Nonlinear dynamics analysis of the human balance control subjected to physical and sensory perturbations.
Postural control after applying perturbation involves neural and muscular efforts to limit the center of mass (CoM) motion. Linear dynamical approaches may not unveil all complexities of body efforts. This study was aimed at determining two nonlinear dynamics parameters (fractal dimension (FD) and largest Lyapunov exponent (LLE)) in addition to the linear standing metrics of balance in perturbed stance. Sixteen healthy young males were subjected to sudden rotations of the standing platform. The vision and cognition during the standing were also interfered. Motion capturing was used to measure the lower limb joints and the CoM displacements. The CoM path length as a linear parameter was increased by elimination of vision (p<0.01) and adding a cognitive load (p<0.01). The CoM nonlinear metric FD was decreased due to the cognitive loads (p<0.001). The visual interference increased the FD of all joints when the task included the cognitive loads (p<0.01). The slightly positive LLE values showed weakly-chaotic behavior of the whole body. The local joint rotations indicated higher LLEs. Results indicated weakly chaotic response of the whole body. Increase in the task difficulty by adding sensory interference had difference effects on parameters. Linear and nonlinear metrics of the perturbed stance showed that a combination of them may properly represent the body behavior.


Are flatfishes (Pleuronectiformes) monophyletic?
All extant species of flatfish (order Pleuronectiformes) are thought to descend from a common ancestor, and therefore to represent a monophyletic group. This hypothesis is based largely on the dramatic bilateral asymmetry and associated ocular migration characteristics of all flatfish. Yet, molecular-based phylogenetic studies have been inconclusive on this premise. Support for flatfish monophyly has varied with differences in taxonomic and gene region sampling schemes. Notably, the genus Psettodes has been found to be more related to non-flatfishes than to other flatfishes in many recent studies. The polyphyletic nature of the Pleuronectiformes is often inferred to be the result of weak historical signal and/or artifact of phylogenetic inference due to a bias in the data. In this study, we address the question of pleuronectiform monophyly with a broad set of markers (from six phylogenetically informative nuclear loci) and inference methods designed to limit the influence of phylogenetic artifacts. Concomitant with a character-rich analytical strategy, an extensive taxonomic sampling of flatfish and potential close relatives is used to increase power and resolution. Results of our analyses are most consistent with a non-monophyletic Pleuronectiformes with Psettodes always being excluded. A fossil-calibrated Bayesian relaxed clock analysis estimates the age of Pleuronectoidei to be 73 Ma, and the time to most recent common ancestor of Pleuronectoidei, Psettodes, and other relative taxa to be 77 Ma. The ages are much older than the records of any fossil pleuronectiform currently recognized. We discuss our findings in the context of the available morphological evidence and discuss the compatibility of our molecular hypothesis with morphological data regarding extinct and extant flatfish forms.


Diffuse alveolar hemorrhage due to donor lymphocyte infusion in a case of acute lymphoblastic leukemia.
Diffuse alveolar hemorrhage, with a mortality rate between 60-100%, is a life-threatening complication in hematopoietic stem cell transplant recipients. A 34-year-old man, with precursor B acute lymphoblastic leukemia diagnosed in July 2003, relapsed after allogeneic peripheral blood hematopoietic stem cell transplantation from his human leukocyte antigen- iden¬tical brother in July 2005. He received a donor lymphocyte infusion of 2 x 107/kg CD3 positive cells. He developed fever, dyspnea and hypoxemia four days after donor lymphocyte infusion. The patient was diagnosed as diffuse alveolar hem¬orrhage based on the clinical, radiological and bronchoscopic data. He was immediately started on high-dose methylpred¬nisolone. Two days after the onset of the steroid therapy, he recovered with significant improvement in oxygenation. Diffuse alveolar hemorrhage can be a late-onset transplant complication that could also be associated with a recent donor lymphocyte infusion.


Paraoxonase-1 (PON1) status in pancreatic cancer: relation to clinical parameters.
Human paraoxonase 1 (PON1) has been shown to decrease the level of systemic oxidative stress, which is thought to contribute to cancer development. The aim of this study was to examine the interrelationships between PON1 status and some clinical characteristics in patients with pancreatic cancer (PC). A group of 73 consecutive patients with PC (stage II-IV) and 73 control subjects were examined. Laboratory studies included five polymorphisms of the PON1 gene (L55M, Q192R, -108C/T, -126C/T, and -162A/G), PON1 arylesterase (PON1-A) and lactonase (PON1-L) activities, as well as some markers of protein metabolism, insulin resistance, and oxidative stress. In comparison with the control group, no difference in the distribution of the PON1 polymorphisms was found in cancer patients, both arylesterase and lactonase activities being significantly lower (-33, -47 %, respectively, both P < 0.001). There was neither statistically significant association of PON1 polymorphisms with tumour stages nor with diabetes mellitus connected with PC. The genotype distribution of L55M and ‑108C/T differed only in a subgroup of patients presenting clinically relevant malnutrition (χ² = 6.50, 6.25, respectively, both P < 0.05). In the PC group, PON1-A and PON1-L activities correlated with Nutritional Risk Index (r = 0.351, 0.409, respectively, both P < 0.01), PON1-L with mid-arm muscle circumference (r = 0.328, P < 0.05), and PON1-A and PON1-L with serum albumin (r = 0.352, 0.391 respectively, both < 0.01). Our results suggest that PON1 plays an important role in PC, especially in cancer-associated malnutrition.


Herbicide runoff along highways. 2. Sorption control.
Controversy remains about the importance of nonlinear sorption isotherms, desorption rate limitations, and aging effects, collectively referred to as nonideal sorption processes, in controlling the fate and transport of organic contaminants. Herbicide runoff from highway soils represents a good test case for assessing the relative importance of nonideal sorption because runoff flow rates are often high, soil-water contacttimes are short, and significant time is available for contaminant aging after application. This study examines the sorption and desorption of five herbicides with a wide range of properties (isoxaben, oryzalin, diuron, clopyralid, and glyphosate) on soil samples from two roadsides in northern California and uses the results to examine field runoff data from multiple rainy seasons. Nonideal sorption processes do not appear to be significant in determining herbicide runoff at the field sites because (i) sorption isotherms were linear or slightly nonlinear for all compounds but glyphosate, (ii) field runoff concentration ratios between isoxaben and oryzalin were consistent with linear partitioning predictions, (iii) runoff leaving the site appeared to be in equilibrium with local soil concentrations, and (iv) desorption distribution coefficients for aged herbicides on soil samples collected from the field site did not differ substantially from those obtained in short-term laboratory adsorption experiments. Collectively, these findings indicate that linear equilibrium models are adequate for predicting the concentration of herbicides in runoff in these field settings and that more complicated nonideal models do not need to be invoked. Vegetated slopes effectively reduced the herbicide loads, with average removals of 35-80% occurring as runoff traversed a 3-m segment 1 m from the edge of the spray zone.


Recombinant HIV envelope expressed in an alpha-glucosidase I-deficient CHO cell line and its parental cell line in the presence of 1-deoxynojirimycin is functional.
alpha-Glucosidase inhibitors-e.g., 1-deoxynojirimycin (DNM)-interfere with HIV infectivity in CD4+ cell cultures but have proven unsuccessful in clinical trials. In vitro, several HIV Env properties, including the cleavage of the Env precursor gp 160, the immunoreactivity of the third variable domain (V3) of Env, the binding to the CD4 receptor, and the induction of the membrane fusion between the virus and the host cell, have been reported to be altered by such inhibitors. We have studied these properties for Env expressed via a recombinant vaccinia virus in two Chinese hamster ovary cell lines, an alpha-glucosidase I-deficient cell line and its parental cell line, treated with DNM under conditions that have been reported to alter Env properties. The glycosylation of Env, but not the quantity produced, varied in accordance with the experimental conditions. However, irrespective of these conditions, Env cleavage, V3 immunoreactivity, CD4 binding, membrane expression, and ability to induce syncytium formation were similar. Thus, neither the alpha-glucosidase I deficiency nor DNM treatment had a significant effect on the properties of Env produced here. Cellular mechanisms that may allow the normal expression of Env are discussed and may offer an explanation for the many discrepant results obtained to date on the effects of DNM on HIV Env.


[Granuloma annulare: apropos of 18 cases].
Granuloma annulare is a benign skin disorder which cause is unknown. The aim of this work is to report the results of a retrospective study dealing with 18 cases of granuloma annulare carried in the dermatology department of la Rabta hospital over a nine year period. We describe 3 clinical forms: localized granuloma annulare: 9 cases, generalized granuloma anulare: 7 cases and deep granuloma annulare: 2 cases. Diabetes mellitus was associated to granuloma annulare in 6 patients, from which 3 presented with multiple lesions. Corticosteroids were used topically in 11 cases. The outcome was marked by a partial resolution in 15 cases. In our study. We didn't found any malignancy with our granuloma annulare patients.


[Effect of Anaerobic Plug-flow on Nitrification Denitrifying Phosphorus Removal Aerobic Granular Sludge with Intermittent Aeration].
Actual domestic sewage has a complex composition and relatively low carbon and nitrogen content. Anaerobic plug-flow influent can enhance the utilization of COD by aerobic granular sludge by providing a locally high concentration of substrate. In this study, intermittent aeration was used to cultivate aerobic granular sludge in a sequencing batch reactor (SBR), and actual domestic sewage was used as the feed water to inoculate the sewage plant sludge. In the R1 experiment, rapid anaerobic feeding was adopted, while in R2, anaerobic plug-flow feeding was adopted, to explore the impact of different feeding modes on the aerobic granular sludge system of domestic sewage. Under rapid anaerobic feeding in R1, the particle structure appeared earlier, but particle breakage occurred after 71 days of operation; the particle structure generated in R2 was denser than that of R1, the particle surfaces were smoother, and the denitrifying phosphorous accumulating organisms (DPAO) had a more enriching effect. In the final R1 and R2 reactors, the proportion of DPAO to phosphorous accumulating organisms (PAO) was 14.17% and 22.07%, respectively. The results show that the anaerobic plug-flow feeding mode can enhance the use of influent COD by granular sludge, which is conducive to enriching DPAO, generating denser and more stable particles, realizing "one carbon dual purpose" operation, and removing more nitrogen and phosphorus.


