Role of Pneumococcal NanA Neuraminidase Activity in Peripheral Blood.
The most frequent form of hemolytic-uremic syndrome (HUS) is associated with infections caused by Shiga-like toxin-producing Enterohaemorrhagic Escherichia coli (STEC). In rarer cases HUS can be triggered by Streptococcus pneumoniae. While production of Shiga-like toxins explains STEC-HUS, the mechanisms of pneumococcal HUS are less well-known. S. pneumoniae produces neuraminidases with activity against cell surface sialic acids that are critical for factor H-mediated complement regulation on cells and platelets. The aim of this study was to find out whether S. pneumoniae neuraminidase NanA could trigger complement activation and hemolysis in whole blood. We studied clinical S. pneumoniae isolates and two laboratory strains, a wild-type strain expressing NanA, and a NanA deletion mutant for their ability to remove sialic acids from various human cells and platelets. Red blood cell lysis and activation of complement was measured ex vivo by incubating whole blood with bacterial culture supernatants. We show here that NanA expressing S. pneumoniae strains and isolates are able to remove sialic acids from cells, and platelets. Removal of sialic acids by NanA increased complement activity in whole blood, while absence of NanA blocked complement triggering and hemolytic activity indicating that removal of sialic acids by NanA could potentially trigger pHUS.


[Electrical cardioversion for atrial fibrillation].
Electrical cardioversion ist often the treatment of first choice for restoring sinus rhythm in patients with atrial fibrillation. This article reviews the management of patients undergoing electrical cardioversion. As risk of formation of an intra-atrial thrombus formation is low after a short duration of AF (less than 48 h), immediate cardioversion can be performed in these patients (except those with a high risk for thrombembolic events). However, if the AF has lasted for more than 48 hours, patients have to be treated either with anticoagulants for at least three weeks or an atrial thrombus has to be excluded by transesophageal echocardiography. Both options achieve the same short- or long-term success rate for cardioversion. Cardioversion is probably safe even if there are spontaneous echocardiographic contrasts as signs of potential thrombogenic slowing of atrial blood flow, but individual factors of risk/indication have to taken into account. Success rate of cardioversion depends on various patient characteristics as well as on some technical variables, biphasic instead of monophasic shocks being more effective. If there is an early recurrence of AF after initially successful cardioversion, administration of amiodarone (for 4 weeks) increases the success rate of subsequent cardioversion. After successful cardioversion subsequent antiarrhythmic therapy can reduce recurrence of AF. Thrombembolic complications are more frequent within the first few days after cardioversion. Indication for and duration of post-cardioversion anticoagulation depends on individual characteristics (CHADS(2) score) as well as on the duration of the preceding episode of AF.


Combination of nucleoside analogues tiazofurin and ribavirin downregulates experimental autoimmune encephalomyelitis.
The effect of combined treatment with ribavirin and tiazofurin on the development of experimental autoimmune encephalomyelitis, the best characterized animal model for human autoimmune disease multiple sclerosis, was investigated. The disease was induced in highly susceptible Dark Agouti rats with spinal cord homogenate in complete Freund's adjuvant. Although ribavirin or tiazofurin alone reduced the clinical and histopathological signs of experimental autoimmune encephalomyelitis, the combination of drugs achieved the same effect with significantly lower doses.


Immunoaffinity purification and properties of a high molecular weight calf thymus DNA alpha-polymerase.
A rapid, three-step purification of DNA alpha-polymerase from calf thymus is described. The key feature is immunoaffinity chromatography using a column of immobilized monoclonal immunoglobulin G (IgG) developed against human KB cell alpha-polymerase. This step is followed by preparative sucrose gradient sedimentation. The highly purified polymerase has a specific activity of 35 000 nmol of nucleotide incorporated per hour per milligram. Its molecular weight is 404 000. This molecular weight is higher than observed in some earlier purifications, possibly because salt concentrations are kept at nearly physiological levels. Also, the rapidity of purification in the presence of multiple protease inhibitors minimizes degradation. The purified enzyme is inhibited by aphidicolin, N-ethylmaleimide, and the specific monoclonal IgG, thereby identifying it as DNA alpha-polymerase. ATP at 4 mM concentration stimulates enzymatic activity up to 4-fold on calf thymus DNA templates. The enzyme is also capable of priming single-stranded DNA with RNA. The procedure represents a significant advance from purifying alpha-polymerase from calf by conventional means, since it avoids ion-exchange chromatography and harsh conditions. It also minimizes the time required to produce sufficient quantities of purified high molecular weight polymerase for analysis.


[Not Available].
This new paper on chemical risk from anaesthetic agents in operating theatres is the natural progression of that published in this journal in supplement 1-2013, as it constitutes a development and complement of the previous work and an applicative confirmation from the highest organ of administrative justice, the Consiglio di Stato, regarding, in particular, the obligation of adopting the technically most advanced "measures" to eliminate or, at least, minimise risk in the use of new generation and the most commonly-used anaesthetic agents (sevoflurane and desflurane). Therefore, in this paper, the authors commence by referring to the starting point, consisting in the conclusions of the previous study, which highlighted the extraordinary convergence of technical and scientific, legislative and case law data on the same result, constituted by the possibility, and consequent obligation, of implementing, also in operating theatres, the greatest technologically possible safety, starting with the choice of the most suitable equipment, methods and quality systems for avoiding the diffusion, dispersion and /or leakage of volatile hazardous agents that may contribute - together with those chemical reactions that are foreseeable and avoidable, given the characteristics of the materials, substances and relative "packaging" - to workplace pollution, which can, in any case, reach levels that are hazardous due to the concentration of anaesthetic gases. Subsequently, once the "scientific" fruit of the previous contributions has been discussed, the authors evaluate the impact of the result already achieved in practice with concrete cases and the judgement expressed with a series of judgements issued in rapid succession by the Consiglio di Stato, showing the application, not merely of the legislative "data" but also of the references and citations that these "data" contain regarding the "knowledge acquired regarding the relationship with technical progress". Lastly, the Authors provide, as a further, definitive conclusion, the singular unit of the guidelines provided by case law, the result of a univocal and continuous multitude of judgements issued at the highest degree of administrative justice, albeit for very diverse situations and circumstances, which provide, therefore, a direction and an operative guide for which they are called on to adopt roles and responsibilities for the choices of "products", "systems" and "methods" destined to affect - for the use of anaesthetic agents - the health and safety of healthcare staff and of patients themselves.


Isolated torticollis may present as an atypical presentation of meningitis.
Background. Bacterial meningitis is a life-threatening medical emergency that requires urgent diagnosis and treatment. Diagnosis is infrequently missed if the patient presents with the classic symptoms of fever, headache, rash, nuchal rigidity, or Kernig or Brudzinski sign. However, it may be less obvious in neonates, elderly, or immunocompromised patients. Meningitis which presents as isolated torticollis, without any other signs or symptoms, is exceedingly rare. Objective. To identify an abnormal presentation of meningitis in an adult immunocompromised patient. Case Report. We present a case of an adult diabetic male who presented multiple times to the ED with complaint of isolated torticollis, who ultimately was diagnosed with bacterial meningitis. Conclusion. We propose that in the absence of sufficient explanation for acute painful torticollis in an immunocompromised adult patient, further evaluation, possibly including a lumbar puncture may be warranted.


Immunoreactive beta-endorphin in ovarian sex cord-stromal tumors.
The possible production of the opioid polypeptide beta-endorphin (beta-EP) was investigated in paraffin-embedded tissue from 17 ovarian tumors with the use of a specific anti-beta-EP antibody and the avidin-biotin-peroxidase staining technique. Only sex cord-stromal tumors (ten cases) showed positive staining. Strong beta-EP immunoreactivity was present in Leydig's cells of Sertoli-Leydig cell tumors; weaker sporadic staining was present in cells of granulosa cell tumors, and faint staining was present in occasional, luteinized theca cells of fibrothecomata. These findings suggest that cells with the sex cord-stromal phenotype that are capable of steroid production can also produce beta-EP. The latter may be a component of the "functional" status associated with some ovarian sex cord-stromal tumors and may serve as a helpful marker in distinguishing this type of tumors from germ cell or epithelial neoplasms.


WIC-based interventions to promote breastfeeding among African-American Women in Baltimore: effects on breastfeeding initiation and continuation.
We evaluated the single and combined effects of introducing a motivational video and peer counseling into four matched WIC clinics on breastfeeding initiation and continuation at 7-10 days among African-American WIC participants. Of the 242 women with complete data, 48% initiated breastfeeding, but only 31% were still breastfeeding at 7-10 days. Initiation was associated with cesarean delivery, infant feeding instruction, no artificial milk discharge pack, attending the peer counselor only-intervention site, and intention to breastfeed. Continuation was influenced by infant feeding instruction, no artificial milk discharge pack, and intention to breastfeed. Overall, trends toward a positive impact of the breastfeeding promotion activities were evident but weak, and largely gone by 7-10 days postpartum.


High prevalence of cestodes in Artemia spp. throughout the annual cycle: relationship with abundance of avian final hosts.
Brine shrimp, Artemia spp., act as intermediate hosts for a range of cestode species that use waterbirds as their final hosts. These parasites can have marked influences on shrimp behavior and fecundity, generating the potential for cascading effects in hypersaline food webs. We present the first comprehensive study of the temporal dynamics of cestode parasites in natural populations of brine shrimp throughout the annual cycle. Over a 12-month period, clonal Artemia parthenogenetica were sampled in the Odiel marshes in Huelva, and the sexual Artemia salina was sampled in the Salinas de Cerrillos in Almería. Throughout the year, 4-45 % of A. parthenogenetica were infected with cestodes (mean species richness = 0.26), compared to 27-72 % of A. salina (mean species richness = 0.64). Ten cestode species were recorded. Male and female A. salina showed similar levels of parasitism. The most prevalent and abundant cestodes were those infecting the most abundant final hosts, especially the Greater Flamingo Phoenicopterus ruber. In particular, the flamingo parasite Flamingolepis liguloides had a prevalence of up to 43 % in A. parthenogenetica and 63.5 % in A. salina in a given month. Although there was strong seasonal variation in prevalence, abundance, and intensity of cestode infections, seasonal changes in bird counts were weak predictors of the dynamics of cestode infections. However, infection levels of Confluaria podicipina in A. parthenogenetica were positively correlated with the number of their black-necked grebe Podiceps nigricollis hosts. Similarly, infection levels of Anomotaenia tringae and Anomotaenia microphallos in A. salina were correlated with the number of shorebird hosts present the month before. Correlated seasonal transmission structured the cestode community, leading to more multiple infections than expected by chance.


