Freeze duration influences postfreeze survival in the frog Rana sylvatica.
Survival, cryoprotection, and the time course for recovery of vital functions were studied in autumn-collected juvenile wood frogs (Rana sylvatica) following freezing at -1.5 degrees C for various periods. Frogs readily tolerated freezing for 3 or 9 d, but only 50% survived a 28-d freezing trial. Generally, the postfreeze return of vital functions (vascular circulation, pulmonary breathing, righting reflex, jumping reflex) occurred later in frogs frozen for longer periods. Augmenting endogenous levels of the cryoprotectant glucose (via injections) prior to freezing substantially increased freeze endurance, as these frogs had excellent survival after remaining frozen for as long as 49 d. The improved freeze endurance of glucose-loaded frogs apparently was not associated with a reduction in ice content but rather may reflect the greater availability of energy substrate needed to support metabolism of frozen ischemic tissues.


A Novel Approach for the Discovery of Biomarkers of Radiotherapy Response in Breast Cancer.
Radiotherapy (RT) is an important treatment modality for the local control of breast cancer (BC). Unfortunately, not all patients that receive RT will obtain a therapeutic benefit, as cancer cells that either possess intrinsic radioresistance or develop resistance during treatment can reduce its efficacy. For RT treatment regimens to become personalised, there is a need to identify biomarkers that can predict and/or monitor a tumour's response to radiation. Here we describe a novel method to identify such biomarkers. Liquid chromatography-mass spectrometry (LC-MS) was used on conditioned media (CM) samples from a radiosensitive oestrogen receptor positive (ER+) BC cell line (MCF-7) to identify cancer-secreted biomarkers which reflected a response to radiation. A total of 33 radiation-induced secreted proteins that had higher (up to 12-fold) secretion levels at 24 h post-2 Gy radiation were identified. Secretomic results were combined with whole-transcriptome gene expression experiments, using both radiosensitive and radioresistant cells, to identify a signature related to intrinsic radiosensitivity. Gene expression analysis assessing the levels of the 33 proteins showed that 5 (YBX3, EIF4EBP2, DKK1, GNPNAT1 and TK1) had higher expression levels in the radiosensitive cells compared to their radioresistant derivatives; 3 of these proteins (DKK1, GNPNAT1 and TK1) underwent in-lab and initial clinical validation. Western blot analysis using CM samples from cell lines confirmed a significant increase in the release of each candidate biomarker from radiosensitive cells 24 h after treatment with a 2 Gy dose of radiation; no significant increase in secretion was observed in the radioresistant cells after radiation. Immunohistochemistry showed that higher intracellular protein levels of the biomarkers were associated with greater radiosensitivity. Intracellular levels were further assessed in pre-treatment biopsy tissues from patients diagnosed with ER+ BC that were subsequently treated with breast-conserving surgery and RT. High DKK1 and GNPNAT1 intracellular levels were associated with significantly increased recurrence-free survival times, indicating that these two candidate biomarkers have the potential to predict sensitivity to RT. We suggest that the methods highlighted in this study could be utilised for the identification of biomarkers that may have a potential clinical role in personalising and optimising RT dosing regimens, whilst limiting the administration of RT to patients who are unlikely to benefit.


[Social equity in the health domain].
In the European debate on equity in health and health care a crucial question has received scant consideration. It concerns the precise specification of a health system's objectives and the manner by which they can be suitably interpreted to permit monitoring of implemented policies. This article is an attempt to review actual and potential contributions to this area of study. It adopts the view that the meaning of equity in the health domain depends crucially on how social justice is defined and that this in turn depends on value judgements or the views of society held by individuals, groups or governments. Such an approach allows one to choose principles of distribution which are in agreement with a society's value set and subsequently to apply them as the correct yardstick for measuring the success of policy. Following an initial exposition of the approach, the main body of the article discusses the question of competing theories of society - Libertarian, Liberal and Democratic Socialist - and appraises the various distribution principles, to be found in the economic and philosophical literature, which they imply. The final section offers some brief conclusions and avenues for further research.


Dairy and Plant-Based Dairy Alternatives Purchasing Habits of Guelph-Based Families with Preschool-Aged Children.
Purpose: To investigate dairy and plant-based dairy alternatives (DPBDA) purchasing habits, including comparisons among locations of purchase and among subtypes of DPBDA, of families with preschool-aged children.Methods: Expenditures on food and DPBDA were calculated using grocery and food receipts collected for 3 weeks from 51 households in and around Guelph, Ontario, Canada. DPBDA were coded by subtypes (alternatives, cheese/yogurt, cow's milk, cream, and ice cream/other) and by locations of purchase, which were coded as big-box, discount, high-end, local/other, and midrange stores. Logistic regression using generalized estimating equations was used to investigate odds of purchasing DPBDA by location of purchase. All models included family income and number of children as potential confounders.Results: Ninety-eight percent of families purchased cheese/yogurt, 92% purchased cow's milk, and 35% of families purchased plant-based dairy alternatives. Families were more likely to purchase DPBDA from big-box stores than discount, midrange, or local/other stores (P < 0.01) and were more likely to purchase cheese/yogurt than dairy alternatives, cream, or ice cream/other subtypes (P < 0.01). Odds of purchasing were not different between cheese/yogurt and cow's milk.Conclusion: Families' DPBDA purchasing habits differ by purchase location and subtype. Further research is warranted to understand the factors affecting these purchasing habits.


Cloning of transforming growth factor-beta 1 (TGF-beta 1) and its type II receptor from zebrafish ovary and role of TGF-beta 1 in oocyte maturation.
TGF-beta is a multifunctional factor involved in regulating a variety of cellular activities. In mammals, TGF-beta is known to regulate reproduction, including ovarian functions. The role of TGF-beta in lower vertebrates, such as fish, is poorly understood. To examine the role of TGF-beta in fish reproduction, cDNAs encoding TGF-beta 1 and the type II TGF-beta receptor (T beta RII) were cloned from the zebrafish ovary using PCR- based strategies. The mature peptide region of the zebrafish TGF-beta 1 shows 70-85% identity with TGF-beta 1 from other species. The zebrafish T beta RII cDNA sequence is the first to be reported from a fish species, and it shows a high level of conservation at the kinase domain. Using RT-PCR, we have detected mRNA expression of TGF-beta 1, T beta RII, as well as its downstream signaling molecules Smad2, 3, and 4 in ovarian follicles at different stages of development. In addition, we have examined the effect of TGF-beta 1 on oocyte maturation. TGF-beta 1 significantly inhibited both gonadotropin- and 17 alpha, 20 beta-dihydroxyprogesterone-induced oocyte maturation in a dose- and time-dependent manner. These findings demonstrate, for the first time, that TGF-beta 1 plays a role in regulating oocyte maturation in fish and suggest that a TGF-beta/Smad signaling pathway is present in the zebrafish ovary.


Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease.
Individuals with serum alpha1-antitrypsin levels below 80 mg/dl are clearly at risk for the development of accelerated panacinar emphysema. One possible approach to the therapy of this disorder would be to raise serum levels of this major antiprotease to establish protease-antiprotease homeostasis within the lung parenchyma. Because danazol, an impeded androgen, elevates levels of C1 inhibitor in patients deficient of that serum antiprotease, we hypothesized that this agent might also increase alpha1-antitrypsin levels in patients with alpha1-antitrypsin deficiency. To evaluate this concept, seven patients with severe emphysema associated with alpha1-antitrypsin deficiency (six PiZ and 1 M(Duarte)Z) and one asymptomatic individual (PiSZ) received 600 mg of danazol daily for 30 d. Five of the six PiZ patients responded to danazol therapy with significant increases in serum alpha1-antitrypsin levels (mean increase of 37%; P < 0.03). The two individuals who were heterozygous for the Z protein increased their serum levels by 85% (PiM(Duarte)Z) and 87% (PiSZ), respectively. These increases in serum alpha1-antitrypsin antigen were accompanied by commensurate increases in serum trypsin inhibition. Crossed immunoelectrophoresis showed no alterations of the microheterogeneity of the alpha1-antitrypsin or the presence of protease-antiprotease complexes in serum during danazol therapy. These data demonstrate that serum alpha1-antitrypsin levels can be augmented by danazol therapy in PiZ individuals as well as those heterozygotes with severe deficiency of alpha1-antitrypsin. The clinical relevance of these increases in serum alpha1-antitrypsin remains speculative, but these findings suggest that danazol may provide a means of improving the protease-antiprotease balance in these individuals and thus impede the progression of their lung disease.


A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa.
HTLV-1 infection is endemic to Central African populations. The risk factors for HTLV-1 acquisition in humans via the interspecies transmission of STLV-1 (its simian counterpart) remain largely unknown. We studied 269 individuals (254 men, 15 women) bitten by a nonhuman primate (NHP), mostly during hunting activities. These, Pygmies and Bantus, living in the southern Cameroonian rainforest, were matched for sex, age, and ethnicity with individuals from the same settlements reporting no NHP bites. HTLV-1 serology was performed by Western blot on plasma samples. PCR was carried out for HTLV-1 provirus on buffy-coat DNAs. The amplified products were sequenced and analyzed by phylogenetic analyses. HTLV-1 prevalence was 8.6% (23/269) in individuals with bites, vs 1.5% (4/269) in matched controls (P < .001). Moreover, HTLV-1 infection was linked to bite severity. The 23 HTLV-1-positive bitten individuals reported being bitten by a gorilla (17), chimpanzee (3), or small monkey (3). Thirteen (56%) were coinfected with a simian foamy virus known to be acquired through severe bites. Mother-to-child infection was excluded in 6 HTLV-1-infected bitten individuals. All the HTLV-1-positive hunters bitten by a gorilla or chimpanzee were infected with a subtype B strain similar to that present in apes from the same area. Two hunters bitten by small monkeys (C. agilis in one case) were infected with a HTLV-1 subtype F strain very similar to the STLV-1 strains present in such monkeys. These results strongly suggest ongoing direct zoonotic acquisition of STLV-1 in humans through severe NHP bites during hunting activities.


Orbital metastasis of prostatic carcinoma.
This paper describes a man with previously undetected prostatic carcinoma who presented with mild symptoms due to an orbital metastasis. The case is unusual in that the patient was relatively asymptomatic and had 6/7 vision. Carcinoma of the prostate metastatic to the orbit is rare; this is only the 22nd case in the literature.