Do progressing myopes show reduced accommodative responses?
Refractive error and accommodative responsivity were monitored at 4-month intervals over a 1-year period to determine whether an increased lag of accommodation either precedes or accompanies the development of myopia. Accommodation was measured for stimulus levels of 2.5, 3, 4, and 5 D, and both the slope of the stimulus-response function and accommodative error were computed. Almost all subjects exhibited accommodative stimulus-response gradients close to unity, although a lower gradient was observed in subjects who were myopic upon entry into the study and whose ametropia remained stable. These stable myopes also exhibited the largest lag of accommodation. These findings do not support the proposal that the development of myopia in young adults is accompanied by a reduced accommodative response during nearwork.


Transformation of Organic Matter and the Emissions of Methane and Ammonia during Storage of Liquid Manure as Affected by Acidification.
Acidification of livestock manure can reduce emission of the greenhouse gases methane (CH) and nitrous oxide (NO), as well as ammonia (NH). We examined the relation between emission of these gases and transformation of organic matter as affected by acidification. Liquid cattle manure was acidified with sulfuric acid to pH 5.5 at a pilot scale (100 L), and we measured effects on CH, NO, CO and NH emissions and on transformation of pH buffer components and organic matter. Acidification reduced NH emissions by 62% (47 d) and emission of CH by 68% (57 d). Emissions of NO were negligible, probably due to the absence of a surface crust. Reductions in NH and CH emission were highest at the start but declined over time concomitantly with a gradual increase in the stored liquid manure pH. Acidification did not significantly affect CO emissions. Emission of CO was high, five- to ten-fold of CH emissions, until Day 16 of storage, after which the CO emission rate declined to around twice the CH emission rate; consequently, the majority of C loss during the early stages of storage was CO. Cumulative emission of C in CO and CH closely matched depletion of dissolved organic carbon (DOC), suggesting that DOC may be a predictor for CH emission from dilute slurries. volatile fatty acid and total ammoniacal nitrogen concentrations in surface layers were substantially higher than at the center of stored liquid manure, perhaps resulting from microbial activity at the surface. This pattern deserves attention when predicting NH emission from stored slurry.


High-content functional genomic screening to identify novel regulators of the PINK1-Parkin pathway.
PINK1/PARK6 and Parkin/PARK2 are amongst the most commonly mutated genes associated with recessive forms of familial Parkinson's disease. Recent evidence indicates that the proteins they encode, PINK1 and Parkin, function in the same pathway to mediate the selective autophagic clearance of dysfunctional mitochondria. Upon mitochondrial damage, PINK1 is stabilized on the outer mitochondrial membrane where it phosphorylates ubiquitin, generating a signal for the recruitment and activation of Parkin. However, key mechanistic questions still exist regarding Parkin recruitment, including whether or not other factors are required for the PINK1 and Parkin pathway. We describe a method below using high-throughput RNA interference technology to interrogate the genome for novel components of the PINK1 and Parkin pathway.


Quantification of the response of rat medullary raphe neurones to independent changes in pH(o) and P(CO2).
The medullary raphe nuclei contain putative central respiratory chemoreceptor neurones that are highly sensitive to acidosis. To define the primary stimulus for chemosensitivity in these neurones, the response to hypercapnic acidosis was quantified and compared with the response to independent changes in P(CO2) and extracellular pH (pH(o)). Neurones from the ventromedial medulla of neonatal rats (P0-P2) were dissociated and maintained in tissue culture for long enough to develop a mature response (up to 70 days). Perforated patch clamp recordings were used to record membrane potential and firing rate while changes were made in pH(o), P(CO2) and/or [NaHCO(3)](o) from baseline values of 7.4, 5 % and 26 mM, respectively. Hypercapnic acidosis (P(CO2) 9 %; pH(o) 7.17) induced an increase in firing rate to 285 % of control in one subset of neurones ('stimulated neurones') and induced a decrease in firing rate to 21 % of control in a different subset of neurones ('inhibited neurones'). Isocapnic acidosis (pH(o) 7.16; [NaHCO(3)](o) 15 mM) induced an increase in firing rate of stimulated neurones to 309 % of control, and a decrease in firing rate of inhibited neurones to 38 % of control. In a different group of neurones, isohydric hypercapnia (9 % P(CO2); [NaHCO(3)](o) 40 mM) induced an increase in firing rate of stimulated neurones by the same amount (to 384 % of control) as in response to hypercapnic acidosis (to 327 % of control). Inhibited neurones also responded to isohydric hypercapnia in the same way as they did to hypercapnic acidosis. In Hepes-buffered solution, both types of neurone responded to changes in pH(o) in the same way as they responded to changes in pH(o) in bicarbonate-buffered Ringer solution. It has previously been shown that all acidosis-stimulated neurones in the medullary raphe are immunoreactive for tryptophan hydroxylase (TpOH-ir). Here it was found that TpOH-ir neurones in the medullary raphe were immunoreactive for carbonic anhydrase type II and type IV (CA II and CA IV). However, CA immunoreactivity was also common in neurones of the hypoglossal motor nucleus, inferior olive, hippocampus and cerebellum, indicating that its presence is not uniquely associated with chemosensitive neurones. In addition, under the conditions used here, acetazolamide (100 microM) did not have a significant effect on the response to hypercapnic acidosis. We conclude that chemosensitivity of raphe neurones can occur independently of changes in pH(o), P(CO2) or bicarbonate. The results suggest that a change in intracellular pH (pH(i)) may be the primary stimulus for chemosensitivity in these putative central respiratory chemoreceptor neurones.


Do executive deficits and delay aversion make independent contributions to preschool attention-deficit/hyperactivity disorder symptoms?
To test whether deficits in executive function and delay aversion make independent contributions to levels of attention-deficit/hyperactivity disorder (ADHD) symptoms exhibited by preschool children. One hundred fifty-six children between 3 and 5.5 years old (78 girls and 78 boys) selected from the community completed an age-appropriate battery of tests measuring working memory, set shifting, planning, delay of gratification, and preference for delayed rewards. Parents completed a clinical interview about their children's ADHD symptoms. Analysis of test performance revealed two factors: executive dysfunction and delay aversion. Multivariate analysis demonstrated that when other factors (i.e., age, IQ, and conduct problems) were controlled, executive dysfunction and delay aversion each made significant independent contributions to predictions of ADHD symptoms. Preschool ADHD symptoms are psychologically heterogeneous. Executive dysfunction and delay aversion may represent two distinct and early appearing neurodevelopmental bases for ADHD symptoms.


Preoperative diagnosis of ovarian malignancies with intravenous digital subtraction angiography.
Intravenous digital subtraction angiography was performed on 59 patients with ovarian tumors. Dilatation of the uterine artery and its ovarian branch was relatively frequent in both benign and malignant tumor groups, while dilation of the ovarian artery, and hypervascularity from the uterine artery or the ovarian artery were fairly specific to the malignant tumor group. These five abnormal vascular patterns were evaluated by a scoring system and approximately 75% of malignant and 87% of benign ovarian tumors were correctly diagnosed preoperatively by digital subtraction angiography alone. Intravenous digital subtraction angiography can be applied as an easy, safe, and valuable diagnostic method for ovarian malignancies and can replace conventional pelvic angiography.


Reprogramming of plants during systemic acquired resistance.
Genome-wide microarray analyses revealed that during biological activation of systemic acquired resistance (SAR) in Arabidopsis, the transcript levels of several hundred plant genes were consistently up- (SAR(+) genes) or down-regulated (SAR(-) genes) in systemic, non-inoculated leaf tissue. This transcriptional reprogramming fully depended on the SAR regulator FLAVIN-DEPENDENT MONOOXYGENASE1 (FMO1). Functional gene categorization showed that genes associated with salicylic acid (SA)-associated defenses, signal transduction, transport, and the secretory machinery are overrepresented in the group of SAR(+) genes, and that the group of SAR(-) genes is enriched in genes activated via the jasmonate (JA)/ethylene (ET)-defense pathway, as well as in genes associated with cell wall remodeling and biosynthesis of constitutively produced secondary metabolites. This suggests that SAR-induced plants reallocate part of their physiological activity from vegetative growth towards SA-related defense activation. Alignment of the SAR expression data with other microarray information allowed us to define three clusters of SAR(+) genes. Cluster I consists of genes tightly regulated by SA. Cluster II genes can be expressed independently of SA, and this group is moderately enriched in H2O2- and abscisic acid (ABA)-responsive genes. The expression of the cluster III SAR(+) genes is partly SA-dependent. We propose that SA-independent signaling events in early stages of SAR activation enable the biosynthesis of SA and thus initiate SA-dependent SAR signaling. Both SA-independent and SA-dependent events tightly co-operate to realize SAR. SAR(+) genes function in the establishment of diverse resistance layers, in the direct execution of resistance against different (hemi-)biotrophic pathogen types, in suppression of the JA- and ABA-signaling pathways, in redox homeostasis, and in the containment of defense response activation. Our data further indicated that SAR-associated defense priming can be realized by partial pre-activation of particular defense pathways.


Botulinum toxin type A in post-stroke lower limb spasticity: a multicenter, double-blind, placebo-controlled trial.
Lower limb spasticity in post-stroke patients can impair ambulation and reduces activities of daily living (ADL) performance of patients. Botulinum toxin type A (BoNTA) has been shown effective for upper limb spasticity. This study assesses the treatment of lower limb spasticity in a large placebo-controlled clinical trial. In this multicenter, randomized, double-blind, parallel-group, placebo-controlled study, we evaluate the efficacy and safety of one-time injections of botulinum toxin type A (BoNTA) in Japanese patients with post-stroke lower limb spasticity. One hundred twenty patients with lower limb spasticity were randomized to a single treatment with BoNTA 300 U or placebo. The tone of the ankle flexor was assessed at baseline and through 12 weeks using the Modified Ashworth Scale (MAS). Gait pattern and speed of gait were also assessed. The primary endpoint was area under the curve (AUC) of the change from baseline in the MAS ankle score. Significant improvement in spasticity with BoNTA 300 U was demonstrated by a mean difference in the AUC of the change from baseline in the MAS ankle score between the BoNTA and placebo groups (-3.428; 95% CIs, -5.841 to -1.016; p = 0.006; t test). A significantly greater decrease from baseline in the MAS ankle score was noted at weeks 4, 6 and 8 in the BoNTA group compared to the placebo group (p < 0.001). Significant improvement in the Clinicians Global Impression was noted by the investigator at weeks 4, 6 and 8 (p = 0.016-0.048, Wilcoxon test), but not by the patient or physical/occupational therapist. Assessments of gait pattern using the Physician's Rating Scale and speed of gait revealed no significant treatment differences but showed a tendency towards improvement with BoNTA. No marked difference was noted in the frequency of treatment-related adverse events between BoNTA and placebo groups. This was the first large-scale trial to indicate that BoNTA significantly reduced spasticity in lower limb muscles.