Drug delivery into microneedle-porated nails from nanoparticle reservoirs.
This study demonstrates the potential of polymeric nanoparticles as drug reservoirs for sustained topical drug delivery into microneedle-treated human nail. Laser scanning confocal microscopy was used to image the delivery of a fluorescent model compound from nanoparticles into the nail. A label-free imaging technique, stimulated Raman scattering microscopy, was applied, in conjunction with two-photon fluorescence imaging, to probe the disposition of nanoparticles and an associated lipophilic 'active' in a microneedle-porated nail. The results provide clear evidence that the nanoparticles function as immobile reservoirs, sequestered on the nail surface and in the microneedle-generated pores, from which the active payload can be released and diffuse laterally into the nail over an extended period of time.


Conflicting Effects of Methylglyoxal and Potential Significance of miRNAs for Seizure Treatment.
According to an update from the World Health Organization, approximately 50 million people worldwide suffer from epilepsy, and nearly one-third of these individuals are resistant to the currently available antiepileptic drugs, which has resulted in an insistent pursuit of novel strategies for seizure treatment. Recently, methylglyoxal (MG) was demonstrated to serve as a partial agonist of the gamma-aminobutyric acid type A (GABAA) receptor and to play an inhibitory role in epileptic activities. However, MG is also a substrate in the generation of advanced glycation end products (AGEs) that function by activating the receptor of AGEs (RAGE). The AGE/RAGE axis is responsible for the transduction of inflammatory cascades and appears to be an adverse pathway in epilepsy. This study systematically reviewed the significance of GABAergic MG, glyoxalase I (GLO1; responsible for enzymatic catalysis of MG cleavage) and downstream RAGE signaling in epilepsy. This work also discussed the potential of miRNAs that target multiple mRNAs and introduced a preliminary scheme for screening and validating miRNA candidates with the goal of reconciling the conflicting effects of MG for the future development of seizure treatments.


Clustered Genes Encoding 2-Keto-l-Gulonate Reductase and l-Idonate 5-Dehydrogenase in the Novel Fungal d-Glucuronic Acid Pathway.
D-Glucuronic acid is a biomass component that occurs in plant cell wall polysaccharides and is catabolized by saprotrophic microorganisms including fungi. A pathway for D-glucuronic acid catabolism in fungal microorganisms is only partly known. In the filamentous fungus Aspergillus niger, the enzymes that are known to be part of the pathway are the NADPH requiring D-glucuronic acid reductase forming L-gulonate and the NADH requiring 2-keto-L-gulonate reductase that forms L-idonate. With the aid of RNA sequencing we identified two more enzymes of the pathway. The first is a NADPH requiring 2-keto-L-gulonate reductase that forms L-idonate, GluD. The second is a NAD+ requiring L-idonate 5-dehydrogenase forming 5-keto-gluconate, GluE. The genes coding for these two enzymes are clustered and share the same bidirectional promoter. The GluD is an enzyme with a strict requirement for NADP+/NADPH as cofactors. The kcat for 2-keto-L-gulonate and L-idonate is 21.4 and 1.1 s-1, and the Km 25.3 and 12.6 mM, respectively, when using the purified protein. In contrast, the GluE has a strict requirement for NAD+/NADH. The kcat for L-idonate and 5-keto-D-gluconate is 5.5 and 7.2 s-1, and the Km 30.9 and 8.4 mM, respectively. These values also refer to the purified protein. The gluD deletion resulted in accumulation of 2-keto-L-gulonate in the liquid cultivation while the gluE deletion resulted in reduced growth and cessation of the D-glucuronic acid catabolism.


TGFß3 / SfaN1 gene variant and the risk factor of nonsyndromic cleft palate only among Indonesian patients.
Non-syndromic cleft palate only (NS CPO) is one of the most common congenital malformations that affect between 1 in 1000 - 2500 live births worldwide. The etiopathogenesis of clefts including NS CPO has been widely studied but is still poorly understood. NS CPO is considered to be a genetically complex, multifactorial disease. Based on several studies, mutations of TGFβ3 gene emerged as the strong candidate gene associated with NS CPO. The purpose of this study was to analyze the relationship between the TGFβ3 / SfaN1 gene variant and the risk of NS CPO in Indonesian patients. This study was case control design using samples from 31 NS CPO subjects and 35 control subjects. DNA was extracted from venous blood and the segment of TGFβ3 gene/ SfaN1 were amplified by using polymerase chain reaction (PCR) technique, then digestion products by SfaN1 restriction enzyme which can detect locus of gene variant / polymorphism from restriction fragment length polymorphisms (RFLP) method were evaluated. The results indicated that the gene variant as substitution of base G into A was identified in TGFβ3 gene and the frequency of heterozygous mutant GA genotype was 63,6% in NS CPO subjects and 36,4% in control subjects. The frequency of heterozygous mutant GA genotype was associated with increased risk of NS CPO (odds ratio (OR) = 2,260, 95% CI = 0,592 - 8,625). In conclusion, TGFβ3 gene / SfaN1 polymorphism can be considered as the risk factor associated with NS CPO in Indonesian patients.


Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial.
We determined if a third of the dose of intravesical bacillus Calmette-Guerin (BCG) has the same efficacy than a standard dose for decreasing the risk of recurrence and progression after transurethral resection in patients with superficial high risk (stages T1G3 and carcinoma in situ) bladder cancer. Also, we evaluated toxic side effects. A total of 155 patients with a mean age +/- SD of 67 +/- 10.1 years with superficial bladder cancer, including stages T1G3 in 90, a Tis primary tumor in 23 and associated Tis disease in 42, were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG, Connaught strain (weekly x 6 and fortnightly x 6 thereafter) with the standard dose of 81 mg or with the decreased dose of 27 mg. Median followup was 61 months (range 3 to 102). Disease recurred in 32 patients (39%) treated with the standard dose and in 33 (45%) treated with the decreased dose. Median time to recurrence was not attained in the standard dose arm and it was 63 months in the decreased dose arm. Kaplan-Meier estimates for time to recurrence did not reveal differences between the 2 doses (p = 0.405). Tumor progressed in 20 patients (24.7%) with the standard dose and in 19 (26%) with the decreased dose. Four patients (6.1%) with Tis had local extension into the prostatic urethra and ducts, including 3 (8.3%) treated with the standard dose and 1 (3.4%) treated with the decreased dose. Median time to progression was not attained in either arm. Kaplan-Meier estimates for time to progression did not differ significantly (p = 0.7997). Deferred cystectomy for progression was performed in 7 patients (8.4%) treated with the standard dose and in 7 (9.5%) of those treated with the decreased dose. Subgroup analysis by patient age, tumor status, number, size and T stage (T1G3 vs Tis) did not differ significantly. The groups did not differ in disease specific mortality, which was 12.2% in the standard dose arm and 16.4% in the decreased dose arm. Mean disease specific survival +/- SE was 86.96 +/- 4.14 and 83.73 +/- 4.73 months, respectively. Our results suggest that a 3-fold decreased dose of intravesical BCG is as effective as the standard dose against progression in patients with high risk stages T1G3 and Tis superficial bladder carcinoma but with significantly less toxicity.


Topologically enabled optical nanomotors.
Shaping the topology of light, by way of spin or orbital angular momentum engineering, is a powerful tool to manipulate matter on the nanoscale. Conventionally, such methods focus on shaping the incident beam of light and not the full interaction between the light and the object to be manipulated. We theoretically show that tailoring the topology of the phase space of the light particle interaction is a fundamentally more versatile approach, enabling dynamics that may not be achievable by shaping of the light alone. In this manner, we find that optically asymmetric (Janus) particles can become stable nanoscale motors even in a light field with zero angular momentum. These precessing steady states arise from topologically protected anticrossing behavior of the vortices of the optical torque vector field. Furthermore, by varying the wavelength of the incident light, we can control the number, orientations, and the stability of the spinning states. These results show that the combination of phase-space topology and particle asymmetry can provide a powerful degree of freedom in designing nanoparticles for optimal external manipulation in a range of nano-optomechanical applications.


Cerebroprotective effects of a novel pyrazoline derivative, MS-153, on focal ischemia in rats.
MS-153 ((R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline) is a novel pyrazoline compound that has potent cerebroprotective effects in the rat focal cerebral ischemia model. Middle cerebral artery (MCA) occlusion in rats allows detailed assessment of both functional and morphological sequelae of brain infarct. Using this model, we evaluated the cerebroprotective effects of MS-153. Treatment with MS-153 (12.5 mg/kg, i.v. bolus followed by 6.25 mg/kg/hr or 25.0 mg/kg, i.v. bolus followed by 12.5 mg/kg/hr infusion for 7 days) significantly reduced infarct volumes and improved neurological deficits in MCA occluded rats 7 days after occlusion. Delayed treatment significantly reduced infarct volume 24 hr after MCA occlusion when MS-153 (25.0 mg/kg, i.v. bolus followed by 12.5 mg/kg/hr infusion for 21 hr) administration was started 3 hr after occlusion. Brain edema was also significantly improved when MS-153 (25.0 mg/kg, i.v. bolus followed by 12.5 mg/kg/hr infusion for 18 hr) administration was started 6 hr after occlusion.


Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs.
Two analogues of sildenafil were detected in herbal dietary supplements marketed as aphrodisiacs. Both compounds were identified as thioketone analogues of sildenafil in which the carbonyl group in the pyrimidine ring of sildenafil was substituted with a thiocarbonyl group. The first compound was identified as thiosildenafil, a compound that has recently been reported as an adulterant in health supplements. The structure of the second compound was established using LC-MS, UV spectroscopy, ESI-MS(n), NMR and a hydrolytic process. A detailed study of the hydrolysis products of sildenafil, thiosildenafil, and the second unknown compound proved that the second compound, named thiomethisosildenafil, had a structure analogous to sildenafil in which the N-methylpiperazine moiety had been replaced with 2,6-dimethylpiperazine and the oxygen atom of the carbonyl group in the heterocyclic ring had been replaced with a sulfur atom. Under the hydrolytic reaction conditions employed in this study, thioketones hydrolyze to ketones (e.g., thiosildenafil-->sildenafil), making this a valuable technique for the structure elucidation of thiosildenafil analogues. Ten herbal dietary supplements, each as a capsule dosage form, were found to contain 8-151 mg of thiomethisosildenafil per capsule, and one herbal dietary supplement was found to contain 35 mg of thiosildenafil per capsule.


