Optimum management of postoperative pain.
After surgery, patients try to minimise discomfort by various manoeuvres including change of posture, immobilisation of injured areas and use of analgesic drugs. The characteristic finding with drug use, revealed by permitting patients to titrate themselves with analgesic from a machine, is that the interindividual dosing rate has a wide range around the mean. Some patients will require almost no drug; others will need 2 to 3 times the mean dosing rate. Wide differences are also seen in the rate at which the need for drug declines. None of these parameters can be predicted with any useful degree of accuracy in the individual patient. Regimens which rigidly fix dosage in advance, which limit dosage rate through an often ill-founded fear of other pharmacological effects, or which cannot guarantee access of the patient to the drug, are unable to cope with such variation. Dose adjustment through feedback of effect from the patient is essential to combat this uncertainty, and is the prime determinant of optimum therapeutic efficacy. Although risk could be increased as well as benefit, experience shows that almost all patients may be trusted with control of their own pain relief without detrimental sequelae. Many of the newer therapeutic regimens represent differing attempts at the trade-off between the individualization (and consequent increased complexity) required for optimum therapeutic efficacy and the rigidity (and consequent increased simplicity) needed for routine implementation. Optimum management results from using a regimen which strikes the right balance for the clinical circumstances of the patient and prescriber.


Recent Trends in Drug Design and Discovery.
Structure-based drug design is a wide area of identification of selective inhibitors of a target of interest. From the time of the availability of three dimensional structure of the drug targets, mostly the proteins, many computational methods had emerged to address the challenges associated with drug design process. Particularly, drug-likeness, druggability of the target protein, specificity, off-target binding, etc., are the important factors to determine the efficacy of new chemical inhibitors. The aim of the present research was to improve the drug design strategies in field of design of novel inhibitors with respect to specific target protein in disease pathology. Recent statistical machine learning methods applied for structural and chemical data analysis had been elaborated in current drug design field. As the size of the biological data shows a continuous growth, new computational algorithms and analytical methods are being developed with different objectives. It covers a wide area, from protein structure prediction to drug toxicity prediction. Moreover, the computational methods are available to analyze the structural data of varying types and sizes of which, most of the semi-empirical force field and quantum mechanics based molecular modeling methods showed a proven accuracy towards analysing small structural data sets while statistics based methods such as machine learning, QSAR and other specific data analytics methods are robust for large scale data analysis. In this present study, the background has been reviewed for new drug lead development with respect specific drug targets of interest. Overall approach of both the extreme methods were also used to demonstrate with the plausible outcome. In this chapter, we focus on the recent developments in the structure-based drug design using advanced molecular modeling techniques in conjunction with machine learning and other data analytics methods. Natural products based drug discovery is also discussed.


Extrasegmental transcutaneous electrical nerve stimulation and mechanical vibratory stimulation as compared to placebo for the relief of acute oro-facial pain.
The present paper describes the pain reducing effect of high and low frequency transcutaneous electrical nerve stimulation (TENS) and 100 Hz mechanical vibratory stimulation as compared to placebo stimulation of the HoKu point in 50 patients suffering acute oro-facial pain. Ten of the 30 patients receiving actual stimulation reported pain reduction during treatment. In the placebo group of 20 patients, 4 of the subjects experienced pain relief during the trial. The findings in the present study showed that extrasegmental superficial stimulation of the HoKu point alters pain intensity in the patients studied to only a minor degree. The number of patients reporting pain alleviation and the magnitude of pain reduction in the groups receiving actual stimulation was comparable to that observed in earlier studies using intrasegmental placebo stimulation.


Villous polyps of the urethra: a report of two cases.
Two patients with villous polyps of the prostatic urethra are described. The article supports previous observations that the lesion has the morphologic appearance of prostatic tissue. A review of the literature reveals that this rare lesion appears to be specific for the prostatic urethra and behaves as a benign tumor.


Atomic force microscopy and high-content analysis: two innovative technologies for dissecting the relationship between epithelial-mesenchymal transition-related morphological and structural alterations and cell mechanical properties.
Epithelial-mesenchymal transition (EMT) is a complex series of cellular reprogramming events culminating in striking alterations in morphology towards an invasive mesenchymal phenotype. Increasingly, evidence suggests that EMT exerts a pivotal role in pathophysiological situations including fibrosis and cancer. Core to these dynamical changes in cellular polarity and plasticity is discrete modifications in cytoskeletal structure. In particular, newly established actin-stress fibres supplant a preceding system of highly organised cortical actin. Although cumulative studies have contributed to elucidation of the detailed signalling pathways that underpin this elaborate molecular process, there remains a deficiency regarding its precise contribution to cellular biomechanics. The advent of atomic force microscopy (AFM) and high-content analysis (HCA) provides two innovative technologies for dissecting the relationship between EMT-related morphological and structural alterations and cell mechanical properties. AFM permits acquisition of high resolution topographical images and detailed analysis of cellular viscoelasticity while HCA facilitates a comprehensive and perspicacious assessment of morphological changes. In combination, they offer the possibility of novel insights into the dynamic traits of transitioning cells. Herein, a detailed protocol describing AFM and HCA techniques for evaluation of transforming growth factor-β1-induced EMT of alveolar epithelial cells is provided.


Inhibition of growth of Leishmania donovani promastigotes by newly synthesized 1,3,4-thiadiazole analogs.
Leishmania donovani, the causative agent of visceral leishmaniasis, is transmitted by sand flies and replicates intracellularly in their mammalian host cells. The emergence of drug-resistant strains has hampered efforts to control the spread of the disease worldwide. Forty-four 1,3,4-thiadiazole derivatives and related compounds were tested in vitro for possible anti-leishmanial activity against the promastigotes of L. donovani. Micromolar concentrations of these agents were used to study the inhibition of multiplication of L. donovani promastigotes. Seven compounds were identified with potential antigrowth agents of the parasite. Compound 4a was the most active at 50 μM followed by compound 3a. These compounds could prove useful as a future alternative for the control of visceral leishmaniasis.


A biodegradable and serum-resistant gene delivery carrier composed of polyamidoamine-poly N,N'-di-(2-aminoethyl) aminoethyl glutamine copolymer.
Polyamidoamine-poly N,N'-di-(2-aminoethyl) aminoethyl glutamine graft copolymers (PAMAM-PAGA) were synthesized by polymerization of BLG-NCA and subsequent aminolysis with tris-(2-aminoethyl)-amine. The chemical structure and composition of the copolymers were characterized by FT-IR and (1)H NMR. The physicochemical and biological performances of the copolymers or copolymer/pDNA complexes were evaluated by enzyme-degradation, agarose gel retardation, stability test against DNase I, DLS measurement, MTT assay, CLSM observation and in vitro transfection. The copolymers were biodegradable and less cytotoxic; the copolymers could self-assemble with pDNA to form complexes which possessed stability against DNase I; the particle sizes were in 140-200 nm and the zeta potentials of the complexes were in +10±0.6 mV; the complexes displayed the enhanced transfection efficiency and excellent serum-resistant capacity. Therefore, the PAMAM-PAGA copolymer can be used as a biodegradable and serum-resistant gene delivery carrier.


Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism.
The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces acetyl-CoA (AcCoA), which fuels essential metabolic pathways and is also the acyl donor for protein lysine acetylation. Histones are abundant and highly acetylated proteins, accounting for 40% to 75% of cellular protein acetylation. Notably, histone acetylation is sensitive to AcCoA availability, and nutrient replete conditions induce a substantial accumulation of acetylation on histones. Deacetylation releases acetate, which can be recycled to AcCoA, suggesting that deacetylation could be mobilized as an AcCoA source to feed downstream metabolic processes under nutrient depletion. While the notion of histones as a metabolic reservoir has been frequently proposed, experimental evidence has been lacking. Therefore, to test this concept directly, we used acetate-dependent, ATP citrate lyase-deficient mouse embryonic fibroblasts (Acly-/- MEFs), and designed a pulse-chase experimental system to trace deacetylation-derived acetate and its incorporation into AcCoA. We found that dynamic protein deacetylation in Acly-/- MEFs contributed carbons to AcCoA and proximal downstream metabolites. However, deacetylation had no significant effect on acyl-CoA pool sizes, and even at maximal acetylation, deacetylation transiently supplied less than 10% of cellular AcCoA. Together, our data reveal that although histone acetylation is dynamic and nutrient-sensitive, its potential for maintaining cellular AcCoA-dependent metabolic pathways is limited compared to cellular demand.


Retinol transport proteins and concentrations in human amniotic fluid, placenta, and fetal and maternal sera.
1. The proteins binding retinol, and retinol concentrations, were determined in amniotic fluid, placental cytosol and in the fetal and maternal circulation. 2. In non-pregnant women, plasma retinol was almost exclusively found in a transthyretin-retinol-binding-protein complex whereas, in pregnant women, retinol-binding-protein-bound retinol was observed not complexed to transthyretin. This latter fraction increased in concentration with fetal age. These two fractions were the major retinol-protein complexes in amniotic fluid and their relative amounts changed with progress of gestation. 3. In fetal blood both of these fractions were again found, with higher proportions of retinol-binding-protein-bound retinol in the umbilical artery than in the umbilical vein.


Plasmonic Gold Nanostar-Enhanced Multimodal Photoacoustic Microscopy and Optical Coherence Tomography Molecular Imaging To Evaluate Choroidal Neovascularization.
Although photoacoustic microscopy (PAM) and optical coherence tomography (OCT) allow visualization of the retinal microvasculature, distinguishing early neovascularization from adjacent vessels remains challenging. Herein, gold nanostars (GNSs) functionalized with an RGD peptide were utilized as multimodality contrast agents for both PAM and OCT. GNSs have great absorption and scattering characteristics in the near-infrared region where most vasculature and tissue generates a less intrinsic photoacoustic signal while having a small size, excellent biocompatibility in vivo, and great photostability under nanosecond pulsed laser illumination. This enabled visualization and differentiation of individual microvasculature in vivo using multimodal PAM and OCT imaging. Detailed three-dimensional imaging of GNSs was achieved in an important choroidal neovascularization model in living rabbits. Through the administration of GNSs, PA contrast increased up to 17-fold and OCT intensities increased 167%. This advanced molecular-imaging platform with GNSs provides a unique tool for detailed mapping of the pathogenesis of the microvasculature.


