Non-motor symptoms in patients with adult-onset focal dystonia: Sensory and psychiatric disturbances.
Dystonia is characterized by the presence of involuntary muscle contractions that cause abnormal movements and posture. Adult onset focal dystonia include cervical dystonia, blepharospasm, arm dystonia and laryngeal dystonia. Besides motor manifestations, patients with focal dystonia frequently also display non-motor signs and symptoms. In this paper, we review the evidence of sensory and psychiatric disturbances in adult patients with focal dystonia. Clinical studies and neurophysiological investigations consistently show that the sensory system is involved in dystonia. Several studies have also demonstrated that neuropsychiatric disorders, particularly depression and anxiety, are more frequent in patients with focal dystonia, whereas data on obsessive compulsive disorders are more contrasting.


De novo tubular nanostructure design based on self-assembly of beta-helical protein motifs.
We present an approach for designing self-assembled nanostructures from naturally occurring building block segments obtained from native protein structures. We focus on structural motifs from left-handed beta-helical proteins. We selected 17 motifs. Copies of each of the motifs are stacked one atop the other. The obtained structures were simulated for long periods by using Molecular Dynamics to test their ability to retain their organization over time. We observed that a structural model based on the self-assembly of a motif from E. coli galactoside acetyltransferase produced a very stable tube. We studied the interactions that help maintain the conformational stability of the systems, focusing on the role of specific amino acids at specific positions. Analysis of these systems and a mutational study of selected candidates revealed that the presence of proline and glycine residues in the loops of beta-helical structures greatly enhances the structural stability of the systems.


Serious invasive Saffold virus infections in children, 2009.
The first human virus in the genus Cardiovirus was described in 2007 and named Saffold virus (SAFV). Cardioviruses can cause severe infections of the myocardium and central nervous system in animals, but SAFV has not yet been convincingly associated with disease in humans. To study a possible association between SAFV and infections in the human central nervous system, we designed a real-time PCR for SAFV and tested cerebrospinal fluid (CSF) samples from children <4 years of age. SAFV was detected in 2 children: in the CSF and a fecal sample from 1 child with monosymptomatic ataxia caused by cerebellitis; and in the CSF, blood, and myocardium of another child who died suddenly with no history of illness. Virus from each child was sequenced and shown to be SAFV type 2. These findings demonstrate that SAFV can cause serious invasive infection in children.


Wingspan experience in the treatment of symptomatic intracranial atherosclerotic disease after antithrombotic failure.
Intracranial stenting with the Wingspan system has been used as a revascularization strategy in symptomatic patients with intracranial atherosclerotic disease (ICAD). The latest results of the Stenting versus Aggressive Medical Therapy for Intracranial Artery Stenosis (SAMMPRIS) trial challenge this approach. Our experience in the treatment of symptomatic ICAD with the Wingspan system is reported. Patients who underwent stenting for symptomatic ICAD were included in the analysis. Demographic data, periprocedural complications, long term radiological and clinical outcomes are reported. 46 lesions were treated in 45 patients. 13 patients (29%) presented with a transient ischemic attack and 32 (71%) with a stroke. 43 patients (95.5%) failed antithrombotic therapy at presentation. One (2%) symptomatic periprocedural (24 h) complication occurred. The 30 day incidence of stroke and vascular death was 6.6%--a fatal hemorrhagic stroke and two non-fatal hemorrhagic strokes. In-stent stenosis (≥50%) was seen in nine (42.8%) lesions, two were symptomatic. This cohort of patients with symptomatic ICAD who failed antithrombotic medications benefited from angioplasty and stenting with the Wingspan system.