Reduced muscle activation during exercise related to brain oxygenation and metabolism in humans.
Maximal exercise may be limited by central fatigue defined as an inability of the central nervous system to fully recruit the involved muscles. This study evaluated whether a reduction in the cerebral oxygen-to-carbohydrate index (OCI) and in the cerebral mitochondrial oxygen tension relate to the ability to generate a maximal voluntary contraction and to the transcranial magnetic stimulated force generation. To determine the role of a reduced OCI and in central fatigue, 16 males performed low intensity, maximal intensity and hypoxic cycling exercise. Exercise fatigue was evaluated by ratings of perceived exertion (RPE), arm maximal voluntary force (MVC), and voluntary activation of elbow flexor muscles assessed with transcranial magnetic stimulation. Low intensity exercise did not produce any indication of central fatigue or marked cerebral metabolic deviations. Exercise in hypoxia (0.10) reduced cerebral oxygen delivery 25% and decreased 11+/-4 mmHg (P<0.001) together with OCI (6.2+/-0.7 to 4.8+/-0.5, P<0.001). RPE increased while MVC and voluntary activation were reduced (P<0.05). During maximal exercise declined 8+/-4 mmHg (P<0.05) and OCI to 3.8+/-0.5 (P<0.001). RPE was 18.5, and MVC and voluntary activation were reduced (P<0.05). We observed no signs of muscular fatigue in the elbow flexors and all control MVCs were similar to resting values. Exhaustive exercise provoked cerebral deoxygenation, metabolic changes and indices of fatigue similar to those observed during exercise in hypoxia indicating that reduced cerebral oxygenation may play a role in the development of central fatigue and may be an exercise capacity limiting factor.


[Reactogenecity and immunogenecity of Cuban trivalent inactivated vaccine against human leptospirosis in different vaccination schedules].
A controlled, randomized assay was performed to evaluate the reactogenecity and immunogenecity of Cuban trivalent vaccine against human leptospirosis (vax-SPIRAL) in healthy volunteers, using different vaccination schemes. A Russian-made vaccine was used as control. Adverse effects were local symptoms and signs (pain, rush, local infiltration, itching, necrosis and abscess) and general symptoms and signs(fever, low-grade fever, headache, lipotimia, nausea, vomiting, rash and general malaise). The results showed that the vaccine is innocuous since no serious adverse effects were observed. Low-grade fever and slight local pain were the symptoms and signs that occurred at acceptable levels. Fever was present in a small number of volunteers. Similar adverse reactions were reported in the groups immunized with Cuban vaccine under different vaccination schemes and in those immunized with the Russian-made vaccine. Most of the symptoms and signs disappeared after 72 hours. Seroconversion was similar to other bacterines against leptospirosis. The achieved results allowed concluding that the Cuban vaccine is safe and low reactogenic for human adults.


[Biosynthesis of the antibiotic, grizin, by prototrophic revertants of Streptomyces griseus biochemical mutants].
Spontaneous and nitrosomethylbiuret-induced prototrophic revertants of various biochemical mutants of Str. griseus producing grisin, a streptothricin antibiotic, were isolated. The antibiotic production level of the revertants was studied. It was found that most of the prototrophic revertants synthesized much higher amounts of grisin than the initial biochemical mutants. It was also shown that a number of the prototrophic revertants of the methionine- and arginine-dependent mutants synthesized 20-23% higher amounts of grisin as compared to the control.


The neuroanatomy of depression: A review.
Depression is the most common psychiatric disorder, the number one cause of disability and affects up to 15% of the population. The aim of this review is to present a brief synopsis of the various biochemical imbalances thought to contribute to depression, aspects of anatomy possibly implicated in depression, and treatments related to targeting these specific locales. Multiple neurotransmitters and parts of the brain are involved with the disorder of depression. Although an exact etiology for depression has not been found in most cases, various treatments, medicinal, psychiatric and surgical, exist for this disabling disease. An improved knowledge of anatomical sites involved in patients with depression will help in future treatment modalities. Clin. Anat. 30:44-49, 2017. © 2016 Wiley Periodicals, Inc.


Low dose of morphine to relieve dyspnea in acute respiratory failure (OpiDys): protocol for a double-blind randomized controlled study.
Dyspnea is common and severe in intensive care unit (ICU) patients managed for acute respiratory failure. Dyspnea appears to be associated with impaired prognosis and neuropsychological sequels. Pain and dyspnea share many similarities and previous studies have shown the benefit of morphine on dyspnea in patients with end-stage onco-hematological disease and severe heart or respiratory disease. In these populations, morphine administration was safe. Here, we hypothesize that low-dose opioids may help to reduce dyspnea in patients admitted to the ICU for acute respiratory failure. The primary objective of the trial is to determine whether the administration of low-dose titrated opioids, compared to placebo, in patients admitted to the ICU for acute respiratory failure with severe dyspnea decreases the mean 24-h intensity of dyspnea score. In this single-center double-blind randomized controlled trial with 2 parallel arms, we plan to include 22 patients (aged 18-75 years) on spontaneous ventilation with either non-invasive ventilation, high flow oxygen therapy or standard oxygen therapy admitted to the ICU for acute respiratory failure with severe dyspnea. They will be assigned after randomization with a 1:1 allocation ratio to receive in experimental arm administration of low-dose titrated morphine hydrochloride for 24 h consisting in an intravenous titration relayed subcutaneously according to a predefined protocol, or a placebo (0.9% NaCl) administered according to the same protocol in the control arm. The primary endpoint is the mean 24-h dyspnea score assessed by a visual analog scale of dyspnea. To our knowledge, this study is the first to evaluate the benefit of opioids on dyspnea in ICU patients admitted for acute respiratory failure. ClinicalTrials.gov NCT04358133 . Registered on 24 April 2020.


Nerve tolerance to high-dose-rate brachytherapy in patients with soft tissue sarcoma: a retrospective study.
Brachytherapy, interstitial tumor bed irradiation, following conservative surgery has been shown to provide excellent local control and limb preservation in patients with soft tissue sarcomas (STS), whereas little is known about the tolerance of peripheral nerves to brachytherapy. In particular, nerve tolerance to high-dose-rate (HDR) brachytherapy has never been properly evaluated. In this study, we examined the efficacy and radiation neurotoxicity of HDR brachytherapy in patients with STS in contact with neurovascular structures. Between 1995 and 2000, seven patients with STS involving the neurovascular bundle were treated in our institute with limb-preserving surgery, followed by fractionated HDR brachytherapy. Pathological examination demonstrated that 6 patients had high-grade lesions with five cases of negative margins and one case with positive margins, and one patient had a low-grade lesion with a negative margin. Afterloading catheters placed within the tumor bed directly upon the preserved neurovascular structures were postoperatively loaded with Iridium-192 with a total dose of 50 Gy in 6 patients. One patient received 30 Gy of HDR brachytherapy combined with 20 Gy of adjuvant external beam radiation. With a median follow-up of 4 years, the 5-year actuarial overall survival, disease-free survival, and local control rates were 83.3, 68.6, and 83.3%, respectively. None of the 7 patients developed HDR brachytherapy-induced peripheral neuropathy. Of 5 survivors, 3 evaluable patients had values of motor nerve conduction velocity of the preserved peripheral nerve in the normal range. In this study, there were no practical and electrophysiological findings of neurotoxicity of HDR brachytherapy. Despite the small number of patients, our encouraging results are valuable for limb-preserving surgery of unmanageable STS involving critical neurovascular structures.


Anticholinergics for overactive bladder therapy: central nervous system effects.
The mainstay of pharmacological treatment of overactive bladder (OAB) is anticholinergic therapy using muscarinic receptor antagonists (tertiary or quaternary amines). Muscarinic receptors in the brain play an important role in cognitive function, and there is growing awareness that antimuscarinic OAB drugs may have adverse central nervous system (CNS) effects, ranging from headache to cognitive impairment and episodes of psychosis. This review discusses the physicochemical and pharmacokinetic properties of OAB antimuscarinics that affect their propensity to cause adverse CNS effects, as observed in phase III clinical trials and in specific investigations on cognitive function and sleep architecture. PubMed/MEDLINE was searched for "OAB" plus "muscarinic antagonists" or "anticholinergic drug." Additional relevant literature was identified by examining the reference lists of papers identified through the search. Preclinical and clinical trials in adults were assessed, focusing on the OAB antimuscarinics approved in the United States. The blood-brain barrier (BBB) plays a key role in protecting the CNS, but it is penetrable. The lipophilic tertiary amines, particularly oxybutynin, are more likely to cross the BBB than the hydrophilic quaternary amine trospium chloride, for which there are very few reports of adverse CNS effects. In fact, in 2008 the US product labels for oral oxybutynin were modified to include the potential for anticholinergic CNS events and a warning to monitor patients for adverse CNS effects. Even modest cognitive impairment in the elderly may negatively affect independence; therefore, selection of an antimuscarinic OAB drug with reduced potential for CNS effects is advisable.


Are ferric compounds useful in treatment of iron deficiency anemia?
The effect of ferric compounds in therapy of iron deficiency anemia is doubtful; however, the absorption of iron is not affected negatively by food or drugs. In our Well Baby Clinic, ferric polymaltose (6 mg/kg/d) was given to 59 infants (Group 1) and ferrous sulphate (same doses) was given to 64 infants (Group 2) (74 +/- 9 d, 70 +/- 7 d, respectively). These infants had iron deficiency anemia, and their therapy was continuous. Ferric polymaltose was not as effective as ferrous sulphate, although it increased hemoglobin and serum iron. Mean corpuscular volume and serum ferritin were not significantly changed after therapy. For this reason, we prefer to use only ferrous salts in therapy.