Magnesium incorporation into hydroxyapatite.
The incorporation of Mg in hydroxyapatite (HA) was investigated using multinuclear solid state NMR, X-ray absorption spectroscopy (XAS) and computational modeling. High magnetic field (43)Ca solid state NMR and Ca K-edge XAS studies of a ∼10% Mg-substituted HA were performed, bringing direct evidence of the preferential substitution of Mg in the Ca(II) position. (1)H and (31)P solid state NMR show that the environment of the anions is disordered in this substituted apatite phase. Both Density Functional Theory (DFT) and interatomic potential computations of Mg-substituted HA structures are in agreement with these observations. Indeed, the incorporation of low levels of Mg in the Ca(II) site is found to be more favourable energetically, and the NMR parameters calculated from these optimized structures are consistent with the experimental data. Calculations provide direct insight in the structural modifications of the HA lattice, due to the strong contraction of the M⋯O distances around Mg. Finally, extensive interatomic potential calculations also suggest that a local clustering of Mg within the HA lattice is likely to occur. Such structural characterizations of Mg environments in apatites will favour a better understanding of the biological role of this cation.


New liver support devices in acute liver failure: a critical evaluation.
Acute liver failure remains a condition with substantial mortality in spite of the best available medical care. Liver transplantation is often not possible or delayed, and liver support systems can be used to maintain the patient during the crisis by bridging to transplantation or allowing recovery of the native liver. Bioartificial devices, using porcine or human hepatocytes, have yielded encouraging results on consciousness levels in a number of studies and have generally been found to be safe, although in one large controlled trial reported to date, benefit was restricted to certain subgroups. Artificial devices, like those based on albumin dialysis, are undoubtedly effective in removing protein-bound toxins, and uncontrolled evidence shows some survival benefit. The large multicenter controlled trials necessary for proving the value of these systems are difficult to design. They have to take into account the influence of transplantation, etiology, and other factors on outcome. Achieving a standard medical regime for these critically ill patients between different centers is also difficult.


Differential patterns of alcohol abuse among normal, neurotic, psychotic, and characterological types.
The MMPIs of 201 male alcoholic inpatients were classified into normal, neurotic, psychotic, and characterological types according to the Goldberg rules (1972). Multivariate analysis of variance of the respective Alcohol Use Inventory ( AUI ) scores showed that the groups differed in a multivariate sense. The pattern of significant univariate differences indicated that both the neurotic and psychotic groups reported more severe symptoms and consequences of alcohol abuse than the normal and characterological types. No univariate differences were found between either the neurotic and psychotic types or the normal and characterological types. Results were discussed in terms of functions that alcohol served among the groups.


Inhibitors of Plasmepsin II-potential antimalarial agents.
In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.


New frog family from India reveals an ancient biogeographical link with the Seychelles.
About 96% of the more than 4,800 living anuran species belong to the Neobatrachia or advanced frogs. Because of the extremely poor representation of these animals in the Mesozoic fossil record, hypotheses on their early evolution have to rely largely on extant taxa. Here we report the discovery of a burrowing frog from India that is noticeably distinct from known taxa in all anuran families. Phylogenetic analyses of 2.8 kilobases of mitochondrial and nuclear DNA unambiguously designate this frog as the sister taxon of Sooglossidae, a family exclusively occurring on two granitic islands of the Seychelles archipelago. Furthermore, molecular clock analyses uncover the branch leading to both taxa as an ancient split in the crown-group Neobatrachia. Our discovery discloses a lineage that may have been more diverse on Indo-Madagascar in the Cretaceous period, but now only comprises four species on the Seychelles and a sole survivor in India. Because of its very distinct morphology and an inferred origin that is earlier than several neobatrachian families, we recognize this frog as a new family.


Renal biopsy interpretation in Alport Syndrome.
Alport Syndrome is a heritable progressive renal disease that, despite the large number of published studies, because of its genetic, clinical, immunohistochemical, and ultrastructural heterogeneity, still remains a diagnostic challenge. The focus of the discussion is on electron microscopy and immunohistochemistry Col (IV) chains. The differential diagnosis from thin glomerular basement membrane disease is discussed in depth, because both are familial, and can have similar clinical presentation and even ultrastructural pathology, but with a different outcome. The diagnostic role of molecular genetics, which identified the presence of collagen IV gene mutations and its relationship to the phenotypic expression of the renal damage, is also discussed.


Non-epileptic seizures: delayed diagnosis in patients presenting with electroencephalographic (EEG) or clinical signs of epileptic seizures.
The clinical differentiation between epileptic seizures (ES) and non-epileptic seizures (NES) is often difficult and mostly based on the presence or absence of widely recognized features of ES such as tongue biting, falling, incontinence or concomitant epileptic abnormalities in the electroencephalogram (EEG). We retrospectively analysed the records of all patients referred to our Epilepsy Centre for refractory epilepsy and finally diagnosed with NES between 1980 and 1999 ( n= 103), half of them also exhibiting ES. The mean time-lapse between first attack and NES diagnosis was 8.7 +/- 1.3 years and 16.5 +/- 1.4 years for the NES and NES + ES groups respectively. At least one of the usual signs associated with generalized tonic-clonic seizures (tongue biting, falling or incontinence) was reported by 66% and 60% of patients with NES or NES + ES respectively. Interictal EEG abnormalities were recorded in 16% of NES patients vs. 80% of NES + ES patients. In the NES group, delay before establishing the correct diagnosis was significantly longer when the patients exhibited > or =1 symptom(s) of generalized seizures, or when patients exhibited interictal EEG abnormalities. Upon admission, 72% of NES patients and all NES + ES patients were being treated with antiepileptic drugs (AEDs).We conclude that EEG or clinical abnormalities suggestive of epileptic seizures are common in undiagnosed NES patients. Such diagnostic pitfalls, besides considerably delaying NES diagnosis, also considerably delay appropriate treatment implementation.


Androgen ablation and blockade in the treatment of benign prostatic hyperplasia.
Antiandrogen therapy appears to produce a 30 to 40 per cent decrease in the volume of the hyperplastic prostate after 3 to 6 months of therapy (Table 5). Longer treatment may result in further prostatic regression, although this remains to be seen. Biopsy studies suggest that epithelial regression occurs to a much more significant degree than does stromal regression, but this finding may simply reflect the relatively longer turnover of the stromal cell population. The significant placebo effect of oral medication in patients with BPH makes interpretation of clinical symptomatology and uro-flow data difficult. Analysis of symptom improvement is further complicated by the relatively slow improvement of patients on antiandrogen therapy, in contrast to surgery, in which relief is immediate. In addition to limited stromal involution and inadequate treatment duration, other biologic factors may limit the clinical efficacy of antiandrogen therapy. Most importantly, prostatic involution may not necessarily decrease urethral resistance. In addition, obstruction-induced detrusor dysfunction may persist after relief of outflow obstruction in some patients, as it does after surgery. Incomplete antiandrogen action of the compounds, as well as compliance issues, may likewise limit efficacy. Although there are no data to suggest that the 5 alpha-reductase inhibitor finasteride will be more effective than other antiandrogen compounds in the treatment of BPH, preliminary studies suggest that it has less toxicity. If long-term studies validate a modest but significant clinical response rate and preservation of sexual function, then finasteride therapy may well be acceptable to a subgroup of men presenting with the symptoms of BPH.(ABSTRACT TRUNCATED AT 250 WORDS)


Disgust is a factor in extreme prejudice.
Understanding intergroup prejudice is a dominant research focus for social psychology. Prejudice is usually conceptualized as a continuum of positive/negative affect, but this has limitations. It neither reflects people's ability to maintain simultaneous positive and negative stereotypes of others nor explains extreme prejudice (bigotry). Some researchers have proposed multidimensional models of prejudice in which different negative emotions are evoked depending on the situation. Extending this to bigotry raises the question of which emotions are most relevant. Therefore, this study looked at 'anti-group' texts--writings which promote extreme intergroup hostility--and analysed the frequency of emotive language. Findings suggest that bigotry may be distinguished by high levels of disgust.


A Study of the Chemical Composition, Acute and Subacute Toxicity of Bulgarian Tanacetum parthenium Essential Oil.
Tanacetum parthenium (L.) Sch.Bip. (T. parthenium) is an aromatic perennial plant belonging to the Asteraceae family, also known as feverfew. It is widely distributed in various regions of Europe and other parts of the world. The plant has a rich background in the traditional medicine of many nations and has been used as a remedy for fever, pain, inflammation, asthma, rheumatism, menstrual disorders, etc. Methods: GC-MS analysis was conducted to determine the chemical composition of the isolated essential oil (EO). Using the method proposed by Litchfield and Wilcoxon, the average lethal dose (LD50) of the EO on Wistar rats was determined for two routes of administration: oral (p.o.) and intraperitoneal (i.p.). The subacute toxicity of the EO was also tested by oral administration of a daily dose of 1.0 g/kg body weight (BW) for 28 days. The toxicity of the EO was evaluated by observing and evaluating changes in behavior, body weight, basic hematological and serum biochemical parameters, and histopathological changes of the internal organs. Thirty-seven volatile organic compounds representing 94.58% of the total oil composition were tentatively detected in the obtained T. parthenium EO. The dominant compounds were camphor (45.47%), trans-chrisantenyl acetate (21.65%), camphene (9.48%), and cis-isogeraniol (5.42%). The results showed that the EO was not toxic when administered in acute oral doses. The acute mean lethal dose for intraperitoneal administration was LD50 i.p. = 2.13 g/kg BW. In the subacute study involving administration of an oral dose of EO for 28 days, there were a number of changes in the hematological and serum biochemical parameters of the blood compared with the control group of animals. However, no symptoms of toxicity, changes in the body weight of the rats, death, or pathological changes in the histological indicators of the examined organs-brain, heart, stomach, liver, spleen and kidney-were found. Extrapolating the results obtained from the rat experiments, we can state that the EO is safe for use in doses below 1 g/kgBW for a period not exceeding one month.