SERS detection of arsenic in water: A review.
Arsenic (As) is one of the most toxic contaminants found in the environment. Development of novel detection methods for As species in water with the potential for field use has been an urgent need in recent years. In past decades, surface-enhanced Raman scattering (SERS) has gained a reputation as one of the most sensitive spectroscopic methods for chemical and biomolecular sensing. The SERS technique has emerged as an extremely promising solution for in-situ detection of arsenic species in the field, particularly when coupled with portable/handheld Raman spectrometers. In this article, the recent advances in SERS analysis of arsenic species in water media are reviewed, and the potential of this technique for fast screening and field testing of arsenic-contaminated environmental water samples is discussed. The problems that remain in the field are also discussed and an outlook for the future is featured at the end of the article.


Rat ribosomal protein L35a multigene family: molecular structure and characterization of three L35a-related pseudogenes.
The rat ribosomal protein L35a gene comprises a multigene family which contains 15-20 members as shown by the Southern blot analysis using L35a cDNA as a probe. We isolated 15 independent clones which contained distinct genes from a rat genomic library. Analysis of the restriction sites showed that all of them lacked the intervening sequences. Thermal stability of the hybrid molecules between these genes and the cDNA indicated that the similarity of the genes to the cDNA sequence varied. The nucleotide sequences of three genes gRL35a-A, gRL35a-B and gRL35a-G were determined. They shared some characteristics; namely: they lacked the intervening sequences, they contained (A)-rich tracts, and they were flanked by direct repeats. Two genes, gRL35a-A and gRL35a-B, contained a sequence completely identical to that of the cDNA. The nucleotide sequence of the 5' flanking region of gRL35a-B showed a significant homology with that of the same region of mouse ribosomal protein L32-related unmutated processed genes. Although this region of gRL35a-B contained the sequences homologous to the TATA box and the CCAAT box, gRL35a-B was not transcribed in an in vitro assay system. Thus, the L35a gene family comprises mostly processed pseudogenes. Further, Southern blot analysis in various animals indicated that the multigene construction of this ribosomal protein gene was a feature of mammalian genes. The origin and the evolutionary aspect of processed pseudogenes are discussed.


Feeding with powdered diet after weaning increases visuospatial ability in association with increases in the expression of N-methyl-D-aspartate receptors in the hippocampus of female rats.
We determined whether feeding with powdered diet improved the visuospatial ability in female rats by checking the expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (NR1) mRNA in the hippocampus. In rats fed standard pelleted diet, males performed better than females in a radial 8-arm maze task as we reported previously. We found that the expression of NR1 mRNA, which may be the key mediator in visuospatial ability in the hippocampus, was also higher in males than in females. However, in rats fed powdered diet, no sex difference was seen in the radial 8-arm maze task and the expression of NR1 mRNA in the hippocampus, since feeding with powdered diet improved the visuospatial ability with increases in the expression of NR1 mRNA in the hippocampus in females. We suggest that the sex difference in visuospatial ability is at least in part due to feeding conditions.


An elderly patient with severe aortic stenosis and myocardial infarction with a huge mobile thrombus as complication in the left ventricle.
An 86-year-old woman was admitted for emergency treatment of increasing dyspnea. Transthoracic echocardiography revealed decreased left ventricular systolic function with dyskinesis at the apex, and severe aortic stenosis. The apex of the left ventricle showed a huge mobile thrombus. Coronary angiography revealed total occlusion at the middle portion of the left anterior descending coronary artery. Emergency operation was successful, and a partially calcified thrombus was observed at the site of the old myocardial infarction area. In this case, myocardial infarction and elevated intraventricular pressure due to aortic stenosis likely contributed to the wall motion abnormality and thrombus formation.


Interaction between noradrenaline and diltiazem in rat isolated atria.
1. The present study describes the effects of diltiazem (DIL) on noradrenaline (NA) activity in the isolated right atria of the rat. 2. Interactions between DIL and NA showed that DIL significantly shifted the concentration-response curve of NA to the right in a concentration-dependent manner. 3. The antagonist between DIL and NA is not consistent with a competitive antagonist since the slope is significantly lower than the unity. 4. A high calcium solution (4.5 mM) significantly increased the chronotropic effects of noradrenaline. 5. These results suggest that influx of calcium through calcium antagonist sensitive channels may be involved in linking of chronotropic responses to activation of alpha 1-adrenoceptors.


Diagnostic importance of platelet parameters in patients with acute coronary syndrome admitted to a tertiary care hospital in southwest region, Saudi Arabia.
Identifying risk factors for acute coronary syndrome (ACS) is important for both diagnostic and prognostic purposes. Abnormal platelet parameters, mainly platelet count (PC), mean platelet volume (MPV) and platelet distribution width (PDW) are thought to be among these risk factors. In this study, the associations between PC, MPV and PDW and ACS were investigated in patients admitted to the tertiary care hospital in the south west region of Saudi Arabia. A retrospective cohort of 212 patients with the diagnosis of ACS admitted to Aseer Central Hospital during the period extending from February 1, 2008 to October 31, 2008 were included. The control group consisted of 49 matched subjects who were admitted for chest pain investigation and subsequently found to be non-cardiac chest pain after performing relevant investigations. Blood samples were taken at the time of admission for platelet parameters. Statistical analysis was made using SPSS software and P-values were considered significant if <0.05. A total of 212 patients with acute coronary syndrome (80 patients with MI and 132 patients with UA) and 49 matched controls were studied. The PC was not statistically different among the three groups (283.3 ± 94.8 × 10(9) L(-1) for MI cases, 262 ± 60.8 × 10(9) L(-1) for UA cases and 275.8 ± 58.9 × 10(9) L(-1) for controls). The MPV was significantly larger in MI cases compared to controls (8.99 ± 1.5 fl vs. 8.38 ± 0.51 fl, respectively, P < 0.009), similarly, the MPV was significantly larger in UA cases compared to controls (9.23 ± 1.19 fl vs. 8.38 ± 0.51 fl, respectively, P < 0.001). The PDW was significantly higher in MI cases compared to controls (15.88 ± 1.5 fl vs. 11.96 ± 1.8 fl, respectively, P < 0.001), similarly, the PDW as also significantly larger in UA cases compared to controls (18.1 ± 18 fl vs. 11.96 ± 1.8 fl, respectively, P < 0.019). Platelet parameters mainly MPV and PDW are readily available and relatively simple and inexpensive laboratory tests which we detected to be significantly raised in patients who have suffered an acute coronary syndrome compared with controls.


Production, purification, and characterization of exoglucanase by Aspergillus fumigatus.
Fungi are considered good producers of industrially valuable enzymes with higher enzymatic activities. Among these cellulases are group of extracellular enzymes commonly employed in many industries for the hydrolysis of cellulolytic material. Aspergillus fumigatus produced exoglucanase having high enzymatic activity (83 U/gds) during the solid-state fermentation of wheat straw under optimum physical and nutritional conditions. Maximum production was obtained after 72 h of fermentation, at 55 °C temperature, pH 5.5, 80 % moisture level, and 2 mL fungal inoculum. Production was further increased by the addition of fructose (0.3 %) as additional carbon source, peptone (0.4 %) as nitrogen source, Tween-80 (0.3 %) as surfactant, and ammonium sulfate (0.2 %) in media. Exoglucanase was 2.30-folds purified by adding 40 % ammonium sulfate with volumetric activity 95.4 U/gds and specific activity 14.74 U/mg. Further, it was 5.18-folds purified by gel filtration chromatography with volumetric activity 115.2 U/gds and specific activity 33.10 U/mg. Purified exoglucanase has maximum activity at 55 °C and pH 4.8 using 1 % Avicel aqueous solution as substrate. The K(m) and V(max) were 4.34 mM and 7.29 μM/min, respectively. Calcium, magnesium, and zinc ions have positive effect on exoglucanase activity.


Management of an extremely displaced maxillary canine.
Aligning a displaced maxillary canine into the dental arch is one of the most complicated problems in orthodontics. In cases of extremely high displacement, the tooth is frequently removed surgically. Because of the upper canines' significance to dental esthetics and functional occlusion, such a decision is a very serious one. This case report illustrates the treatment of an extremely high displaced maxillary canine. The main diagnosis was the displacement and the retention of tooth 13 (in nearly horizontal position, apical to the neighboring teeth); further diagnoses were: transversal maxillary deficiency with frontal crowding and a distal bite of one premolar in width, a deep bite of 6 mm with contact in the palatal mucosa, mandibular midline deviation of 2.5 mm to the right, lingual eruption of teeth 32 and 42, retroinclination of the maxillary incisors, and retarded eruption of the permanent teeth. Initial treatment with active and functional appliances to correct the distal bite, midline deviation and deep bite. Surgical exposure of the high displaced canine at the age of 14. Onset of cuspid elongation with removable appliances and elastics, further movement with a transpalatinal bar and welded arm, and full alignment of the upper and lower arches with fixed appliances in both jaws. Stabilization of the orthodontic treatment results with retention devices. Duration of treatment: 5 years and 8 months. For the alignment of tooth 13, 2 years and 10 months were required; 1 year and 4 months were necessary with complete fixed appliance. The aim of this case report was to demonstrate the potential of aligning an extremely displaced canine. Because of the esthetic and functional importance of the upper canines, therapeutic alignment should be initiated, provided there are no indications to the contrary.


Bi-RADS category 3 nonpalpable breast masses on sonography: long-term results of a prospective cohort study.
To determine the frequency of BI-RADS category 3 nonpalpable masses detected using only sonography (US) and the malignancy rate among these lesions. Second, to validate a proposed short-term follow-up regimen based on long-term observational results. This prospective cohort study was conducted between September 2003 and April 2010. We conducted a 2-year short-term follow-up protocol composed of five US examinations at 3-month intervals for the first 6 months, and at 6-month intervals for the next 18 months, followed with age-appropriate screenings. Biopsy was recommended for the masses increasing in size and with changing imaging features. The frequency of category 3 nonpalpable masses detected only on US in 11,373 consecutive women was 5.3%. Of 562 lesions found in 451 women, 394 (70.1%) remained stable during the short-term and subsequent follow-up. Seventy-four (13.1%) masses showed interval regression and 79 (14.0%) showed interval progression. The malignancy rate was 0.3% (2 of 562), with about 85% of interval changes occurring within the first 2 years. The negative predictive value of US in the detection of cancer was 99.6% (95% CI, 98.7-99.9). The mean follow-up time was 65.5 ± 8.7 months. The frequency of BI-RADS 3 nonpalpable masses detected using sonography alone was 5.3%. During follow-up, the majority of interval changes occurred within the first 2 years. Because these masses have a very low malignancy rate, a 2-year follow-up instead of immediate biopsy is an appropriate option.