Functional genomics in radiation biology: a gateway to cellular systems-level studies.
Cells respond to ionizing radiation through an intricate network of interacting signaling cascades that are engaged in the regulation of diverse cellular functions, such as cell cycle arrest, DNA repair, and apoptosis. While changes in protein modification, activity, and sub-cellular localization may directly mediate these responses, alterations in gene expression also represent a central component of the pathways involved. Studies of altered gene expression have historically played an important role in elucidating the molecular mechanisms underlying cellular radiation response. In recent years, functional genomics approaches, such as microarray profiling, have been developed that can simultaneously monitor changes in gene expression across essentially the entire genome. However, analogous methods for global measurements of protein expression or modification have lagged behind. As global transcription profiling has become increasingly accessible, the quantity of information on gene expression responses to irradiation has increased dramatically. While many such experiments have provided improved insight into various aspects of radiation response, the diversity of experimental models and details of radiation dose, timing, and data analysis that have been employed means that no single consistent picture has emerged yet. More sophisticated methods for data analysis, data mining, and reverse engineering to reconstruct the underlying response pathways are continually being developed, and can extract additional value from profiling studies. As methods for the global study of other biomolecules become more routine, it will be important to integrate the results of radiation response profiling across multiple biological levels, and to build from simpler experimental systems toward more complex multi-cellular and in vivo systems. The future development of "integromic" models of radiation response should add substantially to the understanding gained from gene expression studies alone.


Is There Any Hope? How Climate Change News Imagery and Text Influence Audience Emotions and Support for Climate Mitigation Policies.
Using a national sample, this study experimentally tests the effects of news visuals and texts that emphasize either the causes and impacts of climate change or actions that can be taken to address climate change. We test the effects of variations in text and imagery on discrete emotions (i.e., hope, fear, and anger) and, indirectly, on support for climate mitigation policies. Political ideology is examined as a moderator. The findings indicate that news images and texts that focus on climate-oriented actions can increase hope and, in the case of texts, decrease fear and anger, and these effects generally hold across the ideological spectrum. In turn, the influence of emotions on policy support depends on ideology: Hope and fear increase support for climate policies for all ideological groups but particularly conservatives, whereas anger polarizes the opinions of liberals and conservatives. Implications for climate change communication that appeals to emotions are discussed.


Nuclear face of Tau: an inside player in neurodegeneration.
Tau (Tubulin associated unit) protein is a major hallmark of Alzheimer's disease (AD) and tauopathies. Tau is predominantly an axonal protein with a crucial role in the stabilization and dynamics of the microtubules. Since the discovery of Tau protein in 1975, research efforts were concentrated on the pathophysiological role of Tau protein in the context of the microtubules. Although, for more than three decades, different localizations of Tau protein have been discovered e.g., in the nuclear compartments. Discovery of the role of Tau protein in various cellular compartments especially in the nucleus opens up a new fold of complexity in tauopathies. Data from cellular models, animal models, and the human brain indicate that nuclear Tau is crucial for genome stability and to cope with cellular distress. Moreover, it's nature of nuclear translocation, its interactions with the nuclear DNA/RNA and proteins suggest it could play multiple roles in the nucleus. To comprehend Tau pathophysiology and efficient Tau-based therapies, there is an urgent need to understand whole repertoire of Tau species (nuclear and cytoplasmic) and their functional relevance. To complete the map of Tau repertoire, understanding of various species of Tau in the nucleus and cytoplasm, identification if specific transcripts of Tau, isoforms and post-translational modifications could foretell Tau's localizations and functions, and how they are modified in neurodegenerative diseases like AD, is urgently required. In this review, we explore the nuclear face of Tau protein, its nuclear localizations and functions and its linkage with Alzheimer's disease.


Restorative valve therapy by endogenous tissue restoration: tomorrow's world? Reflection on the EuroPCR 2017 session on endogenous tissue restoration.
The current standard of treatment of valvular diseases with severe functional and/or clinical consequences is the repair or replacement of the valve, which is usually surgical or, in specific scenarios, percutaneous. The available prosthetic valves, however, are not a magic bullet in the physicians' arsenal for the management of valvular diseases, since the age-dependent structural valve deterioration (SVD) and the need for prolonged systemic anticoagulation in the case of metallic prosthetic valves are not inconsequential during the lifespan of a patient with an implanted prosthetic valve. Based on decades of research combining the scientific disciplines of supramolecular chemistry, electrospinning and regenerative medicine, endogenous tissue restoration has emerged as a very promising domain to provide this magic bullet, in the form of valves, which enables functional restoration by the body itself. The concept of a restorative material that will set the framework for the creation of a new, endogenous valve is very appealing and, recently, proof of concept studies have been completed at both preclinical and clinical levels. These studies have shown favourable pathologic, anatomic and haemodynamic characteristics compared to currently available prosthetic valves, in sheep and in young children undergoing right ventricular outflow tract reconstruction, and may represent an alternative to the bioprosthesis made of xenopericardial tissue. The present manuscript reviews the rationale, background knowledge and historic development of endogenous tissue restoration and presents preliminary data about the Xeltis valve, which appears to have the potential to make restorative valve therapy a reality in clinical practice.


[Intensity of free radical oxidation and the blood lipid fatty acid composition in ischemic heart disease].
A comprehensive study of the intensity of free radical oxydation of lipids, of changes in the total polyunsaturated free acids and antiradical activity of the blood lipids undertaken in 73 patients with different forms of ischaemic heart disease showed that in all forms of illness there exists intensification of peroxyde oxydation of lipids, more marked in acute myocardial infarction. Rise of antiradical activity of lipids is a sequel to activation of the compensatory mechanisms, directed at neutralization of the negative action of toxic lipid peroxydes. Correlation between the changes in the total polyunsaturated fatty acids and antiradical activity of the lipids permits one to consider that accumulation of polyene acids may be one of the factors helping the intensification of free radical processes.


Diagnostics in skeletal muscle channelopathies.
Skeletal muscle channelopathies (SMCs) are a heterogenous group of disorders, caused by mutations in skeletal ion channels leading to abnormal muscle excitability, resulting in either delayed muscle relaxation (myotonia) which characterizes non-dystrophic myotonias (NDMs), or membrane transient inactivation, causing episodic weakness, typical of periodic paralyses (PPs). SMCs include myotonia congenita, paramyotonia congenita, and sodium-channel myotonia among NDMs, and hyper-normokalemic, hypokalemic, or late-onset periodic paralyses among PPs. When suspecting an SMC, a structured diagnostic approach is required. Detailed personal and family history and clinical examination are essential, while neurophysiological tests should confirm myotonia and rule out alternative diagnosis. Moreover, specific electrodiagnostic studies are important to further define the phenotype of de novo cases and drive molecular analyses together with clinical data. Definite diagnosis is achieved through genetic testing, either with Sanger sequencing or multigene next-generation sequencing panel. In still unsolved patients, more advanced techniques, as exome-variant sequencing or whole-genome sequencing, may be considered in expert centers. The diagnostic approach to SMC is still mainly based on clinical data; moreover, definite diagnosis is sometimes complicated by the difficulty to establish a proper genotype-phenotype correlation. Lastly, further studies are needed to allow the genetic characterization of unsolved patients.


Vertebrobasilar dolichoectasia: evaluation with CT angiography.
We present three patients who were admitted to our institution with vertebrobasilar dolichoectasia diagnosed at CT angiography. Two patients had associated intraarterial thrombi and one patient had basilar artery dissection. Shaded surface display images were useful in showing arterial anatomy relative to the skull base. Source images and curved-reformatted images were helpful in diagnosing thrombi and dissection. CT angiography is a minimally invasive means of diagnosing and following up these patients.


Benefits of information technology-enabled diabetes management.
To determine the financial and clinical benefits of implementing information technology (IT)-enabled disease management systems. A computer model was created to project the impact of IT-enabled disease management on care processes, clinical outcomes, and medical costs for patients with type 2 diabetes aged >25 years in the U.S. Several ITs were modeled (e.g., diabetes registries, computerized decision support, remote monitoring, patient self-management systems, and payer-based systems). Estimates of care process improvements were derived from published literature. Simulations projected outcomes for both payer and provider organizations, scaled to the national level. The primary outcome was medical cost savings, in 2004 U.S. dollars discounted at 5%. Secondary measures include reduction of cardiovascular, cerebrovascular, neuropathy, nephropathy, and retinopathy clinical outcomes. All forms of IT-enabled disease management improved the health of patients with diabetes and reduced health care expenditures. Over 10 years, diabetes registries saved $14.5 billion, computerized decision support saved $10.7 billion, payer-centered technologies saved $7.10 billion, remote monitoring saved $326 million, self-management saved $285 million, and integrated provider-patient systems saved $16.9 billion. IT-enabled diabetes management has the potential to improve care processes, delay diabetes complications, and save health care dollars. Of existing systems, provider-centered technologies such as diabetes registries currently show the most potential for benefit. Fully integrated provider-patient systems would have even greater potential for benefit. These benefits must be weighed against the implementation costs.


Employing a teen advisory board to adapt an evidence-based HIV/STD intervention for incarcerated African-American adolescent women.
This manuscript assesses priorities and challenges of adolescent females by conducting a meeting with teen advisory board (TAB) members to collect information regarding their lives and experiences pre-, during and post-incarceration in a juvenile detention facility. Multiple themes emerged regarding the impact of incarceration on young African-American females, including experiencing a loss of personal liberties, the importance of making money upon release, unfaithfulness by partners on the 'outside', substance use and lack of control over their environment upon release, including parents, peers and male sexual partners. Based on feedback from TAB members, unique barriers and challenges were identified that suggested areas where adaptations to an evidenced-based HIV/sexually transmitted disease (STD) intervention would be justified to more adequately meet the needs of this particular subgroup of young African-American women. Adaptations to the evidence-based interventions included enhancing activities related to goal setting, emotion regulation skills, decision-making, recognizing and utilizing support networks and addressing the relationship between substance use and risky sexual behavior. Future health education efforts focusing on either the creation of new HIV/STD interventions or adaptations to existing interventions should consider utilizing advisory boards with members of the priority population at the earliest stages of intervention planning.