Co-morbidities in the multiple victims of the silent killer in carbon monoxide poisoning.
Carbon monoxide (CO) remains an insidious and silent killer due to its physical and chemical properties; its lethal effects are encountered in cases of household accidents, occupational hazards or suicide. Deaths due to CO poisoning were studied retrospectively in the period 2000-2018 at the Institute of Forensic Medicine, Timişoara, Romania. These cases represent 1.75% of all the autopsies and 0.63% of all violent deaths. There have been cases of single deaths and cases with multiple victims - concomitant deaths. The analysis of lethal CO intoxication cases that occurred in different circumstances (incomplete burning with CO accumulation, fires - associated with burns, death in the fountain - due to fossil fuel pump failure, suicide due to exhaust gases) was based on the examination of 298 autopsy files. In this type of poisoning, the forensic examination of the body is marked by the non-specific character of most of the macroscopic and microscopic changes. Although inconstant, these types of changes (e.g., red discoloration of livor mortis) raise the suspicion of death by CO poisoning; the essential contribution to establishing cause of death resides in the determination of carboxyhemoglobin (COHb) concentration by spectroscopy. In all cases, the cerebral and cardio-pulmonary modification and their contribution to the cause of death were studied. Co-morbidities interfere with the cause of death in cases with average COHb concentrations, in the 20-50% range, where CO blood levels alone are not reason enough to explain the onset of death.


Kidney Disease After Nonkidney Solid Organ Transplant.
Nonkidney solid organ transplants (NKSOTs) are increasing in the United States with improving long-term allograft and patient survival. CKD is prevalent in patients with NKSOT and is associated with increased morbidity and mortality especially in those who progress to end-stage kidney disease. Calcineurin inhibitor nephrotoxicity is a main contributor to CKD after NKSOT, but other factors in the pretransplant, peritransplant, and post-transplant period can predispose to progressive kidney dysfunction. The management of CKD after NKSOT generally follows society guidelines for native kidney disease. Kidney-protective and calcineurin inhibitor-sparing immunosuppression has been explored in this population and warrants a discussion with transplant teams. Kidney transplantation in NKSOT recipients remains the kidney replacement therapy of choice for suitable candidates, as it provides a survival benefit over remaining on dialysis.


Adherence to a Mediterranean diet in a rural Appalachian food desert.
Rural Appalachian food deserts have disproportionately high cardiovascular disease (CVD) rates. The Mediterranean diet, consisting of plant-based dishes prepared with unsaturated fatty acids, contributes to decreased risk of CVD. Several factors can affect dietary choices in rural food deserts. The purpose of this exploratory study was to identify predisposing, reinforcing and enabling factors that affect eating a Mediterranean diet in a rural Appalachian food desert with disproportionately high rates of cardiovascular disease. The PRECEDE-PROCEED model was used as an assessment framework in this study. Volunteers (n=43) were recruited from four churches in a rural Appalachian county to participate in this mixed methods convergent parallel design study. During each of four sessions with 8-12 participants each, a Mediterranean-style meal was prepared by a local caterer and included plant-based dishes prepared with unsaturated fatty acids. The nature of a Mediterranean diet was explained to participants using an illustrated pamphlet. Nominal group process was used to determine predisposing, reinforcing and enabling factors that would affect adherence to a Mediterranean diet. Multivariate ANOVA and t-tests, using SPSS 18, were performed to determine factors associated with potential future adoption and adherence to a Mediterranean diet among a sample of rural residents and assess whether the factors varied based on age, gender and socioeconomic status. All p values of ≤0.05 were considered significant. Factors affecting future adherence to a Mediterranean diet included difficulty changing personal habits, limited access to healthy foods, cost, difficulty of preparation, limited knowledge of the health benefits of foods, family attitudes toward food and difficulty determining how to incorporate healthy foods into meals. Younger participants and those with lower incomes were more likely to identify food cost as a barrier to adherence compared to those who were older with higher incomes. Participants with lower educational levels were more likely to report family members would be hesitant to try a Mediterranean diet. Women were more likely than men to report an understanding of the health impact of certain foods as motivation to adopt and adhere to a Mediterranean diet. Multiple factors were reported as influencing dietary habits in this sample of rural Appalachian residents. Several of the factors reported are amenable to behavioral interventions. Although Appalachia has more residents per square kilometer than the rest of the country, the population density is not uniform across the region. Because many Appalachians live in sparsely populated counties, rurality plays a significant role in factors that affect dietary choice. Interventions that address barriers related to limited knowledge of nutrition, ease of preparation and changing personal habits as well as promote locally available foods, while considering issues specific to a rural population, may lead to sustained dietary changes.


Surviving blood loss using hydrogen sulfide.
Reduced metabolic activity improves outcome in many clinical and experimental models of injury and diseases that result in insufficient blood supply. Recently, we demonstrated that inhaled hydrogen sulfide gas can be used to reversibly reduce metabolic activity in mice. We hypothesize that hydrogen sulfide will confer benefit in injuries and diseases related to insufficient blood supply. Sprague-Dawley rats were subjected to controlled hemorrhage to remove 60% of total blood. Hydrogen sulfide was administered to rats either via airway as gas, or intravenous infusion as liquid. Outcome was assayed by survival. Using inhaled hydrogen sulfide gas, 75% of treated and 23% of untreated rats survived longer than 24 hours. Using intravenous administered sulfide, 67% of treated and 14% of untreated rats survived longer than 24 hours. Using log-rank analysis, p < 0.001. Surviving rats showed no functional or behavioral abnormalities. Blood chemistry analysis at the end of hemorrhage showed minor but significant differences between treated and control animals. Respirometry results show that hydrogen sulfide stabilized metabolic output during and after hemorrhage. These data indicate that sulfide can protect rats from lethal hemorrhage. Future studies are needed to analyze the mechanism of benefit as well as whether sulfide is beneficial in other models of human injury and disease.


Medication Overuse Headache: The Reason of Headache That Common and Preventable.
Medication overuse headache (MOH) is well-defined clinically and is one of the common reasons of chronic daily headache, but its pathophysiology has not been elucidated yet. MOH has varying clinical features in regard to regional, psychosocial, medical and economic factors. Even though, the studies have shown that many factors may play a role, MOH is likely to occur in patients who are prone to primary headaches. Mainstay of the treatment is to withdraw the excessively used analgesic drugs. The primary prevention with education of the patients as well as early diagnosis and treatment of MOH will reduce its increasing financial burden on both patients and countries. Meticulous and multifactorial evaluation of the disease besides the diagnosis and treatment of the comorbid diseases will reduce the risk of recurrences.


Modeling pneumococcal resistance to penicillin in southern Sweden using artificial neural networks.
In recent decades, penicillin-resistant pneumococci (PRP) have emerged and spread rapidly between and within countries over the world. In this study we developed an iterative artificial neural network (ANN) model to describe and predict the spread of PRP in space and time as a function of antibiotic consumption and a number of different confounders. Retrospective data from 1997 to 2000 on an international epidemic PRP clone (serotype 9V) and antibiotic consumption data from Southern Sweden were used to train the ANN models and data from 2001 to 2003 for evaluation of the model predictions. Five different ANN models were trained, each with independent topology optimization for alternative sets of input variables to find the most descriptive model. The model containing all variables was the only one performing better than the reference linear models, as assessed by the correlation between predictions and observations. The inability to identify a smaller subset of most predictive parameters may reflect either diffuse causal mechanisms or just the absence of critical experimental indicators from the dataset. The iterative ANN model identified is useful to predict future data. The sensitivity analysis of the model suggests that past incidence has a small effect on the number of PRP cases.


Epidemiology and clinical course of liver diseases: identification of candidates for hepatic transplantation.
Among a variety of liver diseases that have been treated by hepatic transplantation, several were chosen for evaluation because of their frequency or high rate of fatality. Information regarding the incidence and prevalence in the United States, the natural history with conventional therapy, and prognostic indicators of a terminal phase is reviewed. Based on this information, specific candidates for hepatic transplantation are identified.


Protective Role of Hepcidin in Polymicrobial Sepsis and Acute Kidney Injury.
Background: Acute kidney injury (AKI) portends worse prognosis following sepsis, with limited available interventions. Host iron acquisition by pathogens and systemic inflammatory response are key events in the pathogenesis of sepsis. In sepsis, hepcidin induces iron sequestration to limit iron availability to pathogens. Hepcidin is also known to limit inflammation. Since its role in pathophysiology of sepsis-associated AKI is unknown, we investigated the effect of exogenous hepcidin in endotoxin- and peritonitis-induced pathology and AKI. Methods: C57BL/6 mice were treated with saline or 50-100 µg of hepcidin, pre- and post-LPS injection, or cecal ligation and puncture (CLP, model of peritonitis). Splenectomized mice were challenged with LPS, with and without hepcidin. Mice were euthanized at 24 h after LPS injection and at different time points after CLP. Systemic inflammation and renal injury markers were assessed. Direct effect of hepcidin on renal tubular and endothelial cells was evaluated using endotoxin-induced cytotoxic serum. Role of heavy chain ferritin (H-ferritin) in mediating hepcidin-induced anti-inflammatory effect on LPS stimulated macrophages was evaluated with siRNA studies. Results: Twenty-four hours pretreatment with hepcidin significantly reduced LPS-induced AKI. Hepcidin ameliorated LPS-induced increase in serum TNFα and renal Cox-2, and prevented loss in PGC1α and cytochrome c oxidase activity. This was associated with reduced glomerular injury and preserved mitochondrial structure. Hepcidin did not exert direct protection on the renal parenchymal cells but reduced endotoxin-induced serum cytotoxicity to mitigate renal injury. Splenectomy reduced LPS-induced early inflammation and AKI, independent of hepcidin, indicating the importance of systemic inflammation. Higher splenic H-ferritin in hepcidin-treated animals was associated with reduced splenocytes apoptosis and inflammation. Hepcidin reduced LPS-induced IL-6 secretion in macrophages in H-ferritin dependent manner. Hepcidin significantly reduced CLP-induced AKI, and mortality (20% hepcidin treated vs 80% PBS treated). Importantly hepcidin reduced bacteremia and AKI even when administered after onset of sepsis. Conclusion: We demonstrate a protective role of hepcidin in endotoxin- and peritonitis-induced pathologies and AKI, exerted primarily through its anti-inflammatory effects, and antibacterial property. Macrophage H-ferritin plays an important role in hepcidin-mediated protection against endotoxin-induced inflammation. We uncover a novel prophylactic and therapeutic role of hepcidin in sepsis-associated bacteremia, AKI, and mortality.