The pelvic digit--a rare developmental anomaly. A case report with CT correlation and review of the literature.
Radiography of the pelvis may incidentally reveal a rare congenital anomaly called "pelvic digit" and it is important to be aware of its existence in order to differentiate it from acquired abnormalities due to trauma. A case of a pelvic digit with CT correlation is presented and the literature is reviewed.


Hippocampal neurons transplanted into ischemically lesioned hippocampus: electroresponsiveness and reestablishment of circuitries.
Severe forebrain ischemia was used to damage selectively the CA1 region of the rat hippocampal formation. One week later the CA1 region was repopulated with suspensions of 18 day old fetal hippocampal tissue. Intracellular recordings were made from single units within the transplants by using the "in vitro" slice preparation, two to nine months following transplantation. Based on firing characteristics during depolarizing current injection, pyramidal-like and interneuron-like cells were identified within the transplants. Synaptic potentials could be evoked in the pyramidal-like neurons by stratum radiatum and stratum oriens stimulation demonstrating that normal afferent contacts had been made. Local inhibitory circuits were not obvious within the transplanted regions as demonstrated by prolonged EPSP's and the absence of early or late after-hyperpolarization. This was supported by the lack of conductance fluctuation in the active membrane when compared with the resting cell. Antidromic spikes could be evoked by applying shocks to the stratum oriens, towards the fimbria and subiculum, suggesting that the transplanted neurons were projecting basal neurites, quite long distances, along the normal efferent pathways. Thus, the transplanted neurons have the capacity to reconstruct damaged circuitries and develop intrinsic properties similar to their normal counterparts.


[Ultrastructure, metabolism and performance of white blood cells during development of the immune response and the effect of glucocorticoids on it. I. Effect of immunization on the number and submicroscopic structure of lymphocytes and monocytes in the blood of rabbits].
As a result of immunization and reimmunization with bovine serum albumin there was a change of the number and correlation of various morphologically identifyable species of lymphocytes in the blood of rabbits. Regular submicroscopic changes in the nucleus and organoids of the cytoplasm pointing to increased functional activity of these cells were revealed at the ultrastructural level in many circulating lymphocytes belonging to various populations.


A case of acute encephalitis with refractory, repetitive partial seizures, presenting autoantibody to glutamate receptor Gluepsilon2.
An 11-year-old male was admitted to our hospital because of high-grade fever, repetitive seizures, and prolonged impairment of consciousness (Glasgow coma scale E1, M5, V1). His seizures were repetitive complex partial seizures that expanded from the unilateral face to the corresponding side of the body. He sometimes developed secondary generalized seizures. While most seizures lasted 1 or 2 min, intractable seizures also frequently (about 5 times/h) occurred. We diagnosed him as encephalitis/encephalopathy, and treated him with artificial respiration, thiamylal sodium, mild hypothermia therapy, steroid pulse therapy, massive gamma-globulin therapy, etc. Afterwards, he had sequelae, such as post-encephalitic epilepsy (same seizures continued to recur), hyperkinesia, impairment of immediate memory, change in character (he became sunny and obstinate), dysgraphia, and mild atrophy of the hippocampus, amygdala, and cerebrum. However, he could still attend a general junior high school. He was diagnosed as acute encephalitis with refractory, repetitive partial seizures (AERRPS). In this case, he was positive for autoantibody to glutamate receptor Gluepsilon2 IgG or IgM in an examination of blood and spinal fluid, and we presumed that this may have influenced his sequelae. In this case, a combination of mild hypothermia therapy, steroid pulse therapy, and massive gamma-globulin therapy was effective.


Risk of new-onset depressive disorders after hearing impairment in adults: A nationwide retrospective cohort study.
Previous studies reported that hearing impairment has been associated with depressive disorders, but little is known about the risk of newly diagnosed depression after hearing impairment diagnosed by a physician and registered with the government. We evaluated the risk of new-onset depressive disorders following hearing impairment in adults. We used data from the Korean National Health Insurance Service-National Sample Cohort and included adults with hearing impairment, and a comparison group without hearing impairment, selected by a 1:3 propensity score matching between 2004 and 2012. The dependent variable was a depressive disorder diagnosis. The hazard ratio of risk of depression was estimated using a Cox proportional hazard model. In the sample of 14,212 adults, 15.0% of people with hearing impairment (n = 3,553) experienced a depressive disorder following their hearing impairment. Those who had not experienced depression previously were more likely to develop a new-onset depressive disorder following hearing impairment than the comparison group. Male, female, old adults (60-74 years) and very-old adults (≥ 75 years) with hearing impairment were associated with an increased risk for a new-onset depressive disorders than their matched counterparts. These findings suggest a need for psychological support along with hearing rehabilitation, especially for older adults.


Synthesis of beta-difluorine-containing amino acids.
A convenient strategy was developed to prepare several beta-difluoroamino acids. As exemplified by the synthesis of 3,3-difluoro-L-homocysteine, 3,3-difluoro-L-homoserine and 3,3-difluoro-L-methionine, the reaction sequence all started from L-isoascorbic acid. This approach holds potential to be extended to make other beta-difluorine-containing amino acids.


Professional collegiality and peer monitoring among nursing staff: an ethnographic study.
Patient safety and professional self-regulation systems both rely on professional colleagues to hold each other accountable for quality of care. To understand how staff nurses manage variations in practices within the group, and negotiate the rules-in-use for quality of care, collegiality, and accountability. Ethnographic case study; participant-observation, semi-structured interviews, policy analysis. In-patient unit in an urban US teaching hospital. Explicit acknowledgment of conflicts and practice variations was perceived as risky to group cohesion. The dependence of staff on mutual assistance, and the absence of a system of group practice, led to the practice of "mutual deference", a strategy of reciprocal tolerance and non-interference that gave wide discretion to each nurse's decisions about care. Efforts to improve professional accountability will need to address material constraints and the organization of nursing work, as well as communication and leadership skills.


Learning and memory in Drosophila: behavior, genetics, and neural systems.
The rich behavioral repertoire that Drosophila use to navigate in their natural environment suggests that flies can use memories to inform decisions. Development of paradigms to examine memories that restrict behavioral choice was essential in furthering our understanding of the genetics and neural systems of memory formation in the fly. Olfactory, visual, and place memory paradigms have proven influential in determining principles for the mechanisms of memory formation. Several parts of the nervous system have been shown to be important for different types of memories, including the mushroom bodies and the central complex. Thus far, about 40 genes have been linked to normal olfactory short-term memory. A subset of these genes have also been tested for a role in visual and place memory. Some genes have a common function in memory formation, specificity of action comes from where in the nervous system these genes act. Alternatively, some genes have a more restricted role in different types of memories.


Child Abuse and Neglect.
Physical, sexual, and emotional abuse and various forms of neglect of children are associated with substantially increased risk for concurrent and subsequent psychopathology and are among the common problems encountered by clinicians in many clinical settings. Such cases pose additional challenges for clinicians because of the many complex family and system forces that engulf these children and their families. Assessing maltreated children generally requires more time than evaluations of children who have not experienced maltreatment. Young children, who experience the highest rates of maltreatment, present especially complex assessments because they are so dependent upon their caregiving environments. Treatment of psychopathology associated with maltreatment, which is often multimodal, requires addressing a variety of external factors that may perpetuate or exacerbate symptoms and impaired functioning. We suggest that the more clinicians understand the different cultures of the legal and child protective services systems will help them advocate more effectively for maltreated children's bests interests so that the complexity of their problems is matched by the comprehensiveness of our efforts to minimize their suffering, enhance their development, and promote their competence.


Data-driven modeling on the global annual soil nitrous oxide emissions: Spatial pattern and attributes.
Previous assessments generated divergent estimates of global terrestrial soil nitrous oxide (N2O) emission and its spatial distributions, which did not match the observed data well. The objectives of this study were to generate a global map of terrestrial soil N2O emissions based on field observations (n = 5549) and quantify the contribution of different variables for predicting the global variation of N2O emissions. We provided spatially explicit maps of annual soil N2O emission rates across forest, grassland and cropland using the random forest approach. The global mean soil N2O emission rate in our data-driven model was 0.059 ± 0.006 g N m-2 year-1, which was lower than the estimates from previous model ensembles. Soil N2O emissions were higher in the northern than southern hemisphere. The average annual soil N2O emission rate of cropland (0.094 ± 0.009 g N m-2 year-1) was higher than that of forest (0.039 ± 0.004 g N m-2 year-1) and grassland (0.045 ± 0.007 g N m-2 year-1). In addition, we found that soil nitrogen substrates dominated the changes in soil N2O emissions and the relative importance of nitrate, ammonium, and fertilizer in predicting soil N2O emissions was greater than that of mean annual temperature and precipitation. Our data-driven model results implied that previous process-based model may overestimate the global soil N2O emission rates due to limited validation data and incomplete assumptions on related-mechanisms. This study highlights the importance of global field observations in N2O emission estimation, which can provide an independent dataset to constrain previous process-based models for better prediction.


Bovine colostrum ultrafiltrate: an effective supplement for the culture of mouse-mouse hybridoma cells.
An ultrafiltrate fraction (UF) of bovine colostrum has been successfully used as a cell culture supplement for growth and monoclonal IgG antibody production of cultured mouse-mouse hybridomas derived from spleen cells. In this study we compared the ability of UF to support growth and antibody production of IgA hybridomas derived from Peyer's patch cells with that of an IgG hybridoma cell line. One IgG (LPC2) and two IgA hybridoma cell lines (RB3 and P2E7) were used as models. The optimal UF concentration for Ig production and cell growth for both the IgA hybridoma RB3 and the IgG hybridomas was 5-10%. Initial plating density was found to be a critical factor for IgA hybridoma cell growth: the IgA hybridomas required a seeding density of at least 70,000 cells/ml to grow compared to 15,000 IgG hybridoma cells/ml (Pakkanen et al., 1992). The addition of small amounts (up to 2%) of FBS in 10% UF supplemented medium did not enhance IgA production or cell growth. RB3 and LPC2 cells seeded at equal density and grown in 10% UF for 8 days attained maximum cell densities at 3-4 days that were 58% (RB3) or 34% (LPC2) lower than those in 10% FBS, but the total amounts of monoclonal antibody produced were 73% and 83%, respectively, of that in 10% FBS. Thus, Ig production per cell was 22-27% higher in 10% UF than in 10% FBS. Hybridoma cells could be cultured for at least 5 weeks without any reduction in growth rates, if medium was partially but not completely replaced twice a week. This suggests that hybridoma cells maintained in UF supplemented medium secrete growth promoting factors. Cells maintained in UF for up to 5 weeks sustained similar monoclonal antibody production rates as in short term culture. These results show that UF can be used as an economical and effective hybridoma culture supplement for the production of both IgG and IgA antibodies.


