient solutions in an open-field soilless system on the quality characteristics and shelf life of fresh-cut red and green lettuces (Lactuca sativa L.) in different seasons.
Little information is available about the impact of nutrient solution ion concentration on quality characteristics and shelf life of fresh-cut lettuce grown in soilless systems in open field. Three lettuce genotypes, lollo rosso and red oak leaf as red-leafed genotypes and butterhead as green-leafed genotype, were studied. The influence of three nutrient solutions with low, medium and high ion concentrations, which varied in the macroanion (NO₃⁻) and macrocations (K⁺, Ca²⁺ and NH₄⁺), were compared in summer and winter. The nutrient solutions evaluated in this study for the production of lettuce in a soilless system did not strongly influence the quality characteristics of the raw material. When the ion concentration of the nutrient solution was increased, fresh weight decreased, although it depended on the genotype and season. Maturity index and dry matter content varied with the season but independently of the nutrient solution. In summer, maturity index was higher and dry matter lower than in winter. Initial texture and visual quality were not influenced by the nutrient solution. Medium ion concentration provided the highest content of vitamin C and phenolic compounds. Our observations pointed out that the genotype had a strong influence on the shelf life of the fresh-cut product with minor differences among nutrient solutions. In general, red-leafed lettuces showed the highest antioxidant content, helping the maintenance of sensory characteristics throughout storage. The combination of optimal nutrient solution ion concentration and suitable cultivar is considered essential to ensure lettuce post-cutting life.


What is New in Pharmacologic Therapy for Cardiac Resuscitation?
Antiarrhythmic therapy can be a critical component of cardiac resuscitation. Therapies in this area have seen little advance in the last decade. Bretylium, a very old drug, has been reintroduced for ventricular tachycardia/ventricular fibrillation (VT/VF) therapy. There are still important questions to be addressed with bretylium: when to administer (first- or second-line) and at which dose. These questions and the development of newer agents will be areas of future research.


Comparison of different PADC materials for neutron dosimetry.
Investigations on track density and track size distributions of different PADC (poly allyl diglycol carbonate) materials have been performed. The PADC used for the tests has been produced by Thermo Electron (USA), Track Analysis System Limited (UK), Chiyoda Technol Corporation (Japan) and Intercast srl (Italy). For each PADC material 120 detectors were randomly selected out of 2 sheets: 60 detectors from one sheet have been irradiated with a personal dose equivalent of 3 mSv in the field of a (241)Am-Be source at the calibration laboratory of PSI, whilst the other 60 detectors from the other sheet have been used as background samples. All detectors have been processed according to an identical etching procedure and have been analysed with TASLImage scanning system. For each set of detectors the value of the average background signal, the average neutron sensitivity and the detection limit with respect to a personal dose equivalent measured with a dosemeter based on PADC have been determined. The results of the investigations allowed a comparison of the neutron sensitivity and background signal behaviours of PADC materials from different manufacturers and the assessment of the variation of neutron sensitivity and background signal over a single sheet.


Influence of Changes in Soft Tissue Composition on Changes in Bone Strength in Peripubertal Girls: The STAR Longitudinal Study.
Obesity and osteoporosis remain two major public health concerns. Soft tissue composition and bone are interrelated; however, it is still not well understood how changes in adiposity during adolescence affect bone development. The aim of this study was to assess how changes in DXA-derived total body lean mass (TBLM) and total body fat mass (TBFM) associate with 2-year changes in bone outcomes at the 20% femur, 66% tibia, 66% radius, and 4% tibia, as measured by pQCT, during the years surrounding the onset of menarche in a cohort of 9- to 12-year-old (baseline) adolescent girls (70% Hispanic). From baseline to 2-year follow-up, girls showed statistically significant increases in all bone outcomes, except radial endosteal circumference. In separate linear regression models, change in TBLM and change in TBFM were both positively associated with 2-year changes in bone outcomes at all measured bone sites, after controlling for relevant covariates. However, when change in TBLM and change in TBFM were included in the same model, change in TBLM was the predominant predictor of bone outcomes, explaining 4% to 14% of the variance in bone strength outcomes. Change in TBFM remained a positive predictor of tibia polar strength strain index (SSIp) (2% variance explained). A significant interaction between change in TBFM and menarcheal status was identified at the radius for SSIp and indicated that greater gains in TBFM were beneficial for SSIp in girls that were premenarcheal at baseline but detrimental for girls who were postmenarcheal at baseline. The overall findings suggest that changes in TBLM during the peripubertal years have a greater influence on bone outcomes than changes in TBFM. While gains in TBFM might benefit the weight bearing 66% tibia, greater gains in TBFM may be detrimental to bone development at the non-weight bearing 66% radius after the onset of menarche. © 2020 American Society for Bone and Mineral Research (ASBMR).


Rice domestication.
Rice is a staple food crop for more than one-third of the global population (http://www.sustainablerice.org/), of which 90% live at or near the poverty line. Thus, rice genetic improvement is important for global food security and is critical for enhancing socioeconomic benefits and reducing the environmental impacts of agriculture. In continued efforts to address the long-standing problem of food security and sustainable agriculture, scientists are utilizing genes from diverse varieties of rice to improve the resilience of rice to pests, diseases and environmental stress. This Primer describes the history of rice domestication, the importance of wild relatives of rice for crop improvement, and the domestication of wild species of rice not previously planted by farmers - a new approach called neodomestication.


Aqueous formulations and ointments.
The development of ocular drug delivery systems has progressed greatly during the past four decades. This has resulted from better understanding of the pertinent physiological processes and from the availability of new synthetic polymers. More must be learned about the distribution of polymer solutions during the blink and their interactions with biosurfaces. In addition, awareness of the limitations placed on vehicle characteristics (e.g., viscosity, surface activity) by the variation in human eyes and more accurate extrapolation of data from relatively uncomplicated experimental models to the human eye will result in the development of even more effective ophthalmic vehicles designed for specific purposes and for particular drugs.


[Oral lesions in a group of heroin addicts].
Lesions of the oral mucous membrane are studied in 100 heroin dependent people compared with 100 control, other habits like smoking, alcohol ingesting and sexual oral practices are also taking in consideration. Salival flux and other salival characteristics are also analyzed. The heroin dependent people show significative increase in salival filament but this difference that's not exit of we also analyze in the lesions of lips, tongue, palate and vestibule in relation to controls. Nevertheless in the take into account only smokers and drinkers of both groups the only lesions significantly more frequent are those on the lips.


A small amount of dietary carbohydrate can promote the HFD-induced insulin resistance to a maximal level.
Both dietary fat and carbohydrates (Carbs) may play important roles in the development of insulin resistance. The main goal of this study was to further define the roles for fat and dietary carbs in insulin resistance. C57BL/6 mice were fed normal chow diet (CD) or HFD containing 0.1-25.5% carbs for 5 weeks, followed by evaluations of calorie consumption, body weight and fat gains, insulin sensitivity, intratissue insulin signaling, ectopic fat, and oxidative stress in liver and skeletal muscle. The role of hepatic gluconeogenesis in the HFD-induced insulin resistance was determined in mice. The role of fat in insulin resistance was also examined in cultured cells. HFD with little carbs (0.1%) induced severe insulin resistance. Addition of 5% carbs to HFD dramatically elevated insulin resistance and 10% carbs in HFD was sufficient to induce a maximal level of insulin resistance. HFD with little carbs induced ectopic fat accumulation and oxidative stress in liver and skeletal muscle and addition of carbs to HFD dramatically enhanced ectopic fat and oxidative stress. HFD increased hepatic expression of key gluconeogenic genes and the increase was most dramatic by HFD with little carbs, and inhibition of hepatic gluconeogenesis prevented the HFD-induced insulin resistance. In cultured cells, development of insulin resistance induced by a pathological level of insulin was prevented in the absence of fat. Together, fat is essential for development of insulin resistance and dietary carb is not necessary for HFD-induced insulin resistance due to the presence of hepatic gluconeogenesis but a very small amount of it can promote HFD-induced insulin resistance to a maximal level.


The pattern of suicide in Pakistan.
There is paucity of information on suicide from Pakistan, an Islamic country in which data collection poses formidable challenges. A variety of social, legal, and religious factors make reporting and diagnosing suicide difficult. Paradoxically, incidents of suicide are regularly reported in newspapers in Pakistan. In the absence of other means these reports serve a useful, though basic information source for suicidal deaths. A 2-year analysis of all such reports in a major newspaper in Pakistan showed 306 suicides reported from 35 cities. Men (n = 208) outnumbered women by 2:1. While there were more single than married men, the trend was reversed in women. The majority of subjects were under 30 years of age and "domestic problems" was the most common reason stated. More than half the subjects used organophosphate insecticides, while psychotropics and analgesics were used infrequently. The study challenges the widely held belief that suicide is a rare phenomena in an Islamic country like Pakistan, and underscores the need for more culture specific research on this important public health problem.