Myocyte cell death and ventricular remodeling.
The recognition that cell death in the myocardium is not only necrotic in nature but is also mediated by activation of the suicide program of myocytes has raised several questions concerning the magnitude of this phenomenon, and whether these two distinct forms of cell death are disease-dependent or coexist in the pathologic heart. Additionally, the times required for the completion of apoptotic and necrotic myocyte cell death are unknown, making the analysis of their respective rates in the myocardium impossible at present. The documentation that mechanical forces in vitro, mimicking diastolic Laplace overloading in vivo, can transmit a death signal to myocytes suggests that programmed cell death may be triggered in the stressed myocardium independently from the etiology of the overload. Because increasing pressure or volume loads, or both, in the failing heart induce myocyte hypertrophy and proliferation, a challenging question is whether the induction of genes regulating these cellular growth processes may activate programmed cell death as well. Finally, the identification of the mechanisms responsible for the translation of a diffuse environmental condition into a death signal in a limited number of cells scattered across the ventricular wall is a major challenge of future research.


Percutaneous transluminal angioplasty: importance of anticoagulant and fibrinolytic drugs.
At the Medical University of Pécs, Hungary, percutaneous transluminal angioplasty was performed on 252 lesions in 235 patients. Primary success rate was 75%. Long femoral artery occlusions were recanalized with a 66% patency rate in lesions 10-20 cm long and a 47% patency rate in lesions longer than 20 cm. These relatively high patency rates were attributed to the use of SP 54, a fibrinolytic agent. In a group of 52 patients treated with SP 54 there were only four reocclusions, two of these occurring 12 months after angioplasty when SP 54 was discontinued. It was concluded that long occlusions may be amenable to angioplasty provided that appropriate fibrinolytic therapy is instituted after the procedure.


Comparative study of normal condyle and temporomandibular joint prosthesis movement during mouth opening by dynamic magnetic resonance imaging and computed tomography.
To analyze and compare the trajectory of condylar motion during mouth opening in normal volunteers and patients after total joint replacement (TJR) of the temporomandibular joint (TMJ). Condylar movement during mouth opening was recorded by dynamic magnetic resonance imaging (MRI) for volunteers with normal TMJs and dynamic computed tomography (CT) for patients after TMJ TJR. Trajectories of the points selected every 5 mm from the superior point of the condyle (P0) along its axis to the mandibular angle (P-25) were recorded. The arc length and curvature radius of average trajectories for each point were calculated and compared between the normal joints and TJRs, especially P-10 which is the corresponding point of the prosthesis apex without lateral pterygoid muscle (LPM) attachment at the normal joint with LPM attachment. The location of the point with the most similar trajectory was identified in the normal joints and compared with the condylar prosthesis. A total of 9 volunteers with 18 normal TMJs, and 5 patients with 6 prostheses were included in this study. For normal TMJs, the average condylar trajectories during mouth opening were a concave upward curve. Meanwhile, the trajectories of contralateral normal joints in patients with unilateral TJR and all condylar prostheses were significantly decreased. The arc length and curvature radius of average trajectories gradually decreased from P0. In the normal joints, P-20 had the most similar trajectories with the average arc lengths and a curvature radius of 13.0/4.2 mm. In P-10, the average arc lengths and curvature radius of the normal cases, natural TMJ of the unilateral replacement patients, prosthetic TMJ of the unilateral replacement patients, and prosthetic TMJ of the bilateral replacement patient, were 15.6/6.6 mm, 13.1/4.9 mm, 4.7/4.4 mm, and 6.4/5.8 mm, respectively. P-20 in the normal joint exhibited the most similar trajectory among individuals. The trajectory difference between the prosthesis apex without LPM attachment and the corresponding point at the normal joint with LPM attachment provides a reference for fossa prosthesis functional surface design.


Association of uremic pruritus in hemodialysis patients with the number of days of high mean 24-hour particulate matter with a diameter of <2.5 μm.
Uremic pruritus (UP) is a common and incapacitating symptom in patients undergoing hemodialysis (HD). The pathogenesis of UP is multifactorial and complex. Particulate matter (PM), a major air pollutant, is a mixture of particles with various chemical compositions. PM is associated with several allergic diseases, including dermatitis. To assess the role of PM (PM with a diameter of <10 μm [PM10] and PM with a diameter of <2.5 μm [PM2.5]) and other clinical variables in UP in patients on HD, we recruited 866 patients on maintenance HD (MHD). We analyzed the number of days of mean 24-hour PM10 ≥125 μg/m3/12 months (NDPM10) or the number of days of mean 24-hour PM2.5 ≥35 μg/m3/12 months (NDPM2.5) exceeding the standard level in the past 12 months respectively to determine the association with UP. In a multivariate logistic regression, HD duration, serum ferritin levels, low-density lipoprotein (LDL) levels, and NDPM2.5 ≥116 days/12 months were positively associated with UP. This cross-sectional study showed that the number of days on which the environmental PM2.5 exceeds the standard level might be associated with UP in patients on MHD.


The use of musculoskeletal ultrasound by rheumatologists in the United States.
Fewer United States rheumatologists perform or utilize musculoskeletal ultrasound (MSUS) than those in Europe, though this disparity is narrowing. To document perceptions and use of MSUS in the U.S. rheumatology community, we sent an anonymous electronic survey to American College of Rheumatology (ACR) physicians and tailored versions to fellows and program directors. A separately-conducted survey was sent to a smaller group of rheumatologists already utilizing MSUS. Acknowledging survey bias, we found that 20% of rheumatologists and fellows who responded are utilizing MSUS, and those using it primarily do so for diagnosis and injection guidance. Many rheumatologists across the country think that ultrasound should become a standard tool in rheumatology training, practice, and research. Despite an inherent survey bias likely overstating interest in MSUS, this study is valuable as the first to document this trend among U.S. rheumatologists.


Innovation strategies for generic drug companies: moving into supergenerics.
Pharmaceutical companies that market generic products generally are not regarded as innovators, but rather as companies that produce copies of originator products to be launched at patent expiration. However, many generics companies have developed excellent scientific innovative skills in an effort to circumvent the defense patents of originator companies. More patents per product, in terms of both drug substances (process patents and polymorph patents) and formulations, are issued to generics companies than to companies that are traditionally considered to be 'innovators'. This quantity of issued patents highlights the technical knowledge and skill sets that are available in generics companies. In order to adopt a completely innovative model (ie, the development of NCEs), a generics company would require a completely new set of skills in several fields, including a sufficient knowledge base, project and risk management experience, and capability for clinical data evaluation. However, with relatively little investment, generics companies should be able to progress into the so-called 'supergeneric' drug space - an area of innovation that reflects the existing competencies of both innovative and generics companies.


Increased forearm vascular resistance after dopamine blockade.
The peripheral haemodynamic effects of a 40 mg intravenous injection of domperidone (a dopamine antagonist) have been studied in 10 normal subjects. In four subjects domperidone was infused directly into the brachial artery and the effects on forearm blood flow were measured. When administered systemically, domperidone significantly decreased forearm blood flow by 9% (P less than 0.01) and significantly increased calculated forearm vascular resistance by 11% (P less than 0.01). The drug produced no measurable changes in forearm blood flow at any dose when infused directly into the brachial artery. A further study was carried out into the effects of a systemic injection of domperidone on peripheral sympathetic tone. Reduction of sympathetic tone in the forearm was achieved by passively raising the legs of eight recumbent subjects. Before domperidone administration, passive leg elevation significantly increased forearm blood flow by 39% and decreased forearm vascular resistance by 13%. After drug administration the absolute values of vascular resistance increased and the changes between the supine and elevated position values when compared with those of the corresponding values prior to drug administration were significantly lower. These results suggest that the role of domperidone in increasing peripheral vascular tone is unlikely to be mediated by a direct local effect on peripheral resistance vessels. Any effect the drug may have is suggested to be mediated via a central control mechanism.


Image distortion of intra-oral photographs: The root coverage model.
Clinical photographs have been advocated in studies dealing with the quantity of root coverage. Changes in different angles of the camera when taking a photograph may lead to parallax errors resulting in inaccurate measurements. The aim of this study was to explore the distortion of the photographs according to the shooting angle. A dental simulation model with a recession defect on tooth 21 was used. Photographs were taken with a digital camera at 5° intervals between 0° to 35°, by shifting the position of the model. Recession depth and root surface area were calculated with ImageJ and implemented in a mathematical model. The relationship between the experimental measurements and the outcomes of the mathematical model was statistically evaluated. The model was confirmed by clinical data. When the central axis of the lens of the camera focused on the experimental tooth is within a cone angle ≤36°, the maximum distortion of the recession area ranges from 0% to 14%, the maximum percentage occurring when the angle is coronal to the central axis. Photographs without an external device connected to the camera provide a valuable support for root coverage assessment when using ImageJ as a measuring tool.


Transport properties of incipient gels.
We investigate the behavior of the shear viscosity eta(p) and the mass-dependent diffusion coefficient D(m,p) in the context of a simple model that, as the cross link density p is increased, undergoes a continuous transition from a fluid to a gel. The shear viscosity diverges at the gel point according to eta(p) approximately (p(c)-p)(-s) with s approximately 0.65. The diffusion constant shows a remarkable dependence on the mass of the clusters: D(m,p) approximately m(-0.69), not only at p(c) but well into the liquid phase. We also find that the Stokes-Einstein relation Deta proportional, variant k(B)T breaks down already quite far from the gel point.


Hemorrhoidectomy for thrombosed external hemorrhoids.
External hemorrhoids represent distended vascular tissue in the anal canal distal to the dentate line. Persons with thrombosed external hemorrhoids usually present with pain on standing, sitting or defecating. Acutely tender, thrombosed external hemorrhoids can be surgically removed if encountered within the first 72 hours after onset. Hemorrhoidectomy is performed through an elliptic incision over the site of thrombosis with removal of the entire diseased hemorrhoidal plexus in one piece. Caution must be exercised to avoid cutting into the muscle sphincter below the hemorrhoidal vessels. Infection after suture closure is rare secondary to the rich vascular network in the anal area. Stool softeners must be prescribed postoperatively to help prevent tearing at the suture line. Training and experience in general and skin surgery are necessary before the physician attempts this procedure unsupervised.