Recent advances in antitumor vaccines.
Immunization with anti-idiotypic antibodies can induce cell-mediated and humoral antitumor immunity in animal models. This immunity can sometimes cause tumor destruction. However, more needs to be learned about how best to induce the type of immune response that is responsible for tumor destruction, since the presence of anti-idiotypic antibodies has been shown occasionally to enhance, rather than to inhibit, tumor growth. There is evidence suggesting that immunization of human cancer patients with Ab2 can have therapeutic benefit, and also that patients who mount a vigorous Ab2 response following treatment with an Ab1 may do clinically better than those who do not make any Ab2. Although the generation of Ab2 related to infused antitumor Ab1 does not cause tumor rejection in the majority of patients, and although the clinical data from patients given Ab2 are scarce, the suggestion that Ab2 may cause destruction of human cancers indicates that further work in this area may become rewarding.


The effect of somatostatin on epinephrine-induced free fatty acid release in normal man.
Epinephrine and saline or cyclic somatostatin were infused into normal persons to study the effect of somatostatin on free fatty acid (FFA) release. Somatostatin had no effect on epinephrine-induced hyperglycaemia. It enhanced basal and epinephrine-induced FFA release, while the release of both immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) was inhibited. We suggest that the rise in FFA levels may be due to either inhibition of IRI or another effect of somatostatin on fatty acid metabolism.


Effects of opiates on the discriminative stimulus properties of dopamine agonists.
Two groups of rats were trained to discriminate the dopamine agonists amphetamine (0.75 mg/kg) or apomorphine (0.38 mg/kg) from saline in a two-lever operant task. Various doses of morphine and pentazocine were tested for generalization to and interference with the discriminative stimulus complexes produced by the dopamine agonists. Low doses of morphine appeared to produce a stimulus complex which is similar to that produced by apomorphine, but which differs from the produced by amphetamine. Pentazocine showed no evidence of generalization to either the apomorphine or the amphetamine cue. Neither opiate interfered with discriminative stimuli produced by the dopamine agonists, although decreases in the number of animals responding occurred.


Induction of tetraspanin 13 contributes to the synergistic anti-inflammatory effects of parasympathetic and sympathetic stimulation in macrophages.
The autonomic nervous system plays an important role in the regulation of peripheral inflammation. Sympathetic nervous activation stimulates inflammatory gene expression and cytokines, whereas parasympathetic nervous activation suppresses the production of inflammatory cytokines by immune cells. However, most studies on the relationship between the autonomic nervous system and immune processes have analyzed a single branch of the autonomic nerves in isolation. Therefore, this study aimed to examine the effects of sympathetic and parasympathetic stimulation on macrophages, which are controlled by autonomic regulation. Macrophages were stimulated with lipopolysaccharide (LPS) to induce TNF-α. Then, the effects of β2 adrenergic receptor and α7 nicotinic acetylcholine receptor activation on TNF-α production were assessed using concentration-dependent assays. RNA-seq data were also used to identify genes whose expression was enhanced by parasympathetic and sympathetic stimulation. The simultaneous activation of β2 adrenergic receptors and α7 nicotinic acetylcholine receptors suppressed LPS-induced TNF-α production in a concentration-dependent manner. Moreover, simultaneous activation of these receptors had synergistic anti-inflammatory effects and induced Tspan13 expression, thereby contributing to anti-inflammatory mechanisms in macrophages. Our study revealed the synergistic anti-inflammatory effects of the parasympathetic and sympathetic stimulation of macrophages. Our results suggest that targeting both sympathetic and parasympathetic signaling is a promising therapeutic approach for inflammatory diseases.


Orthogonal outlier detection and dimension estimation for improved MDS embedding of biological datasets.
Conventional dimensionality reduction methods like Multidimensional Scaling (MDS) are sensitive to the presence of orthogonal outliers, leading to significant defects in the embedding. We introduce a robust MDS method, called DeCOr-MDS (Detection and Correction of Orthogonal outliers using MDS), based on the geometry and statistics of simplices formed by data points, that allows to detect orthogonal outliers and subsequently reduce dimensionality. We validate our methods using synthetic datasets, and further show how it can be applied to a variety of large real biological datasets, including cancer image cell data, human microbiome project data and single cell RNA sequencing data, to address the task of data cleaning and visualization.


Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology.
Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.


The mechanisms responsible for 2-dimensional pattern formation in bacterial macrofiber populations grown on solid surfaces: fiber joining and the creation of exclusion zones.
When Bacillus subtilis is cultured in a complex fluid medium under conditions where cell separation is suppressed, populations of multicellular macrofibers arise that mature into ball-like structures. The final sedentary forms are found distributed in patterns on the floor of the growth chamber although individual cells have no flagellar-driven motility. The nature of the patterns and their mode of formation are described in this communication. Time-lapse video films reveal that fiber-fiber contact in high density populations of macrofibers resulted in their joining either by entwining or supercoiling. Joining led to the production of aggregate structures that eventually contained all of the fibers located in an initial area. Fibers were brought into contact by convection currents and motions associated with macrofiber self-assembly such as walking, pivoting and supercoiling. Large sedentary aggregate structures cleared surrounding areas of other structures by dragging them into the aggregate using supercoiling of extended fibers to power dragging. The spatial distribution of aggregate structures in 6 mature patterns containing a total of 637 structures was compared to that expected in random theoretical populations of the same size distributed in the same surface area. Observed and expected patterns differ significantly. The distances separating all nearest neighbors from one another in observed populations were also measured. The average distance obtained from 1451 measurements involving 519 structures was 0.73 cm. These spacings were achieved without the use of flagella or other conventional bacterial motility mechanisms. A simple mathematical model based upon joining of all structures within an area defined by the minimum observed distance between structures in populations explains the observed distributions very well. Bacterial macrofibers are capable of colonizing a solid surface by forming large multicellular aggregate structures that are distributed in unique two-dimensional patterns. Cell growth geometry governs in an hierarchical way the formation of these patterns using forces associated with twisting and supercoiling to drive motions and the joining of structures together. Joining by entwining, supercoiling or dragging all require cell growth in a multicellular form, and all result in tightly fused aggregate structures.


MRI of the brain in childhood-onset mitochondrial disorders with central nervous system involvement.
We retrospectively studied the brain MRIs of 66 pediatric patients with mitochondrial disorder with central nervous system involvement. Forty-one patients had an identified genetic etiology. A predominance of cerebrocortical lesions was mainly seen in patients with MELAS and Alpers syndrome. Basal ganglia were predominantly affected in patients with Leigh syndrome. All patients with leukoencephalopathy had pathological spectroscopy. Cerebrocortical atrophy with agenesis/atrophy of the corpus callosum was seen in patients with congenital lactic acidosis with or without pyruvate dehydrogenase complex deficiency. The diagnostic approach used in our study--from the neuroanatomical/neurofunctional lesion to disease identification--assists the physician in the use of brain neuroimaging early in the diagnostic work-up of suspected mitochondrial disorders.


Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration.
The human Y chromosome is intriguing not only because it harbours the master-switch gene that determines gender but also because of its unusual evolutionary history. The Y chromosome evolved from an autosome, and its evolution has been characterized by massive gene decay. Recent whole-genome and transcriptome analyses of Y chromosomes in humans and other primates, in Drosophila species and in plants have shed light on the current gene content of the Y chromosome, its origins and its long-term fate. Furthermore, comparative analysis of young and old Y chromosomes has given further insights into the evolutionary and molecular forces triggering Y-chromosome degeneration and into the evolutionary destiny of the Y chromosome.


[Analytical microelectrophoresis of cells and the means for using it in oncological research].
Analysis of data on the study of electrophoretic cell mobility in the field of oncology is reviewed. Much attention is paid to the application of cell surface phenomena for the development of different diagnostic methods, especially for immunological diagnosis of cancer.


The association of prenatal cocaine exposure with expressive and receptive language skills, phonological processing and reading ability at age 17.
Prenatal cocaine exposure (PCE) has been associated with small but significant effects on language development in childhood and early adolescence. This study examined whether this association persists into later adolescence and what relationship language skills may have with reading proficiency in this population. Enrolled were 338 (167 with PCE, 171 with NCE or no cocaine exposure) 17-year-olds recruited at birth who, together with their current caregiver, were seen as part of a 17-year follow-up. Participants were given assessments of reading achievement (WIAT-III), receptive and expressive language (CELF-IV), and phonological processing (CTOPP). Relationships between PCE status and language outcomes were modeled using multiple linear regression controlling for environmental and caregiver factors, and other prenatal substance exposures. Adolescents with PCE scored lower in areas of phonological processing and reading related skills compared to adolescents with NCE. PCE by sex interactions were identified on language, memory and spoken language comprehension, with lower scores for girls with PCE compared to girls with NCE. These findings suggest the persistence of PCE's relationship with phonological awareness well into adolescence. PCE was also associated with lower scores on measures of skills related to reading ability, which may be a manifestation of the observed deficits in phonological processing.


Pregnancy in Henoch-Schönlein purpura.
A 22-year-old white woman with Henoch-Schönlein purpura was treated with frequent plasmapheresis for increased severity of the disease activity during pregnancy. Hypertension, azotemia, and placental dysfunction were not observed. A healthy infant was delivered by cesarean section, and evidence of vasculitis was not detected in the placenta.