Penile warts: an update on their evaluation and management.
Penile warts are the most common sexually transmitted disease in males. Clinicians should be familiar with the proper evaluation and management of this common condition. To provide an update on the current understanding, evaluation, and management of penile warts. A PubMed search was completed in Clinical Queries using the key terms 'penile warts' and 'genital warts'. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Penile warts are caused by human papillomavirus (HPV), notably HPV-6 and HPV-11. Penile warts typically present as asymptomatic papules or plaques. Lesions may be filiform, exophytic, papillomatous, verrucous, hyperkeratotic, cerebriform, fungating, or cauliflower-like. Approximately one-third of penile warts regress without treatment and the average duration prior to resolution is approximately 9 months. Active treatment is preferable to watchful observation to speed up clearance of the lesions and to assuage fears of transmission and autoinoculation. Patient-administered therapies include podofilox (0.5%) solution or gel, imiquimod 3.75 or 5% cream, and sinecatechins (polypheron E) 15% ointment. Clinician-administered therapies include podophyllin, cryotherapy, bichloroacetic or trichloroacetic acid, oral cimetidine, surgical excision, electrocautery, and carbon dioxide laser therapy. Patients who do not respond to first-line treatments may respond to other therapies or a combination of treatment modalities. Second-line therapies include topical/intralesional/intravenous cidofovir, topical 5-fluorouracil, and topical ingenol mebutate. No single treatment has been shown to be consistently superior to other treatment modalities. The choice of the treatment method should depend on the physician's comfort level with the various treatment options, the patient's preference and tolerability of treatment, and the number and severity of lesions. The comparative efficacy, ease of administration, adverse effects, cost, and availability of the treatment modality should also be taken into consideration.


Utility of HbA1c assessment in people with diabetes awaiting liver transplantation.
To investigate the relationship between HbA1c and glucose in people with co-existing liver disease and diabetes awaiting transplant, and in those with diabetes but no liver disease. HbA1c and random plasma glucose data were collected for 125 people with diabetes without liver disease and for 29 people awaiting liver transplant with diabetes and cirrhosis. Cirrhosis was caused by non-alcoholic fatty liver disease, hepatitis C, alcoholic liver disease, hereditary haemochromatosis, polycystic liver/kidneys, cryptogenic/non-cirrhotic portal hypertension and α-1-antitrypsin-related disease. The median (interquartile range) age of the diabetes with cirrhosis group was 55 (49-63) years compared to 60 (50-71) years (P=0.13) in the group without cirrhosis. In the diabetes with cirrhosis group there were 21 men (72%) compared with 86 men (69%) in the group with diabetes and no cirrhosis (P=0.82). Of the group with diabetes and cirrhosis, 27 people (93%) were of white European ethnicity, two (7%) were South Asian and none was of Afro-Caribbean/other ethnicity compared with 94 (75%), 16 (13%), 10 (8%)/5 (4%), respectively, in the group with diabetes and no cirrhosis (P=0.20). Median (interquartile range) HbA1c was 41 (32-56) mmol/mol [5.9 (5.1-7.3)%] vs 61 (52-70) mmol/mol [7.7 (6.9-8.6)%] (P<0.001), respectively, in the diabetes with cirrhosis group vs the diabetes without cirrhosis group. The glucose concentrations were 8.4 (7.0-11.2) mmol/l vs 7.3 (5.2-11.5) mmol/l (P=0.17). HbA1c was depressed by 20 mmol/mol (1.8%; P<0.001) in 28 participants with cirrhosis but elevated by 28 mmol/mol (2.6%) in the participant with α-1-antitrypsin disorder. Those with cirrhosis and depressed HbA1c had fewer larger erythrocytes, and higher red cell distribution width and reticulocyte count. This was reflected in the positive association of glucose with mean cell volume (r=0.39) and haemoglobin level (r=0.49) and the negative association for HbA1c (r=-0.28 and r=-0.26, respectively) in the diabetes group with cirrhosis. HbA1c is not an appropriate test for blood glucose in people with cirrhosis and diabetes awaiting transplant as it reflects altered erythrocyte presentation.


Predicting others' actions from their social contexts.
Contextual cues have been shown to inform our understanding and predictions of others' actions. In this study, we tested whether observers' predictions about unfolding actions depend upon the social context in which they occur. Across five experiments, we showed participants videos of an actor walking toward a piece of furniture either with (joint context) or without (solo context) a partner standing by it. We found greater predictive bias, indicative of stronger action expectations when videos contained a second actor (Experiment 1), even when the solo condition had a perceptually-matched control object in place of the actor (Experiment 2). Critically, belief manipulations about the actions the walking actor would perform suppressed the difference between social context conditions when the manipulation specified an action possible in both contexts (Experiment 5) but not when the action was one that would be difficult without a partner (Experiment 4). Interestingly, the social context effect persisted when the belief manipulation specified an unlikely action given the depicted scene (Experiment 3). These findings provide novel evidence that kinematically-identical actions can elicit different predictions depending on the social context in which they occur.


Non-alcoholic fatty liver disease: a brief review.
The term 'non-alcoholic fatty liver disease' (NAFLD) includes cases with steatosis alone and those with non-alcoholic steatohepatitis (NASH). Usually there are no signs or symptoms, sometimes fatigue or pain, and apart from hepatomegaly the condition is revealed by abnormal liver biochemistry or by abdominal ultrasound. Most cases are associated with overweight or diabetes. Liver enzymes are usually elevated, especially GGT, ASAT and ALAT. Other conditions, including alcohol abuse and autoimmune hepatitis, have to be excluded. The diagnosis of steatosis can be made with ultrasound or CT scan. A liver biopsy is often needed to exclude other disease and to assess inflammation and fibrosis. Cirrhosis can develop. NAFLD is usually caused by two 'hits': the 'first hit' is peripheral insulin resistance, causing steatosis. The 'second hit' is caused by reactive oxygen species, inducing vicious cycles leading to inflammation. Weight loss, metformin or thiazolidinediones can improve NAFLD by increasing insulin sensitivity. Radical scavengers such as vitamin E, betaine and perhaps also urodeoxycholic acid may improve the hepatitis component. Further studies on treatment are needed.


Thioctic acid protection against ethanol and indomethacin induced gastric mucosal lesions in rats.
The gastric protective effect of thioctic acid, a sulfhydryl compound, against chemically induced mucosal lesions has not been reported. Fasted Wistar rats (24 h) were treated (gavage administration) with graded doses of thiotic acid (12.5, 25, 37.5, 50 mg/kg) followed 0.5 h later by the gavage administration of 1 ml 96% ethanol or intraperitoneal administered indomethacin. The gastric mucosa was examined grossly and histologically for an evaluation of the lesions. Pretreatment of rats with thiotic acid has shown a significant decline in the mean number, size, incidence and severity of mucosal lesions induced by both ethanol and indomethacin. This is the first evidence that thiotic acid protects the rat gastric mucosa against chemically induced damage. Its is speculated that this finding may prove to be important in the development of improved therapies for the prevention and treatment of gastric ulcers in humans.


Adhesion frequency assay for in situ kinetics analysis of cross-junctional molecular interactions at the cell-cell interface.
The micropipette adhesion assay was developed in 1998 to measure two-dimensional (2D) receptor-ligand binding kinetics. The assay uses a human red blood cell (RBC) as adhesion sensor and presenting cell for one of the interacting molecules. It employs micromanipulation to bring the RBC into contact with another cell that expresses the other interacting molecule with precisely controlled area and time to enable bond formation. The adhesion event is detected as RBC elongation upon pulling the two cells apart. By controlling the density of the ligands immobilized on the RBC surface, the probability of adhesion is kept in mid-range between 0 and 1. The adhesion probability is estimated from the frequency of adhesion events in a sequence of repeated contact cycles between the two cells for a given contact time. Varying the contact time generates a binding curve. Fitting a probabilistic model for receptor-ligand reaction kinetics to the binding curve returns the 2D affinity and off-rate. The assay has been validated using interactions of Fcγ receptors with IgG Fc, selectins with glycoconjugate ligands, integrins with ligands, homotypical cadherin binding, T cell receptor and coreceptor with peptide-major histocompatibility complexes. The method has been used to quantify regulations of 2D kinetics by biophysical factors, such as the membrane microtopology, membrane anchor, molecular orientation and length, carrier stiffness, curvature, and impingement force, as well as biochemical factors, such as modulators of the cytoskeleton and membrane microenvironment where the interacting molecules reside and the surface organization of these molecules. The method has also been used to study the concurrent binding of dual receptor-ligand species, and trimolecular interactions using a modified model. The major advantage of the method is that it allows study of receptors in their native membrane environment. The results could be very different from those obtained using purified receptors. It also allows study of the receptor-ligand interactions in a sub-second timescale with temporal resolution well beyond the typical biochemical methods. To illustrate the micropipette adhesion frequency method, we show kinetics measurement of intercellular adhesion molecule 1 (ICAM-1) functionalized on RBCs binding to integrin α(L)β(2) on neutrophils with dimeric E-selectin in the solution to activate α(L)β(2).