Identification of beta-amyloid-binding sites on transthyretin.
Transthyretin (TTR) binds to the Alzheimer-related peptide beta-amyloid (Aβ), and may protect against Aβ-induced neurotoxicity. In this work, the specific domains on TTR involved with binding to Aβ were probed. An array was constructed of peptides derived from overlapping sequences from TTR. Strong binding of Aβ to TIAALLSPYSYS (residues 106-117) was detected, corresponding to strand G on the inner β-sheet of TTR. Aβ bound weakly to four contiguous peptides spanning residues 59-83, which includes strand E through the E/F helix and loop. To further pinpoint specific residues on TTR involved with Aβ binding, nine alanine mutants were generated: I68A, I73A, K76A, L82A, I84A, S85A, L17A, T106A and L110A. Aβ binding was significantly inhibited only in L82A and L110A, indicating that Aβ binding to TTR is mediated through these bulky hydrophobic leucines. Aβ binding to L17A and S85A was significantly higher than to wild-type TTR. Enhancement of binding in L17A is postulated to arise from reduced steric restriction to the interior L110 site, since these two residues are adjacent in the native protein. The S85A mutation caused a reduction in TTR tetramer stability; increased Aβ binding is postulated to be a direct consequence of the reduced quaternary stability.


Revisiting noncovalent So2- amine chemistry: an indicator-displacement assay for colorimetric detection of So2.
A supramolecular approach for potential detection of SO2 is presented, which is based on the "old" donor-acceptor chemistry between SO2 and amines and includes an indicator-displacement assay. When amines were added to Zn-tetraphenylporphyrin 1 in CHCl3, the solution changed from red to dark green. A bathochromic shift of Deltalambda approximately 10 nm was observed for the Soret band, indicating the formation of 1*amine complexes. After this, SO2 gas was introduced, and the original red color of the solution was restored. The Soret band returned to its position for free porphyrin 1. The 1*amine complexes dissociated, and new SO2*amine adducts formed. Porphyrin 1 thus served as an indirect colorimetric indicator for SO2. The system discriminates between SO2 and such typical exhaust gases as COX, NOX, and H2O. From the indicator-displacement assay, the Kassoc values between 1000 and 30 000 M-1 for SO2*amine complexes were determined, which are comparable to those obtained by direct titration experiments between SO2 and the amines. Spectroscopic features of SO2*amine complexes are also presented.


Mechanism for lactate-color stabilization in injection-enhanced beef.
In two experiments, the relationship between metmyoglobin (MMb) reduction and lactate to pyruvate conversion with concomitant production of reduced nicotinamide adenine dinucleotide (NADH) via lactic dehydrogenase (LDH) was investigated. In experiment 1, nonenzymatic reduction of horse MMb occurred in a lactate-LDH-NAD system. Exclusion of NAD+, L-lactic acid, or LDH resulted in minimal MMb reduction. Increasing NAD+ and L-lactic acid concentrations increased reduction. In experiment 2, beef strip loins (longissimus lumborum muscle) were injected with combinations of potassium lactate, sodium tripolyphosphate, sodium chloride, and/or sodium acetate. Steaks were packaged in high-oxygen (80% oxygen/20% carbon dioxide) modified-atmosphere packaging and stored for 2-9 days and then placed in a fluorescent-lighted, open-top display case for 5 days at 1 degrees C. Enhancing loins with 2.5% potassium lactate significantly increased LDH activity, NADH concentration, MMb-reducing activity, and subsequent color stability during display. These research results support the hypothesis that enhancing beef with lactate replenishes NADH via increased LDH activity, ultimately resulting in greater meat color stability.


Phytochemical, Morphological, and Physiological Variation in Different Ajowan (Trachyspermum ammi L.) Populations as Affected by Salt Stress, Genotype × Year Interaction and Pollination System.
In the present research, 28 populations of ajowan (Trachyspermum ammi L.) were evaluated for agro-morphological traits and essential oil yield in two consecutive years. Then, selected ajowan populations from these two years were used for further morphophysiological and biochemical studies under different salinity levels (control, 60, 90, and 120 mM NaCl). The main components of the oil were thymol (32.7-54.29%), γ-terpinene (21.71-32.81%), and p-cymene (18.74-26.16%). Salt stress caused an increase in essential oil content in the Esfahfo and Qazvin populations. The highest total phenolic and flavonoid contents were found in the Arak population grown in 60 mM NaCl (183.83 mg TAE g-1 DW) and the Yazd population grown in 90 mM NaCl (5.94 mg QE g-1 DW). Moreover, the Yazd population exhibited the strongest antioxidant activity based on DPPH (IC50 = 1566 µg/mL) under 60 mM NaCl and the highest reducing power (0.69 nm) under 120 mM NaCl. The results revealed that low and moderate salt stress improves the phytochemicals of ajowan seeds, which are useful for pharmaceutical and food applications. In this research, some morphological traits, as well as essential oil yield, were evaluated in open pollinated versus self-pollinated plants. As a result, plant height, number of flowering branches, and crown diameter significantly decreased in some populations, while a significant increase was obtained for number of flowers per umbel and seed numbers per umbel. Finally, self-pollination of ajowan might provide new insights for further breeding programs to increase oil or thymol content in ajowan.


A dual-center validation of the PIRAMD scoring system for assessing the severity of ischemic Moyamoya disease.
Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD) is a recently proposed imaging-based scoring system that incorporates the severity of disease and its impact on parenchymal hemodynamics in order to better support clinical management and evaluate response to intervention. In particular, PIRAMD may have merit in identifying symptomatic patients that may benefit most from revascularization. Our aim was to validate the PIRAMD scoring system. Patients with ischemic Moyamoya disease, who underwent catheter angiographic [modified Suzuki Score (mSS) and collateralization status], morphological MRI and a parenchymal hemodynamic evaluation with blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR) at two transatlantic centers, were retrospectively included. The primary outcome was the presence of neurological symptoms. The diagnostic capacity of each PIRAMD feature alone was evaluated, as well as combined and the inter-institutional differences of each parameter were evaluated. Seventy-two hemispheres of 38 patients were considered for analysis, of which 39 (54%) were classified as symptomatic. The presence of a prior infarct had the highest odds ratio [odds ratio (OR) =24; 95% CI: 6.7-87.2] for having neurological symptoms, followed by impaired CVR (OR =17; 95% CI: 5-62). No inter-institutional differences in the odds ratios or area under the curve (AUC) were found for any study parameter. The PIRAMD score had an AUC of 0.88 (95% CI: 0.80-0.96) with a similar AUC for the PIRAMD grading score. Our multicentric validation of the recently published PIRAMD scoring system was highly effective in rating the severity of ischemic Moyamoya disease with excellent inter-institutional agreement. Future studies should investigate the prognostic value of this novel imaging-based score in symptomatic patients with Moyamoya disease.


Mast cells contribute to double-stranded RNA-induced augmentation of airway eosinophilia in a murine model of asthma.
Clinical studies showed the contribution of viral infection to the development of asthma. Although mast cells have multiple roles in the pathogenesis of allergic asthma, their role of in the virus-associated pathogenesis of asthma remains unknown. Most respiratory viruses generate double-stranded (ds) RNA during their replication. dsRNA provokes innate immune responses. We recently showed that an administration of polyinocinic polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13. The effect of poly IC on allergen-induced airway eosinophilia was investigated for mast cell-conserved Kit+/+ mice and -deficient KitW/KitW-v mice. The outcome of mast cell reconstitution was further investigated. Airway eosinophilia and IL-13 production were augmented by poly IC in Kit+/+ mice but not in KitW/KitW-v mice. When KitW/KitW-v mice were reconstituted with bone marrow-derived mast cells (BMMCs), the augmentation was restored. The augmentation was not induced in the mice systemically deficient for TIR domain-containing adaptor-inducing IFN-β (TRIF) or interferon regulatory factor (IRF)-3, both mediate dsRNA-triggered innate immune responses. The augmentation was, however, restored in KitW/KitW-v mice reconstituted with TRIF-deficient or IRF-3-deficient BMMCs. Although leukotriene B4 and prostaglandin D2 are major lipid mediators released from activated mast cells, no their contribution was shown to the dsRNA-induced augmentation of airway eosinophilia. We conclude that mast cells contribute to dsRNA-induced augmentation of allergic airway inflammation without requiring direct activation of mast cells with dsRNA or involvement of leukotriene B4 or prostaglandin D2.


Geometry-selective synthesis of E or Z N-vinyl ureas (N-carbamoyl enamines).
N-Vinyl ureas are emerging as a valuable class of compounds with both nucleophilic and electrophilic reactivity. They may be made by capturing the enamine tautomer of an imine with an isocyanate, a reaction which in general leads to the E isomer of the vinyl urea. Deprotonation of such a vinyl urea, or of an allyl urea, generates a dipole stabilized Z-allyl anion which may be protonated to return the Z-vinyl urea. Isomerization of an allyl urea with a Ru complex provides an alternative route to E-vinyl ureas.


Randomised-control trial of family intervention for 78 first-episode male schizophrenic patients. An 18-month study in Suzhou, Jiangsu.
At the time of discharge from their first stay in psychiatric hospital, 78 male schizophrenic patients were randomly assigned to a family intervention (experimental) group or a 'standard care' control group and were followed for the next 18 months. The family intervention consisted of both group and individual counselling sessions every 1-3 months that focused on education about the illness and on methods of dealing with the patient. There was a significantly lower rate of hospital readmission in the family intervention group than in the control group (15.4% versus 53.8%, chi 2 = 12.75, P < 0.01), and the mean hospital-free period for those who were readmitted was significantly longer in the experimental group than in the control group (245 days versus 130 days, t = 2.91, P < 0.01). Moreover, the clinical status and overall level of functioning in patients who were not readmitted were significantly better in experimental subjects than in control subjects. Stratified analysis showed that family intervention and regular use of medication had independent and additive effects on the outcome. During the 18 months after the index discharge patients who did not take medication regularly and who did not receive family intervention were 7.9 times as likely to be readmitted to hospital as patients who took medication regularly and received family intervention.