Granulocyte-dendritic cell unbalance in the non-obese diabetic mice.
Several investigators, including ourselves, have reported lower yield of GM-CSF bone marrow-derived dendritic cells (DC) with altered MHC class II and co-stimulatory molecules expression in the non-obese diabetic (NOD) mice. However, whether this defect was intrinsic to the DC lineage and/or related to abnormal expansion of other cell types responding to GM-CSF remained an opened issue. We performed phenotypical and morphological analysis of cells from GM-CSF-supplemented-bone marrow-cultures and of freshly isolated bone marrow and blood cells from unmanipulated prediabetic NOD mice. The results show a heretofore undescribed bias towards generation of granulocytes in NOD mice, concomitant with quantitative and qualitative alterations of the DC lineage in both the bone marrow and the blood of this mouse strain. We propose that increased generation of granulocytes in NOD mice might contribute to autoimmunity. First, high numbers of granulocytes per se might favor inflammatory environment. Second, granulocytes, by interfering with DC development, might favor unbalanced antigen presenting cell function leading to T cell autoimmunity.


Ethnic differences in the prevalence of polymorphisms in CYP7A1, CYP7B1 AND CYP27A1 enzymes involved in cholesterol metabolism.
It is well known that drug disposition and response are greatly determined by the activities of drug metabolizing enzymes, which are polymorphic. Some of these polymorphisms are clinically relevant and presented an ethnic-dependent pattern of distribution. The characterization of the genetic distribution of different populations allows the selection of therapeutic options in accordance with the genetic background, with the objective to avoid adverse reactions and inefficacy of the treatment. In this work, we studied selected genetic polymorphisms in drug metabolizing enzymes in three different ethnic groups - Portugal, Mozambique and Colombia. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping methods were developed for drug metabolizing enzymes, namely, cholesterol 7α-hydroxylase (CYP7A1) (-203A>C, -346C>T, -496C>T, N233S, G347S), sterol 27-hydroxylase (CYP27A1) (R164W, A169V, D273N, V400A) and oxysterol 7α-hydroxylase (CYP7B1) (-116C>G, R324H, 1774C>T) to characterize the allelic distribution of these polymorphisms among three different ethnic/geographic origins. A total of 12 CYP7A1, CYP27A1 and CYP7B1 genetic variants were genotyped in a sample of 92 Portuguese, 151 Mozambican and 91 Colombian subjects. The variants N233S in CYP7A1 and 1774C>T in CYP7B1 were not detected in any population studied. The promoter polymorphisms in CYP7A1 (-203A>C, -346C>T, -496C>T) had high frequency in the three ethnic groups. G347S (CYP7A1), R164W, A169V and V400A (CYP27A1) were present in a low frequency but with a similar distribution in the three ethnic groups. Significant differences were observed for D273N (CYP27A1), -346C>T (CYP7A1), -116C>G and R324H (CYP7B1)Our results demonstrate a high variability of drug metabolizing enzymes between the different populations analyzed, indicating that at least some of these polymorphisms are ethnic specific.


Identification of the novel HLA-B*46:83 allele by sequencing-based typing in a Chinese individual.
HLA-B*46:83 differs from HLA-B*46:03 by one single nucleotide substitution at position 539G>T.


Re-awakening Innate Immune Signaling in Cancer: The Development of Highly Potent ENPP1 Inhibitors.
Activation of innate immune signaling in the tumor microenvironment is central to a successful anti-tumor immune response, and it is in large part mediated by cytosolic double-stranded DNA sensing. Here, Carozza et al. (2020b) report potent and selective inhibitors of ENPP1, a negative regulator of innate immune signaling, which are shown to potentiate anti-tumor immune responses.


Modified Malyugin ring iris expansion technique in small-pupil cataract surgery with posterior capsule defect.
We describe a simple technique involving modification of iris expansion with the Malyugin ring (MicroSurgical Technology) in nondilating small-pupil cataract surgery with preexisting posterior capsule defect or intraoperative posterior capsule tear. A 6-0 polyglactin suture is placed in the leading scroll of the Malyugin ring, and the end of the suture is secured at the main port incision. This prevents the iris expander from inadvertently dropping into the vitreous during intraoperative manipulation.


Utility of measuring remoralization in addition to symptoms in efficacy research: a preliminary study.
Remoralization as an outcome measure for psychological treatments was compared with symptom reduction (agoraphobic avoidance and cognitions). Twenty-four patients with panic disorder and agoraphobia received empirically supported treatment and were monitored across multiple time points for 28 weeks. Treatment resulted in reduced symptoms and enhanced remoralization (Cohen's d=1.19-1.45). Slopes of symptoms and remoralization were obtained from latent growth model analyses. The slopes correlated highly (r=- .50 to -.55), which indicates similar patterns of change over time. The slope of remoralization also correlated with a number of aspects of health-related quality of life, while the slope of symptom reduction did not. Although strongly related to symptom reduction, the measurement of remoralization is expected to provide unique information for treatment efficacy research.


Non-IgG1 nature of cutaneous basophil hypersensitivity factor in contact sensitivity. II. Demonstration of antigen-dependent basophil chemotactic activity of cutaneous basophil hypersensitivity factor.
It was recently demonstrated that there was a specific activity to induce basophil-rich skin reaction in the sera of contact-sensitized guinea pigs (CBH factor, CBH-F). In the in vitro chemotactic assay system, CBH-F was shown to have weak basophil chemotactic activity but enhanced its activity in the presence of corresponding antigen(s). Furthermore, basophil chemotaxis in reaction to the antigen(s) was observed when the cells were preincubated with CBH-F. It worked mainly for Percoll-separated bone marrow basophils but not for oil-induced peritoneal macrophages. Immunological analysis revealed that CBH-F was a protein with a small molecular weight (MW 4-6 X 10(4] with an antigen binding site and isoelectric point of between 4.5 and 5.0. It did not show any characteristics of IgG1 or IgG2 on immunoadsorbent column and immunoelectrophoresis. Enzyme treatment with insoluble trypsin eliminated the chemotactic activity but this was not the case with neuraminidase treatment.


Toxicity mechanism of Nylon microplastics on Microcystis aeruginosa through three pathways: Photosynthesis, oxidative stress and energy metabolism.
Nylon has been widely used all over the world, and most of it eventually enters the aquatic environment in the form of microplastics (MPs). However, the impact of Nylon MPs on aquatic ecosystem remains largely unknown. Thus, the long-term biological effects and toxicity mechanism of Nylon MPs on Microcystis aeruginosa (M. aeruginosa) were explored in this study. Results demonstrated that Nylon MPs had a dose-dependent growth inhibition of M. aeruginosa at the initial stage, and the maximum inhibition rate reached to 47.62% at the concentration of 100 mg/L. Meanwhile, Nylon MPs could obstruct photosynthesis electron transfer, reduce phycobiliproteins synthesis, destroy algal cell membrane, enhance the release of extracellular polymeric substances, and induce oxidative stress. Furthermore, transcriptomic analysis indicated that Nylon MPs dysregulated the expression of genes involved in tricarboxylic acid cycle, photosynthesis, photosynthesis-antenna proteins, oxidative phosphorylation, carbon fixation in photosynthetic organisms, and porphyrin and chlorophyll metabolism. According to the results of transcriptomic and biochemical analysis, the growth inhibition of M. aeruginosa is inferred to be regulated by three pathways: photosynthesis, oxidative stress, and energy metabolism. Our findings provide new insights into the toxicity mechanism of Nylon MPs on freshwater microalgae and valuable data for risk assessment of MPs.


The thigh as a model for free style free flaps.
Following a set of principles, free style free flaps may be harvested from any region of the body where a Doppler signal is heard. By using a retrograde dissection technique, the skin vessel is traced through its subfascial course (intramuscular or septocutaneous), until adequate length or vessel size is achieved. If a "free style free flap" is not originally planned, this approach can be usedwhen anatomic variations or unexpected events are encountered. The thigh, a region that is familiar to the surgical team at Chang Gung Memorial Hospital, was chosen as the site to begin exploring this style of flap harvest. Nine flaps were harvested as free style free flaps from the thigh and were used successfully for the reconstruction of complex defects.


Hypertrophied tonsils impair velopharyngeal function after palatoplasty.
When tonsillar hypertrophy obstructing the airway is encountered in a child with a repaired cleft palate and velopharyngeal insufficiency, the surgeon may opt for tonsillectomy to relieve the airway obstruction, with possible effects on velopharyngeal closure. The aim of this study was to assess the impact of hypertrophied tonsils on velopharyngeal function in children with repaired cleft palate and to measure the effect of tonsillectomy on velopharyngeal closure and speech resonance. Case series. Twelve children with repaired cleft palate and tonsillar hypertrophy underwent tonsillectomy to relieve airway obstruction. Preoperative and postoperative evaluation of velopharyngeal function was performed. Auditory perceptual assessment of speech and nasalance scores were measured, and velopharyngeal closure was evaluated by flexible nasopharyngoscopy. Preoperative impairment of velopharyngeal function was detected. However, significant postoperative improvement of speech parameters (hypernasality, nasal emission of air, and weak pressure consonants measured with auditory perceptual assessment) was achieved, and the overall postoperative nasalance score was improved significantly for nasal and oral sentences. Reduction of velopharyngeal gap size was detected after removal of hypertrophied tonsils. Although the improvement of velopharyngeal closure was not significant, three cases demonstrated complete postoperative closure with no gap. Hypertrophied tonsils may impair velopharyngeal function in children with repaired cleft palate, and tonsillectomy is beneficial for such patients as it can improve the velopharyngeal closure and speech resonance. Secondary corrective surgery may be avoided in some cases after tonsillectomy.