Puberty, ovarian steroids, and stress.
Puberty is accompanied by a number of changes, among them increased risk for development of major depression. The most common etiology of major depression is stressful life events, being present in approximately 90% of first episodes of depression. The hypothalamic-pituitary-adrenal (HPA) axis is one of the major systems involved in responses to stress, and this system is clearly influenced by ovarian hormones. Normal women demonstrate resistance to negative feedback of both cortisol in the fast-feedback paradigm and dexamethasone in the standard delayed-feedback paradigm. Depressed premenopausal women show greater increases in baseline cortisol than postmenopausal depressed women and than depressed men. Studies in rodents suggest a similar resistance to glucocorticoid feedback but suggest that estradiol can function to inhibit stress responsiveness. Studies of premenopausal depressed women demonstrate lower estradiol, which suggests that there is less inhibitory feedback of estradiol on the HPA axis, while normal progesterone continues to augment stress responses further. The onset of these reproductive hormonal changes modulating stress systems at puberty may sensitize girls to stressful life events, which become more frequent at the transition to puberty and young adulthood.


Complications and death following anaesthesia. A prospective study with special reference to the influence of patient-, anaesthesia-, and surgery-related risk factors.
The present study describes risk factors, the incidence of complications and mortality in the anaesthetized patient. The aims were further to identify additional patient-, anaesthesia-, technique-, and surgery-related factors associated with cardiopulmonary complications and mortality, to describe the value of preoperative radionuclide cardiography in patients with cardiopulmonary insufficiency, and to evaluate the importance of perioperative manual evaluation of the response to train-of-four nerve stimulation for the occurrence of residual neuromuscular blockade in the recovery room. Complications attributable to anaesthesia-complications caused mainly by the anaesthetic procedure-occurred in 0.6% (1:170) of the patients, and mortality attributable to anaesthesia was found to be 0.04% (1:2500). An analysis of the patient data suggests that the seriously ill patients (ASA-class > or = 3) were more likely to be affected by errors and a substantial negative outcome such as acute myocardial infarction, irreversible cerebral damage or death, than were more healthy patients (ASA 1-2). One-third of the complications attributable to anaesthesia are judged preventable. Cardiopulmonary complications associated with anaesthesia and surgery and requiring intervention occurred in 1:11 of the anesthetized patients. The cardiopulmonary complications were associated with elderly patients (> or = 70 yr), patients with preoperative clinical signs of ischaemic heart disease and recent myocardial infarction, chronic heart failure, and chronic obstructive lung disease, as well as perioperative and emergency procedures involving major abdominal surgery. In patients with severe cardiovascular or pulmonary insufficiency (high-risk patients) preoperative radionuclide cardiography could distinguish between different levels of cardiopulmonary risk in the anaesthetized patient. Patients with a preoperative left ventricular ejection fraction < 50% or > 70% demonstrated a high incidence of cardiopulmonary complications following anaesthesia (70%). It is recommended that left ventricular ejection fraction be measured in patients referred for major surgery who have an increased risk of cardiopulmonary complications as evidenced clinically by heart failure or severe ischaemic heart disease. Hypotension before anaesthetic induction is associated with a high incidence of cardiopulmonary morbidity and mortality. Postoperative pulmonary complications in comparable groups of patients depend primarily on the type of surgery, as major abdominal surgery was related to the highest incidence of pulmonary complications. Regional anaesthesia may be a superior technique to general anaesthesia, especially in elderly patients with chronic obstructive lung disease admitted to major orthopaedic surgery. Furthermore, in avoidance of postoperative complications such as residual neuromuscular blockade, the choice of muscle relaxant was more decisive than was manual evaluation of the response to train-to-four nerve stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)


Epididymoorchitis and pancytopenia caused by brucellosis.
A 15 year old boy presented with fever and acute painful scrotal swelling. Complete blood count showed pancytopenia. Serum brucella antibodies were positive. Pancytopenia and epididymoorchitis are rare complications of brucellosis and clinicians must consider this entity in the differential diagnosis of adolescents with epididiymoorchitis associated with pancytopenia.


A Between Ethnicities Comparison of Chronic Obstructive Pulmonary Disease Genetic Risk.
Heterogeneity of lung function levels and risk for developing chronic obstructive pulmonary disease (COPD) among people exposed to the same environmental risk factors, such as cigarette smoking, suggest an important role of genetic factors in COPD susceptibility. To investigate the possible role of different genetic factors in COPD susceptibility across ethnicities. We used a population-stratified analysis for: (i) identifying ethnic-specific genetic susceptibility loci, (ii) developing ethnic-specific polygenic risk prediction models using those SNPs, and (iii) validating the models with an independent dataset. We elucidated substantial differences in SNP heritability and susceptibility loci for the disease across ethnicities. Furthermore, the application of three ethnic-specific prediction models to an independent dataset showed that the best performance is achieved when the prediction model is applied to a dataset with the matched ethnic sample. Our study validates the necessity of considering ethnic differences in COPD risk; understanding these differences might help in preventing COPD and developing therapeutic strategies.


Antitumor activity of celastrol nanoparticles in a xenograft retinoblastoma tumor model.
Celastrol, a Chinese herbal medicine, has shown antitumor activity against various tumor cell lines. However, the effect of celastrol on retinoblastoma has not yet been analyzed. Additionally, the poor water solubility of celastrol restricts further therapeutic applications. The goal of this study was to evaluate the effect of celastrol nanoparticles (CNPs) on retinoblastoma and to investigate the potential mechanisms involved. Celastrol-loaded poly(ethylene glycol)-block-poly(ɛ-caprolactone) nanopolymeric micelles were developed to improve the hydrophilicity of celastrol. The 2-(2-methoxy-4- nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulf-ophenyl)-2H tetrazolium monosodium salt (WST-8) assay was used to determine the inhibitory effect of CNPs on SO-Rb 50 cell proliferation in vitro. Immunofluorescence was used to evaluate the apoptotic effect of CNPs on nuclear morphology, and flow cytometry was used to quantify cellular apoptosis. The expression of Bcl-2, Bax, NF-κB p65, and phospo-NF-κB p65 proteins was assessed by Western blotting. A human retinoblastoma xenograft model was used to evaluate the inhibitory effects of CNPs on retinoblastoma in NOD-SCID mice. Hematoxylin and eosin staining was used to assess the apoptotic effects of CNPs on retinoblastoma. CNPs inhibit the proliferation of SO-Rb 50 cells in a dose- and time-dependent manner with an IC(50) of 17.733 μg/mL (celastrol-loading content: 7.36%) after exposure to CNPs for 48 hours. CNPs induce apoptosis in SO-Rb 50 cells in a dose-dependent manner. The expression of Bcl-2, NF-κB p65, and phospo-NF-κB p65 proteins decreased after exposure to CNPs 54.4 μg/mL for 48 hours. Additionally, the Bax/Bcl-2 ratio increased, whereas the expression of Bax itself was not significantly altered. CNPs inhibit the growth of retinoblastoma and induce apoptosis in retinoblastoma cells in mice. CNPs inhibit the growth of retinoblastoma in mouse xenograft model by inducing apoptosis in SO-Rb 50 cells, which may be related to the increased Bax/Bcl-2 ratio and the inhibition of NF-κB. CNPs may represent a potential alternative treatment for retinoblastoma.


Region C of the Escherichia coli heat shock sigma factor RpoH (sigma 32) contains a turnover element for proteolysis by the FtsH protease.
Transcription of most heat shock genes in Escherichia coli is initiated by the alternative sigma factor sigma(32) (RpoH). At physiological temperatures, RpoH is rapidly degraded by chaperone-mediated FtsH-dependent proteolysis. Several RpoH residues critical for degradation are located in the highly conserved region 2.1. However, additional residues were predicted to be involved in this process. We introduced mutations in region C of RpoH and found that a double mutation (A131E, K134V) significantly stabilized RpoH against degradation by the FtsH protease. Single-point mutations at these positions only showed a slight effect on RpoH stability. Both double and single amino acid substitutions did not impair sigma factor activity as demonstrated by a groE-lacZ reporter gene fusion, Western blot analysis of heat shock gene expression and increased heat tolerance in the presence of these proteins. Combined mutations in regions 2.1 and C further stabilized RpoH. We also demonstrate that an RpoH fragment composed of residues 37-147 (including regions 2.1 and C) is degraded in an FtsH-dependent manner. We conclude that in addition to the previously described turnover element in region 2.1, a previously postulated second region important for proteolysis of RpoH by FtsH lies in region C of the sigma factor.


Epidermal polymeric immunoglobulin receptors: leads from intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus.
In this study, we attempted to identify unknown autoantigen for intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus by novel IgA-specific immunoprecipitation. Mass-spectrometry study identified polymeric immunoglobulin receptor (PIGR) as the candidate protein, and we confirmed that PIGR expressed in both epidermis and cultured keratinocytes. Eukaryotic recombinant protein of PIGR expressed in COS7 cells was reacted with both patient and normal sera, indicating that PIGR binds physiologically to IgA. To detect antigen-specific binding by IgA autoantibodies, we performed several experiments using deglycosylated PIGR and F(ab)2 fragments from patient sera. However, these analyses suggested that patient IgA bound physiologically, but not immunologically, to PIGR. Nevertheless, our study provided two important insights. Newly developed IgA-immunoprecipitation system should be a useful tool in the future study of identification of antigens for IgA autoantibodies. Detection of epidermal PIGR in this study confirmed previous results and indicated possible immunological role of PIGR in epidermis.