Genome-wide small nucleolar RNA expression analysis of lung cancer by next-generation deep sequencing.
Emerging evidence indicates that small nucleolar RNAs (snoRNAs), a class of small noncoding RNAs, may play important function in tumorigenesis. Nonsmall-cell lung cancer (NSCLC) is the number one cancer killer for men and women. Systematically characterizing snoRNAs in NSCLC will develop biomarkers for its early detection and prognostication. We used next-generation deep sequencing to comprehensively characterize snoRNA profiles in 12 NSCLC tissues. We used quantitative reverse transcription polymerase chain reaction (qRT-PCR) to verify the findings in 40 surgical Stage I NSCLC specimens and 126 frozen NSCLC tissues of different stages. The 126 NSCLC tissues were divided into a training set and a testing set. Deep sequencing identified 458 snoRNAs, of which, 29 had a ≥3.0-fold expression level change in Stage I NSCLC tissues versus normal tissues. qRT-PCR analysis showed that 16 of 29 snoRNAs exhibited consistent changes with deep sequencing data. The 16 snoRNAs exhibited 0.75-0.94 area under receiver-operator characteristic curve values in distinguishing lung tumor from normal lung tissues (all ≤0.0001) with 70.0-95.0% sensitivity and 70.0-95.0% specificity. Six genes (snoRA47, snoRA68, snoRA78, snoRA21, snoRD28 and snoRD66) were identified whose expressions were associated with overall survival of the NSCLC patients. A prediction model consisting of three genes (snoRA47, snoRA68 and snoRA78) was developed in the training set of 77 cases, which could significantly predict overall survival of the NSCLC patients (p < 0.0001). The prognostic performance of the prediction model was confirmed in the testing set of 49 NSCLC patients. The identified snoRNA signatures may provide potential biomarkers for the early detection and prognostication of NSCLC.


Gene regulation mediates host specificity of a bacterial pathogen.
Many bacterial plant pathogens have a gene-for-gene relationship that determines host specificity. However, there are pathogens such as the xylem-limited bacterium Xylella fastidiosa that do not carry genes considered essential for the gene-for-gene model, such as those coding for a type III secretion system and effector molecules. Nevertheless, X. fastidiosa subspecies are host specific. A comparison of symptom development and host colonization after infection of plants with several mutant strains in two hosts, grapevines and almonds, indicated that X. fastidiosa virulence mechanisms are similar in those plants. Thus, we tested if modification of gene regulation patterns, by affecting the production of a cell-cell signalling molecule (DSF), impacted host specificity in X. fastidiosa. Results show that disruption of the rpfF locus, required for DSF synthesis, in a strain incapable of causing disease in grapevines, leads to symptom development in that host. These data are indicative that the core machinery required for the colonization of grapevines is present in that strain, and that changes in gene regulation alone can lead X. fastidiosa to exploit a novel host. The study of the evolution and mechanisms of host specificity mediated by gene regulation at the genome level could lead to important insights on the emergence of new diseases.


"New age" pulp therapy: personal thoughts on a hot debate.
This article outlines the counterpoint delivered in the debate "Is Formocresol Obsolete?" It addresses the opinion supporting the need to move away from formaldehyde-containing preparations in the dental care of children. It is suggested that such a move should be made not just because of concerns relating to the possible toxicity of formaldehyde but to reflect a more contemporary, biologic approach to pulp therapy in the primary dentition.


Stimulation of human damaged sperm motility with hydrogen molecule.
Sperm motility is a critical factor in male fertility. Low motility can be caused by a variety factors including abnormal spermatogenesis, oxidative damage, or depletion of intracellular ATP. Recent findings indicate that hydrogen molecule (H2) selectively reduces toxic reactive oxygen species. In this study, we investigated the effects of H2 on human sperm motility in vitro. Experimentally damaged sperm suspensions from patients left at room temperature for > 5 days or frozen immediately after ejaculation were used. After exposure with H2, their forward motility was measured with a counting chamber. A time-lapse movie was recorded to analyze sperm swimming speed. Mitochondria were stained with a membrane potential-sensitive dye. H2 treatment significantly improved the rate of forward motility, whereas treatment with nitrogen gas did not. While treatment for 30 min was sufficient to improve motility, it did not affect sperm swimming speed. After 24 h, retreatment with H2 increased the motility again. H2 treatment also increased mitochondrial membrane potential. Forward motility of low motile frozen-thawed sperm from patients significantly improved with cleavage medium containing H2. Our results illustrated that H2 treatment stimulates low sperm motility. H2 is a new promising tool for male infertility treatments.


Self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics for magnetic resonance/photoacoustic/fluorescence imaging-guided synergistic photo-chemotherapy.
Carrier-free nanotheranostics directly assembled by using clinically used photosensitizers and chemotherapeutic drugs are a promising alternative to tumor theranostics. However, the weak interaction-driven assembly still suffers from low structural stability against disintegration, lack of targeting specificity, and poor stimulus-responsive property. Moreover, almost all exogenous ligands possess no therapeutic effect. Enlightened by the concept of metal-organic frameworks, we developed a novel self-recognizing metal-coordinated nanotheranostic agent by the coordination-driven co-assembly of photosensitizer indocyanine green (ICG) and chemo-drug methotrexate (MTX, also served as a specific "targeting ligand" towards folate receptors), in which ferric (FeIII) ions acted as a bridge to tightly associate ICG with MTX. Such carrier-free metal-coordinated nanotheranostics with high dual-drug payload (∼94 wt%) not only possessed excellent structural and physiological stability, but also exhibited prolonged blood circulation. In addition, the nanotheranostics could achieve the targeted on-demand drug release by both stimuli of internal lysosomal acidity and external near-infrared laser. More importantly, the nanotheranostics could self-recognize the cancer cells and selectively target the tumors, and therefore they decreased toxicity to normal tissues and organs. Consequently, the nanotheranostics showed strongly synergistic potency for tumor photo-chemotherapy under the precise guidance of magnetic resonance/photoacoustic/fluorescence imaging, thereby achieving highly effective tumor curing efficiency. Considering that ICG and bi-functional MTX are approved by the Food and Drug Administration, and FeIII ions have high biosafety, the self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics may hold potential applications in tumor theranostics.


Transgender and gender diverse health education for future nurses: Students' knowledge and attitudes.
Compared to cisgender peers, transgender and gender diverse (TGD) people experience significant health disparities associated with discrimination and limited access to appropriate care in healthcare settings. Nurses represent the largest segment of the United States (US) healthcare workforce; however, US nursing programs only dedicate approximately 2.12 h to Lesbian, Gay, Bisexual, and TGD (LGBT)-related content. To fill the gap in TGD-related nursing education, the Transgender Curriculum Integration Project (TCIP) developed and integrated an evidence-based curriculum specific to TGD health into the pre-licensure accelerated Bachelor's in Nursing Science (BSN) program at Johns Hopkins School of Nursing. The purpose of this study was to assess the preliminary efficacy and feasibility (i.e., attrition, engagement, acceptability) of the TCIP in improving the TGD-related health knowledge and attitudes among a sample of pre-licensure nursing students. TCIP utilized a self-administered online survey to assess students' knowledge and attitudes about TGD health prior to (time point 1) and following (time points 2 and 3) the integration of TGD-specific content into five nursing pre-licensure courses. Rank-based nonparametric testing using Kruskal-Wallis H and Mann-Whitney U were conducted to determine if there were statistically significant differences in responses between the three time points. Thematic content analysis was used to determine themes present among short answers. Findings indicate TGD-specific content improved student's gender sensitivity overtime, with improvements in self-reported skills in providing care for TGD people and knowledge of additional TGD-specific resources. However, gender sensitivity remains low among student's and students requested more TGD content suggesting room for further improvement. Findings support the efficacy of TCIP and highlight complexities of curricular change that can guide future curricular integration and evaluation in nursing programs nation-wide.


Maintenance of effects of the home environmental skill-building program for family caregivers and individuals with Alzheimer's disease and related disorders.
Few studies evaluate whether short-term intervention effects are maintained over time for families caring for persons with dementia. This article examines whether treatment effects found at 6 months following active treatment were sustained at 12 months for 127 family caregivers who participated in an occupational therapy intervention tested as part of the National Institutes of Health Resources for Enhancing Alzheimer's Caregiver Health (REACH) initiative. A randomized two-group design was implemented with three assessment points: baseline, 6 months, and 12 months. Caregivers were randomly assigned to a usual care control group or intervention that consisted of six occupational therapy sessions to help families modify the environment to support daily function of the person with dementia and reduce caregiver burden. Following 6-month active treatment, a maintenance phase consisted of one home and three brief telephone sessions to reinforce strategy use and obtain closure. Non-inferiority statistical analysis was used to evaluate whether intervention caregivers maintained treatment benefits from 6 to 12 months in comparison to controls. For the sample of 127 at 6 months, caregivers in intervention reported improved skills (p = .028), less need for help providing assistance (p = .043), and fewer behavioral occurrences (p = .019) compared to caregivers in control. At 12 months, caregiver affect improved (p = .033), and there was a trend for maintenance of skills and reduced behavioral occurrences, but not for other outcome measures. An in-home skills training program helps sustain caregiver affect for those enrolled for more than 1 year. More frequent professional contact and ongoing skills training may be necessary to maintain other clinically important outcomes such as reduced upset with behaviors.


A review of bioanalytical quantitative methods for selected sphingosine 1-phosphate receptor modulators.
Sphingosine 1-phosphate (S1P1 ) modulators provide an emerging therapeutic approach for various autoimmune disorders such as multiple sclerosis and psoriasis. Fingolimod is the first approved orally active, selective and potent drug of this class. Other drugs belonging to this class include siponimod, ponesimod, ceralifimod, amiselimod, CS-0777 and GSK2018682. However, owing to the high protein binding, polarity and zwitter-ionic nature of the phosphate metabolite of parent drugs, it becomes challenging to optimize the extraction method for this class of compounds. Although, there are individual published bioanalytical methods for the analysis of selected S1P1 modulators to support preclinical and clinical drug development, no extensive review compiling all the bioanalytical methods for the important drugs in the class is available. Thus, we attempted to prepare a comprehensive review on various bioanalytical methods for selected S1P1 modulators which will provide all the relevant bioanalytical information as required by bioanalytical researchers. This review focuses on the various liquid chromatography with tandem mass spectrometry methods that have been used to quantify S1P1 modulators in various biological matrices. Extraction methods included liquid-liquid extraction, solid-phase extraction and one-step protein precipitation for extracting the analytes. This review captures key information regarding sample processing options and chromatographic/detection conditions.