The mammary gland: a unique organ for the study of development and tumorigenesis.
The microanatomy and development of the mammary gland are unique and a reflection of its function to synthesize and deliver milk to the newborn offspring. The uniqueness of the mammary gland resides in several factors. First, the mammary parenchyma undergoes the vast majority of its growth postpubertally, thus enabling experiments on development to be performed in the juvenile or adult and presenting opportunities for experimental manipulation of the gland not available with other organs. On the basis of this characteristic, the fat pad transplantation method was developed, which resulted in the elaboration of important concepts in senescence, immortalization, and preneoplasia. Second, the accessibility of the gland and the ductal organization allows delivery and localization of specific molecules to mammary parenchyma cells, the cells which are the site of origin of neoplastic development. Third, the organ is the target of viral, chemical, and physical carcinogens, allowing development of unique and complex models for neoplastic development. Finally, the complexity of hormone and growth factor regulation of mammary gland function allows a sophisticated approach to the study of hormone action. The purpose of this review is to illustrate some unique properties of the gland which provide the basis for specialized approaches to developmental, neoplastic, and functional problems.


Testing for the presence of magnetite in the upper-beak skin of homing pigeons.
We carried out magnetic and nonmagnetic experiments on fresh, upper-beak skin tissue samples isolated from six pairs of homing pigeons to test whether the tissue contains magnetite particles. Results of (1) room-temperature isothermal remanent magnetization (IRM) acquisition and alternating field (AF) demagnetization, (2) low-temperature demagnetization of saturation IRM acquired at 5 K in a field of 5 tesla (T) (SIRM(5 K)) after zero-field cooled (ZFC) and field cooled (FC) treatments, and (3) cycling of the saturation IRM acquired at 300 K in a field of 5 T (SIRM(300 K)) between 5 and 300 K, indicate the presence of magnetite in the measured samples. A significant loss of SIRM(5 K) below 20 K suggests the dominance of superparamagnetic (SPM) particles. The SIRM acquisition capacity of the female pigeon is stronger than that of the male pigeon in all four measured pairs, suggesting for the first time that the magnetite concentration is probably sex dependent. Light microscopic observation on the histological sections stained with Prussian Blue detected the presence of some tiny, dotted, dark-blue staining Fe3+ aggregates (size 1-4 microm) located directly beneath the subcutis within strands of connective tissue, nearby the rim of the regions full of red nuclei. The results of this study support the idea that homing pigeons may have a magnetite-based receptor, which potentially could be used for sensing the Earth's magnetic field during navigation.


Statistical thermodynamics of amphiphile chains in micelles.
The probability distribution of amphiphile chain conformations in micelles of different geometries is derived through maximization of their packing entropy. A lattice model, first suggested by Dill and Flory, is used to represent the possible chain conformations in the micellar core. The polar heads of the chains are assumed to be anchored to the micellar surface, with the other chain segments occupying all lattice sites in the interior of the micelle. This "volume-filling" requirement, the connectivity of the chains, and the geometry of the micelle define constraints on the possible probability distributions of chain conformations. The actual distribution is derived by maximizing the chain's entropy subject to these constraints; "reversals" of the chains back towards the micellar surface are explicitly included. Results are presented for amphiphiles organized in planar bilayers and in cylindrical and spherical micelles of different sizes. It is found that, for all three geometries, the bond order parameters decrease as a function of the bond distance from the polar head, in accordance with recent experimental data. The entropy differences associated with geometrical changes are shown to be significant, suggesting thereby the need to include curvature (environmental)-dependent "tail" contributions in statistical thermodynamic treatments of micellization.


A study of erythrocyte deformability in sickle cell disease.
Erythrocyte deformability was studied in patients with sickle cell disease, using a filtration method under standard conditions. The erythrocyte deformability index (Vrbc) from homozygous (HbSS) patients was zero compared to 0.55 +/- 0.13 ml min-1 for controls with haemoglobin genotype HbAA. In the heterozygous (HbAS) sickle cell trait the mean Vrbc was 0.21 +/- 0.16 min-1 was significantly less (p less than 0.001) than in the HbAA cases. One patient with haemoglobin genotype HbAC had a normal Vrbc index of 0.53 ml min-1 while one HbSC patient had zero Vrbc index. It appears that erythrocyte deformability is independent of both the haemotocrit and haemoglobin concentration provided the haemoglobin remains normal. The results have been interpreted in the light of variation in red-cell morphology and clinical status of the patients.


Enhancing patient safety: A national standard for cyber resiliency in healthcare.
With support from Public Safety Canada's Cyber Security Cooperation Program, HealthCareCAN and the Digital Governance Council developed a new standard to support cyber resiliency in Canada's healthcare system. With a clear framework and enhanced cybersecurity capabilities, healthcare organizations will be better protected from cybercrime, allowing them to respond more effectively to evolving threats and defend critical infrastructure. Health and information technology leaders can derive practical guidance and next steps from this three-year national project to enhance cyber resilience and improve safety within their organizations.


A functionally relevant tool for the body following spinal cord injury.
A tool such as a prosthetic device that extends or restores movement may become part of the identity of the person to whom it belongs. For example, some individuals with spinal cord injury (SCI) adapt their body and action representation to incorporate their wheelchairs. However, it remains unclear whether the bodily assimilation of a relevant external tool develops as a consequence of altered sensory and motor inputs from the body or of prolonged confinement sitting or lying in the wheelchair. To explore such relationships, we used a principal component analysis (PCA) on collected structured reports detailing introspective experiences of wheelchair use in 55 wheelchair-bound individuals with SCI. Among all patients, the regular use of a wheelchair induced the perception that the body's edges are not fixed, but are instead plastic and flexible to include the wheelchair. The PCA revealed the presence of three major components. In particular, the functional aspect of the sense of embodiment concerning the wheelchair appeared to be modulated by disconnected body segments. Neither an effect of time since injury nor an effect of exposure to/experience of was detected. Patients with lesions in the lower spinal cord and with loss of movement and sensation in the legs but who retained upper body movement showed a higher degree of functional embodiment than those with lesions in the upper spinal cord and impairment in the entire body. In essence, the tool did not become an extension of the immobile limbs; rather, it became an actual tangible substitution of the functionality of the affected body part. These findings suggest that the brain can incorporate relevant artificial tools into the body schema via the natural process of continuously updating bodily signals. The ability to embody new essential objects extends the potentiality of physically impaired persons and can be used for their rehabilitation.


[Autologous rib cartilage harvesting: operative procedure and postoperative pain reduction].
In reconstructive surgery there is a growing demand for cartilage grafts. For small amounts of autologous tissue, cartilage from the nasal septum or ear concha is a sufficient and reliable tissue, but in cases of extensive defects or higher mechanical load autologous rib cartilage is a commonly used transplant. Nevertheless, a serious donor-site morbidity, especially postoperative pain, has to be taken into consideration. We present a modified technique for harvesting rib cartilage with a consecutive local pain therapy. In contrast to the commonly used incision through all layers of tissue the described technique follows the anatomical structures of skin tension-lines, the fascial and muscle fibers and tissue sliding-planes. Starting with a transversal skin incisions 1.5 cm above the costal arch, longitudinal splitting of the rectus abdominis fascia and muscle, the rib cartilage of the ribs 6 to 8 can be exposed. Grafts in the size of at least 3 to 8 cm can be harvested under preservation of the perichondrium. This technique causes a high degree of stability and good function of the abdominal wall. POSTOPERATIVE PAIN THERAPY: After harvesting rib cartilage most patients complain about extensive postoperative pain. For adequate treatment the local application of a long-lasting anesthetic substance close to the intercostal nerves is helpful. The introduction of a peridural catheter opens the feasibility of continuously applying a local anesthetic for 3 to 4 days directly into the donor-site. This procedure reduces the need for general anesthetics dramatically and prevents further complications. This modified technique for harvesting rib cartilage diminishes the donor-site morbidity by reducing the risk of pneumothorax, hernias and functional deficits. Moreover, the local pain therapy assures postoperative wellness and mobility.


European Union's public fishing access agreements in developing countries.
The imperative to increase seafood supply while dealing with its overfished local stocks has pushed the European Union (EU) and its Member States to fish in the Exclusive Economic Zones of other countries through various types of fishing agreements for decades. Although European public fishing agreements are commented on regularly and considered to be transparent, this is the first global and historical study on the fee regime that governs them. We find that the EU has subsidized these agreements at an average of 75% of their cost (financial contribution agreed upon in the agreements), while private European business interests paid the equivalent of 1.5% of the value of the fish that was eventually landed. This raises questions of fisheries benefit-sharing and resource-use equity that the EU has the potential to address during the nearly completed reform of its Common Fisheries Policy.