Behavioural responses of the snail Lymnaea acuminata to carbohydrates and amino acids in bait pellets.
Snail control could play an important role in programmes against fascioliasis, especially if the methods used for molluscicide delivery could be improved, such as by the development of bait formulations containing both an effective attractant and a molluscicide, to ensure good levels of contact between the molluscicide and the target snail populations. In a recent study, the attractiveness to Lymnaea acuminata (an intermediate host of the digenean trematode Fasciola gigantica) of potential components of snail-attractant pellets was investigated. Carbohydrates (glucose, maltose, sucrose or starch, each at 10 mM) and amino acids (citrulline, tryptophan, proline or serine, each at 20 mM), were tested in aquaria, with the snails initially placed 22.5, 30 or 45 cm from an agar pellet containing the component under test. Under these conditions, starch and proline emerged as the strongest attractants for L. acuminata, followed by maltose and serine.


Validation of the Early Development Instrument for children with special health needs.
Population-level data on the development of children with special health needs attending primary school can assist special education, health and service delivery strategies. This study aims to determine whether results of the Early Development Instrument (EDI) can be interpreted and used with the same confidence for children with special health needs as for those who are typically developing. Psychometric properties of the EDI for kindergarteners with identified special health needs are examined. Data for children with a special health need designation come from a database of all Canadian provincial implementations of the EDI between 2004 and 2014. Item and domain characteristics (distributions of scores and measures of internal consistency) of the EDI were examined. Construct validation was assessed by correlating EDI scores with gender and age. The fit of the original factor structure of the EDI was evaluated using confirmatory factor analysis. Data for 29 692 children (69.8% male) were analysed. The performance of items and domains was similar to that of typically developing children. As expected, boys scored lower on all EDI domains (Cohen's d: 0.03-0.46) and a general, but non-significant, positive trend was observed between age and EDI scores. The factor structure of the EDI in this population yielded similar goodness-of-fit statistics as those reported in studies with typically developing children. Results of this investigation support the validity of the EDI in children with special health needs, paving the way for a more extensive use of EDI data for this vulnerable, yet often neglected, population.


Exploring the effect of estrogen on Candida albicans hyphal cell wall glycans and ergosterol synthesis.
Increased levels of 17-β estradiol (E2) due to pregnancy in young women or to hormonal replacement therapy in postmenopausal women have long been associated with an increased risk of yeast infections. Nevertheless, the effect underlying the role of E2 in Candida albicans infections is not well understood. To address this issue, functional, transcriptomic, and metabolomic analyses were performed on C. albicans cells subjected to temperature and serum induction in the presence or absence of E2. Increased filament formation was observed in E2 treated cells. Surprisingly, cells treated with a combination of E2 and serum showed decreased filament formation. Furthermore, the transcriptomic analysis revealed that serum and E2 treatment is associated with downregulated expression of genes involved in filamentation, including HWP1, ECE1, IHD1, MEP1, SOD5, and ALS3, in comparison with cells treated with serum or estrogen alone. Moreover, glucose transporter genes HGT20 and GCV2 were downregulated in cells receiving both serum and E2. Functional pathway enrichment analysis of the differentially expressed genes (DEGs) suggested major involvement of E2 signaling in several metabolic pathways and the biosynthesis of secondary metabolites. The metabolomic analysis determined differential secretion of 36 metabolites based on the different treatments' conditions, including structural carbohydrates and fatty acids important for hyphal cell wall formation such as arabinonic acid, organicsugar acids, oleic acid, octadecanoic acid, 2-keto-D-gluconic acid, palmitic acid, and steriacstearic acid with an intriguing negative correlation between D-turanose and ergosterol under E2 treatment. In conclusion, these findings suggest that E2 signaling impacts the expression of several genes and the secretion of several metabolites that help regulate C. albicans morphogenesis and virulence.


[The usefulness of virtual endoscopy and CT urography in the diagnosis of upper urinary tract tumors].
Upper urinary tract (UUT) tumors are a relatively low incidence pathology which often represents a diagnostic challenge for the urologist, because several imaging tests are usually necessary to achieve the final diagnosis. Over the last years CT scan has suffered a notable development and nowadays, with the arrival of new image processing hardware and software, it is possible to detect small urothelial lesions and to perform 3-D urinary tract reconstruction and virtual endoscopic navigation. Between January 2004 and June 2005 we performed a total of 15 examinations in 15 patients for the study of asymptomatic hematuria of probable upper urinary tract origin. The technique included three phases to obtain images: basal phase, vascular phase and excretory phase. Processing and image analysis was performed by one radiologist. A total of 10 tumors were diagnosed, with pathological confirmation in all cases. We did not register any complication secondary to the technique, and all patients tolerated well the exam. The CT urography is a safe, well-tolerated, highly sensitive and efficient imaging test, very useful in the diagnosis of renal and UUT pathology. It may become the only imaging test performed in the study of asymptomatic hematuria and the test of choice for the study of urological tumoral pathology.


Subcellular redistribution of HTLV-1 Tax protein by NF-kappa B/Rel transcription factors.
The viral oncogene Tax derived from human T cell leukemia virus type I (HTLV-I) is a positive transcriptional activator of HTLV-1 gene expression. Tax is also able to indirectly stimulate transcription of several growth regulatory genes by an indirect mechanism via association with host transcription factors. One of the cellular targets of the trans-activating effects of Tax is the NF-kappa B/Rel family transcription factors, pleiotropic regulators of immunoregulatory, cytokine, and viral gene expression. Recent studies demonstrated that specific subunits of NF-kappa B (NFKB2(p 100) and c-Rel) were overexpressed in HTLV-I-infected and Tax-expressing cells. Furthermore, Tax physically associated with NFKB2(p 100). Monospecific antibodies directed against individual NF-kappa B subunits were generated and used to investigate the consequences of the interactions between Tax and NF-kappa B in a cotransfection-immunofluorescence assay. These studies demonstrate: (1) distinct compartmentalization of NF-kappa B precursors and products, (2) differential induction of the endogenous I kappa B alpha protein by transfected NF-kappa B subunits, (3) subcellular relocalization of Tax to the cytoplasm or nucleus depending on the coexpressed NF-kappa B subunit, and (4) Tax interaction with the Rel homology domain region of NFKB2. These studies indicate that the transcription modulatory influence of HTLV-I Tax may be significantly influenced by cytoplasmic-nuclear partitioning associated with the NF-kappa B proteins.


Early Rehabilitation of Incisors with Dentinogenesis Imperfecta Type II - Case Report.
Dentinogenesis imperfecta is an phenotypic alteration in the formation of the organic matrix. It causes the rapid and progressive wear of tooth structure, which may compromise tooth function and aesthetics. This is a case of a 1y, 8m-old child with dentinogenesis imperfecta. All teeth presented with an opalescent appearance and grayish color hue. Compromised structural integrity was noted as excessive wear and fracturing of the enamel from the dentin layer. With low doses of midazolam (oral) and chloral hydrate (rectal) administration, in a hospital environment, sedation was used to aid full mouth rehabilitation. Direct bonded restorations were performed on primary maxillary incisors and indirect restorations, pre-made on a plaster model using composite resin, were performed on primary mandibular incisors. After 32 months, we observed that diagnosis and early treatment allowed preventive maintenance of the patient's primary dentition, maintaining tooth function and esthetics.


A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells.
There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln4]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs.


[Chronic recurrent multifocal osteomyelitis with interstitial myositis].
Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious disorder of skeletal system mainly seen in children. We report a case of CRMO presenting with fever and leg pain. The patient was an 11-year-old boy complaining of a fever, swelling and pain on his right foot, and pain on both legs. Although serum levels of CK and aldolase were not increased, MRI imaging suggested polymyositis. Muscle biopsy showed interstitial infiltration of inflammatory cells without any evidences of dermatomyositis or polymyositis. One month later, he complained of a swelling, pain and redness of his left clavicle as recurrently experienced during the recent 6 months, and MRI investigation indicated the diagnosis of osteomyelitis. Bone biopsy was performed and showed chronic inflammatory changes with negative bacterial culture. Multiple bone lesions and muscle uptake of FDG in his legs were revealed by whole body FDG-PET/CT, and he was diagnosed as having CRMO with interstitial myositis. The combinatorial administration of non-steroidal anti-inflammatory drugs and bisphosphonate successfully improved his clinical symptoms and laboratory abnormalities. To our knowledge, there is no report of a patient of CRMO associated with interstitial myositis.


Network Pharmacology Analysis of the Mechanisms of Compound Herba Sarcandrae (Fufang Zhongjiefeng) Aerosol in Chronic Pharyngitis Treatment.
This study aimed to investigate the molecular mechanisms of compound herba Sarcandrae aerosol, also known as the Fufang Zhongjiefeng (FFZJF) aerosol, in treating chronic pharyngitis (CP) using network pharmacology and in vivo experimental approaches. Active compounds and putative targets of five herbs in FFZJF were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Chemistry Database, and Swiss Target Prediction databases. The therapeutic targets of CP were obtained from OMIM, Durgbank, DisGeNT, and GAD databases. The active compounds-target networks were constructed using Cytoscape 3.6.1. The overlapping targets of FFZJF active compounds and CP targets were further analyzed using the String database to construct protein-protein interaction (PPI) network. KEGG pathway and Gene Ontology enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery. The predicted targets and pathways were validated in a group A β-hemolytic streptococcus-induced rat CP model. There were 45 active compounds identified from FFZJF and 11 potential protein targets identified for CP treatment. PPI network demonstrated that IL6, PTGS2, TLR-4, and TNF may serve as the key targets of FFZJF for the treatment of CP. The main functional pathways involving these key targets include cytokine secretion, inflammatory response, MyD88-dependent toll-like receptor signaling pathway, toll-like receptor signaling pathway, TNF signaling pathway, and NF-κB signaling pathway. In a rat CP model, the elevation of serum TNF-α, IL1β, and IL6 levels, as well as the upregulation of TLR-4, MyD88, NF-κB P65 in the pharyngeal mucosal tissues could be effectively reduced by FFZJF treatment in a dose-dependent manner. Through a network pharmacology approach and animal study, we predicted and validated the active compounds of FFZJF and their potential targets for CP treatment. The results suggest that FFZJF can markedly alleviate GAS-induced chronic pharyngitis by modulating the TLR-4/MyD88/NF-κB signaling pathways.