Clinicians' Perspectives on Diagnostic Markers for Depression Among Adolescents in India: An Embedded Mixed-Methods Study.
Limited research has investigated whether clinicians around the world find diagnostic criteria for depression that were originally developed in the West are useful with diverse populations. Using an embedded mixed-methods design in India, we examined (a) clinicians' and trainees' (n = 143) ratings of the usefulness of the criteria for Major Depressive Disorder (MDD) outlined in two major diagnostic systems (Diagnostic and Statistical Manual of Mental Disorders-5; DSM-5 and International Classification of Mental and Behavioral Disorders-Tenth Edition; ICD-10), and (b) narrative descriptions of clinical cases of adolescent depression and usefulness of diagnostic and screening instruments in day-to-day practice using semi-structured interviews in a subsample of clinicians (n = 24). Qualitative findings demonstrated that Indian clinicians identified markers of depression that were consistent with the current diagnostic manuals (affective, cognitive, somatic symptoms), and the numeric ratings suggested that clinicians found a majority of DSM-5 and ICD-10 criteria for MDD to be useful. However, Indian clinicians also identified additional markers of adolescent depression (i.e., interpersonal conflicts and issues, impairment in school-related functioning, anger-based symptoms, anxiety-based symptoms, additional somatic complaints not included in DSM-5 or ICD-10), highlighting the need to modify existing diagnostic criteria to be more inclusive. The findings suggest the need for culturally informed diagnostic practices that consider a wide range of clinical presentations of depression among adolescents worldwide.


Synchronous intraductal papillary mucinous neoplasm and a pancreatic neuroendocrine tumor: more than a coincidence?
Although the association between intraductal papillary mucinous neoplasm of the pancreas (IPMN) and pancreatic neuroendocrine tumor (PNET) has been increasingly reported, whether this association is real or coincidence remains unclear. We report a case of synchronous IPMN and a PNET which were diagnosed preoperatively and discuss the tumorigenesis, clinicopathological features and management of these rare tumors based on the published literature. A 56-year-old male was incidentally diagnosed with a 14 mm branch duct IPMN and a 3.6 mm non-functional PNET during an evaluation due to persistent upper abdominal pain via endoscopic ultrasound. Close follow-up of the patient was decided as the IPMN had no worrisome features. A review of twenty-two previously reported cases of synchronous IPMN and PNET indicated that: a) only seven cases were diagnosed preoperatively; b) abdominal pain was the main presenting symptom; c) IPMN was the dominant tumor and presented with low grade dysplasia; d) the PNET was small and non-functional and had an indolent behavior; and e) only one case underwent radiologic follow-up. IPMN are associated with other pancreatic and extrapancreatic malignancies. Thus, the entire pancreatic parenchyma should be examined closely during the evaluation of an IPMN in order to exclude other pancreatic lesions, for example, a PNET.


Electrospray ionization mass spectrometry: a major tool to investigate reaction mechanisms in both solution and the gas phase.
Electrospray ionization mass spectrometry (ESI-MS), in conjunction with its tandem version ESI-MS/MS, is now established as a major tool to study reaction mechanisms in solution. This suitability results mainly from the ability of ESI to "fish" ions directly from solution to the gas phase environment of mass spectrometers. In this review, we summarize recent studies from our laboratory on the use of on-line monitoring by ESI-MS ion fishing of several types of reactions that permitted us to follow how these reactions progress as a function of both time and conditions using the ultra-high sensitivity and speed of ESI-MS to detect and even characterize transient reaction intermediates. We also show that the intrinsic reactivity of each key gaseous species fished by ESI can be further investigated via ESI-tandem mass spectrometry experiments, searching for the most active species via gas-phase ion/molecule reactions. In the gas-phase, solvent and counter-ion effects are absent. These studies often permit a detailed overview of major steps via the interception, characterization and reactivity investigation of key reaction players.


DNA damage and cytotoxicity in pancreatic beta-cells expressing human CYP2E1.
Epidemiological studies have identified nitrosamines as a risk factor for Type I (insulin dependent) diabetes mellitus. These compounds require bioactivation by cytochrome P450 2E1 (CYP2E1) for exertion of their toxic effects. Two mammalian insulin secreting pancreatic beta-cell lines BRIN BD11h2E1 and INS-1h2E1, which express human full length CYP2E1 cDNA, were used to elucidate the role of CYP2E1-mediated nitrosamine bioactivation in pancreatic beta-cell dysfunction and destruction. These cell lines were shown to metabolise dimethylnitrosamine to produce formaldehyde at rates of 3.41 +/- 0.24 and 3.65 +/- 0.26 nmol/minmg microsomal protein, respectively. Following incubation with various concentrations of the nitrosamines dimethylnitrosamine, N-nitrosopyrrolidine and 1-nitrospiperidine, all of which are bioactivated by CYP2E1, cytotoxicity and DNA damage were assessed using either the neutral red assay or comet assay respectively. Exposure of CYP2E1 expressing cells to nitrosamines resulted in significant dose-dependent decreases in cell viability, which were not seen in cells which did not express CYP2E1. Following culture with nitrosamine concentrations as low as 2.5mM 1-nitrosopiperidine, cell viability was significantly lower in BRIN BD11h2E1 and INS-1h2E1 cell lines in comparison to the BRIN BD11 and INS-1 parental cell lines (72.5 +/- 4.96 and 66.4 +/- 3.09% in BRIN BD11h2E1 and INS-1h2E1 versus 109.0 +/- 3.40 and 100.0 +/- 3.25% in BRIN BD11 and INS-1 respectively, P < 0.001). The highest dose of any of the nitrosamines tested failed to significantly reduce cell viability in the cells which lacked CYP2E1. Expression of CYP2E1 did not cause any change in the basal level of DNA damage in any of the cell lines. However, 16 h exposure to various nitrosamines resulted in significant dose-dependent DNA damage in the BRIN BD11h2E1 and INS-1h2E1 cells compared to their respective non CYP2E1-expressing parental controls, e.g. DNA damage increased from 34.38 +/- 1.25 to 44.01 +/- 1.56% DNA in comet tail in BRIN BD11h2E1 cells incubated with 10 or 40 mM N-nitrosopyrrolidine, respectively (P < 0.001). Similar treatment of the BRIN BD11 and INS-1 cell lines did not result in a significant increase in DNA damage (20.33 +/- 1.0 and 22.4 +/- 0.98% DNA in comet tail). The pancreatic beta-cell is richly vascularised and expresses CYP2E1. This study suggests that expression of human CYP2E1 in pancreatic beta-cells make them highly susceptible to cytotoxicity and DNA damage by nitrosamines and other agents bioactivated by CYP2E1.


Primary and secondary prevention of ischemic stroke.
Prevention of stroke and transient ischemic attack includes both conventional approaches to vascular risk factor management (blood pressure lowering, cholesterol reduction with statins, smoking cessation and antiplatelet therapy) and more specific interventions, such as carotid revascularization or anticoagulation for atrial fibrillation. The objective of this review is to discuss effective interventions for optimal primary and secondary stroke prevention.


C3 glomerulopathy associated to multiple myeloma successfully treated by autologous stem cell transplant.
A 32-year-old male presented with advanced renal failure and nephrotic proteinuria due to lambda light chain multiple myeloma. Renal biopsy showed a proliferative glomerulonephritis with isolated C3 deposits. Renal recovery was obtained after chemotherapy and autologous stem cell transplant. We review previously described cases of C3 glomerulopathy associated with monoclonal gammopathy.


Possible role of DNA topoisomerase II on transcription of the homeobox gene Hox-2.1 in F9 embryonal carcinoma cells.
The Hox-2.1 gene is one of homeobox-containing genes located in the Hox-2 cluster on mouse chromosome 11. In this study, we have examined transcription of the Hox-2.1 gene during differentiation of F9 embryonal carcinoma cells induced by treatment with retinoic acid. The level of Hox-2.1 mRNA increases rapidly after induction of differentiation and then falls. Nuclear run-on experiments demonstrate that the rate of transcription for the Hox-2.1 gene also increases upon differentiation. Treatment of F9 cells with a DNA topoisomerase II inhibitor etoposide (VP-16) during differentiation blocks the accumulation of Hox-2.1 mRNA. Nuclear run-on analyses reveal that etoposide inhibits transcription of the Hox-2.1 gene during F9 cell differentiation. Measurements of the level of Hox-2.1 mRNA after blocking transcription by actinomycin D show that etoposide does not affect stability of the mRNA. These observations indicate that DNA topoisomerase II is involved in the control of Hox-2.1 gene transcription.


A cytochemical and immunohistochemical approach to malignant histiocytosis.
Malignant histiocytosis (MH) is a true histiocytic disorder, whose identification is still based on too broad morphologic criteria. Using routine histology, cytochemical and immunohistochemical techniques on involved lymph nodes, 15 cases of MH have been investigated. Pleomorphism and cellular atypia, phagocytosis, lack of cohesiveness between proliferating cells, sinusoidal involvement, and plasmacytic infiltrate were the most common histologic features. MGG-stained imprints from 14 cases showed a composite tumor population mainly consisting of histiocyte-appearing cells, poorly differentiated atypical cells, and multinucleated giant cells. These cells, irrespective of cytologic features, revealed a diffuse, moderately to strongly positive reaction with acid phosphatase and nonspecific esterase. Naphthol-AS-D-chloroacetate esterase, Sudan black B, alkaline phosphatase, and beta-glucuronidase reactions were completely negative. Immunoperoxidase studies in 11 cases demonstrated that tumor cells stained positively for both kappa and lambda chains. These cells were also positive for albumin. Polytypic staining for IgG was observed in two cases, and a weak staining for lysozyme was found in two other nodes. Global results confirm the value of these studies for functional profile determination of MH proliferating cells. A combined approach using a variety of cytochemical and immunohistochemical techniques should be routinely considered in MH as useful additional studies for a more precise diagnostic definition of the disease.


Visual Performance of a Multifocal Contact Lens versus Monovision in Established Presbyopes.
To compare subjective and objective visual performance of the Air Optix Aqua Multifocal lens to monovision in a group of subjects requiring a medium level of reading-addition power. Fifty participants with reading additions between 1.25 and 2.00 diopters (inclusive) were randomized into a prospective, crossover clinical trial. They wore monovision and multifocals for 2 weeks in a randomized order. High- and low-contrast logMAR (logarithm of the minimum angle of resolution) acuity and stereopsis were measured at the beginning and end of each period. During each phase, participants performed specific tasks followed by subjective rating surveys and also completed satisfaction rating surveys on days 3, 7, and 12; all were transferred in real time using BlackBerry smartphones. A general rating survey was completed at the dispensing and 2-week visits. Forty-nine participants completed the study (mean age, 52 years). Distance and near high- and low-contrast acuities were significantly better (p < 0.05) with monovision at all visits. High-contrast intermediate acuity was only better (p < 0.05) with multifocals after 2 weeks. Stereopsis was equivalent after 2 weeks, but better (p < 0.05) with multifocals at dispensing. Subjective ratings were generally equivalent between modalities although there was a trend for multifocals to be rated higher for focus changing and driving, whereas monovision tended to be rated higher for near tasks. For both corrections, the satisfaction survey showed no significant change between days 3, 7, and 12, and the general survey showed that comfort was maintained but subjective vision ratings decreased significantly over the 2 weeks. Twenty-five participants (51%) preferred multifocals, 18 (37%) preferred monovision, and the remaining 6 (12%) declared both unacceptable. In this cohort, distance and near acuities were better with monovision, whereas the subjective ratings tended to favor the Air Optix Aqua Multifocal, with the exception of near performance. Preference was statistically similar between both corrections, with a trend toward preferring the multifocal.