Cardiovascular inflammation in healthy women: multilevel associations with state-level prosperity, productivity and income inequality.
Cardiovascular inflammation is a key contributor to the development of atherosclerosis and the prediction of cardiovascular events among healthy women. An emerging literature suggests biomarkers of inflammation vary by geography of residence at the state-level, and are associated with individual-level socioeconomic status. Associations between cardiovascular inflammation and state-level socioeconomic conditions have not been evaluated. The study objective is to estimate whether there are independent associations between state-level socioeconomic conditions and individual-level biomarkers of inflammation, in excess of individual-level income and clinical covariates among healthy women. The authors examined cross-sectional multilevel associations among state-level socioeconomic conditions, individual-level income, and biomarkers of inflammation among women (n = 26,029) in the Women's Health Study, a nation-wide cohort of healthy women free of cardiovascular diseases at enrollment. High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and fibrinogen were measured between 1993 and 1996. Biomarker levels were examined among women within quartiles of state-level socioeconomic conditions and within categories of individual-level income. The authors found that favorable state-level socioeconomic conditions were correlated with lower hsCRP, in excess of individual-level income (e.g. state-level real per capital gross domestic product fixed effect standardized Βeta coefficient [Std B] -0.03, 95% CI -0.05, -0.004). Individual-level income was more closely associated with sICAM-1 (Std B -0.04, 95% CI -0.06, -0.03) and fibrinogen (Std B -0.05, 95% CI -0.06, -0.03) than state-level conditions. We found associations between state-level socioeconomic conditions and hsCRP among healthy women. Personal household income was more closely associated with sICAM-1 and fibrinogen than state-level socioeconomic conditions. Additional research should examine these associations in other cohorts, and investigate what more-advantaged states do differently than less-advantaged states that may influence levels of cardiovascular inflammation among healthy women.


Regional arterial infusion with lipoxin A4 attenuates experimental severe acute pancreatitis.
Investigate the therapeutic effect of regional arterial infusion (RAI) with Aspirin-Triggered Lipoxin A4 (ATL) in experimental severe acute pancreatitis (SAP) in rats. SAP was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with ATL (the ATL group) or physiological saline (the SAP group) infused via the left gastric artery 30 min after injection of sodium taurocholate. The sham group was subjected to the same surgical procedure, though without induction of SAP. Serum levels of amylase, phospholipase A2 (PLA2), interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were measured at 12 and 24 h after induction of SAP. Ascitic fluid, the pancreatic index (wet weight ratio) and myeloperoxidase (MPO) levels in the pancreas were determined and histopathological findings were evaluated. The expression of intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), NF-κB p65, and heme oxygenase-1 (HO-1) in the pancreas were estimated by immunofluorescence and western blot, respectively. ATL rats had lower serum levels of TNF-α, IL-1β, and IL-6 (P<0.01), PLA2 (P<0.05), and amylase levels (P<0.05) studied as compared with the SAP group. The pancreatic index in the ATL group decreased only at 24 h as compared with the SAP group (P<0.05). The histopathological findings and MPO levels in the pancreas significantly decreased in the ATL group as compared to the SAP group (P<0.05 and P<0.01, respectively). Immunofluorescence and western blot showed that ATL attenuated the expression of NF-κB p65, ICAM-1 and PECAM-1 in the pancreas, and increased the expression of HO-1 in SAP animals. We demonstrated that RAI with ATL attenuated the severity of experimental SAP, maybe achieved by improving the expression of HO-1, and down-regulating the NF-κB signaling pathway, with decreased expression of ICAM-1 and PECAM-1 and reduced generation of pro-inflammatory cytokines.


Mechanistic studies on the indole prenyltransferases.
Covering: up to 2014. Prenylated indole alkaloids comprise a large and structurally diverse family of natural products that often display potent biological activities. In recent years a large family of prenyltransferases that install prenyl groups onto the indole core have been discovered. While the vast majority of these enzymes are evolutionarily related and share a common protein fold, they are remarkably versatile in their ability to catalyze reverse and normal prenylations at all positions on the indole ring. This highlight article will focus on recent studies of the mechanisms utilized by indole prenyltransferases. While all of the prenylation reactions may follow a direct electrophilic aromatic substitution mechanism, studies of structure and reactivity suggest that in some cases prenylation may first occur at the nucleophilic C-3 position, and subsequent rearrangements then generate the final product.


[The clinical immunologic characteristics of different variants of course of ulcer colitis].
The study was carried out to determine clinical and immunologic predictors of unfavorable variant of course of ulcer colitis. The sample included 89 patients (48 females--53.9% and 41 males--46.1%) with ulcer colitis established on the basis of clinical, endoscopic and morphologic data. The age of patients was 18-79 years and mean age--42.49 +/- 1.61 years. The patients were divided on two groups depending on clinical course of disease: group 1 with favorable course and group 2 with unfavorable course. The group 2 included patients with frequently relapsing form of disease, patients with hormone-depended/hormone-resistant form of disease and patients with severe exacerbation ua ulcer colitis at the moment of examination. The groups were compared by gender and age. All patients underwent medical history and complaints acquisition and total clinical examination. The clinical and biochemical analysis of blood was made too. The severity of disease was established using the calculation of Trulove- Witts indicator The anti-neutrophil cytoplasmic antibodies of classes IgG and IgA were analyzed using indirect immunofluorescence (Euroimmun AG, Germany). The diagnostic anti-neutrophil cytoplasmic antibodies titer was established in 58 out of 87 of examined patients (66.6%). The antineutrophil cytoplasmic antibodies of class IgG was revealed in 42 patients and anti-neutrophil cytoplasmic antibodies of class IgA in 27 patients. The combination of both classes of anti-neutrophil cytoplasmic antibodies was established in 11 examined patients. In the group of favorable course of disease the diagnostic titer of anti-neutrophil cytoplasmic antibodies was revealed in 20 patients (51%). At the same time, in the subgroups with frequently relapsing, hormone-depended/hormone-resistant and severe forms of disease these antibodies were revealed with rate of 76, 77 and 86.3% correspondingly. Hence, the anti-neutrophil cytoplasmic antibodies can be used both in diagnostic of ulcer colitis and in prognosis of course of disease.


Association Between Postoperative Fever and Readmission Rates in Lumbar Fusion Patients.
This is a retrospective observational study. This study evaluates the impact of postoperative fever on the rate of readmission among lumbar fusion patients. Postoperative fever is a common event across surgical specialties that often triggers an extensive work-up that can significantly increase hospital costs and length of stay, although the results are usually negative for infection. There is a paucity of literature studying postoperative fever in lumbar fusion patients. A retrospective chart review of all the patients who underwent elective posterior lumbar spinal fusion from January, 2018 to November, 2018 was conducted. Fever was defined as a temperature >100.4ºF. Patients were categorized into 4 groups based on their highest recorded temperature postoperatively. The association between demographic variables, tests ordered per patient, length of stay, and readmission rates per group were analyzed using a t test, and 1-way analysis of variance for continuous outcomes, and the Fisher exact test for categorical variables. Of 107 patients, 58% had no fever recorded, 17.75% had temperatures between 100.5 and 100.90ºF, 18.69% temperatures between 101 and 101.90ºF, and 4.67% of patients temperatures equal or higher than 102.0ºF. The number of tests per patient increase with the range of temperatures analyzed (P<0.01), but the rate of readmission of all the 4 groups are not significantly different (0.107). There is no significant difference in the number of febrile episodes per day between patients who were and who were not readmitted (0.209). A diagnostic testing policy guided by clinician assessment of symptoms and physical exam may limit unnecessary testing and reduce hospital length of stay and cost without sacrificing patient safety.


Risk factors for neonatal nosocomial enteric infection and the effect of intervention with BIFICO.
This study aims to investigate the risk factors for neonatal nosocomial enteric infection (NNEI) and the effect of intervention with BIFICO. Between May 2013 and June 2015, 215 neonates admitted to our institution were randomly divided into the study group and the control group, 47 for each group. Patients in the study group were treated for primary diseases combined with the oral admission of BIFICO, whereas patients in the control group were treated for primary disease alone. Statistical analysis was performed to obtain the occurrence of enteric infection and univariate, as well as multivariate analysis of clinical data, were performed to investigate the underlying risk factors. Univariate and multivariate analysis of variance showed that gestational age, birth weight, length of hospital stay, invasive procedures and underlying diseases were risk factors affecting NNEI. The occurrence of NNEI in the study group was significantly lower than that in the control group [17.02% (8/47) vs. 29.79% (14/47), X2 = 19.394, p = 0.004]. Preterm infant, low-birth-weight infant, length of hospital stay, invasive procedures and comorbidity are independent risk factors for NNEI. Prophylactic therapy with BIFICO can effectively decrease the occurrence of infections and can be widely used in clinical practice.