Increased risk of preterm premature rupture of membranes at early gestational ages among maternal cigarette smokers.
To examine the effect of cigarette smoking during pregnancy on the development of preterm premature rupture of membranes (PPROM) categorized by gestational age. We conducted a retrospective cohort study of 17,961 births using data from the McGill Obstetric and Neonatal Database between years 2001 and 2006. Our exposure was defined according to self-reported maternal cigarette smoking status categorized as nonsmoker, smoker of 1 to 10 cigarettes per day, and smoker of > 10 cigarettes per day. The outcome was measured as incidence of premature rupture of membranes (PROM) among gestational age categories of < 28, < 32, < 37, and > 37 weeks. Unconditional logistic regression analysis and Wald test for trend were used to estimate the adjusted risk of PPROM according to smoking status. Among the study population, 640 cases of PPROM (<37 weeks) and 40 cases of PROM (>37 weeks). After adjusting for confounding variables, smoking > 10 cigarettes per day was associated with an increased risk of PPROM at < 28 weeks (odds ratio [OR] 5.28; 95% confidence interval [CI] 2.20 to 12.7); < 32 weeks (OR 2.36; 95% CI 1.09 to 5.11; < 37 weeks (OR 1.97; 95% CI 1.32 to 2.94); and > 37 weeks (OR 3.19; 95% CI 0.92 to 11.0). Smoking 1 to 10 cigarettes per day was not associated with a significant risk of PPROM at any gestational age. Heavy cigarette smoking increases the risk of PPROM more so at early gestational age than at term.


Validation of qualitative test for phosphine gas in human tissues.
Phosphine has been known to science since the birth of modern chemistry. WHO reports that the technical product usually has a foul odour, like "fishy" or "garlicky" because of the presence of substituted phosphines and diphosphine (P2H4). Many medico-legal autopsy cases have been reported positive for aluminium phosphide even though there was neither any suspicion of consuming aluminium phosphide nor any clinical findings, postmortem findings or circumstantial evidences. The present study was carried out to validate the qualitative test, presently applied in many laboratories for testing phosphine. It was observed that 65% of human tissues in saturated solution of common salt show positivity for phosphine gas on the first day of autopsy.


Chronic Chagas' heart disease: a disease on its way to becoming a worldwide health problem: epidemiology, etiopathology, treatment, pathogenesis and laboratory medicine.
Chagas' disease, caused by Trypanosoma cruzi infection, is ranked as the most serious parasitic disease in Latin America. Nearly 30% of infected patients develop life-threatening complications, and with a latency of 10-30 years, mostly Chagas' heart disease which is currently the major cause of morbidity and mortality in Latin America, enormously burdening economic resources and dramatically affecting patients' social and labor situations. Because of increasing migration, international tourism and parasite transfer by blood contact, intrauterine transfer and organ transplantation, Chagas' heart disease could potentially become a worldwide problem. To raise awareness of this problem, we reflect on the epidemiology and etiopathology of Chagas' disease, particularly Chagas' heart disease. To counteract Chagas' heart disease, in addition to the general interruption of the infection cycle and chemotherapeutic elimination of the infection agent, early and effective causal or symptomatic therapies would be indispensable. Prerequisites for this are improved knowledge of the pathogenesis and optimized patient management. From economic and logistics viewpoints, this last prerequisite should be performed using laboratory medicine tools. Consequently, we first summarize the mechanisms that have been suggested as driving Chagas' heart disease, mainly those associated with the presence of autoantibodies against G-protein-coupled receptors; secondly, we indicate new treatment strategies involving autoantibody apheresis and in vivo autoantibody neutralization; thirdly, we present laboratory medicine tools such as autoantibody estimation and heart marker measurement, proposed for diagnosis, risk assessment and patient guidance and lastly, we critically reflect upon the increase in inflammation and oxidative stress markers in Chagas' heart disease.


Asthma exacerbations during Santa Ana winds in southern California.
This study investigated the relationship between Santa Ana wind conditions and visits for asthma at a southern California emergency department. Visits to the emergency department for asthma were analyzed retrospectively to determine whether the incidence increased during Santa Ana wind conditions. These northeasterly winds are common during fall and winter in southern California and belong to a class known as Foehn winds. They are characterized by gusty winds, decreased relative humidity, warm temperatures, and decreased levels of airborne pollutants. During a 4-year period, we noted that emergency department visits for asthma increased (3.12 vs. 2.16 visits per day, P < 0.0001) during SantaAna winds compared with other weather conditions. Asthmatics presenting during Santa Ana winds appeared to be more ill, as judged by higher admission rates (21.9 vs. 18.7%, P < 0.05). These winds were also associated with reduced particulate matter (PM10) counts (P < 0.0001). Although the magnitude of the increase in emergency department visits was small, it occurred at a time when typical inciters of respiratory disease should be minimal. An as yet unidentified factor associated with these winds may be a stimulant for some asthmatics. Similar wind patterns in other localities might affect respiratory disease as well.


Combustion Synthesis of Magnetic Nanomaterials for Biomedical Applications.
Combustion synthesis is a green, energy-saving approach that permits an easy scale-up and continuous technologies. This process allows for synthesizing various nanoscale materials, including oxides, nitrides, sulfides, metals, and alloys. In this work, we critically review the reported results on the combustion synthesis of magnetic nanoparticles, focusing on their properties related to different bio-applications. We also analyze challenges and suggest specific directions of research, which lead to the improvement of the properties and stability of fabricated materials.


An adaptation of a macroscale methodology to assess the direct economic losses caused by Tropical Cyclone Idai in Zimbabwe.
Tropical cyclones are among the costliest disasters in the world, with reported losses amounting to billions of US dollars on an annual basis. To reduce the impact of disasters including cyclones, Zimbabwe signed the Sendai Framework whose Target C is aimed at reducing the direct economic losses of disasters. Under the direction of the United Nations Office for Disaster Risk Reduction (UNDRR), an open-ended intergovernmental expert working group (OIEWG) developed a simple methodology for estimating direct disaster-economic loss. Therefore, this study tested the applicability of the OIEWG methodology in assessing the direct economic losses induced by Tropical Cyclone Idai (TCI) in Zimbabwe. The results revealed that TCI inflicted huge losses in most sectors of the economy, notably the housing, agriculture and the critical infrastructure. The sectoral analysis approach of the OIEWG methodology worked well in distinguishing direct and indirect loses as well as in underlining the need to adopt and effectively implement adequate risk reduction strategies in the built environment. Strengthening such strategies such as the 'build back better' principle, cyclone forecasting and warning systems and constructing cyclone-resilient infrastructure is critical in order to minimise direct losses attributed to cyclones.


Loss of multi-epitope specificity in memory CD4(+) T cell responses to B. pertussis with age.
Pertussis is still occurring in highly vaccinated populations, affecting individuals of all ages. Long-lived Th1 CD4(+) T cells are essential for protective immunity against pertussis. For better understanding of the limited immunological memory to Bordetella pertussis, we used a panel of Pertactin and Pertussis toxin specific peptides to interrogate CD4(+) T cell responses at the epitope level in a unique cohort of symptomatic pertussis patients of different ages, at various time intervals after infection. Our study showed that pertussis epitope-specific T cell responses contained Th1 and Th2 components irrespective of the epitope studied, time after infection, or age. In contrast, the breadth of the pertussis-directed CD4(+) T cell response seemed dependent on age and closeness to infection. Multi-epitope specificity long-term after infection was lost in older age groups. Detailed knowledge on pertussis specific immune mechanisms and their insufficiencies is important for understanding resurgence of pertussis in highly vaccinated populations.


The osmotic stress-activated receptor-like kinase DPY1 mediates SnRK2 kinase activation and drought tolerance in Setaria.
Plant genomes encode many receptor-like kinases (RLKs) that localize to the cell surface and perceive a wide variety of environmental cues to initiate downstream signaling cascades. Whether these RLKs participate in dehydration stress signaling in plants is largely unknown. DROOPY LEAF1 (DPY1), a leucine-rich repeat (LRR)-RLK, was recently shown to regulate plant architecture by orchestrating early brassinosteroid signaling in foxtail millet (Setaria italica). Here, we show that DPY1 is essential for the acclimation of foxtail millet to drought stress. DPY1 can be phosphorylated and activated in response to osmotic stress and is required for more than half of osmotic stress-induced global phosphorylation events, including the phosphorylation of sucrose nonfermenting kinase 2s (SnRK2s), the central kinases involved in osmotic stress. DPY1 acts upstream of STRESS-ACTIVATED PROTEIN KINASE 6 (SAPK6, a subclass I SnRK2) and is required for full SAPK6 activation, thereby allowing regulation of downstream genes to mount a response against drought stress. These signaling events are largely independent of DPY1-mediated brassinosteroid signaling. The DPY1-SAPK6 module is specific to seed plants and is absent in ancestral nonseed plants. Our findings reveal a dehydration stress-activated RLK that plays an indispensable role in osmotic stress signaling and mediates SnRK2 activation at the cell surface.


Value of Proton-MR-Spectroscopy in the Diagnosis of Temporal Lobe Epilepsy; Correlation of Metabolite Alterations With Electroencephalography.
Epilepsy, a well-known mostly idiopathic neurologic disorder, has to be correctly diagnosed and properly treated. Up to now, several diagnostic approaches have been processed to determine the epileptic focus. The aim of this study was to discover whether proton-MR-spectroscopic imaging (MRSI) aids in the diagnosis of temporal lobe epilepsy in conjunction with classical electroencephalography (EEG) findings. Totally, 70 mesial temporal zones consisting of 39 right hippocampi and 31 left hippocampi of 46 patients (25 male, 21 female) were analyzed by proton MRSI. All patients underwent a clinical neurologic examination, scalp EEG recording and prolonged video EEG monitoring. Partial seizures on the right, left or both sides were recorded in all patients. All patients were under medical treatment and none of the patients underwent amygdalohippocampectomy and similar surgical procedures. The normal average lactate (Lac), phosphocreatine, N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), myo-inositol, glutamate and glutamine (Glx) peaks and Nacetyl aspartate/Cr, NAA/ Cho + Cr, Cho/Cr ratios were measured from the healthy opposite hippocampi or from the control subjects. The Lac, glutamate and glutamine (Glx), myo-inositol, phosphocreatine and NAA metabolites plus Cho/Cr ratio showed statistical difference between the normal and the epileptic hippocampi. Cho, Cr metabolites plus NAA/Cr, NAA/ Cho + Cr ratios were almost the same between the groups. The sensitivity of Proton-MR-Spectroscopy for lateralization of the epileptic foci in all patients was 96% and the specificity was 50%. Proton-MRSI can easily be considered as an alternative modality of choice in the diagnosis of temporal lobe epilepsy and in the future; Proton-MR-Spectroscopy may become the most important technique used in epilepsy centers.