Coronary blood flow assessment after successful angioplasty for acute myocardial infarction predicts the risk of long-term cardiac events.
Analysis of coronary flow velocity (CFV) in the recanalized infarct-related coronary artery (IRA) with a Doppler guidewire is useful for predicting recovery of regional left ventricular function, in-hospital complications, and survival. We postulated that the CFV pattern after IRA reperfusion for acute myocardial infarction (AMI) would predict long-term adverse cardiac events. Sixty-eight consecutive patients with a first AMI underwent CFV measurement with a Doppler guidewire after successful reopening of the IRA by coronary angioplasty. At the end of follow-up, 3.8+/-1.7 years after AMI, 44 of the 65 surviving patients (67.7%) were free of long-term cardiac events. Univariate analysis showed that the following factors were predictive of an end point combining cardiac death, recurrent MI, and congestive heart failure: hypertension, age > or =65 years, time from onset of chest pain to PTCA > or =6 hours, peak creatine kinase >4000 IU/L, ejection fraction < or =50%, proximal left anterior descending artery occlusion, resting average peak velocity < or =10 cm/s, average systolic peak velocity < or =5 cm/s, a rapid diastolic deceleration time (< or =600 ms), and early retrograde systolic flow. In the final multivariate model, only age > or =65 years (OR, 3.6; 95% CI, 1.1 to 11.8; P=0.03), time to PTCA > or =6 hours (OR, 2.9; 95% CI, 1.0 to 8.3; P=0.04), and a rapid diastolic deceleration time (OR, 5.4; 95% CI, 1.5 to 19.3; P=0.01) were independent predictors. The CFV pattern appears to be an accurate predictor of long-term cardiac events in patients having undergone successful reopening of the IRA after AMI, identifying a subset of at-risk patients.


A rare case of malposition of central venous catheter detected by ultrasonography-guided saline flush test.
Central venous catheter (CVC) insertion is associated with many potential complications; malposition of the catheter is one of them. A chest X-ray is routinely done to detect the malposition of catheter, but sometimes it has been seen that X-ray is time-consuming and its accuracy is also low for determining the exact position of the catheter tip. In our case, an ultrasonography (USG)-guided CVC was placed into the right internal jugular vein of the patient. As there was no ECG change obtained during insertion of guidewire and catheter, malposition was suspected, which was easily detected by a novel USG-guided saline flush test. We present a case report where USG was used for detection of a misplaced CVC (from right internal jugular vein to right subclavian vein). With ultrasound, the location of the catheter tip can be confirmed in very less time compared with chest X-ray.


Therapeutic Hypothermia in Critically Ill Patients: A Systematic Review and Meta-Analysis of High Quality Randomized Trials.
To investigate the effect of the application of therapeutic hypothermia (32-35°C) on survival and major clinical endpoints in critically ill patients. We searched online database and clinical trial registries dated up to April 30, 2019, and references of relevant studies. Low risk of bias randomized trials which compared hypothermia applied for at least 24 hours and conventional therapy in critically ill patients were included. We excluded trials investigating therapeutic hypothermia in indications already supported by international guidelines (adult cardiac arrest and hypoxic-ischemic encephalopathy of newborns) or intraoperative hypothermia. Titles and abstracts were reviewed independently by two authors. If the articles seemed eligible, full-text articles were reviewed, and data were abstracted using a structured template. Our search retained 14 low risk of bias randomized trials (2,670 patients) performed in three different settings: traumatic brain injury, serious infections, and stroke. Therapeutic hypothermia was associated with an increase in mortality at longest follow-up available (432/1,375 [31%] vs 330/1,295 [25%]; risk ratio, 1.24; 95% CI, 1.10-1.39; p = 0.0004; I = 0%). Pooled results showed no difference of good neurologic outcome among survivors between the two treatment arms (493/1,142 [43%] vs 486/1,067 [46%]; risk ratio, 1.04; 95% CI, 0.97-1.12; p = 0.27; I = 1%). Arrhythmias were significantly increased among patients undergoing therapeutic hypothermia. We found no difference between groups in pneumonia, serious infections, any infection, hemorrhage, renal failure, deep vein thrombosis, and uncontrollable intracranial hypertension. High-quality randomized evidence indicates that therapeutic hypothermia is associated with higher mortality and no difference in good neurologic outcome compared with normothermia in critically ill patients. Although there still might be a possibility that therapeutic hypothermia is beneficial in a specific setting, routine application of therapeutic hypothermia would better be avoided outside the settings indicated by international guidelines (adult cardiac arrest and hypoxic-ischemic encephalopathy of newborns).


Unusual presentation of nasopharyngeal carcinoma with rectal metastasis.
Nasopharyngeal carcinoma (NPC) is a rare tumour that mainly metastasizes in lymph nodes, bones, lungs and liver. Colorectal metastases of NPC are extremely rare phenomenon and associated with a poor prognosis. We reported here a case of NPC with rectal metastasis, we discussed the treatment modalities and the prognosis after reviewing the similar cases described in the literature.


Pharmacological preconditioning with resveratrol: role of nitric oxide.
Resveratrol (trans-3,4',5-trihydroxystilbene), a recently described grape-derived polyphenolic antioxidant, has been found to protect the heart from ischemic-reperfusion injury. The present study sought to determine the mechanism of cardioprotection by investigating the ability of resveratrol to precondition the heart. Isolated perfused rat hearts were randomly divided into six groups: group I was perfused for 15 min with Kreb-Henseleit buffer (KHB) only; group II was perfused with 10 microM resveratrol; group III was perfused with 10 microM resveratrol plus 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide (NO) synthase (NOS) inhibitor; group IV was perfused with 10 microM resveratrol plus 100 microM aminoguanidine (AG), an inducible NOS (iNOS) blocker; and groups V and VI consisted of hearts perfused with L-NAME and AG, respectively. The perfusion was then switched to working mode, and all hearts were made globally ischemic for 30 min followed by 2 h of reperfusion. Preconditioning of the hearts with resveratrol provided cardioprotection as evidenced by improved postischemic ventricular functional recovery (developed pressure and aortic flow) and reduced myocardial infarct size and cardiomyocyte apoptosis. Resveratrol-mediated cardioprotection was completely abolished by both L-NAME and AG. In a separate study, hearts were examined for iNOS mRNA induction. Resveratrol caused an induction of the expression of iNOS mRNA beginning at 30 min after reperfusion, increasing steadily up to 60 min of reperfusion, and then decreasing progressively up to 2 h after reperfusion. Preperfusion of the hearts with AG almost completely blocked the induction of iNOS. The results of our study demonstrate that resveratrol can pharmacologically precondition the heart in a NO-dependent manner.


Frost resistance in alpine woody plants.
This report provides a brief review of key findings related to frost resistance in alpine woody plant species, summarizes data on their frost resistance, highlights the importance of freeze avoidance mechanisms, and indicates areas of future research. Freezing temperatures are possible throughout the whole growing period in the alpine life zone. Frost severity, comprised of both intensity and duration, becomes greater with increasing elevation and, there is also a greater probability, that small statured woody plants, may be insulated by snow cover. Several frost survival mechanisms have evolved in woody alpine plants in response to these environmental conditions. Examples of tolerance to extracellular freezing and freeze dehydration, life cycles that allow species to escape frost, and freeze avoidance mechanisms can all be found. Despite their specific adaption to the alpine environment, frost damage can occur in spring, while all alpine woody plants have a low risk of frost damage in winter. Experimental evidence indicates that premature deacclimation in Pinus cembra in the spring, and a limited ability of many species of alpine woody shrubs to rapidly reacclimate when they lose snow cover, resulting in reduced levels of frost resistance in the spring, may be particularly critical under the projected changes in climate. In this review, frost resistance and specific frost survival mechanisms of different organs (leaves, stems, vegetative and reproductive over-wintering buds, flowers, and fruits) and tissues are compared. The seasonal dynamics of frost resistance of leaves of trees, as opposed to woody shrubs, is also discussed. The ability of some tissues and organs to avoid freezing by supercooling, as visualized by high resolution infrared thermography, are also provided. Collectively, the report provides a review of the complex and diverse ways that woody plants survive in the frost dominated environment of the alpine life zone.


Editorial Commentary: Avoiding Complications in Elbow Arthroscopy: Know the Indications, Learn the Anatomy, and Master a Safe Technique.
Elbow arthroscopy enables surgeons to treat a vast range of elbow injuries and pathologies in a minimally invasive manner. It has a lower morbidity rate and is often followed by a faster recovery than traditional open surgery unless it is followed by a serious complication. Although most complications are minor and transient, the incidence of both minor and major complications is considerably higher than that after arthroscopy of other joints, specifically the risk of neurovascular injury including permanent nerve injury because of the proximity of neurovascular structures. A recent review of 114 studies reported a median 3% incidence of complications and 2% incidence of reoperation, with transient nerve palsies accounting for about one third. Surgeon experience may influence complication rates; a survey suggested that surgeons need to experience more than 200 cases to be considered expert. In addition, patient-related factors such as obesity, female gender, age over 65 years, elevated blood sugar levels, hypercoagulable disorder, tobacco or alcohol use or both, as well as history of previous surgery and perioperative corticosteroid injections are identified as risk factors for complications after elbow arthroscopy. Keys to avoiding complications include precise surgical indications and understanding the 3-dimensional anatomy-especially the relationship of the various nerves to the portals and joint capsule.