[H(+)-transporting ATP synthases: insights into how their electrochemically driven motor might serve as a drug target].
ATP synthases, widely distributed in bacteria, eukaryotic mitochondria and chloroplasts, are highly conserved multi-subunit complexes. Although the conserved acidic residue in the transmembrane helix of the c subunit functions in proton transport, the surrounding residues differ among species. Such divergence could lead to different regulatory modes since pH-dependent proton transport has been demonstrated in Escherichia coli with a c subunit carrying an additional acidic residue in the helix. There is further divergence in the number of c subunits that form the ring structure in F(0). Recently, it was also suggested that certain chemicals recognize the a and c subunits of pathogenic bacterial F(0). Since there may be structural divergence even in well-conserved ATP synthases, the c subunit-ring as well as the a subunit in F(0) could be targets for drugs for specific bacterial species.


Conducting Maximal and Submaximal Endurance Exercise Testing to Measure Physiological and Biological Responses to Acute Exercise in Humans.
Regular physical activity has a positive effect on human health, but the mechanisms controlling these effects remain unclear. The physiologic and biologic responses to acute exercise are predominantly influenced by the duration and intensity of the exercise regimen. As exercise is increasingly thought of as a therapeutic treatment and/or diagnostic tool, it is important that standardizable methodologies be utilized to understand the variability and to increase the reproducibility of exercise outputs and measurements of responses to such regimens. To that end, we describe two different cycling exercise regimens that yield different physiologic outputs. In a maximal exercise test, exercise intensity is continually increased with a greater workload resulting in an increasing cardiopulmonary and metabolic response (heart rate, stroke volume, ventilation, oxygen consumption and carbon dioxide production). In contrast, during endurance exercise tests, the demand is increased from that at rest, but is raised to a fixed submaximal exercise intensity resulting in a cardiopulmonary and metabolic response that typically plateaus. Along with the protocols, we provide suggestions on measuring physiologic outputs that include, but are not limited to, heart rate, slow and forced vital capacity, gas exchange metrics, and blood pressure to enable the comparison of exercise outputs between studies. Biospecimens can then be sampled to assess cellular, protein, and/or gene expression responses. Overall, this approach can be easily adapted into both short- and long-term effects of two distinct exercise regimens.


[Syphilis in sixteenth-century in Bologna. Health care and social assistance (part two)].
Syphilis arrived in Bologna in the summer of 1495, after Fornovo's battle on the Taro where Charles VIII's army, following the invasion of Naples, fought against the anti-French league who faced up to the invaders as they withdrew. It was the battle-weary Bolognesi, prisoners, deserters and probably some prostitutes following the French and mercenary army who introduced the infection into the city. At the beginning of the syphilis epidemic, the disease was very aggressive with particularly visible symptoms and many resulting deaths. Subsequently, contemporaries mention an abatement of this aggressivity in time spans that varied, but in no cases exceeded 60 years. In 1507 Bologna lost its political autonomy, becoming dependent on Rome. This was symptomatic of the upheavals throughout Italy in the sixteenth century. In this situation of economic and institutional crisis the Bolognesi were able to react with decision to the epidemic, re-converting the municipal hospital dedicated to S. Maria dei Guarini during the sixteenth century. This hospital, specializing in treating syphilis, was called "Ospedale di San Giobbe". It was closed in 1798, after the entry of the French army into Bologna. In 1560 the Bolognesi, realising that the most important causes of the spread of syphilis were social degradation, prostitution and poverty, founded another institution for the poor and for the prevention of prostitution. This institution was developed by the Opera dei Mendicanti and provided hospitality during the 1590 famine, in a city of 55,000 inhabitants, for as many as 1400 poor and sick. We also present the cure (guaiac and mercury) that they used at the time against syphilis. In such a difficult historical period beset with political and economic problems, the Bolognesi established two important institutions and showed that social solidarity is a value for the whole population.


Dynamics of photoconversion processes: the energetic cost of lifetime gain in photosynthetic and photovoltaic systems.
The continued development of solar energy conversion technologies relies on an improved understanding of their limitations. In this review, we focus on a comparison of the charge carrier dynamics underlying the function of photovoltaic devices with those of both natural and artificial photosynthetic systems. The solar energy conversion efficiency is determined by the product of the rate of generation of high energy species (charges for solar cells, chemical fuels for photosynthesis) and the energy contained in these species. It is known that the underlying kinetics of the photophysical and charge transfer processes affect the production yield of high energy species. Comparatively little attention has been paid to how these kinetics are linked to the energy contained in the high energy species or the energy lost in driving the forward reactions. Here we review the operational parameters of both photovoltaic and photosynthetic systems to highlight the energy cost of extending the lifetime of charge carriers to levels that enable function. We show a strong correlation between the energy lost within the device and the necessary lifetime gain, even when considering natural photosynthesis alongside artificial systems. From consideration of experimental data across all these systems, the emprical energetic cost of each 10-fold increase in lifetime is 87 meV. This energetic cost of lifetime gain is approx. 50% greater than the 59 meV predicted from a simple kinetic model. Broadly speaking, photovoltaic devices show smaller energy losses compared to photosynthetic devices due to the smaller lifetime gains needed. This is because of faster charge extraction processes in photovoltaic devices compared to the complex multi-electron, multi-proton redox reactions that produce fuels in photosynthetic devices. The result is that in photosynthetic systems, larger energetic costs are paid to overcome unfavorable kinetic competition between the excited state lifetime and the rate of interfacial reactions. We apply this framework to leading examples of photovoltaic and photosynthetic devices to identify kinetic sources of energy loss and identify possible strategies to reduce this energy loss. The kinetic and energetic analyses undertaken are applicable to both photovoltaic and photosynthetic systems allowing for a holistic comparison of both types of solar energy conversion approaches.


Translational profiling of cardiomyocytes identifies an early Jak1/Stat3 injury response required for zebrafish heart regeneration.
Certain lower vertebrates like zebrafish activate proliferation of spared cardiomyocytes after cardiac injury to regenerate lost heart muscle. Here, we used translating ribosome affinity purification to profile translating RNAs in zebrafish cardiomyocytes during heart regeneration. We identified dynamic induction of several Jak1/Stat3 pathway members following trauma, events accompanied by cytokine production. Transgenic Stat3 inhibition in cardiomyocytes restricted injury-induced proliferation and regeneration, but did not reduce cardiogenesis during animal growth. The secreted protein Rln3a was induced in a Stat3-dependent manner by injury, and exogenous Rln3 delivery during Stat3 inhibition stimulated cardiomyocyte proliferation. Our results identify an injury-specific cardiomyocyte program essential for heart regeneration.


Design of an Artificial Neural Network Algorithm for a Low-Cost Insole Sensor to Estimate the Ground Reaction Force (GRF) and Calibrate the Center of Pressure (CoP).
As an alternative to high-cost shoe insole pressure sensors that measure the insole pressure distribution and calculate the center of pressure (CoP), researchers developed a foot sensor with FSR sensors on the bottom of the insole. However, the calculations for the center of pressure and ground reaction force (GRF) were not sufficiently accurate because of the fundamental limitations, fixed coordinates and narrow sensing areas, which cannot cover the whole insole. To address these issues, in this paper, we describe an algorithm of virtual forces and corresponding coordinates with an artificial neural network (ANN) for low-cost flexible insole pressure measurement sensors. The proposed algorithm estimates the magnitude of the GRF and the location of the foot plantar CoP. To compose the algorithm, we divided the insole area into six areas and created six virtual forces and the corresponding coordinates. We used the ANN algorithm with the input of magnitudes of FSR sensors, 1st and 2nd derivatives of them to estimate the virtual forces and coordinates. Eight healthy males were selected for data acquisition. They performed an experiment composed of the following motions: standing with weight shifting, walking with 1 km/h and 2 km/h, squatting and getting up from a sitting position to a standing position. The ANN for estimating virtual forces and corresponding coordinates was fitted according to those data, converted to c script, and downloaded to a microcontroller for validation experiments in real time. The results showed an average RMSE the whole experiment of 31.154 N for GRF estimation and 8.07 mm for CoP calibration. The correlation coefficients of the algorithm were 0.94 for GRF, 0.92 and 0.76 for the X and Y coordinate respectively.


Thiols as myeloperoxidase-oxidase substrates.
Nine low-Mr thiols were compared with regard to their ability to function as myeloperoxidase-oxidase substrates under conditions where no auto-oxidation of the thiols could be observed. The methyl and ethyl esters of cysteine were found to be about twice as active as cysteamine at pH 7.0, in terms of increased O2 consumption. Cysteine itself was poorly active, whereas glutathione, N-acetylcysteine and penicillamine were completely inactive as myeloperoxidase-oxidase substrates under these conditions. The structure-activity relationships indicated that both a free thiol and free amino group were required for peroxidase-oxidase activity, and also that a free carboxy group abolished activity. In analogy with cysteamine, the activities of both cysteine esters were inhibited by superoxide dismutase (less than 5 micrograms/ml) and by catalase and not by the hydroxyl-radical scavenger mannitol. In contrast with cysteamine, the activities of both cysteine esters were stimulated more than 2-fold by high concentrations (greater than 5 micrograms/ml) of superoxide dismutase. The activities of both cysteine esters exhibited broad pH optima at pH 7. A mechanism for the myeloperoxidase-oxidase oxidation of the cysteine esters is proposed, which is partly different from that previously proposed for cysteamine.