Associations of long-term particulate matter exposure with cardiometabolic diseases: A systematic review and meta-analysis.
This review aimed to establish a holistic perspective of long-term PM exposure and cardiometabolic diseases, identify long-term PM-related cardiovascular and metabolic risk factors, and provide practical significance to preventative measures. A combination of computer and manual retrieval was used to search for keywords in PubMed (2903 records), Embase (2791 records), Web of Science (5488 records) and Cochrane Library (163 records). Finally, a total of 82 articles were considered in this meta-analysis. Stata 13.0 was accustomed to inspecting the studies' heterogeneity and calculating the combined effect value (RR) by selecting the matching models. The subgroup analysis, sensitivity analysis and publication bias tests were also performed. Meta-analysis figured an association between PM and cardiometabolic diseases. PM2.5 (per 10 μg/m3 increase) boosted the risk of hypertension (RR = 1.14, 95 % CI: 1.09-1.19), coronary heart disease (CHD) (RR = 1.21, 95 % CI: 1.08-1.35), diabetes (RR = 1.16, 95 % CI: 1.11-1.21) and stroke (including ischemic stroke and hemorrhagic stroke). PM10 (per 10 μg/m3 increase) elevated the incidence of hypertension (RR = 1.11, 95 % CI: 1.07-1.16) and diabetes (RR = 1.26, 95 % CI: 1.08-1.47). PM1 (per 10 μg/m3 increase) exposure increased the risk of total dyslipidemia, yielding the RR of 1.10 (95 % CI: 1.01-1.18). Furthermore, the elderly, overweight and higher background pollutant level were potentially susceptible to related diseases. There was a virtual connection between long-term exposure to PM and cardiometabolic diseases. PM2.5 or PM10 (per 10 μg/m3) increased the risk of hypertension, CHD, diabetes, stroke and dyslipidemia, causing cardiovascular "multimorbidity" in high-risk populations.


Instruments for assessing professional nursing practice environments: An integrative review.
To identify the instruments used to evaluate the professional nursing practice environments in the hospital context. An integrative review, whose research process was conducted independently by two researchers in the period from July to August 2019 in the CINHAL, PubMed and SciELO databases. Based on the inclusion and exclusion criteria, 53 studies published between 2009 and 2019 were considered for analysis. Ten instruments and three thematic areas were identified: instruments for the assessment of the nursing professional practice environments; implications of the use of instruments for the assessment of nursing professional practice environments; limitations of the instruments for the assessment of nursing professional practice environments. Despite the relevance of the instruments identified, this integrative review provides contributions that support the need to use specific tools to assess the nursing practice environments that include the structure, process and outcome components.


[Biological process in patients having been impregnated through GIFT or IVF-ET. Clinical experience].
There were analyzed in a retrospective way the results of pre-retrieval hormonal levels as well as the number of retrieved oocytes, mature oocytes and transferred embryos in three groups of patients (2 GIFT, 1 IVF-ET) which achieved a pregnancy, and were matched with groups with no pregnancy. There were no statistically significant differences in most of the analyzed parameters, by the aforementioned we can suppose that pregnancy depends of endometrial quality and in this moment we are not able to modify it satisfactorily.


[Review of the presently accepted theories of teeth positioning in complete prostheses].
The review paper describing the presently used principles of the theory of teeth positioning in complete prostheses. The author indicates their advantages and disadvantages, and the possibility of their application in general prosthetic practice.


Human beta defensin 2 promotes intestinal wound healing in vitro.
Limiting microbial threats, maintenance and re-establishment of the mucosal barrier are vital for intestinal homeostasis. Antimicrobial peptides have been recognized as essential defence molecules and decreased expression of these peptides has been attributed to chronic inflammation of the human intestinal mucosa. Recently, pluripotent properties, including stimulation of proliferation and migration have been suggested for a number of antimicrobial peptides. However, it is currently unknown, whether the human beta-defensin 2 (hBD-2) in addition to its known antimicrobial properties has further effects on healing and protection of the intestinal epithelial barrier. Caco-2 and HT-29 cells were stimulated with 0.1-10 microg/ml hBD-2 for 6-72 h. Effects on cell viability and apoptosis were monitored and proliferation was quantified by bromo-deoxyuridine incorporation. Migration was quantified in wounding assays and characterized by immunohistochemistry. Expression of mucins was determined by quantitative PCR and slot-blot analysis. Furthermore, anti-apoptotic capacities of hBD-2 were studied. Over a broad range of concentrations and stimulation periods, hBD-2 was well tolerated by IECs and did not induce apoptosis. hBD-2 significantly increased migration but not proliferation of intestinal epithelial cells. Furthermore, hBD-2 induced cell line specific the expression of mucins 2 and 3 and ameliorated TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. In addition to its known antimicrobial properties, hBD-2 might have further protective effects on the intestinal epithelium. Results of this in vitro study suggest, that hBD-2 expression may play a dual role in vivo, i.e. in impaired intestinal barrier function observed in patients with inflammatory bowel disease.


Submicron particle exposure and stroke hospitalization: An individual-level case-crossover study in Guangzhou, China, 2014-2018.
Short-term exposure to ambient PM2.5 and PM10 (particulate matter with aerodynamic diameters ≤2.5 μm and 10 μm, respectively) has been linked with hospitalization and mortality from stroke. However, the effect of PM1 (≤1 μm) exposure on the risk of hospitalization from stroke and its subtypes has rarely been investigated, in particular, on the basis of fine-scale exposure assessment at the individual level. We collected data on hospital admissions due to stroke and its subtypes in Guangzhou, China from January 1, 2014 to December 31, 2018. Daily exposures to PM1, PM2.5, and PM10 were assessed from satellite-derived estimates at a 1-km2 spatial resolution based on residential addresses. A time-stratified case-crossover analysis combined with a conditional logistic regression model was performed to examine the associations of stroke hospitalization risks with short-term exposure to size-fractional particles. We conducted stratified analyses by sex, age, season, and ambient temperature. A total of 178,586 stroke hospitalizations were recorded during the study period, among which 141,709 cases were ischemic stroke and 25,255 cases were hemorrhagic stroke. The mean concentrations on the day of hospitalization were 20.0 μg/m3 (control days: 19.9 μg/m3) for PM1, 37.6 μg/m3 (37.4 μg/m3) for PM2.5, and 59.3 μg/m3 (59.0 μg/m3) for PM10. Short-term exposure to size-fractional particles was significantly associated with increased risks of hospital admission for overall stroke and ischemic stroke, whereas null or negative associations were observed for hemorrhagic stroke. Compared with PM2.5 and PM10, PM1 was associated with greater excess risks of stroke hospitalizations. For each 10-μg/m3 increase in PM1, PM2.5, and PM10 exposure at lag 03-day, the odds ratios were 1.016 (95% confidence interval: 1.008, 1.024), 1.007 (1.003, 1.011), and 1.007 (1.004, 1.010) for overall stroke hospitalization, and were 1.023 (1.014, 1.033), 1.010 (1.005, 1.014), and 1.009 (1.006, 1.013) for ischemic stroke, respectively. These associations were robust to co-pollutant adjustments and did not vary by sex and age, while significantly elevated risks were identified in cold months (October to March of the next year) and low-temperature days (<23.8 °C) only. Short-term exposure to particulate matter air pollution, particularly PM1, was associated with increased risks of hospitalization for overall stroke and ischemic stroke.


Circulating inflammatory cytokines and adipokines are associated with increased risk of Barrett's esophagus: a case-control study.
Obesity is associated with Barrett's esophagus (BE) and with changes in circulating levels of adipokines (leptin and adiponectin) and cytokines. Although studies have reported that adipokines and inflammatory cytokines are necessary for the development of BE, their role is controversial. We performed a case-control study; cases (n = 141) were patients who underwent esophagogastroduodenoscopy and were found to have BE, which was based on endoscopy and histology, and controls (n = 139) were primary care patients eligible for screening colonoscopies who agreed to undergo esophagogastroduodenoscopy. We examined the association between BE and circulating levels of adipokines and cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, and IL-12p70; tumor necrosis factor-α; and interferon-γ). Cases and controls were compared by calculating odds ratios (ORs) and 95% confidence intervals (CIs) and using unadjusted and multiple logistic regression, adjusting for age, sex, race, waist-hip ratio, use of proton pump inhibitors and nonsteroidal anti-inflammatory drugs, and Helicobacter pylori infection. The adjusted ORs for BE were 2.62 (95% CI, 1.0-6.8), 5.18 (95% CI, 1.7-15.7), and 8.02 (95% CI, 2.79-23.07) for the highest quintile vs the lowest quintile of levels of IL-12p70, IL-8, and leptin, respectively, but the OR was not significant for IL-6 (2.39; 95% CI, 0.84-6.79). The adjusted OR for BE was 0.14 for highest quintile of IL-10 compared with lowest quintile (95% CI, 0.05-0.35) and 0.03 for IL-1β ≥ median vs none detected (95% CI, 0.006-0.13). Higher levels of IL-8 and leptin and lower levels of IL-10 and IL-1β were associated with the presence of long-segment (≥3 cm) and short-segment BE. There were no differences between cases and controls in levels of interferon-γ, tumor necrosis factor-α, adiponectin, or insulin. BE is associated with circulating inflammatory cytokines and leptin and low levels of anti-inflammatory cytokines. These findings could partly explain the effect of obesity on BE.


Cognitive flexibility improves in cognitive behavioral therapy for irritable bowel syndrome but not nonspecific education/support.
This study tested the novel hypothesis that CBT-treated IBS patients who learn to self-manage painful GI symptoms by targeting rigid cognitive style show improvement in cognitive flexibility, GI symptoms (e.g., abdominal pain), and quality of life. Participants included 130 Rome-III diagnosed IBS patients (M age = 40.3, F = 83%) with moderate-to-severe symptoms randomly assigned to either cognitive behavioral therapy (CBT; N = 86) or a nonspecific education/support (EDU) comparator (N = 44). Participants completed an assessment battery at baseline and post-treatment 2 weeks after 10-week acute treatment phase. Measures included cognitive flexibility, psychological flexibility, emotion regulation strategies, IBS symptom severity, quality of life (QOL), and distress. CBT but not EDU patients showed significant GI sympton improvement from baseline to post-treatment in cognitive flexibility. For CBT patients, changes in cognitive flexibility were significantly associated with changes in IBS symptom severity, abdominal pain, and IBS QOL. Neither condition showed significant changes in psychological flexibility (Acceptance and Action Questionnaire-II) or use of emotion regulation strategies (Emotion Regulation Questionnaire). The ability to self-manage painful IBS symptoms refractory to conventional medical and dietary treatments is related to the ability to respond flexibly across shifting contexts using cognitive change procedures featured in CBT for IBS.