Glutamine Transport and Mitochondrial Metabolism in Cancer Cell Growth.
The concept that cancer is a metabolic disease is now well acknowledged: many cancer cell types rely mostly on glucose and some amino acids, especially glutamine for energy supply. These findings were corroborated by overexpression of plasma membrane nutrient transporters, such as the glucose transporters (GLUTs) and some amino acid transporters such as ASCT2, LAT1, and ATB0,+, which became promising targets for pharmacological intervention. On the basis of their sodium-dependent transport modes, ASCT2 and ATB0+ have the capacity to sustain glutamine need of cancer cells; while LAT1, which is sodium independent will have the role of providing cancer cells with some amino acids with plausible signaling roles. According to the metabolic reprogramming of many types of cancer cells, glucose is mainly catabolized by aerobic glycolysis in tumors, while the fate of Glutamine is completed at mitochondrial level where the enzyme Glutaminase converts Glutamine to Glutamate. Glutamine rewiring in cancer cells is heterogeneous. For example, Glutamate is converted to α-Ketoglutarate giving rise to a truncated form of Krebs cycle. This reprogrammed pathway leads to the production of ATP mainly at substrate level and regeneration of reducing equivalents needed for cells growth, redox balance, and metabolic energy. Few studies on hypothetical mitochondrial transporter for Glutamine are reported and indirect evidences suggested its presence. Pharmacological compounds able to inhibit Glutamine metabolism may represent novel drugs for cancer treatments. Interestingly, well acknowledged targets for drugs are the Glutamine transporters of plasma membrane and the key enzyme Glutaminase.


Ubiquitylation and cell signaling.
Ubiquitylation is an emerging mechanism implicated in a variety of nonproteolytic cellular functions. The attachment of a single ubiquitin (Ub) or poly-Ub (lysine 63) chains to proteins control gene transcription, DNA repair and replication, intracellular trafficking and virus budding. In these processes, protein ubiquitylation exhibits inducibility, reversibility and recognition by specialized domains, features similar to protein phosphorylation, which enable Ub to act as a signaling device. Here, we highlight several recent examples on how Ub regulates signaling and how signaling regulates ubiquitylation during physiological and pathological cellular processes.


The Anti-Obesity Effect of Traditional Chinese Medicine on Lipid Metabolism.
With the improvement of living conditions and the popularity of unhealthy eating and living habits, obesity is becoming a global epidemic. Obesity is now recognized as a disease that not only increases the risk of metabolic diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), and cancer but also negatively affects longevity and the quality of life. The traditional Chinese medicines (TCMs) are highly enriched in bioactive compounds and have been used for the treatment of obesity and obesity-related metabolic diseases over a long period of time. In this review, we selected the most commonly used anti-obesity or anti-hyperlipidemia TCMs and, where known, their major bioactive compounds. We then summarized their multi-target molecular mechanisms, specifically focusing on lipid metabolism, including the modulation of lipid absorption, reduction of lipid synthesis, and increase of lipid decomposition and lipid transportation, as well as the regulation of appetite. This review produces a current and comprehensive understanding of integrative and systematic mechanisms for the use of TCMs for anti-obesity. We also advocate taking advantage of TCMs as another therapy for interventions on obesity-related diseases, as well as stressing the fact that more is needed to be done, scientifically, to determine the active compounds and modes of action of the TCMs.


Hybrid phonon-polaritons at atomically-thin van der Waals heterointerfaces for infrared optical modulation.
Surface phonon polaritons (SPhPs) in polar dielectrics are potential candidates for infrared nanophotonics due to their low optical loss and long phonon life-time. However, the small confinement factors of bulk SPhPs, limits their applications that require small footprint and strong light-matter interaction. Here, we report that ultrathin van der Waals dielectrics (e.g., MoS2 and h-BN) on Silicon Carbide enable ultra-confined dielectric tailored surface phonon polaritons (d-SPhPs) where the confinement factor can exceed 100. By creating a heterostructure of these vdW dielectrics with graphene, the d-SPhPs can hybridize with graphene plasmons which can be electrically tuned. By subwavelength patterning of the vdW dielectrics, these hybrid polaritons can be localized into ultra-small antenna volumes (λ03/vantenna 3~1003) with high-quality factor resonances (Q~85). Further, electric gating of graphene enables active tunability of these localized resonances which results in an electro-optic modulator with modulation depth exceeding 95%. Our report of manipulating and controlling ultra-confined SPhPs in van der Waals heterostructures, serves as a possible route for non-plasmonic platforms for infrared photodetectors, modulators and sensors.


Immature oocytes in "apparent empty follicle syndrome": a case report.
Empty follicle syndrome (EFS) is a condition in which no oocytes are obtained after an apparently successful ovarian stimulation. Genuine EFS (GEFS) is differentiated from false EFS by an optimal level of human chorionic gonadotropin on the day of oocyte retrieval. Some believe that GEFS does not exist and that it is only a reflection of the margin of error attendant upon the procedure of oocyte aspiration. Others believe that GEFS is caused by dysfunctional folliculogenesis, resulting in early atresia of oocytes. In this report, we present a case of apparent GEFS, in which immature oocytes were identified after filtration of follicular aspirates. Our findings suggest that delayed maturation of oocyte cumulus complexes in response to HCG might be an etiologic mechanism in some cases of GEFS. This creates a situation similar to the aspiration of immature follicles, where germinal vesicle-stage oocytes with dense scanty cumulus cells are often difficult to identify under a dissecting microscope.


Inclusion statistics and particle condensation in two dimensions.
We propose a type of quantum statistics which we call inclusion statistics, in which particles tend to coalesce more than ordinary bosons. Inclusion statistics is defined in analogy with exclusion statistics, in which statistical exclusion is stronger than in Fermi statistics, but now extrapolating beyond Bose statistics, resulting in statistical inclusion. A consequence of inclusion statistics is that the lowest space dimension in which particles can condense in the absence of potentials is d=2, unlike d=3 for the usual Bose-Einstein condensation. This reduction in the dimension happens for any inclusion stronger than bosons, and the critical temperature increases with stronger inclusion. Possible physical realizations of inclusion statistics involving attractive interactions between bosons may be experimentally achievable.


Cholecystokinin antagonist prevents hyperamylasemia and improves pancreatic exocrine function in cerulein-induced acute pancreatitis.
Supramaximal cerulein administration induces acute pancreatitis, which markedly impairs pancreatic secretion in conscious rats. We hypothesized that pretreatment with the potent cholecystokinin antagonist, L-364,718, improves the pancreatic secretory impairment associated with cerulein-induced acute pancreatitis. Rats were surgically prepared with gastric, duodenal, bile, and pancreatic fistulas and jugular vein catheters. On postoperative day 4, groups of rats were administered (a) L-364,718 1 mg/kg intraduodenally, (b) cerulein 5 micrograms/kg/h for 6 h intravenously, (c) L-364,718 1 mg/kg intraduodenally followed by cerulein 5 micrograms/kg/h for 6 h intravenously, and (d) safflower oil carrier intraduodenally. On postoperative day 5, we studied cholecystokinin (CCK)-stimulated pancreatic secretion. Plasma amylase was measured at the time of surgery and at the conclusion of experiments on postoperative days 4 and 5. The duodenally administered CCK antagonist had no effect, 24 h later, on CCK-evoked protein secretion and prevented the pancreatic exocrine impairment and hyperamylasemia caused by supramaximal cerulein administration. These observations suggest that cerulein-induced acute pancreatitis is mediated by a CCK-receptor mechanism.


Clinical efficacy and safety of recruitment maneuver in patients with acute respiratory distress syndrome using low tidal volume ventilation: a multicenter randomized controlled clinical trial.
The recruitment maneuver (RM) has been shown to improve oxygenation in some patients with acute respiratory distress syndrome. But there is a lack of standardization and lack of clinical studies to prove the improvement on clinical outcome. We conducted this study to evaluate the clinical efficacy and safety of the RM in patients with acute respiratory distress syndrome (ARDS) using low tidal volume ventilation. We randomly assigned 110 patients with ARDS from 14 Chinese intensive care units (ICUs) at the tertiary teaching hospitals. Patients with PaO2 ≤ 200 mmHg at FiO2 1.0 and PEEP ≥ 10 cmH2O were included in the study. Patients were randomized into two groups: control group and RM group. The tidal volume was set to 6 - 8 ml per kilogram of predicted body weight (PBW) in both groups. RM was performed by continuous positive airway pressure (CPAP) of 40 cmH2O maintained for 40 seconds. RMs was conducted every eight hours for the first five days, or stopped within five days if the patient reached the weaning standard. One hundred and ten patients had completed the requirements for the primary study goals, 55 from the RM group and 55 control patients. Baseline characteristics remained similar in the two groups. In the RM group the PaO2/FiO2 was significantly increased compared to baseline at 120 minutes after RM on day one and day two (P = 0.007 and P = 0.001). There were no significant differences between the RM and control group in hospital mortality (41.8% vs. 56.4%, P = 0.13), 28-day mortality (29.1% vs. 43.6%, P = 0.11) and ventilator-free days at day 28 (10.8 ± 10.1 vs. 7.4 ± 10.0, P = 0.08). ICU mortality (32.7% vs. 52.7%, P = 0.03), the rate of survival with unassisted breathing for at least 48 consecutive hours at day 28 (58.2% vs. 36.2%, P = 0.02), and nonpulmonary organ failure-free days at day 28 (17.4 ± 11.1 vs. 13.0 ± 12.0, P = 0.03) favored the RM group. There was no significant difference in mean blood pressure and heart rate before RM and at 30, 60, 120 minutes after RM. There was no incidence of barotraumas. RM was safe and useful for improving oxygenation in patients with ARDS who were ventilated with a low tidal volume, with a beneficial impact on their clinical outcome.