Amyloid-Related Imaging Abnormalities with Emerging Alzheimer Disease Therapeutics: Detection and Reporting Recommendations for Clinical Practice.
Monoclonal antibodies are emerging disease-modifying therapies for Alzheimer disease that require brain MR imaging for eligibility assessment as well as for monitoring for amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities result from treatment-related loss of vascular integrity and may occur in 2 forms. Amyloid-related imaging abnormalities with edema or effusion are transient, treatment-induced edema or sulcal effusion, identified on T2-FLAIR. Amyloid-related imaging abnormalities with hemorrhage are treatment-induced microhemorrhages or superficial siderosis identified on T2* gradient recalled-echo. As monoclonal antibodies become more widely available, treatment screening and monitoring brain MR imaging examinations may greatly increase neuroradiology practice volumes. Radiologists must become familiar with the imaging appearance of amyloid-related imaging abnormalities, how to select an appropriate imaging protocol, and report findings in clinical practice. On the basis of clinical trial literature and expert experience from clinical trial imaging, we summarize imaging findings of amyloid-related imaging abnormalities, describe potential interpretation pitfalls, and provide recommendations for a standardized imaging protocol and an amyloid-related imaging abnormalities reporting template. Standardized imaging and reporting of these findings are important because an amyloid-related imaging abnormalities severity score, derived from the imaging findings, is used along with clinical status to determine patient management and eligibility for continued monoclonal antibody dosing.


Respiratory response of phagocytes: terminal NADPH oxidase and the mechanisms of its activation.
The chemical composition, properties and activation mechanism of the O2(-)-forming NADPH oxidase of phagocytes were investigated, using partially purified enzyme preparations. Highly active NADPH oxidase was extracted as an aggregate of high Mr from the membranes of neutrophils and macrophages. The enzyme complex contained phospholipids and cytochrome b-245, very little FAD and almost no quinones or NAD(P)H-dye reductase activity. The purification of a polypeptide with a relative molecular mass of 31 500 strictly paralleled the purification of NADPH oxidase, suggesting that this polypeptide is a component of the enzyme. This protein was identified as cytochrome b -245 after dissociation of the proteolipid complex and purification of the cytochrome moiety. The 31 500 Mr protein was phosphorylated in enzyme preparations from activated but not from resting cells. The results indicate that: cytochrome b-245 is a major component of NADPH oxidase; the involvement of NAD(P)H dye reductases in the O2(-)-forming activity is questionable; the cytochrome b-245: FAD ratio in the enzyme complex is much higher than that indicated in crude preparations; the Mr of pig neutrophil cytochrome b-245 is 31 500; the activation of the O-2-forming system involves a process of phosphorylation of cytochrome b-245.


Management of patients needing antibiotic prophylaxis in a dental education setting.
The management of antibiotic prophylaxed (ABX) patients at an educational institution was evaluated to identify areas for improvement. Management criteria, reflecting guidelines to prevent oral-induced hematogenous microbial seeding, were pretested and applied to 1,225 record entries of eighty-five patients needing ABX for dental treatment between 1991 and 1996. Seven hundred twenty-two of the visits had 857 management or documentation problems, including no documentation indicating whether or not patients premedicated (n = 281); incomplete, insufficient, or repeated treatment (n = 214); and preventive concerns (n = 172), among others. The proportion of providers' patient visits with one or more management problems differed significantly (p < 0.001) by provider type, as did the distribution of problem categories (documentation, treatment, preventive, and scheduling concerns p < 0.001; compliance issues p < 0.005). Fifty-one percent of postgraduates' and 39 percent of faculty's record entries omitted patients' ABX status. Improved documentation, outcome measures, and patient, faculty and student education are indicated.


Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation.
Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled "Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease" held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group.


Is autotopoagnosia real? EC says yes. A case study.
We report a case of pure autotopagnosia (AT) following a left subcortical vascular accident. The absence of any language disorder, general mental deterioration or other cognitive impairments in this patient allowed an in-depth study of AT. Several tests of body representation and object and animal representation, as well as tests assessing semantic skills were administered to verify current interpretations of AT. Results showed a clear-cut dissociation between defective performances in body representation tests and normal performances on tests involving other kinds of stimuli. The patient's performances were particularly defective on tests relying on visuo-spatial body representation, but her semantic and linguistic knowledge seemed to be spared. This dissociation between different aspects of body representation supports Sirigu et al.'s hypothesis that multiple, partially independent systems are involved in body knowledge. In agreement with this hypothesis, in the present patient AT seems be due to a deficit in a system that processes the structural properties and relative position of single body parts. The present results, reporting the first observation of a subject not affected by any cognitive impairment other than AT, strongly support the existence of a system specifically devoted to body representation.


The influence of coffee consumption on bioelectrical impedance parameters: a randomized, double-blind, cross-over trial.
Bioelectrical impedance analysis (BIA) is a widely used method for estimating body composition. Avoiding foods/beverages containing caffeine is a frequently enforced pre-test protocol to ensure reliability of BIA measurements. However, few studies have evaluated whether this is necessary, with conflicting results. We aimed to determine whether the coffee consumption differing in caffeine content influences BIA parameters in healthy adults. Twenty-five healthy adults were enrolled in a randomized, double-blind cross-over trial. Three amounts of caffeine were given with 200 mL of coffee: 0 mg (11 g of decaffeinated), 200 mg (5.5 g of caffeinated plus 5.5 g of decaffeinated), and 400 mg of caffeine (11 g of caffeinated). BIA measurements were conducted at 6 different times, and coefficient variations (CV) explored. No differences were observed for group × time interaction on impedance, resistance, or reactance (p > 0.05). Values of BIA parameters increased after 30-min of coffee consumption, independently of the caffeine dosage (all p < 0.001). Body fat percentage followed the same pattern and increased after 45-min (p < 0.05). Median CV for consecutive impedance, resistance, and reactance measurements were >95%CI of expected device measurement error over 70-min, without difference between groups. Urine output volume was not different between groups (decaffeinated: 440.45 ± 197.57 mL; 200 mg: 471.80 ± 171.88 mL; 400 mg: 489.30 ± 204.10 mL, p > 0.05). Coffee consumption influenced BIA-derived results after 70-min but was not related to caffeine content, likely due to water intake.


Fracture toughness and fatigue crack propagation rate of short fiber reinforced epoxy composites for analogue cortical bone.
Third-generation mechanical analogue bone models and synthetic analogue cortical bone materials manufactured by Pacific Research Laboratories, Inc. (PRL) are popular tools for use in mechanical testing of various orthopedic implants and biomaterials. A major issue with these models is that the current third-generation epoxy-short fiberglass based composite used as the cortical bone substitute is prone to crack formation and failure in fatigue or repeated quasistatic loading of the model. The purpose of the present study was to compare the tensile and fracture mechanics properties of the current baseline (established PRL "third-generation" E-glass-fiber-epoxy) composite analogue for cortical bone to a new composite material formulation proposed for use as an enhanced fourth-generation cortical bone analogue material. Standard tensile, plane strain fracture toughness, and fatigue crack propagation rate tests were performed on both the third- and fourth-generation composite material formulations using standard ASTM test techniques. Injection molding techniques were used to create random fiber orientation in all test specimens. Standard dog-bone style tensile specimens were tested to obtain ultimate tensile strength and stiffness. Compact tension fracture toughness specimens were utilized to determine plane strain fracture toughness values. Reduced thickness compact tension specimens were also used to determine fatigue crack propagation rate behavior for the two material groups. Literature values for the same parameters for human cortical bone were compared to results from the third- and fourth-generation cortical analogue bone materials. Tensile properties of the fourth-generation material were closer to that of average human cortical bone than the third-generation material. Fracture toughness was significantly increased by 48% in the fourth-generation composite as compared to the third-generation analogue bone. The threshold stress intensity to propagate the crack was much higher for the fourth-generation material than for the third-generation composite. Even at the higher stress intensity threshold, the fatigue crack propagation rate was significantly decreased in the fourth-generation composite compared to the third-generation composite. These results indicate that the bone analogue models made from the fourth-generation analogue cortical bone material may exhibit better performance in fracture and longer fatigue lives than similar models made of third-generation analogue cortical bone material. Further fatigue testing of the new composite material in clinically relevant use of bone models is still required for verification of these results. Biomechanical test models using the superior fourth-generation cortical analogue material are currently in development.