Randomised comparison of three tools for improving compliance with occlusion therapy: an educational cartoon story, a reward calendar, and an information leaflet for parents.
We previously demonstrated that compliance with occlusion therapy for amblyopia was improved by the use of an educational programme, especially in children of parents of foreign origin and who spoke Dutch poorly. The programme consisted of: (i) a cartoon story for amblyopic children that explained without words why they should patch, (ii) a calendar with reward stickers, and (iii) an information leaflet for parents. In the current study, we assessed the individual effect of each component on compliance. We recruited 120 3- to 6-year-old children who lived in a low socio-economic status (SES) area in The Hague and were starting occlusion therapy for the first time. They were randomised to receive one of the components (three intervention groups), or a picture to colour (control group). The randomisation was blinded for treating orthoptist and researcher. Compliance was measured electronically using the Occlusion Dose Monitor (ODM). Primary outcome was percentage of compliance (actual/prescribed occlusion time). Secondary outcome was absolute occlusion hours per day. Parental fluency in Dutch was rated on a five-point scale. Compliance could be measured electronically in 88 of the 120 children; in 32 others, it failed for various reasons. Parental fluency in Dutch was moderate or worse in 36.4 % (p = 0.327). Average compliance was 55 % standard deviation (SD) 40 (n = 18) in the control group, 89 % SD 25 in the group receiving the educational cartoon (n = 25, P = 0.002 compared with control group), 67 % SD 33 (n = 24, P = 0.301) in the reward-calendar group and 73 % SD 40 (n = 21, P = 0.119) in the parent-information-leaflet group. On average, children in the control group occluded 1:46 SD1:19 hours/day, 2:33 SD 1:18 hours/day in the group receiving the educational cartoon, 1:59 SD 1:13 hours/day in the reward-calendar group and 2:18 SD 1:13 hours/day in the parent-information-leaflet group. No child who received the cartoon story occluded less than 1 hour per day, against seven in the reward-calendar group, five in the parent-information-leaflet group and five in the control group. Although all three components of the programme improved compliance with occlusion therapy in children in low-SES areas, the educational cartoon had the strongest effect, as it explained without words to a 4- to 5-year-old child why it should wear the eye patch.


Constitutional 3p26.3 terminal microdeletion in an adolescent with neuroblastoma.
Neuroblastoma (NB) is a common and often lethal cancer of early childhood that accounts for 10% of pediatric cancer mortality. Incidence peaks in infancy and then rapidly declines, with less than 5% of cases diagnosed in children and adolescents ≥ 10 y. There is increasing evidence that NB has unique biology and an chronic disease course in older children and adolescents, but ultimately dismal survival. We describe a rare constitutional 3p26.3 terminal microdeletion which occurred in an adolescent with NB, with apparently normal phenotype without neurocognitive defects. We evaluated the association of expression of genes involved in the microdeletion with NB patient outcomes using R2 platform. We screened NB patient's tumor cells for CHL1 protein expression using immunofluorescence. Constitutional and tumor DNA were tested by array-comparative genomic hybridization and single nucleotide-polymorphism-array analyses. Peripheral blood mononuclear cells from the patient showed a 2.54 Mb sub-microscopic constitutional terminal 3p deletion that extended to band p26.3. The microdeletion 3p disrupted the CNTN4 gene and the neighboring CNTN6 and CHL1 genes were hemizygously deleted, each of these genes encode neuronal cell adhesion molecules. Low expression of CNTN6 and CNTN4 genes did not stratify NB patients, whereas low CHL1 expression characterized 417 NB patients having worse overall survival. CHL1 protein expression on tumor cells from the patient was weaker than positive control. This is the first report of a constitutional 3p26.3 deletion in a NB patient. Since larger deletions of 3p, indicative of the presence of one or more tumor suppressor genes in this region, occur frequently in neuroblastoma, our results pave the way to the identification of one putative NB suppressor genes mapping in 3p26.3.


Microneedle-Mediated Delivery of Copper Peptide Through Skin.
Copper peptide (GHK-Cu) plays an important role in skin regeneration and wound healing. However, its skin absorption remains challenging due to its hydrophilicity. Here we use polymeric microneedle array to pre-treat skin to enhance GHK-Cu skin penetration. Two in vitro skin models were used to assess the capability of microneedles in facilitating skin delivery of GHK-Cu. Histological assay and confocal laser scanning microscopy were performed to characterize and quantify the microconduits created by the microneedles inside skin. Cellular and porcine models were used to evaluate the safety of microneedle-assisted copper peptide delivery. The depth and percentage of microneedle penetration were correlated with application forces, which in turn influenced the extent of enhancement in the skin permeability of GHK-Cu. In 9 h, 134 ± 12 nanomoles of peptide and 705 ± 84 nanomoles of copper permeated though the microneedle treated human skin, while almost no peptide or copper permeated through intact human skin. No obvious signs of skin irritation were observed with the use of GHK-Cu after microneedle pretreatment. It is effective and safe to enhance the skin permeation of GHK-Cu by using microneedles. This approach may be useful to deliver similar peptides or minerals through skin.


Characterization and biologic activities of an anti-idiotype-specific T cell line and its derived clones.
Monoclonal anti-idiotypic antibodies were prepared against monoclonal antibodies (mAb103) specific to the synthetic polypeptide antigen (T,G)-A-L. A cell line was established by the stimulation of C3H.SW mouse T cells with one of the monoclonal anti-idiotypes (mAbA-6) that reacted with both mAb103 and conventional (T,G)-A-L-specific antibodies. The T cell line proliferated specifically in the presence of the homologous mAbA-6 and to a lesser degree when triggered with (T,G)-A-L. The line could help (T,G)-A-L primed B cells in the production of (T,G)-A-L-specific antibodies when stimulated in vitro with either (T,G)-A-L or mAbA-6. Clones obtained from the line were stimulated and maintained in culture in presence of mAbA-6 whereas others were stimulated and grown in the presence of (T,G)-A-L. Both types of clones proliferated only in the presence of mAbA-6 although (T,G)-A-L could inhibit efficiently and specifically the latter proliferation. A significant number of the (T,G)-A-L-stimulated clones could collaborate with (T,G)-A-L primed B cells in the presence of either (T,G)-A-L or mAbA-6 for the production of specific antibodies. Immunoblotting experiments indicated that mAbA-6 reacted with both the T cell receptor of the mAbA-6-specific T cell line and of a (T,G)-A-L-specific T cell line but not with that of a line specific to a nonrelated antigen.


The relationship between knowledge of ergonomic science and the occupational health among nursing staff affiliated to Golestan University of Medical Sciences.
Occupational hazards are much higher for nurses than many other jobs and neglecting this fact may reduce the quality of nursing services. The aim of this study was to investigate the relationship between knowledge of ergonomics and occupational health among the nursing staff affiliated to Golestan University of Medical Sciences. It was a cross-sectional analytical study on 423 nursing staff working in various medical centers affiliated to Golestan University of Medical Sciences in 2008, selected by quota randomized sampling. Data collection instrument was Ergonomics Questionnaire, which consisted of 72 questions. Cronbach's alpha for main sections of the questionnaire was 0.8, 0.8 and 0.9. Descriptive and analytical tests were used for data analysis and an alpha error of 5% was considered. Of all the subjects, 36.1% had 5-10 years of work experience, 61.9% had a good knowledge of ergonomic principles, and 83% were exposed to a mild level of occupational hazards. There was no significant relationship between knowledge of ergonomics and occupational health (p = 0.08). The relationships between knowledge of ergonomics and age, gender, marital status, work experience, the type, and the location of service were significant (p < 0.05). The relationship between occupational health and age, work experience, employment type, and location of service were also statistically significant (p < 0.05). Training staff to do their job in the best way, taking breaks between long working hours, using appropriate tools and facilities and paying attention to ergonomics can provide a healthier work environment for nurses and optimize human resource efficiency.


Early detection of pancreatic cancer following the diagnosis of chronic pancreatitis.
To assess whether patients with misdiagnoses of chronic pancreatitis (CP), followed at an early stage by a diagnosis of pancreatic cancer (PCr), present different epidemiological characteristics from patients suffering either from CP alone or from CP with late degeneration to PCr. We arbitrarily subdivided our patient series into three groups: (1) 12 CP who developed PCr within 4 years after onset of symptoms; (2) 12 CP developing PCr after the 4th year, and (3) 701 CP with no subsequent development of PCr. The variables studied were age, sex, drinking and smoking habits, tumor localization, and presence of intraductal calcifications and diabetes mellitus at the time of diagnosis of CP. There were no significant differences between CP and 'late' PCr in any of the study variables considered. As compared with the CP group, the 'early' PCr cases were older (58.7 vs. 40.7 years; p < 0.0001), with a lower proportion of males (58 vs. 88%; p < 0.01), smaller proportions of both smokers (42 vs. 88%; p < 0.0001) and subjects drinking more than 40 g of alcohol/day (42 vs. 86%; p < 0. 0001), and a greater incidence of non-insulin-dependent diabetics at the time of diagnosis of CP (25 vs. 3.7%; p < 0.012). As compared with the 'late' PCr group, the malignancies in the 'early' PCr cases were more often located in the head of the pancreas (100 vs. 50%; p < 0.01). Multivariate logistic regression analysis selected age over 50 (odds ratio OR 13.5, 95% confidence interval CI 2.79-65.5; p < 0. 001), smoking habits (OR 0.14, 95% CI 0.04-0.49; p < 0.002), and non-insulin-dependent diabetes (OR 5.91, 95% CI 1.20-29.1; p < 0. 028) as variables identifying subjects with 'early' PCr. A high suspicion of a pancreatic tumor is necessary when CP is diagnosed in a patient with atypical epidemiological characteristics for this condition, possibly female, aged over 50, who is not a smoker or drinker, and suffers from non-insulin-dependent diabetes.


Severe migratory granulomatous reactions to silicone gel in 3 patients.
In humans implanted with silicone gel breast prostheses, a mild foreign body response results in the formation of a collagenous capsule around the prosthesis. Although many such patients may show evidence of a microscopic granulomatous foreign body reaction upon examination of capsular material at explantation of a prosthesis, it is unusual to have large, palpable granulomas, even in the presence of rupture or leakage. Rare patients have had severe local inflammation and complications resulting from silicone migration to the axilla, arm, or abdominal wall. We describe 3 patients who had deforming granulomas after implant rupture, along with other consequences of silicone gel migrating down the upper extremity. Silicone gel, once it leaves the implant, is not biologically inert and in some persons can elicit profound pathologic responses.