Further survey of the occurrence of Fusarium toxins in wheat grown in southwest Germany.
A total of 53, 54, 57, 52 and 60 wheat samples for feed use were collected randomly after the 1989, 1990, 1991, 1992 and 1993 crops, respectively, from farms in an area of southwest Germany. Deoxynivalenol (DON), 3- and 15-acetyldeoxynivalenol (3-, 15-ADON), nivalenol (NIV), HT-2 toxin (HT-2), T-2 toxin (T-2), diacetoxyscirpenol (DAS), and fusarenon-X (FUS-X) were determined by gas chromatography, combined with mass selective detection (GC-MS), zearalenone (ZEA), alpha- and beta-zearalenol (alpha-beta-ZOL) were determined by HPLC. DON was the major toxin, with incidences at 77 to 93% and mean contents at 167 to 735 micrograms/kg. In contrast, incidences of ZEA, 3-ADON, NIV, HT-2, and T-2 were at 13 to 37%, 10 to 44%, 15 to 67%, 0 to 11%, and 0 to 12%, respectively, with mean contents in positive samples between 2 and 73 micrograms/kg, except for 948 micrograms/kg 3-ADON in samples from 1993. 15-ADON and FUS-X were assayed in samples from 1991, 1992 and 1993. 15-ADON was found in 0 to 11% of samples at mean levels < or = 17 mu/kg, DAS, alpha- and beta-ZOL, and FUS-X were not detected in any sample. Over the years, incidences and levels of toxins remained constant, decreased or increased, with most differences between years being slight and insignificant. The risk for livestock due to DON, HT-2 and ZEA was estimated based on maximum tolerated levels recommended for these toxins in some countries.


Two different motor systems are needed to generate human speech.
Vocalizations such as mews and cries in cats or crying and laughter in humans are examples of expression of emotions. These vocalizations are generated by the emotional motor system, in which the mesencephalic periaqueductal gray (PAG) plays a central role, as demonstrated by the fact that lesions in the PAG lead to complete mutism in cats, monkeys, as well as in humans. The PAG receives strong projections from higher limbic regions and from the anterior cingulate, insula, and orbitofrontal cortical areas. In turn, the PAG has strong access to the caudal medullary nucleus retroambiguus (NRA). The NRA is the only cell group that has direct access to the motoneurons involved in vocalization, i.e., the motoneuronal cell groups innervating soft palate, pharynx, and larynx as well as diaphragm, intercostal, abdominal, and pelvic floor muscles. Together they determine the intraabdominal, intrathoracic, and subglottic pressure, control of which is necessary for generating vocalization. Only humans can speak, because, via the lateral component of the volitional or somatic motor system, they are able to modulate vocalization into words and sentences. For this modulation they use their motor cortex, which, via its corticobulbar fibers, has direct access to the motoneurons innervating the muscles of face, mouth, tongue, larynx, and pharynx. In conclusion, humans generate speech by activating two motor systems. They generate vocalization by activating the prefrontal-PAG-NRA-motoneuronal pathway, and, at the same time, they modulate this vocalization into words and sentences by activating the corticobulbar fibers to the face, mouth, tongue, larynx, and pharynx motoneurons.


Single nephron glomerular filtration rate measured by linescan multiphoton microscopy compared to conventional micropuncture.
Renal micropuncture, which requires the direct access to the renal tubules, has for long time been the technique of choice to measure the single nephron glomerular filtration rate (SNGFR) in animal models. This approach is challenging by virtue of complex animal preparation and numerous technically difficult steps. The introduction of intravital multiphoton microscopy (MPM) offers another approach to the measure of the SNGFR by mean of the high laser-tissue penetration and the optical sectioning capacity. Previous MPM studies measuring SNGFR in vivo relied on fast full-frame acquisition during the filtration process obtainable with high performance resonant scanners. In this study, we describe an innovative linescan-based MPM method. The new method can discriminate SNGFR variations both in conditions of low and high glomerular filtration, and shows results comparable to conventional micropuncture both for rats and mice. Moreover, this novel approach has improved spatial and time resolution and is faster than previous methods, thus enabling the investigation of SNGFR from more tubules and improving options for data-analysis.


Exercise training improves acetylcholine-induced endothelium-dependent hyperpolarization in type 2 diabetic rats, Otsuka Long-Evans Tokushima fatty rats.
We investigated whether endothelium-derived relaxing (EDRF) and hyperpolarizing factor (EDHF) is impaired in type 2 diabetic rats (Otsuka Long-Evans Tokushima Fatty (OLETF) rat) and whether the exercise training improves impaired EDRF and EDHF. Diabetic rats were divided into the sedentary and exercise-trained groups at the age of 16 weeks. Long-Evans Tokushima Otsuka (LETO) rats were used as age-matched non-diabetic controls. EDRF as well as EDHF induced by acetylcholine in the presence of indomethacine and L-nitro N-arginine was significantly attenuated in the diabetic rats, and was further impaired with age. Exercise training significantly improved it. Both insulin resistance and abdominal fat accumulation were significantly greater in the diabetic rats, compared with the non-diabetic rats, but were decreased in exercise-trained rats. Urinary NO(2) secretion was decrease in the diabetic rats at each age, and it was improved by exercise training. The results of the study indicated that exercise training prevented impairment of EDHF, as well as EDRF in type 2 diabetic rats, presumably due to improvement of hyperglycemia and insulin resistance and increase in the production of nitric oxide by exercise training.


Increasing the accuracy of radiotracer monitoring in one-dimensional flow using polynomial deconvolution correction.
Factors such as type of fluid movement and gamma-ray scattering may decrease the precision of the radiotracer monitoring as the response to a short tracer injection. Practical experiences using polynomial deconvolution techniques are presented. These techniques were successfully applied for correcting the obtained experimental results and increasing the time resolution of the method.


Delusions in the transference. Psychotherapy with the paranoid patient.
This article has attempted to combine a theoretical and practical approach to the challenge presented in psychotherapy of paranoid and delusional patients. The essential ingredients of psychotherapy of non-psychotic patients--such as the frame, the therapeutic alliance, transference, countertransference, and interpretation--all play roles in the psychotherapy of paranoid, psychotic, delusional patients as well. Differences in defense mechanisms and dynamics and their working through, however, can make unfamiliar the factors that are basic to any psychotherapy. A familiarity with the unique problems of psychotic individuals in psychotherapy may help to make the work less bewildering and frightening, although no less challenging.


Identification of good responders to rhythm control of paroxysmal and persistent atrial fibrillation by transthoracic and transesophageal echocardiography.
Identification of good responders to rhythm control in the management of atrial fibrillation (AF) is worthwhile in terms of increasing hemodynamic benefit and decreasing the likelihood of unstable anticoagulation even after the Atrial Fibrillation Follow-Up Investigation of Rhythm Management. We tested the hypothesis that atrial substrate determines the risk of recurrence on rhythm control both in patients with paroxysmal AF (PAF) and in those with persistent or sustained AF (> or =1 week, SAF). There were 90 consecutive patients (mean age 63 +/- 12 years, 67 males and 23 females) with previous PAF (n = 66) or SAF (n = 24). They were maintained in sinus rhythm successfully for at least 1 month after conversion and then studied by transthoracic and transesophageal echocardiography. All of the patients were followed regularly by determination of symptoms, 12-lead ECG and intermittent Holter recording to determine recurrence of AF after echocardiographic study. After 9.1 +/- 3.8 (range 3-12) months of follow-up, 23 of the 90 (26%) patients had documented recurrence of AF (67 without recurrence). Univariate analysis of demographic characteristics, medications, ECG and echocardiographic parameters revealed that, compared with the group of patients without recurrent AF, the group of those with it included more members of the SAF group (11/27 vs. 13/67, p = 0.039), included more male subjects (22/23 vs. 45/67, p = 0.045), had a larger left atrial volume index (LAVI; 27 +/- 9 vs. 22 +/- 9 ml/m2, p = 0.024) and had lower LA appendage peak emptying velocity (LAAPEV; 42 +/- 15 vs. 55 +/- 22 cm/s, p = 0.01). Multivariate Cox proportional hazards regression analysis adjusted for age, gender and AF group revealed that patients with LAVI <30 ml/m2 and LAAPEV >46 cm/s had the least recurrence of AF (relative risk 0.18, 95% confidence interval 0.06-0.55, vs. with LAVI >30 ml/m2 or LAAPEV <46 cm/s, p = 0.002). Kaplan-Meier probability of freedom from AF recurrence was significantly better when LAVI <30 ml/m2 (log-rank p = 0.02), LAAPEV > 46 cm/s (p = 0.013) or both (p = 0.004). The superiority to predict the rate of sinus rhythm maintenance was the same in the PAF and SAF groups. Good responders to rhythm control in the PAF and SAF groups share the characteristics of smaller LA volume and better LAA contractile function, emphasizing the critical role of atrial substrate remodeling in recurrence of AF.


Voices from Pupil Participation in the Health Promotion Intervention "Pulse for Learning and Health [PuLH]" in Primary and Middle School.
In order to improve the learning conditions and health of schoolchildren, the Pulse for Learning and Health [PuLH] program in Sweden has introduced additional mandatory moderate to vigorous physical activity [MVPA] that lasts for 30 min three times a week. The PE teachers used a child-centered coaching approach to support all pupils. The aim of this study was to explore pupils' perception and experience of PuLH that has been implemented in primary and middle schools in Sweden. We have taken into account children's rights perspectives and adopted an exploratory and interpretive approach. In total, 73 pupils (34 girls, 39 boys, grades 4-9) were recruited through purposive sampling. 13 focus group interviews (n = 71) and individual interviews (n = 2) were carried out. All interviews were analyzed using qualitative content analysis. The analysis resulted in three major themes: 'promotes academic performance and a learning school environment', 'promotes health and well-being', and 'individual and structural barriers'. From children's perspective, the results highlight the importance of teachers and principals taking into account the interests and needs of all pupils, to have a well-planned MVPA intervention and to deal with issues regarding body ideals.


Are sex steroids involved in the sexual growth dimorphism in Eurasian perch juveniles?
Individual growth and food intake were monitored in Eurasian perch (Perca fluviatilis L.) juveniles (13.5+/-3.4 g initial body weight) to determine whether androgens and estrogens may mediate sex-related growth differences. Fish were individually tagged with chips and implanted with cocoa butter containing 20 microg of either 17alpha-methyltestosterone (MT) or 17beta-estradiol (E(2)) per gram of fish body; controls were implanted with cocoa butter without hormones. All fish were bled at the end of the experiment for measurement of E(2) in females and testosterone (T) in males (MT was not measured) and triiodothyronine (T3) in both genders. Survival, gonadosomatic index and hepatosomatic index were not affected by steroid treatments. Relative food intake (RFI), feed efficiency (FE) and specific growth rate (SGR) were higher in females than in males in all treatments. MT treatment significantly lowered RIF, FE and SGR in both sexes, while E(2) treatment showed no significant effect on growth and feeding parameters. In contrast to E(2) and T concentrations, T3 levels were significantly and positively correlated with SGR and RFI. The results provide evidence that MT may affect sexually related growth dimorphism by decreasing food intake and FE in Eurasian perch.