Effects of Zoledronate on Mortality and Morbidity after Surgical Treatment of Hip Fractures.
We aimed to evaluate the effects of intertrochanteric femoral fractures on mortality, morbidity, and cost of zoledronate treatment in elderly patients treated by osteosynthesis. Based on Evans classification, 114 patients with unstable intertrochanteric femoral fractures were treated with osteosynthesis. After the surgical treatment of intertrochanteric fractures, the treatment group (M/F, 24/32; mean age, 76.7 ± SD years) received zoledronate infusion, and the control group (M/F, 20/38; mean age, 80.2 ± SD years) received placebo. Postoperative control visits were performed at 6-week, 3-month, 6-month, and 12-month time points. Functional level of patients was evaluated by the modified Harris hip score and Merle d'Aubigné hip score. By 12 months, the mean HHS in treatment and control groups was 81.93 and 72.9, respectively. For time of death of the patients, mortality was found to be 57.1% (16/28) on the first 3 months and 92.9% (26/28) on the first six months. The mortality rate in the treatment and control groups was 14.3% (8/56) and 34.5% (20/58), respectively. The use of zoledronic acid after surgical treatment of intertrochanteric femoral fractures in osteoporotic elderly patients is a safe treatment modality which helps to reduce mortality, improves functional outcomes, and has less side effects with single dose use per year.


Impact of a community-based pilot intervention to tackle childhood obesity: a 'whole-system approach' case study.
Go-Golborne was a three-year pilot programme to test an innovative, community-based 'whole system' approach to preventing overweight in children in Golborne ward, London. Whilst there is a growing interest in local whole systems approaches to obesity, understandings of what they look like in practice are newly emerging. Go-Golborne was designed, implemented and evaluated within this context. The evaluation used a case-study design and theory of change approach to assess the effectiveness of the intervention. Height/weight measurements of children in the six participating primary schools were recorded annually for 4 years. For behavioural outcomes, children aged six-11 completed four annual on-line surveys (total 4331 responses). Parents were surveyed in year one and year four (177 responses). Three focus group discussions were held with children aged 10-11 (N = 21); interviews were conducted with parents (N = 11), and school representatives (N = 4). Stakeholders were surveyed twice (37 responses), and interviews were conducted with key stakeholders (N = 11). An extensive range of programme documents were reviewed and additional process data was collected from the programme team. The RE-AIM framework was used to synthesise findings and examine public health impact. Go-Golborne reached a diverse range of partners across Golborne. Events were attended by over 3360 local children and families and all six primary schools in the ward actively engaged in activities. The proportion of children in the above healthy weight categories remained stable over time. A number of changes in home, school and neighbourhood environments to support healthy behaviour change were evidenced. There was some qualitative evidence of positive changes in children's behaviours, though significant or sustained changes were not evidenced by the quantitative data. Go-Golborne helped stakeholders and parents to develop a shared commitment to improving healthy weight in children, to identify barriers to a healthy lifestyle, and to start to make changes in their services/behaviours. The campaigns and changes made at micro-level appeared to be insufficient, in the face of counteracting forces and personal factors, to achieve significant behaviour change within 3 years. This highlights the need for local initiatives to be reinforced by supporting action at regional, national and global levels.


Labelling of the cyclitol permease in Klebsiella aerogenes.
The protein component(s) of the cyclitol-transport system in Klebsiella aerogenes has been labelled by using three different procedures. One method is based on differential alkylation with N-ethylmaleimide, and another on incorporation of amino acids during the induction process. A protein of mol.wt. 34 000 was labelled by both procedures; by alkylation with N-ethylmaleimide two other proteins of mol.wts. 55 000 and 67 000 were also labelled. The third uses diazotized [35S]sulphanilic acid after protection by substrate and the comparison of labelling of induced cells with non-induced cells; the label was also concentrated in a mol.wt.-33 000 peak. The labelled protein is, from the evidence, the cyclitol carrier.


Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.
There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS). Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively. CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.


Adjusted Maximum Likelihood Method in Small Area Estimation Problems.
For the well-known Fay-Herriot small area model, standard variance component estimation methods frequently produce zero estimates of the strictly positive model variance. As a consequence, an empirical best linear unbiased predictor of a small area mean, commonly used in the small area estimation, could reduce to a simple regression estimator, which typically has an overshrinking problem. We propose an adjusted maximum likelihood estimator of the model variance that maximizes an adjusted likelihood defined as a product of the model variance and a standard likelihood (e.g., profile or residual likelihood) function. The adjustment factor was suggested earlier by Carl Morris in the context of approximating a hierarchical Bayes solution where the hyperparameters, including the model variance, are assumed to follow a prior distribution. Interestingly, the proposed adjustment does not affect the mean squared error property of the model variance estimator or the corresponding empirical best linear unbiased predictors of the small area means in a higher order asymptotic sense. However, as demonstrated in our simulation study, the proposed adjustment has a considerable advantage in the small sample inference, especially in estimating the shrinkage parameters and in constructing the parametric bootstrap prediction intervals of the small area means, which require the use of a strictly positive consistent model variance estimate.


[Anterior decompression of the spinal cord at the level of the thoracic vertebrae].
Anterior compression of the spinal cord at the level of the thoracic vertebrae cannot be corrected adequately through a posterior approach (laminectomy). This widely encountered form of spinal cord compression calls for a differentiated use of the anterolateral or lateral approach to the vertebral canal, i.e. combination of osteotransversectomy with hemilaminectomy. A lateral access to the vertebral canal is indicated in most cases.


Predicting the effect of vaccination on the transmission dynamics of heartwater (Cowdria ruminantium infection).
We used a mathematical description of the transmission dynamics of the tick-borne infection Cowdria ruminantium in commercial beef enterprises in Zimbabwe to consider the potential impact of a candidate vaccine to prevent heartwater. The important characteristics of the vaccine were (1) a delay in development of full protection, (2) prevention of clinical disease but not of infection and (3) a waning period of protection in the absence of challenge. We considered three different scenarios in which the vaccine might be used: prophylactically in susceptible cattle prior to the introduction of infection into a herd; in susceptible cattle in the face of an epidemic (i.e., when the infection is introduced and disease is first noticed); and at equilibrium (i.e., when parasite, vector and host have been co-existing for some time). The epidemic rise in infection was modelled assuming two different patterns (i.e., resulting from slow and fast increases in tick challenge). Vaccination (administered both in the face of an epidemic and prophylactically) reduced and delayed the peak of the epidemic. With insufficiently frequent revaccination, this can result in the epidemic occurring during a period of susceptibility, so that the benefit derived from a more-efficacious vaccine is lower than that from a less-efficacious vaccine. A vaccine of only 30% or 50% efficacy (if given to the whole herd) can have important effects on both morbidity and mortality if administered with sufficient frequency. However, a highly efficacious vaccine (e.g., 90%) can have only minimal effect if revaccination occurs too infrequently - especially if the epidemic of disease occurs when tick challenge is high and vaccination-related immunity has waned. There was a fairly consistent pattern of decreasing returns on increasing protection, although this was reversed in the situation of annual vaccination undertaken prophylactically combined with an epidemic of infection that occurred when the tick challenge was relatively low. Vaccination in equilibrium situations was most beneficial at low and intermediate tick challenges. There was very little effect of vaccination in high-transmission areas regardless of vaccine efficacy and/or frequency of revaccination because most animals were infected during periods of innate or maternally derived immunity (i.e., under endemic stability). Our results suggest that where relatively high tick challenge can be achieved and consistently maintained, vaccination may be used in susceptible herds to minimise losses in a policy of transition to endemic stability.


The Natural (non-invasive) Erection Test: Is it a reliable alternative to the artificial erection test?
To test the accuracy and reliability of the natural erection test (NET) as compared to the artificial erection test in assessing penile curvature in hypospadias. 50 children underwent both natural and artificial erection tests intraoperatively between January 2020 and October 2021. These included 5 glandular, 26 distal, 9 proximal, and 10 perineal hypospadias patients with curvature. The mean follow up period was 20 months (range 16-37). Under anesthesia, the curvature was assessed before degloving, then after degloving using both the natural and the artificial erection test. The NET test was repeated after curvature correction (3 times per patient). The measurements were analyzed using paired t-test. Two fingers of the left hand press just below the symphysis pubis to stop blood drainage from the penis and two fingers of the right hand massage the blood from the perineum distally into the penis until it becomes hard without tourniquet. The standard artificial erection test was performed using saline injected through a butterfly needle into the corporeal bodies without tourniquet. Photos were taken of both tests using the exact angle and angle of curvature was measured using Angle Meter App. There was no statistically significant difference between both erection tests with a P value of 0.705. The Bland-Altman plot also showed that all studied children have a difference in their natural and artificial erection tests within the limits of agreements. Erection is commonly induced using the artificial saline injected erection test first described by Gittes and less commonly using pharmaceutical erection test first described by Perovic. The severity of chordee apparent during artificial erection test varies with the amount of pressure used during injection. Also, it is difficult to place the tourniquet proximal enough to detect chordee at the base of the penis. It may be associated with hematoma formation, oedema, postoperative pain and the need for multiple punctures to assess the curvature before and after repair. Disadvantages of the pharmacological-induced erections in hypospadias include increased blood loss during erection, additional cost, and the need for a reversal agent. The natural erection test mimic the normal erection mechanism and may avoid all these potential disadvantages. The study showed that the natural erection test is easy to perform, non-invasive, non-traumatic and can be repeated several times intraoperatively without the need of repeated puncturing of the corpora cavernosa and avoids the potential risks and complications of the artificial erection test.