Clinical impact of incidental diagnosis of disease on non-contrast-enhanced helical CT for acute ureteral colic.
The role of un enhanced helical CT (UHCT) in the evaluation of acute flank pain suggestive of urinary tract calculi is increasingly appreciated in the last few years. Recent studies have identified the advantages of UHCT in recognizing alternative findings within or outside the urinary tract. These incidental diagnoses on UHCT alter a patient's management and demonstrate the pivotal role of UHCT in rapidly triaging these patients for appropriate management. Clinical impact of incidental diagnoses is maximal in identifying alternate emergent conditions mimicking reno-ureteric colic and in identifying malignancies at an early stage when they are potentially curable.


Gastrointestinal disorders among shift workers.
Our aim was to review published literature on the association between shift work and gastrointestinal (GI) disorders. A systematic review of the literature was conducted of studies that have reported GI symptoms and diseases among shift workers. We used Medline to search for articles from 1966-2009. Next, we manually searched articles in the reference list of each article and previous reviews. Twenty studies met the inclusion criteria. Four of six studies showed a significant association between shift work and GI symptoms, and five of six studies reported an association between shift work and peptic ulcer disease. Two of three studies showed an association between shift work and functional GI disease. Only a few studies have examined gastroesophageal reflux disease, chronic inflammatory bowel diseases, or GI cancers in relation to shift work. Our general judgment is that shift workers appear to have increased risk of GI symptoms and peptic ulcer disease. However, control for potential confounders (eg, smoking, age, socioeconomic status, and other risk factors) was often lacking or insufficient in many of the studies we examined.


Caenorhabditis elegans germ granules are present in distinct configurations that differentially associate with RNAi-targeted RNAs.
RNA silencing pathways are complex, highly conserved, and perform widespread, critical regulatory roles. In C. elegans germlines, RNA surveillance occurs through a series of perinuclear germ granule compartments-P granules, Z granules, SIMR foci, and Mutator foci-multiple of which form via phase separation and exhibit liquid-like properties. The functions of individual proteins within germ granules are well-studied, but the spatial organization, physical interaction, and coordination of biomolecule exchange between compartments within germ granule "nuage" is less understood. Here we find that key proteins are sufficient for compartment separation, and that the boundary between compartments can be reestablished after perturbation. Using super-resolution microscopy, we discover a toroidal P granule morphology which encircles the other germ granule compartments in a consistent exterior-to-interior spatial organization. Combined with findings that nuclear pores primarily interact with P granules, this nuage compartment organization has broad implications for the trajectory of an RNA as it exits the nucleus and enters small RNA pathway compartments. Furthermore, we quantify the stoichiometric relationships between germ granule compartments and RNA to reveal discrete populations of nuage that differentially associate with RNAi-targeted transcripts, possibly suggesting functional differences between nuage configurations. Together, our work creates a more spatially and compositionally accurate model of C. elegans nuage which informs the conceptualization of RNA silencing through different germ granule compartments.


GEE estimation of a misspecified time-varying covariate: an example with the effect of alcoholism treatment on medical utilization.
The generalized estimation equation (GEE) method is widely used in longitudinal data analysis, particularly when the outcome variable is non-Gaussian distributed. Under mild regulatory conditions, the parameter estimates are consistent and their asymptotic variances are efficient. In an observational study focusing on alcoholism patients, we applied the GEE method to longitudinal count data from medical utilization records from a large national managed care organization. The health services research question was whether there was a change in medical utilization for patients after engaging in alcoholism treatment as compared to before treatment. Thus, the main effect of interest was a time-varying covariate indicating whether the patient had undergone treatment yet or not. GEE under five different working correlations was employed and mixed results regarding the significance of the treatment effect were found. Because of the large sample size, i.e. 8485 patients with an average of 46 repeated measurements per patient, differences across the estimates produced by the different working correlation structures was suspicious. It is shown that these differences are maybe caused by the fact that the time-varying covariate in the marginal mean model is misspecified. A simulation study is performed to demonstrate that misspecification of the time-varying covariate in the marginal mean structure can cause differences in GEE results across various choices of working correlation structure.


Marked amelioration of alcohol-responsive posthypoxic myoclonus by gamma-hydroxybutyric acid (Xyrem).
We conducted an open-label, dose-finding, blinded-rating trial of gamma-hydroxybutyric acid (Xyrem) in a single patient with severe alcohol-responsive posthypoxic myoclonus refractory to treatment with standard antimyoclonic agents. Xyrem was given in divided doses during the day and was well tolerated. Intensity of myoclonus was measured using the Unified Myoclonus Rating Scale, and blinded videotape review demonstrated complete resolution of myoclonus at rest and stimulus-sensitive myoclonus. Action myoclonus and functional performance also improved in ways that were practically meaningful, allowing her to feed herself, to accomplish daily hygiene tasks, and to walk with assistance. The possible mechanisms of action and potential uses of this agent in other alcohol-responsive movement disorders are discussed.


Expanded intrathoracic space in fetal cases of isolated congenital diaphragmatic hernia contributes to disparity between percent predicted lung volume and observed to expected total lung volume.
The aim of this study was to determine whether fetal lung volume and visceral herniation are associated with changes in intrathoracic space in congenital diaphragmatic hernia(CDH). We retrospectively examined the relationship between magnetic resonance imaging-derived measurements of intrathoracic space [predicted lung volume (PLV)] and residual lung volume or visceral herniation among isolated left-sided CDH fetuses. Data from fetal magnetic resonance imaging studies of 60 isolated left-sided CDH cases were analyzed. The median PLV of the CDH fetuses was found to be much greater than the expected total lung volume (eTLV) of a normal fetus at the same gestational age. Surprisingly, liver herniation and observed TLV(oTLV) were positively correlated with the PLV. Although the PPLV was consistently less than the o/eTLV, both indices were greater in survivors than in non-survivors, whereas no significant difference was seen in the PLV/eTLV ratio in regard to survivorship. The intrathoracic domain available for lungs and viscera is expanded in CDH fetuses and positively affected by the lung volume and the presence of liver herniation, leading to the difference in the PPLV and o/eTLV. Future study of intrathoracic space as it relates to the growth of the lung and herniated viscera is needed to better characterize the relationship between these parameters.


Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: fumonisin B(1) as an example.
The rates of cell proliferation and cell loss in conjunction with the differentiation status of a tissue are among the many factors contributing to carcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F(1) mice, the mycotoxin fumonisin B(1) caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BD-IX rats, fumonisin B(1) caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B(1) exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following fumonisin B(1) administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by fumonisin B(1). Fumonisin B(1) is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA-synthesis assay. Fumonisin B(1) may be the first example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration.


Expression of epidermal growth factor receptors in human brain tumors.
The expression of receptors for epidermal growth factor (EGF-R) was determined in 29 samples of brain tumors from 22 patients. Primary gliogenous tumors, of various degrees of cancer, five meningiomas, and two neuroblastomas were examined. Tissue samples were frozen in liquid nitrogen immediately after the operation and stored at -70 degrees until use. Cerebral tissue samples from 11 patients who died from diseases not related to the central nervous system served as controls. Immunoprecipitation of functional EGF-R-kinase complexes revealed high levels of EGF-R in all of the brain tumors of nonneuronal origin that were examined. The level of EGF-R varied between tumors from different patients and also between specimens prelevated from different areas of the same tumor. In contrast, the levels of EGF-R from control specimens were invariably low. The biochemical properties of EGF-R in brain tumor specimens were found to be indistinguishable from those of the well-characterized EGF-R from the A-431 cell line, derived from human epidermoid carcinomas. Human brain EGF-R displays a molecular weight of 170,000 by polyacrylamide-sodium dodecyl sulfate gel electrophoresis. It is phosphorylated mainly in tyrosine residues and shows a 2-dimensional phosphopeptide map similar to that obtained with the phosphorylated EGF-R from membranes of A-431 cells. Our observations suggest that induction of EGF-R expression may accompany the malignant transformation of human brain cells of nonneuronal origin.


Dideoxynucleoside triphosphate-sensitive DNA polymerase from rice is involved in base excision repair and immunologically similar to mammalian DNA pol beta.
A single polypeptide with ddNTP-sensitive DNA polymerase activity was purified to near homogeneity from the shoot tips of rice seedlings and analysis of the preparations by SDS-PAGE followed by silver staining showed a polypeptide of 67 kDa size. The DNA polymerase activity was found to be inhibitory by ddNTP in both in vitro DNA polymerase activity assay and activity gel analysis. Aphidicolin, an inhibitor of other types of DNA polymerases, had no effect on plant enzyme. The 67 kDa rice DNA polymerase was found to be recognized by the polyclonal antibody (purified IgG) made against rat DNA polymerase beta (pol beta) both in solution and also on Western blot. The recognition was found to be very specific as the activity of Klenow enzyme was unaffected by the antibody. The ability of rice nuclear extract to correct G:U mismatch of oligo-duplex was observed when oligo-duplex with 32P-labeled lower strand containing U (at 22nd position) was used as substrate. Differential appearance of bands at 21-mer, 22-mer, and 51-mer position in presence of dCTP was visible only with G:U mismatch oligo-duplex, but not with G:C oligo-duplex. While ddCTP or polyclonal antibody against rat-DNA pol beta inhibits base excision repair (BER), aphidicolin had no effect. These results for the first time clearly demonstrate the ability of rice nuclear extract to run BER and the involvement of ddNTP-sensitive pol beta type DNA polymerase. Immunological similarity of the ddNTP-sensitive DNA polymerase beta of rice and rat and its involvement in BER revealed the conservation of structure and function of ddNTP-sensitive DNA pol beta in plant and animal.


Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer's Disease.
This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.