Investigating Jordanian nurses' handwashing beliefs, attitudes, and compliance.
Low rates of handwashing compliance among nurses are still reported in literature. Handwashing beliefs and attitudes were found to correlate and predict handwashing practices. However, such an important field is not fully explored in Jordan. This study aims at exploring Jordanian nurses' handwashing beliefs, attitudes, and compliance and examining the predictors of their handwashing compliance. A cross-sectional multicenter survey design was used to collect data from registered nurses and nursing assistants (N = 198) who were providing care to patients in governmental hospitals in Jordan. Data collection took place over 3 months during the period of February 2011 to April 2011 using the Handwashing Assessment Inventory. Participants' mean score of handwashing compliance was 74.29%. They showed positive attitudes but seemed to lack knowledge concerning handwashing. Analysis revealed a 5-predictor model, which accounted for 37.5% of the variance in nurses' handwashing compliance. Nurses' beliefs relatively had the highest prediction effects (β = .309, P < .01), followed by skin assessment (β = .290, P < .01). Jordanian nurses reported moderate handwashing compliance and were found to lack knowledge concerning handwashing protocols, for which education programs are recommended. This study raised the awareness regarding the importance of complying with handwashing protocols.


Active Surveillance: Pathologic and Clinical Variables Associated with Outcome.
Over the past 10 years, active surveillance has emerged as a primary management option for men diagnosed with low-risk prostate cancer. Given the morbidity associated with curative treatment, active surveillance maintains quality of life for men whose disease may never become symptomatic. In order to confidently and safely offer this approach to as many patients as possible, improved metrics are needed to fully assess risk. While pathologic and clinical variables currently help determine whether active surveillance is a reasonable approach, emerging biomarkers and imaging technologies demonstrate promise for more precise identification of ideal candidates.


The item generation methodology of an empiric simulation project.
The American Board of Family Practice (ABFP) is developing a computer-based testing system that will create realistic clinical encounters using an adaptation of an item generation process. Simulated patients' entire lives will be stochastically produced from a knowledge base, with constraints applied to prevent implausible simulations. The constraint mechanisms include knowledge acquisition decisions about grouping closely related medical concepts and widespread use of Bayesian networks to manage dependencies between concepts. Bayesian networks and fuzzy definitions provide stochastic variability between simulations produced from the same data. Examinees will interact with these patients using a large and stable set of queries and interventions. Multiple management plans associated with patient simulations provide a framework for scoring performance. All major components, including Health States, history generating "Lead To" objects, and Plans are reusable and often substitutable. Although initial knowledge acquisition demands are enormous, the system has good potential for low cost maintenance of content areas, and economies of scale as simulations and components are reused.


High and individually variable enzymatic activity precludes accurate determination of pemetrexed, methotrexate and their polyglutamate metabolite concentrations in plasma.
Most drugs are metabolized in the human body. Therefore, it is essential for therapeutic drug monitoring studies to also take into account the concentrations of drug metabolites. One of the possible metabolic activities on drugs such as pemetrexed or methotrexate is (poly)glutamation. Here, we report on a series of experiments that we performed to investigate the stability of polyglutamate metabolites in plasma. Removal of glutamate residues from pemetrexed polyglutamate by most likely proteases in human plasma is influenced by temperature as it is observed at 25°C and even more strongly at 37°C, but not at 4°C. The observed protease activity is highly variable among patients; in approximately 15-20% of the patients tested it is not observed, whereas in other individuals the activity is so extensive that after 10min, more than 50% of spiked polyglutamated pemetrexed is degraded at room temperature (5-10% of the tested individuals). Similar observations also pertain to methotrexate polyglutamates. These observations do not extend to pemetrexed and methotrexate themselves which are unaffected by this activity. Due to the considerable and, among individuals, variable protease activities on polyglutamated drug metabolites in plasma, these metabolites are virtually impossible to quantify if no precautions are taken.


High-density Lipoprotein-cholesterol Subfractions and Coronary Artery Calcium: The ELSA-Brasil Study.
Although elevated high-density lipoprotein cholesterol (HDL-C) is considered protective against atherosclerotic cardiovascular disease, no causal relationship has been demonstrated. HDL-C comprises a group of different subfractions that might have different effects on atherosclerosis. Our objective was to investigate the association between HDL-C subfractions with the coronary artery calcium (CAC) score. We included 3,674 (49.8 ± 8.3 years, 54% women) participants from the ELSA-Brasil study who had no prior history of CVD and were not currently using lipid-lowering medications. We measured the fasting lipoprotein cholesterol fractions (in mmol/l) by a zonal ultracentrifugation method (VAP). We analyzed the independent predictive values of total HDL-C, HDL2-C, and HDL3-C subfractions and in the HDL2-C/HDL3-C ratio using linear regression to predict Ln(CAC+1) and logistic regression to predict the presence of CAC. Overall 912 (24.8%) of the participants had CAC>0, and 294 (7.7%) had CAC>100. The mean total HDL-C, HDL2-C, and HDL3-C were: 1.42 ± 0.37, 0.38 ± 0.17 and 1.03 ± 0.21 mmol/l, respectively. Individuals with CAC>0 had lower levels of total HDL-C as well as of each subfraction (p < 0.001). When adjusted for age, gender, smoking, hypertension, alcohol use, physical activity, and LDL-C, we observed an inverse association between HDL-C and its subfractions and CAC (p < 0.05). However, by adding triglycerides in the adjustment, neither total HDL-C nor its subfractions remained independently associated with the presence or extent of CAC. In this cross-sectional analysis, neither the total HDL-C nor its subfractions (HDL2-C and HDL3-C, as well as HDL2-C/HDL3-C ratio) measured by VAP are independently associated with the presence or extent of coronary calcification.


Long-term Clinical Outcomes of Yttrium-90 Transarterial Radioembolization for Hepatocellular Carcinoma: A 5-Year Institutional Experience.
To examine the clinical outcomes of yttrium-90 (Y90) transarterial radioembolization (TARE) for primary hepatocellular carcinoma (HCC) through the evaluation of a 5-year institutional experience. This retrospective study evaluated 88 consecutive patients with primary HCC receiving Y90 TARE treatment at an academic medical center from 2017 to 2021. Disease distribution was bilobar in 60.2% of patients with an average lesion diameter of 5.0 ± 3.4 cm and Barcelona Clinic Liver Cancer stage B or C in 77% of the participants. Clinical outcomes were elucidated by examination of complications, liver function tests, biochemical response, and radiographic response. Objective response ratio (ORR) and progression-free survival (PFS) were also calculated. The mean administered Y90 radiation dose was 127.8 ± 20.2 Gy. No significant complications or LFT elevations occurred post-therapy. Of the 73.9% of patients with α-fetoprotein-producing tumors, 67.8% experienced a complete or partial biochemical response 1 month post-treatment. The ORR was 83.3% on 6-month imaging and PFS was 9.6 ± 8.5 months. Functional outcomes (Eastern Cooperative Oncology Group) were maintained or improved in 79.6% and 76.1% of patients by 6 months and 1 year post-treatment, respectively. The mean survival was 14.7 ± 12.1 months. At 6 months post-treatment, 77.3% of patients were downstaged to or maintained Milan criteria, which was sustained for 74.4% and 70.0% of patients 1 year and 2 years after treatment, respectively. Y90-TARE is a safe and effective therapy for primary HCC. Enduring outcomes further act as a realistic bridge to liver transplantation, with a majority of patients maintaining Milan criteria and preserving their functional status long term.


Histopathology of prostate tissue after vascular-targeted photodynamic therapy for localized prostate cancer.
Low-risk prostate adenocarcinoma is classically managed either with active surveillance or radical therapy (such as external radiotherapy or radical prostatectomy), but both have significant side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy proposed as an alternative approach for localized, low-volume, and low-Gleason score (≤6) carcinomas. We report histological modifications observed in prostate biopsies of 56 patients, performed 6 months after VTP using the photosensitizer TOOKAD® Soluble (WST11) and low-energy laser administered in the tumor area transperineally by optic fibers. In 53 patients, we observed sharply demarcated hyaline fibrotic scars, with or without rare atrophic glands, sometimes reduced to corpora amylacea surrounded by giant multinuclear macrophages. Mild chronic inflammation, hemosiderin, and coagulative necrosis were also observed. When residual cancer was present in a treated lobe (17 patients), it was always located outside the scar, most often close to the prostate capsule, and it showed no therapy-related modification. Histopathological interpretation of post-WST11 VTP prostate biopsies was straightforward, in contrast with that of prostate biopsies after radio or hormonal therapy, which introduces lesions difficult to interpret. VTP resulted in complete ablation of cancer in the targeted area.


Repeat pancreatic resection for metachronous pancreatic metastasis from renal cell carcinoma: A case report.
Pancreatic metastasis (PM) from renal cell carcinoma (RCC) is relatively rare. Surgical resection of PM from RCC is considered as the first choice treatment for achieving long-term prognosis. Herein, we report a case of secondary multiple metastases from RCC to the remnant pancreas following pancreatectomy, with a review of the relevant literature. A 69-year-old man who underwent left nephrectomy for RCC (T2N0M0, stage II) 12 years ago was referred to our hospital. Multiple metastases to the pancreatic head from RCC occurred 2 years after the primary surgery, for which pancreaticoduodenectomy was performed. Nine years after metastatic resection, multiple tumors of the remnant pancreas were detected on dynamic computed tomography (CT); all tumors showed strong enhancement in the early phase, which persisted into the late phase. The tumors were round, the maximum diameter of the tumor was 20 mm, and they were hyperintense on T2-weighted magnetic resonance imaging. Positron emission tomography-CT revealed slight fluorodeoxyglucose uptake in the tumor. Multiple PMs were diagnosed, and the remnant pancreas was completely resected. Two years later, the patient was alive and showed no recurrence. Surgical resection could provide long-term prognosis, even if secondary PM from RCC occurs metachronously. Long-term follow-up is recommended after primary resection, and vigilance regarding the occurrence of PM is needed.