Comparison of clinical values between cone beam computed tomography and conventional intraoral radiography in periodontal and infrabony defect assessment.
The use of CBCT for periodontal diagnosis and treatment plan is limited. The aim of this study is to compare the assessment of periodontal conditions and infrabony defects between conventional intraoral radiography (IOR) and CBCT. The study included 25 subjects who had periodontitis and at least two infrabony defects. All subjects received clinical periodontal examination, IOR and CBCT. Three periodontists assigned periodontal diagnosis and prognosis of each tooth. For teeth with infrabony defects, the number of defect walls and treatment was determined. IOR and CBCT assessment was compared. There were 666 teeth and 123 infrabony defects. The overall concordance between IOR and CBCT for periodontal diagnosis, prognosis, infrabony defect type and infrabony defect treatment were 79.3%, 69.5%, 44.7% and 64.2%, respectively. IOR underestimated diagnosis, prognosis and the number of infrabony defect walls at 16.4%, 24% and 37.4%, respectively. IOR and CBCT had poor concordance for periodontal regeneration (43.3%). Tooth extraction was more prevalent when assessed by CBCT (35.0% vs 22.7%). CBCT had excellent interexaminer agreement (Fleiss' kappa 0.87-0.94) and higher percentage of complete agreement among examiners than IOR for all assessments. IOR underestimated the severity and prognosis of periodontal disease. CBCT was superior to IOR for evaluation of infrabony defect morphology and treatment. CBCT provides excellent agreement among examiners on periodontal and infrabony defect assessment.


A fish keeper's life lessons: Implications for resilience promotion.
A self-care crisis follows a predictable, four-step pattern: Tension-building, flood zone, recovery, equilibrium. When we learn to identify our tension-building signals and intervene quickly by using tailored coping strategies, we often are able to alleviate emotional distress and regain equilibrium. This article identifies three self-reflective exercises that could be used to increase insight, identify early signals of self-care tension-building, and encourage intentional selection of coping strategies.


Strongyloides stercoralis Infection Causing Obstructive Jaundice and Refractory Pancreatitis: A Lesson Learned from a Case Study.
A 58-year-old Japanese woman came to our institution because of leg edema and abdominal distention. She had developed acute pancreatitis 5 times in the past 3 years. Dilation of the bile duct and main pancreatic duct without obstruction was observed on computed tomography and magnetic resonance cholangiopancreatography. The presence of Strongyloides stercoralis was highly suspected from the biopsy sample from the duodenal papilla. Polymerase chain reaction amplification and sequencing of small subunit rDNA from paraffin-embedded specimens identified the worm as S. stercoralis. All of the symptoms were considered to be associated with S. stercoralis infection. Therefore, the patient was treated with oral administration of ivermectin. Subsequently, symptoms and laboratory data improved. There has been no recurrence of the symptoms to date.


Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects.
SPR741 is a novel polymyxin B derivative, with minimal intrinsic antibacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in two studies, after single and multiple intravenous (i.v.) doses in healthy adult subjects and after coadministration with partner antibiotics. In the single and multiple ascending-dose study, SPR741 or placebo was administered as a 1-h infusion at single doses of 5 to 800 mg and in multiple doses of 50 to 600 mg every 8 h (q8h) for 14 days. In the drug-drug interaction study, a single 400-mg i.v. dose of SPR741 was administered alone and in combination with piperacillin-tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using noncompartmental analysis. After single doses, a dose-linear and proportional increase in mean maximum concentration in plasma (Cmax) and area under the concentration-time curve (AUC) was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 h postdose. After multiple doses, the mean half-life was 2.2 h on day 1 and up to 14.0 h on day 14, with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with coadministration. SPR741 was generally well tolerated at doses up to 1,800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria. (These studies have been registered at ClinicalTrials.gov under identifiers NCT03022175 and NCT03376529.).


Metastatic male breast cancer: a retrospective cohort analysis.
Metastasized male breast cancer (MMBC) is a rare disease. Given its low incidence, data regarding tumor biology, current treatment options, and survival rates are scarce. A chart review was performed of MMBC patients consecutively registered in regional cancer registries in Germany between 1995 and 2011. Tumor characteristics, treatment, and survival rates were documented and statistically evaluated. 41 men with MMBC represented 25.6% of a total of 160 patients with MBC. 16 (39%) patients showed primary metastases, and 25 (61%) had recurrent metastases. Median survival from occurrence of metastasis was 32 months. Median overall survival (OS) was 68 months. 68.3% (n = 28) of the cohort received systemic therapy favoring endocrine therapy (n = 25, 61.9%). Prolonged metastatic OS (p = 0.02) was observed in patients having had a systemic treatment. Metastatic patients having received endocrine treatment showed significantly prolonged survival rates. Furthermore, patients receiving palliative chemotherapy had a significant survival benefit compared to those in whom chemotherapy was omitted. Our results suggest that systemic treatment in the form of both palliative chemotherapy and endocrine therapy improves outcome of R. Foerster and L. Schroeder contributed equally to this article and are listed in alphabetical order. MMBC. Therefore, it seems reasonable that treatment of MMBC should be based on the guidelines for female breast cancer.


Microwaves and tea: new tools to process plant tissue for transmission electron microscopy.
Optimizing sample processing, reducing the duration of the preparation of specimen, and adjusting procedures to adhere to new health and safety regulations, are the current challenges of plant electron microscopists. To address these issues, plant processing protocols for TEM, combining the use of polyphenolic compounds as substitute for uranyl acetate with microwave technology are being developed. In the present work, we optimized microwave-assisted processing of different types of plant tissue for ultrastuctural and immunocytochemical studies. We also explored Oolong tea extract as alternative for uranyl acetate for the staining of plant samples. We obtained excellent preservation of cell ultrastructure when samples were embedded in epoxy resin, and of cell antigenicity, when embedded in LR-White resin. Furthermore, Oolong tea extract successfully replaced uranyl acetate as a counterstain on ultrathin sections, and for in block staining. These novel protocols reduce the time spent at the bench, and improve safety conditions for the investigator. The preservation of the cell components when following these approaches is of high quality. Altogether, they offer significant simplification of the procedures required for electron microscopy of plant ultrastructure.


Seeds, fermented foods, and agricultural by-products as sources of plant-derived antibacterial peptides.
The emergence of bacterial resistance against conventional antibiotics and the growing interest in developing alternative, natural antibacterial agents have prompted the search for plant-derived antibacterial peptides in recent decades. Different classes of endogenous antibacterial peptides have been identified from various plant species. Moreover, protein hydrolysates and hydrolysate-derived peptides with potent antibacterial effects have also been identified from numerous plant sources. Antibacterial peptides are often cationic and amphipathic, consisting of fewer than 100 amino acids. They are able to disrupt bacterial membrane integrity via pore formation and/or compromise bacterial metabolic processes. In this review, we summarize current knowledge on the characteristics and modes of action of antibacterial peptides, as well as salient points concerning the production of antibacterial protein hydrolysates from plant proteins. Examples of plant-derived antibacterial hydrolysates and peptides will be highlighted, with particular attention to less explored seeds, fermented plant foods and agricultural by-products. Promising future research directions with regards to the application of plant-derived antibacterial hydrolysates and peptides in food preservation, farm animal disease management, and nutraceutical/functional food development will be proposed.


Persistence of SARS-CoV-2 in saliva: Implications for late-stage diagnosis and infectious duration.
Saliva has been a COVID-19 diagnostic specimen of interest due to its simple collection, scalability, and yield. Yet COVID-19 testing and estimates of the infectious period remain largely based on nasopharyngeal and nasal swabs. We sought to evaluate whether saliva testing captured prolonged presence of SARS-CoV-2 and potential infectiousness later in the disease course. We conducted an observational study of symptomatic COVID-19 patients at University Hospital in Newark, NJ. Paired saliva and nasal specimens from 96 patients were analyzed, including longitudinal analysis of paired observations from 28 of these patients who had multiple time-points. Saliva detected significantly more cases of COVID-19 beyond 5 days (86.1% [99/115] saliva vs 48.7% [56/115] nasal, p-value < 0.001), 9 days (79.4% [50/63] saliva vs 36.5% [23/63] nasal, p-value < 0.001) and 14 days (71.4% [20/28] saliva vs 32.1% [9/28] nasal, p-value = 0.010) of symptoms. Additionally, saliva yielded lower cycle thresholds across all time periods, indicative of higher viral loads in saliva. In the longitudinal analysis, a log-rank analysis indicated that the survival curve for saliva was significantly different from the curve for nasal swabs (p<0.001) with a median survival time for saliva of 18 days compared to 13 days for nasal swabs. We additionally performed saliva viral cultures among a similar COVID-19 patient cohort and noted patients with positive saliva viral cultures between 7 to 28 days of symptoms. Findings from this study suggest that SARS-CoV-2 RNA persists longer and in higher abundance in saliva compared to nasal swabs, with potential of prolonged propagating virus. Testing saliva may thus increase yield for detecting potentially infectious virus even beyond the first five days of symptomatic COVID-19.


Dispositional Mindfulness Predicts Adaptive Affective Responses to Health Messages and Increased Exercise Motivation.
Feelings can shape how people respond to persuasive messages. In health communication, adaptive affective responses to potentially threating messages constitute one key to intervention success. The current study tested dispositional mindfulness, characterized by awareness of the present moment, as a predictor of adaptive affective responses to potentially threatening health messages and desirable subsequent health outcomes. Both general and discrete negative affective states (i.e., shame) were examined in relation to mindfulness and intervention success. Individuals (n=67) who reported less than 195 weekly minutes of exercise were recruited. At baseline, participants' dispositional mindfulness and exercise outcomes were assessed, including self-reported exercise motivation and physical activity. A week later, all participants were presented with potentially threatening and self-relevant health messages encouraging physical activity and discouraging sedentary lifestyle, and their subsequent affective response and exercise motivation were assessed. Approximately one month later, changes in exercise motivation and physical activity were assessed again. In addition, participants' level of daily physical activity was monitored by a wrist worn accelerometer throughout the entire duration of the study. Higher dispositional mindfulness predicted greater increases in exercise motivation one month after the intervention. Importantly, this effect was fully mediated by lower negative affect and shame specifically, in response to potentially threatening health messages among highly mindful individuals. Baseline mindfulness was also associated with increased self-reported vigorous activity, but not with daily physical activity as assessed by accelerometers. These findings suggest potential benefits of considering mindfulness as an active individual difference variable in theories of affective processing and health communication.