Relation of high plasma triglyceride levels associated with obesity and regional adipose tissue distribution to plasma lipoprotein-lipid composition in premenopausal women.
Abdominal obesity is associated with high plasma triglyceride (TG) and with low plasma high density lipoprotein (HDL)-cholesterol (CHOL) levels. As plasma TG and HDL-CHOL are negatively correlated, the associations between obesity, the regional distribution of body fat, plasma TG levels, and plasma lipoprotein concentration and composition were studied in a sample of 76 premenopausal women (52 obese and 24 non-obese). Obese women had significantly higher plasma levels of VLDL-TG, low density lipoprotein (LDL)-CHOL, LDL-TG, LDL-apolipoprotein (apo) B and reduced HDL-CHOL levels compared to non-obese controls (p less than 0.01). However, plasma concentrations of HDL-apo A-I and HDL-TG were not different between obese and non-obese women. Partial correlation analyses revealed that both fat mass and abdominal fat accumulation significantly contributed to VLDL-TG and HDL-CHOL variances. After control for body fat mass, the waist-to-hip circumference ratio (WHR) remained significantly correlated with plasma LDL-apo B levels and with the LDL-apo B/LDL-CHOL ratio (0.01 greater than p less than 0.05). Body fat mass was, however, associated with TG enrichment of LDL (p less than 0.01). After control for WHR, body fat mass showed no significant association with plasma HDL-TG levels, whereas the WHR was positively correlated with HDL-TG levels (p less than 0.05). Partial correlation analyses indicated that adjustment for fat mass or for the WHR failed to eliminate the associations between plasma VLDL-TG levels and lipoprotein lipid composition. This study emphasizes the importance of plasma VLDL-TG level as a correlate of plasma LDL and HDL lipid composition in abdominal obesity.


Vitamin D treatment and mortality in chronic kidney disease: a systematic review and meta-analysis.
Hypovitaminosis D has been associated with an increased cardiovascular mortality in the general population and in patients with chronic kidney disease (CKD). Still, whether prescribing vitamin D reduces the risk of mortality in renal patients remains controversial. We searched PubMed, ClinicalTrials.gov and the Cochrane Library for long-term longitudinal studies comparing vitamin D compounds (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and synthetic derivatives) to placebo or no treatment in renal patients, and which evaluated mortality, to perform a meta-analysis. Data concerning study quality, population and effect size were extracted independently by two investigators using predefined forms. Fourteen observational studies (194,932 patients) met all eligibility criteria. Most studies were performed in hemodialysis patients and all used calcitriol or synthetic analogues. In a random effects meta-analysis, receiving any vitamin D therapy significantly reduced the risk of all-cause mortality (relative risk 0.73, 95% CI 0.65-0.82). The relative risk of death was 0.72 (95% CI 0.65-0.80) after 3 years of therapy and 0.67 (95% CI 0.45-0.98) after 5 years. In meta-regression, the risk reduction was shown to be greater in patients with higher parathyroid hormone serum levels (p = 0.01). The risk of cardiovascular mortality was also significantly reduced in patients receiving any vitamin D derivative (relative risk 0.63, 95% CI 0.44-0.92). Therapies with 1,25-dihydroxyvitamin D and analogues are associated with reduced mortality in CKD patients, and particularly in those suffering from secondary hyperparathyroidism. These results, based on observational evidence, are supportive of prescribing vitamin D therapies to CKD patients, while respecting good practice guidelines.


The LysR-type virulence activator AphB regulates the expression of genes in Vibrio cholerae in response to low pH and anaerobiosis.
AphB is a LysR-type activator that initiates the expression of the virulence cascade in Vibrio cholerae by cooperating with the quorum-sensing-regulated activator AphA at the tcpPH promoter on the Vibrio pathogenicity island (VPI). To identify the ancestral chromosomal genes in V. cholerae regulated by AphB, we carried out a microarray analysis and show here that AphB influences the expression of a number of genes that are not associated with the VPI. One gene strongly activated by AphB is cadC, which encodes the ToxR-like transcriptional activator responsible for activating the expression of lysine decarboxylase, which plays an important role in survival at low pH. Other genes activated by AphB encode a Na(+)/H(+) antiporter, a carbonic anhydrase, a member of the ClC family of chloride channels, and a member of the Gpr1/Fun34/YaaH family. AphB influences each of these genes directly by recognizing a conserved binding site within their promoters, as determined by gel mobility shift assays. Transcriptional lacZ fusions indicate that AphB activates the expression of these genes under aerobic conditions in response to low pH and also under anaerobic conditions at neutral pH. Further experiments show that the regulation of cadC by AphB in response to low pH and anaerobiosis is mirrored in the heterologous organism Escherichia coli, is independent of the global regulators Fnr and ArcAB, and depends upon the region of the promoter that contains the AphB binding site. These results raise the possibility that the activity of AphB is influenced by the pH and oxygen tension of the environment.


Myths that persist about orofacial myology.
This article addresses many myths that have persisted over the years in dentistry and orofacial myology regarding the nature of orofacial myofunctional disorders (OMD's). Myths include 1) the concept that the term "tongue thrusting" includes the rest posture; 2) that there is an excessive amount of pressure exerted against the anterior teeth in swallows, that swallowing pressures add up, and the frequency of swallowing has an impact on the dentition; 3) the idea that the tongue is the strongest muscle in the body; 4) the view that a muscle will be the winner in any tug of war between muscle and bone; 5) the claim that a tongue thrust can cause an open bite malocclusion; 6) the claim that a tongue thrust can cause a Class II malocclusion; 7) the claim that the tongue molds the palatal vault; 8) the notion that a low tongue tip posture at rest presents a problem; and 9) the claim that OMD's represent a muscle imbalance that can be brought into balance with therapy. Each of these false claims or "myths" is discussed and corrected, with the positive acknowledgement that clinicians are abandoning the incorrect notion of muscle balance and imbalance as had been claimed previously.


Expression of listeriolysin O and ActA by intracellular and extracellular Listeria monocytogenes.
Listeria monocytogenes requires listeriolysin O (LLO) and ActA, the products of hly and actA, respectively, to establish a productive intracellular infection. LLO is essential for vacuolar lysis and entry into the cytosol, while ActA is required for bacterial spread to adjacent cells. We have used a transcriptional reporter gene system to compare the expression of actA and hly during intracellular growth to that during growth in broth cultures. The hly and actA genes were transcriptionally fused to Escherichia coli lacZ and Bacillus pumilus cat-86 (cat), and the fusions were integrated in single copies into the L. monocytogenes chromosome. A chloramphenicol resistance assay indicated that the hly fusion but not the actA fusion was significantly activated in Luria-Bertani (LB) broth, and this finding correlated with LLO and ActA levels detectable in broth cultures. Quantitation of promoter activity on the basis of beta-galactosidase activity revealed up to 10-fold-higher level of expression of the hly fusion relative to the actA fusion in LB broth. In contrast, both fusions were active in the cytosol of J774 cells, and the activity of the actA fusion was approximately 3-fold higher than that of the hly fusion under these conditions. However, quantitative immunoprecipitation of ActA and LLO from infected J774 cells demonstrated approximately 70-fold more cytosolic ActA than cytosolic LLO. Finally, in comparison to induction in broth cultures, actA was highly induced (226-fold) and hly was moderately induced (20-fold) in J774 cells. Collectively, these results indicate that actA and hly are differentially regulated in response to the growth environment and that both genes are preferentially expressed during intracellular growth. Further, while the lower level of production of ActA than of LLO in broth can be accounted for by transcriptional regulation, the relative abundance of intracellular ActA compared to that of intracellular LLO is a function of additional, possibly host-mediated, factors.


Arabidopsis RNA-dependent RNA polymerases and dicer-like proteins in antiviral defense and small interfering RNA biogenesis during Turnip Mosaic Virus infection.
Plants respond to virus infections by activation of RNA-based silencing, which limits infection at both the single-cell and system levels. Viruses encode RNA silencing suppressor proteins that interfere with this response. Wild-type Arabidopsis thaliana is immune to silencing suppressor (HC-Pro)-deficient Turnip mosaic virus, but immunity was lost in the absence of DICER-LIKE proteins DCL4 and DCL2. Systematic analysis of susceptibility and small RNA formation in Arabidopsis mutants lacking combinations of RNA-dependent RNA polymerase (RDR) and DCL proteins revealed that the vast majority of virus-derived small interfering RNAs (siRNAs) were dependent on DCL4 and RDR1, although full antiviral defense also required DCL2 and RDR6. Among the DCLs, DCL4 was sufficient for antiviral silencing in inoculated leaves, but DCL2 and DCL4 were both involved in silencing in systemic tissues (inflorescences). Basal levels of antiviral RNA silencing and siRNA biogenesis were detected in mutants lacking RDR1, RDR2, and RDR6, indicating an alternate route to form double-stranded RNA that does not depend on the three previously characterized RDR proteins.


Glucocorticoid receptor mRNA and protein isoform alterations in the orbitofrontal cortex in schizophrenia and bipolar disorder.
The orbitofrontal cortex (OFC) may play a role in the pathogenesis of psychiatric illnesses such as bipolar disorder and schizophrenia, in which hypothalamic-pituitary-adrenal (HPA) axis abnormalities are observed and stress has been implicated. A critical component of the HPA axis which mediates cellular stress responses in the OFC, and has been implicated in psychiatric illness, is the glucocorticoid receptor (GR). In the lateral OFC, we employed quantitative real-time PCR and western blotting to investigate GR mRNA and protein expression in 34 bipolar disorder cases, 35 schizophrenia cases and 35 controls. Genotype data for eleven GR gene (NR3C1) polymorphisms was also used to explore possible effects of NR3C1 sequence variation on GR mRNA and protein expression in the lateral OFC. We found no diagnostic differences in pan GR, GR-1C or GR-1F mRNA expression. However, the GR-1B mRNA transcript variant was decreased (14.3%) in bipolar disorder cases relative to controls (p < 0.05), while GR-1H mRNA was decreased (22.0%) in schizophrenia cases relative to controls (p < 0.005). By western blotting, there were significant increases in abundance of a truncated GRα isoform, putative GRα-D1, in bipolar disorder (56.1%, p < 0.005) and schizophrenia (31.5% p < 0.05). Using genotype data for eleven NR3C1 polymorphisms, we found no evidence of effects of NR3C1 genotype on GR mRNA or GRα protein expression in the OFC. These findings reveal selective abnormalities of GR mRNA expression in the lateral OFC in psychiatric illness, which are more specific and may be less influenced by NR3C1 genotype than those of the dorsolateral prefrontal cortex reported previously. Our results suggest that the GRα-D1 protein isoform may be up-regulated widely across the frontal cortex in psychiatric illness.