The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.


The impact of childhood maltreatment on biological systems: Implications for clinical interventions.
Childhood maltreatment represents a significant risk factor for the development of a number of mental and physical health outcomes. Converging evidence suggests that early adversity induces significant and persistent biological changes in individuals ('biological embedding'). The present review focuses on the impact of childhood maltreatment on the hypothalamic-pituitary-adrenal axis and immune system function in both children and adults. Research suggests that childhood maltreatment is associated with hypothalamic-pituitary-adrenal axis dysregulation and diurnal cortisol profiles, as well as stress reactivity. Furthermore, childhood maltreatment is associated with disruptions in various immune system markers including pro- and anti-inflammatory substances, and markers of cell-mediated immunity. The potential of interventions to reduce these negative biological effects in maltreated children is also discussed.


Genetic Silencing of Fatty Acid Desaturases Modulates α-Synuclein Toxicity and Neuronal Loss in Parkinson-Like Models of C. elegans.
The molecular basis of Parkinson's disease (PD) is currently unknown. There is increasing evidence that fat metabolism is at the crossroad of key molecular pathways associated with the pathophysiology of PD. Fatty acid desaturases catalyze synthesis of saturated fatty acids from monounsaturated fatty acids thereby mediating several cellular mechanisms that are associated with diseases including cancer and metabolic disorders. The role of desaturases in modulating age-related neurodegenerative manifestations such as PD is poorly understood. Here, we investigated the effect of silencing Δ9 desaturase enzyme encoding fat-5 and fat-7 genes which are known to reduce fat content, on α-synuclein expression, neuronal morphology and dopamine-related behaviors in transgenic PD-like models of Caenorhabditis elegans (C. elegans). The silencing of the fat-5 and fat-7 genes rescued both degeneration of dopamine neurons and deficits in dopamine-dependent behaviors, including basal slowing and ethanol avoidance in worm models of PD. Similarly, silencing of these genes also decreased the formation of protein aggregates in a nematode model of PD expressing α-synuclein in the body wall muscles and rescued deficits in resistance to heat and osmotic stress. On the contrary, silencing of nhr-49 and tub-1 genes that are known to increase total fat content did not alter behavioral and pathological endpoints in the PD worm strains. Interestingly, the genetic manipulation of all four selected genes resulted in differential fat levels in the PD models without having significant effect on the lifespan, further indicating a complex fat homeostasis unique to neurodegenerative pathophysiology. Overall, we provide a comprehensive understanding of how Δ9 desaturase can alter PD-like pathology due to environmental exposures and proteotoxic stress, suggesting new avenues in deciphering the disease etiology and possible therapeutic targets.


Frequency doubling perimetry in resolved optic neuritis.
To study the visual field with frequency doubling technology (FDT) in patients with recovered optic neuritis and to detect loss of magnocellular projecting cells (M cells) in the extrafovea. Fourteen patients who had undergone one attack of optic neuritis and recovered normal vision (1.0 or better) and critical fusion frequency were examined with conventional Humphrey automated perimetry central 30-2 and FDT c-20 threshold tests. After 1 year, 12 patients were reexamined with central 30-2 and FDT c-20 tests. The visual fields examined by both perimeters were divided into three zones. The mean sensitivity in each zone in involved eyes, uninvolved eyes, and involved eyes after 1 year was compared with that in healthy eyes. Conventional automated perimetry showed depression toward the fovea. However, FDT demonstrated general depression, especially midperipheral deficits. After 1 year, the midperipheral deficits with frequency doubling perimetry (FDP) improved, as did central depression, as observed with central 30-2 tests. FDT was developed to detect early glaucomatous damage, which was thought to be caused by a loss of M cells. Our study suggested that patients with resolved optic neuritis also had a loss of M-cell function in the extrafoveal area, as observed by field damage and its recovery.


A conserved HOTAIRM1-HOXA1 regulatory axis contributes early to neuronal differentiation.
HOTAIRM1 is unlike most long non-coding RNAs in that its sequence is highly conserved across mammals. Such evolutionary conservation points to it having a role in key cellular processes. We previously reported that HOTAIRM1 is required to curb premature activation of downstream HOXA genes in a cell model recapitulating their sequential induction during development. We found that it regulates 3' HOXA gene expression by a mechanism involving epigenetic and three-dimensional chromatin changes. Here we show that HOTAIRM1 participates in proper progression through the early stages of neuronal differentiation. We found that it can associate with the HOXA1 transcription factor and contributes to its downstream transcriptional program. Particularly, HOTAIRM1 affects the NANOG/POU5F1/SOX2 core pluripotency network maintaining an undifferentiated cell state. HOXA1 depletion similarly perturbed expression of these pluripotent factors, suggesting that HOTAIRM1 is a modulator of this transcription factor pathway. Also, given that binding of HOTAIRM1 to HOXA1 was observed in different cell types and species, our results point to this ribonucleoprotein complex as an integral part of a conserved HOTAIRM1-HOXA1 regulatory axis modulating the transition from a pluripotent to a differentiated neuronal state.


Effect of temperature during the incubation period on tibial growth plate chondrocyte differentiation and the incidence of tibial dyschondroplasia.
Tibial dyschondroplasia (TD) is one of the most prevalent skeletal abnormalities in avian species, causing enormous economic losses and major animal welfare problems. Irregular cell differentiation of the chondrocytes that populate the growth plate has been hypothesized to be involved in the etiology of the disease. We evaluated the effect of incubation temperature at various stages of embryo development and bone formation on growth plate chondrocyte differentiation and the incidence of TD. Eggs were incubated either at a control temperature of 37.8 degrees C, or at 36.9 or 39 degrees C, each for 6 h/ d, during early (0 to 8 d) or late (10 to 18 d) embryo development. At 14 d of incubation and at hatch, tibias were collected and weighed, and their ash and calcium contents were determined. Growth plate chondrocyte differentiation was evaluated by alkaline phosphatase activity and collagen type II and osteopontin gene expression. In addition, the level of the heat-shock protein 90 (Hsp90) was evaluated by immunohistochemistry. The rest of the chicks were raised to 49 d and the incidence of TD was recorded. The incidence of TD increased only when the temperature was altered at the early stages of embryo development, and it was correlated with an increase in tibia ash but not with tibia weight or calcium content. Moreover, increased TD incidence was correlated with delayed chondrocyte differentiation. Early changes in incubation temperature caused an increase in the level of Hsp90 in articular and differentiated chondrocytes of the hypertrophic zone and in the numbers of distinct undifferentiated chondrocytes arranged in columns in the proliferative zone of the growth plate. In summary, the early stages of embryo development and bone formation are of utmost importantance for appropriate growth plate chondrocyte differentiation, and any temperature deviation will increase the subsequent incidence of TD. The increase in TD incidence is probably the result of delayed Hsp90-driven chondrocyte differentiation, supporting the hypothesis that TD is the result of abnormal chondrocyte differentiation.


The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals.
It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population. The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of 13 017 French adults (7876 women aged 35-60 years and 5141 men aged 45-60 years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium, and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], 0.53-0.91]) but not in women (relative risk, 1.04 [95% CI, 0.85-1.29]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, 0.42-0.93] in men vs 1.03 [95% CI, 0.64-1.63] in women; P = .11 for interaction). After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene.


The Impact of Coping With Stressful Events on Negative Affect and Cravings Among Smokers With Mood Disorders.
Smokers with mental illness report elevated levels of stress and negative affect. Craving is often cited as a key precipitant of smoking. Coping with stress has been associated with reduced cravings among smokers attempting to quit. However, the effect of coping with stress on negative affect and craving among smokers with mental illness is not well understood. This study investigated whether coping with stress predicts lower subsequent craving, mediated by reduced negative affect, among socioeconomically disadvantaged smokers with mood disorders. This study used ecologically momentary assessment (EMA) data from a randomized controlled trial involving smokers with mood disorders. The final sample included 39 participants. Traditional mediation path analyses showed that coping with stress predicts lower craving (p = .02) through its impact on negative affect (p < .001) for the contemporaneous model (ie, when craving was measured at the same report as coping). However, coping with stress did not have a prospective effect on craving (ie, when craving was measured at the next report, up to 12 hours later) (p = .11). The results suggest that coping with stress reduces craving through negative effect, but only for a limited timeframe. The findings could guide future research on the length of time that the effect of coping lasts and research on interventions to increase coping with stress among smokers with mental illness. This is the first study to use EMA to demonstrate that coping with stressful events effectively reduces craving through reducing negative affect among smokers with mood disorders. This finding suggests that individuals heavily burdened with stress and negative affect benefit from coping with stress. We utilized within-subject analyses of EMA data which allowed us to understand these effects within an individual near real time. Our sample is hard to reach and ethnoculturally diverse. Findings could guide intervention research on helping smokers with mental illness cope when experiencing stress.