Boredom effects on sleepiness/alertness in the early afternoon vs. early evening and interactions with warm ambient temperature.
During the usual waking day there is a circadian propensity for sleepiness in the early afternoon. This contrasts with the circadian peak of alertness in the early evening. The former is apt to be masked by various exogenous factors. Alertness was compared at these times of day ('afternoon': 1200-1600 hours and 'evening': 1800-2200 hours) under contrasting environmental conditions: boring vs. stimulating ('interest') x warm vs. cool ambient environment ('temperature'); making four combinations, with two times of day--i.e. eight independent conditions, each containing six subjects (N = 48). The emphasis of the study was to make the conditions 'natural' and not unpleasant--e.g. the environmental temperatures were not extreme and kept within a comfortable range. All conditions were run in a climatic chamber. Alertness was measured by reaction times and subjective sleepiness scales. Heart rate and body temperature were monitored continuously. Apart from time of day, 'interest' exerted a powerful effect that was significant for all variables, and was particularly potent in the afternoon. By comparison, the 'temperature' effects were minor. For our subjects the afternoon 'dip' centred between 1500 and 1530 hours, and displayed bicircadian characteristics.


Tinea versicolor hypopigmentation: histochemical and therapeutic studies.
One hundred and thirty-four patients with tinea versicolor were divided into 3 treatment groups: (1) 30% sodium thiosulfate application, (2) 30% sodium thiosulfate application plus ultraviolet light, and (3) 30% sodium thiosulfate application, ultraviolet light, and meladinine tablets (amoidin 0.01 g and amidin 0.005 g). Analysis of the 79 patients who completed the 6-week study showed no statistical difference. Therefore, topical treatment should be instituted as quickly as possible to prevent pigmentary changes. Ultraviolet light should be used only after the fungus has cleared in order not to darken the skin further.


Ultrasound and analysis of the deformation patterns of the masseter muscle: comparing surgical anatomy, ultrasound and functional anatomy.
We have tried to demonstrate whether the analysis of the muscle strain allows us to identify the three distinct functional areas of the architecture of the masseter, as one would see them by performing or viewing an anatomical dissection of said muscle, and whether these sections have behave differently in terms of origin and coping of the strain they face (quantitative analysis). This work has been elaborated by the use of an ultrasound machine (MicrUs ext-1H Telemed Medical Systems Milano) and a linear probe (L12-5l40S-3 5-12 MHz 40 mm) which allowed us to record a 45 frame per second video (DCM). Videos has been elaborated by use of an ultrasound machine (MicrUs ext-1H Telemed Medical Systems Milano) and a linear probe (L12-5l40S-3 5-12 MHz 40 mm) which allowed us to record a 45 frame per second video (DCM). We applied to the resulting video a software (Mudy 184.108.40.206 AMID Sulmona Italy) for the analysis of muscle deformation patters (contraction, dilatation, cross-plane, vertical strain, horizontal strain, vertical shear, horizontal shear, horizontal displacement, vertical displacement). The number of videos of masseter muscles in contraction at maximum exertion due to dental clenching made during this research is around 12,000. Out of these we chose 1,200 videos which examine 200 patients (100 females, 100 males). The deformation pattern analysis of the skeletal muscle on ultrasound basis seems to be an adequate instrument to use during the investigation of the functional structure of the masseter muscle given its ability to highlight the distinct activity of each separate part of the muscle. Moreover the strain does not apply to the muscle uniformly; instead it varies according to the observed area.


[Supernumerary liver. A case with a particular location in an omphalocele].
The authors report one case of a supernumerary liver lobe contained in the omphalocele of a new born. An accessory hepatic lobe was attached to the liver by a pedicle. Its histological structure was that of an immature liver. The authors review the different symptoms, varieties, and frequencies of supernumerary liver lobes. The importance of this embryological anomaly is underlined as it is normally latent and benign. It should be evoked whenever a radiological or palpable abdominal mass is discovered and in those cases where there are complications of unknown etiology.


Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growth in vitro and in vivo.
Breast cancer stem cells (BCSC) have been identified in breast carcinoma as CD44(+)/CD24(-/low) cells, which display tumorigenic activity and have the ability to self-renew, differentiate and metastasize. Previous studies showed that extracellular HSP90 (eHSP90) participates in the invasion and metastatic processes of various cancers including breast cancer. Here, we show for the first time that eHSP90 is over-expressed in mammosphere cultures that are derived from the MDA-MB-231, MDA-MB-453 and MCF-7 breast cancer cell lines. These mammospheres are highly enriched in cells of the CD44(+)/CD24(-/low) BCSC phenotype and additionally show high expression of the BCSC markers CD49f and Sox2. Thus our results indicate that eHSP90 represents a potential novel BCSC marker. Moreover, we present evidence that eHSP90 is functionally involved in BCSC activity in vitro and in vivo. Selective neutralization of eHSP90, using the monoclonal antibody mAb 4C5, has the capacity to inhibit stem cell activity in vitro because the formation of mammosphere-derived colonies is dramatically reduced in its presence. In vivo, the treatment of mice with mAb4C5 using a prophylactic protocol, significantly inhibited the primary growth of MDA-MB-231 and mammosphere-derived tumors. More importantly, administration of this antibody in a therapeutic protocol caused a statistically significant regression of established tumors derived from MDA-MB-231 originating mammospheres. Tumor regression was even greater when mAb 4C5 was administered in combination with paclitaxel. Overall, our findings implicate eHSP90 as a potential novel BCSC biomarker. Moreover they show that eHSP90 participates in BCSC-derived primary tumor growth. Finally, we provide additional support for the possible therapeutic value of mAb4C5 in the treatment of breast cancer.


Recombinant chimeric Japanese encephalitis virus/tick-borne encephalitis virus is attenuated and protective in mice.
Tick-borne encephalitis virus (TBEV) represents one of the most dangerous human pathogens circulating in Europe and East Asia. No effective treatment for TBEV infection currently exists, and vaccination is the primary preventive measure. Although several inactivated vaccines have been licensed, the development of novel vaccines against TBEV remains a high priority in disease-endemic countries. In the present study, a live chimeric recombinant TBEV (ChinTBEV) was created by substituting the major structural genes of TBEV for the corresponding regions of Japanese encephalitis virus (JEV) live vaccine strain SA14-14-2. The resulting chimera had a small-plaque phenotype, replicated efficiently in both mammalian and mosquito cells. The preliminary data from in vitro passaging indicated the potential for stability of ChinTBEV. ChinTBEV also exhibited significantly attenuated neuroinvasiveness in mice upon either intraperitoneal or subcutaneous inoculation in comparison with its parental TBEV. Importantly, a single immunisation with ChinTBEV elicited TBEV-specific IgG and neutralising antibody responses in a dose-dependent manner, providing significant protection against lethal TBEV challenge in mice. Taken together, the results of this proof-of-concept study indicate that ChinTBEV can be further developed as a potential vaccine candidate against TBEV infection. Moreover, the construction of this type of flavivirus chimera using a JEV vaccine strain as the genetic backbone represents a universal vaccine approach.


Detection of poly(ADP-ribose) by immunocytochemistry: a sensitive new method for the early identification of UVB- and H2O2-induced apoptosis in keratinocytes.
Apoptosis is an active form of cell death that is initiated by a variety of stimuli, including reactive oxygen species (ROS) and ultraviolet (UV) radiation. Poly (ADP-ribose) (PAR) is formed upon activation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), and therefore was suggested as a new marker of apoptosis. Since DNA of epidermal cells represents a well-known chromophore for UVB irradiation, and UVB is known to generate H2O2 in keratinocytes, we hypothesized that PAR is a very sensitive marker of UVB- and H2O2-induced apoptosis in keratinocytes. In order to test this hypothesis, human immortalized keratinocytes (HaCaT) were UVB-irradiated or treated with H2O2, and subsequently apoptosis was identified by comparing conventional parameters such as morphological analysis, DNA laddering, and TUNEL assay, with PAR formation. Both, UVB and H2O2 treatment induced PAR formation in HaCaT cells in a dose-dependent manner, and its formation was detected as early as 4 h after irradiation, and at lower UVB doses (10 mJ/cm2) than observed by DNA laddering and the TUNEL assay. In conclusion, the detection of PAR formation is a very sensitive and early method for the identification of apoptotic cells in UVB-induced apoptosis of human keratinocytes.


Topical carbonic anhydrase inhibitors.
Ethoxzolamide and several derivatives (1-6) were synthesized and evaluated for carbonic anhydrase inhibition (CAI), solubility, pKa, distribution, and corneal permeability. The 6-hydroxy (5) and, particularly, the 6-chloro (6) analogues have the best combination of properties for penetrating the site of action and reducing intraocular pressure. Both 5 and 6 exhibited topical effectiveness in the normal rabbit, with 6 showing greater potency.


Comparison of the effective orifice area of prosthetic mitral valves using two-dimensional versus three-dimensional transesophageal echocardiography.
This study compared the continuity equation-based effective orifice area (EOA) of prosthetic mitral valves between two-dimensional (2D) and 3D transesophageal echocardiography (TEE). Thirty-four patients without major aortic valve abnormalities underwent mitral valve replacement surgery. The EOAs of prosthetic mitral valves were calculated using the continuity equation with 2D and 3D TEE. For 18/34 patients using a biological valve prosthesis, the EOA of the prosthesis was obtained from commercial records. The EOA of prosthetic mitral valves significantly varied between the 2D and 3D methods (2.22 ± 0.71 vs 2.35 ± 0.70 cm2, n = 34). The area of the diameter of the left ventricular outflow tract as determined by the 3D method was significantly higher than that by the 2D method (mean difference: -0.14 ± 0.20 cm2), with 95% coherence boundaries of -0.53 and 0.25 cm2. The regression equation for the EOA by 3D and 2D TEE was y = 0.27 + 0.94x, with a good correlation. The EOA of prosthetic mitral valves is underestimated using the 2D TEE method compared with the 3D TEE method. The 3D-TEE method has the advantage of higher precision over the 2D TEE method, and it may be helpful for better assessment of prosthetic mitral valves intraoperatively.