Microbiome Composition and Function Drives Wound-Healing Impairment in the Female Genital Tract.
The mechanism(s) by which bacterial communities impact susceptibility to infectious diseases, such as HIV, and maintain female genital tract (FGT) health are poorly understood. Evaluation of FGT bacteria has predominantly been limited to studies of species abundance, but not bacterial function. We therefore sought to examine the relationship of bacterial community composition and function with mucosal epithelial barrier health in the context of bacterial vaginosis (BV) using metaproteomic, metagenomic, and in vitro approaches. We found highly diverse bacterial communities dominated by Gardnerella vaginalis associated with host epithelial barrier disruption and enhanced immune activation, and low diversity communities dominated by Lactobacillus species that associated with lower Nugent scores, reduced pH, and expression of host mucosal proteins important for maintaining epithelial integrity. Importantly, proteomic signatures of disrupted epithelial integrity associated with G. vaginalis-dominated communities in the absence of clinical BV diagnosis. Because traditional clinical assessments did not capture this, it likely represents a larger underrepresented phenomenon in populations with high prevalence of G. vaginalis. We finally demonstrated that soluble products derived from G. vaginalis inhibited wound healing, while those derived from L. iners did not, providing insight into functional mechanisms by which FGT bacterial communities affect epithelial barrier integrity.


Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium.
This study was aimed at evaluating the in vitro effects of phosphodiesterase inhibitors and beta2-adrenoceptor agonists on spontaneous contractions of human term myometrium. Rolipram, RP 73401 (3-cyclopentyloxy-N-(3,5(-dichloro-4-pyridil)-4-methoxybenzamide) and Ro 20-1724 (1-4-(3-butoxy-4-methoxybenzyl)-2-imidozolidinone) (phosphodiesterase 4 inhibitors) inhibited spontaneous myometrial contractions (Emax approximately 100%; pD2 of 6.80+/-0.28, 6.84+/-0.32 and 6.31+/-0.03, respectively). Salbutamol and formoterol were less effective (Emax=40+/-6% and 35+/-12%, respectively) than phosphodiesterase 4 inhibitors to reduce myometrial contractility. Inhibitors of phosphodiesterase 3 (milrinone and siguazodan) and 5 (zaprinast) were marginally effective. Rolipram (10-30 nM) and siguazodan (0.1 microM) potentiated the response to salbutamol (Emax=75+/-12%, 88+/-8% and 73+/-12% and pD2=6.51+/-0.20, 6.93+/-0.29 and 6.48+/-0.16, respectively). Sodium nitroprusside (pD2=6.76+/-0.29) and theophylline (pD2=5.15+/-0.22) were effective inhibitors of myometrial contractions. Chromatographic separation of phosphodiesterase isoenzymes demonstrated that phosphodiesterase 4 is predominant but other phosphodiesterase isoenzymes were also identified. In conclusion, phosphodiesterase 4 inhibitors alone or combined with beta2-adrenoceptor agonists have potential interest as tocolytic agents.


Urinary incontinence in women: assessment and management in the primary care setting.
Urinary incontinence, the unwanted loss of urine, is a condition that affects millions of women and yet is often not addressed by the primary care provider. The unfortunate consequence of this ignorance is that, if correctly diagnosed and managed 80% of these patients could have marked improvement in clinical symptoms. The intent of this report is to familiarize the reader with a systematic approach to the assessment, diagnosis, and management strategies for urinary incontinence in the outpatient setting.


Pleural fluid lysozyme in human disease.
Lysozyme content was measured in the plasma and pleural fluid of 110 patients with pleural effusions of various causes. The concentration of pleural fluid lysozyme was significantly higher (P less than .001) in patients with tuberculous pleurisy than in those with primary pulmonary carcinoma, metastatic carcinoma of the lung, connective tissue disease, nonspecific pleurisy, or congestive heart failure. Tuberculous patients also had a significantly higher (P less than .001) pleural fluid-to-plasma lysozyme ratio than did the other patients. Plasma lysozyme activity did not differ significantly among the various patient groups. Lysozyme was identified immunohistochemically in epithelioid cell granulomas in tuberculosis, in activated macrophages in lymph nodes adjacent to tuberculous lesions, and in granulocytes in pleural empyema. No lysozyme was detected in neoplastic cells in pulmonary carcinoma. The results show that the determination of pleural fluid lysozyme is a simple, fast method for obtaining corroborative information in the differential diagnosis of tuberculous pleurisy.


Sensory and Emotional Perception of Wooden Surfaces through Fingertip Touch.
Previous studies on tactile experiences have investigated a wide range of material surfaces across various skin sites of the human body in self-touch or other touch modes. Here, we investigate whether the sensory and emotional aspects of touch are related when evaluating wooden surfaces using fingertips in the absence of other sensory modalities. Twenty participants evaluated eight different pine and oak wood surfaces, using sensory and emotional touch descriptors, through the lateral motion of active fingertip exploration. The data showed that natural and smooth wood surfaces were perceived more positively in emotional touch than coated surfaces. We highlight the importance of preserving the naturalness of the surface texture in the process of wood-surface treatment so as to improve positive touch experiences, as well as avoid negative ones. We argue that the results may offer possibilities in the design of wood-based interior products with a view to improving consumer touch experiences.


Multinodular and vacuolating neuronal tumor of the cerebrum. A rare entity. New case and review of the literature.
Multinodular and vacuolating neuronal tumor has been recently described and included in the World Health Organization Classification of Tumors of The Central Nervous System, even though its consideration as a true tumor is controversial. Patients with these lesions usually present with refractory seizures and inconclusive imaging findings that may be confused with other more common diagnoses such as dysembryoplastic neuroepithelial tumors or low-grade gliomas. Therefore, surgical resection is warranted to reach a pathologic diagnosis and seizure control. To the best of our knowledge, only 16 cases have been published in the English literature. We present the case of a 52-year-old male who presented at our institution with a 2-year-history of absence of seizures. Brain MRI showed a T2-hyperintense lesion with no contrast enhancement affecting his temporal lobe. Temporal craniotomy and microsurgical resection was scheduled. The procedure was uneventful and a grayish, gluey mass was sent for pathologic analysis. The tumor was formed by immature neuronal cells organized in nodules with a vacuolated matrix. A thorough immunohistochemical analysis showed positivity for: Protein Gene Product 9.5. ATRX. OLIG2. SOX10. p16. Nestin. Synaptophysin. The findings were consistent with multinodular and vacuolating neuronal tumor. The patient has been seizure-free after surgery and with no signs of tumor progression. We present a thorough review addressing this uncommon tumor along with a description of the 17th reported case of MVNT, a tumor that was described for the first time in 2013. Further studies and case studies are necessary to establish a well-defined morphological and immunohistochemical profile along with knowledge about its natural history.


Hyponatremia in Children and Adults with Prader-Willi Syndrome: A Survey Involving Seven Countries.
In Prader-Willi syndrome (PWS), conditions that are associated with hyponatremia are common, such as excessive fluid intake (EFI), desmopressin use and syndrome of inappropriate antidiuretic hormone (SIADH) caused by psychotropic medication. However, the prevalence of hyponatremia in PWS has rarely been reported. Our aim was to describe the prevalence and severity of hyponatremia in PWS. In October 2020, we performed a retrospective study based on the medical records of a large cohort of children and adults with PWS from seven countries. Among 1326 patients (68% adults), 34 (2.6%) had at least one episode of mild or moderate hyponatremia (125 ≤ Na < 135 mmol/L). The causes of non-severe hyponatremia were often multi-factorial, including psychotropic medication in 32%, EFI in 24% and hyperglycemia in 12%. No obvious cause was found in 29%. Seven (0.5%) adults experienced severe hyponatremia (Na < 125 mmol/L). Among these, five recovered completely, but two died. The causes of severe hyponatremia were desmopressin treatment for nocturnal enuresis (n = 2), EFI (n = 2), adrenal insufficiency (n = 1), diuretic treatment (n = 1) and unknown (n = 1). In conclusion, severe hyponatremia was very rare but potentially fatal in PWS. Desmopressin treatment for nocturnal enuresis should be avoided. Enquiring about EFI and monitoring serum sodium should be included in the routine follow-ups of patients with PWS.


Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines.
Live attenuated vaccines remain the safest, most cost-effective intervention against viral infections. Because live vaccine strains are generated empirically and the basis for attenuation is usually ill defined, many important viruses lack an efficient live vaccine. Here, we present a general strategy for the rational design of safe and effective live vaccines that harnesses the microRNA-based gene-silencing machinery to control viral replication. Using poliovirus as a model, we demonstrate that insertion of small miRNA homology sequences into a viral genome can restrict its tissue tropism, thereby preventing pathogenicity and yielding an attenuated viral strain. Poliovirus strains engineered to become targets of neuronal-specific miRNAs lost their ability to replicate in the central nervous system, leading to significant attenuation of neurovirulence in infected animals. Importantly, these viruses retained the ability to replicate in nonneuronal tissues. As a result, these engineered miRNA-regulated viruses elicited strong protective immunity in mice without producing disease.


Tapered whiskers are required for active tactile sensation.
Many mammals forage and burrow in dark constrained spaces. Touch through facial whiskers is important during these activities, but the close quarters makes whisker deployment challenging. The diverse shapes of facial whiskers reflect distinct ecological niches. Rodent whiskers are conical, often with a remarkably linear taper. Here we use theoretical and experimental methods to analyze interactions of mouse whiskers with objects. When pushed into objects, conical whiskers suddenly slip at a critical angle. In contrast, cylindrical whiskers do not slip for biologically plausible movements. Conical whiskers sweep across objects and textures in characteristic sequences of brief sticks and slips, which provide information about the tactile world. In contrast, cylindrical whiskers stick and remain stuck, even when sweeping across fine textures. Thus the conical whisker structure is adaptive for sensor mobility in constrained environments and in feature extraction during active haptic exploration of objects and surfaces. DOI: http://dx.doi.org/10.7554/eLife.01350.001.