Use of electrokinetic measurements for characterization of columns used in capillary electrochromatography.
The separation mechanism in capillary electrochromatography (CEC) is a hybrid differential migration process, which entails the features of both high-performance liquid chromatography (HPLC) and capillary zone electrophoresis (CZE), i.e., chromatographic retention and electrophoretic migration. The focus of this paper is on the use of electrokinetic data, such as current, electroosmotic flow (EOF) and column efficiency measurements, that are readily available, for an improved understanding of CEC separations. A framework is presented here for the use of this data for evaluation of a variety of performance parameters including, conductivity ratio, interstitial EOF mobility, porosity, and zeta potential. This framework is applied for characterization of two monolithic columns with different chemistry that were manufactured in-house. The above-mentioned performance parameters were calculated for the two columns and it is found that the poly(VBC-EGDMA-SWNT) monolithic column with the GPTMS-PEI coating offers a significantly improved flow distribution in comparison to the poly(VBC-EGDMA) monolithic column. This observation is confirmed by performing separation of peptides on the two columns and height equivalent of a theoretical plate (HETP) measurements on the resulting peaks. It is shown that following our approach leads to an improved understanding of the separations achieved with the columns and to better column design.


L1CAM: Cell adhesion and more.
L1CAM is a cell adhesion molecule of the immunoglobulin superfamily which was originally discovered as a major player in the development of the nervous system. L1CAM was demonstrated to have prognostic value in different cancers and to be a promising target for anti-cancer therapy. Here we overview the present data on L1CAM structure and function, regulation of its expression, role in cancer and therapeutic potential.


Anomalous switching in Nb/Ru/Sr₂RuO₄ topological junctions by chiral domain wall motion.
A spontaneous symmetry breaking in a system often results in domain wall formation. The motion of such domain walls is utilized to realize novel devices like racetrack-memories, in which moving ferromagnetic domain walls store and carry information. Superconductors breaking time reversal symmetry can also form domains with degenerate chirality of their superconducting order parameter. Sr₂RuO₄ is the leading candidate of a chiral p-wave superconductor, expected to be accompanied by chiral domain structure. Here, we present that Nb/Ru/Sr₂RuO₄ topological superconducting-junctions, with which the phase winding of order parameter can be effectively probed by making use of real-space topology, exhibit unusual switching between higher and lower critical current states. This switching is well explained by chiral-domain-wall dynamics. The switching can be partly controlled by external parameters such as temperature, magnetic field and current. These results open up a possibility to utilize the superconducting chiral domain wall motion for future novel superconducting devices.


Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins.
One of the possible therapies for Duchenne muscular dystrophy (DMD) is the introduction of a functional copy of the dystrophin gene into the patient. For this approach to be effective, therapeutic levels and long-term expression of the protein need to be achieved. However, immune responses to the newly expressed dystrophin have been predicted, particularly in DMD patients who express no dystrophin or only very truncated versions. In a previous study, we demonstrated a strong humoral and cytotoxic immune response to human dystrophin in the mdx mouse. However, the mdx mouse was tolerant to murine dystrophin, possibly due to the endogenous expression of dystrophin in revertant fibres or the other nonmuscle dystrophin isoforms. In the present study, we delivered human and murine dystrophin plasmids by electrotransfer after hyaluronidase pretreatment to increase gene transfer efficiencies. Tolerance to murine dystrophin was still seen with this improved gene delivery. Tolerance to exogenous recombinant full-length human dystrophin was seen in mdx transgenic lines expressing internally deleted versions of human dystrophin. These results suggest that the presence of revertant fibres may prevent the development of serious immune responses in patients undergoing dystrophin gene therapy.


Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion.
To evaluate the angiographic findings in eyes from 2 clinical trials of the dexamethasone intravitreal implant (DEX implant) 0.7 mg in the treatment of macular edema (ME) after branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Post hoc analysis of pooled data from 2 identical phase 3 clinical trials. Patients with vision loss as a result of ME (≥ 6 weeks' duration) after BRVO or CRVO for whom angiographic data were available (n = 329 eyes). Fluorescein angiography (FA) results assessed by masked, certified graders using standardized grading protocols. The primary outcome measure in the parent studies was change from baseline in best-corrected visual acuity. Prospectively defined secondary outcomes included FA measurements (to assess macular capillary leakage, neovascularization, and nonperfusion) and optical coherence tomography results (to assess central retinal thickness [CRT]). At baseline, 42% of eyes in the DEX implant group and 38% of eyes in the sham group had unreadable assessments because of hemorrhage. At day 180, significantly fewer DEX implant-treated eyes (2%) than sham-treated eyes (9%) had unreadable assessments because of hemorrhage (P = 0.029). Among eyes with gradable assessments, the incidence of nonperfusion remained fairly steady from baseline to day 180. The proportion of eyes with active neovascularization increased from baseline to day 180 in the sham group, but stayed relatively constant in the DEX implant group (P = 0.026 for DEX vs. sham). The mean area of overall nonperfusion and the mean area of macular capillary nonperfusion increased from baseline to day 180 in both treatment groups (no statistically significant between-group difference). There was a statistically significant positive correlation between changes in macular leakage and changes in CRT in both the DEX implant group (r = 0.22; 95% confidence interval, 0.03-0.40; P = 0.023) and the sham group (r = 0.29; 95% confidence interval, 0.10-0.46; P = 0.003). This study demonstrated that the clinical improvements observed with the DEX implant were accompanied by significant improvements in vascular parameters and suggests that treatment with the DEX implant may be associated with some clinically significant improvements in angiographic findings, specifically active neovascularization.


Functional DNAzymes organized into two-dimensional arrays.
DNAzymes are catalytically active DNA molecules, which have previously been described in solution. Here, we organize these molecules into a series of two-dimensional (2D) arrays using a periodic arrangement of DNA structures based on the DNA double crossover motif. We demonstrate by means of atomic force microscopy that the DNAzymes are organized according to the design and that they retain their activity when attached in linear strings within the context of the 2D array.


Measurement of torso skin temperature under clothing.
The influence of clothing on skin temperature distributions of the torso was investigated during and after cold exposure. Volunteers were cooled for one hour at 5 degrees C while wearing clothing designed to have insulation which was intended to be relatively uniformly distributed. Three different thicknesses of clothing were used. Following thermistor measurements of skin temperatures during the cold exposures, clothing was quickly removed from the upper parts of the body to enable thermographic investigations of the temperature distributions of the front of the bare torso. The evolution of temperature distributions were then studied at different ambient temperatures (5 degrees C and 20 degrees C) as a function of the thickness of the insulation which had previously been worn. The patterns of the temperature distributions, and the range and standard deviation of torso temperatures were all found to be relatively constant in spite of the different thicknesses of clothing worn or in the time-variant mean torso temperatures which resulted. The front torso sites normally used for the determination of mean skin temperatures were found to be on portions of the torso which were cooler than the surrounding regions. It was concluded that a site midway between the umbilicus and a nipple yields a more accurate estimate of mean torso temperature in the conditions of the present study.


The ultrastructure of normal digital flexor tendon sheath and of the tissue formed around silicone and polyethylene implants in man.
Three normal digital flexor tendon sheaths and the corresponding tissue formed around five silicone rod tendon implants, two silicone rubber mammary prostheses and one polyethylene tubing implant have been examined by light microscopy and by transmission and scanning electron microscopy. No principal difference in morphology was found. The surface facing tendon or implant was almost invariably covered with an irregular layer of amorphous material and filaments; only occasionally were collagen fibrils or cells exposed. Beneath the surface there were abundant collagen fibrils and some cells; besides fibroblasts, cells rich in filaments and often with numerous glycogen granules, mitochondria and peripherally located vesicles were found. These cells were frequently surrounded by a thick layer of an amorphous matrix. The results indicate that the implants caused remarkably little tissue reaction.


Use of the EIE-recombinant-Chagas-biomanguinhos kit to monitor cure of human Chagas' disease.
We used the EIE-Recombinant-Chagas-Biomanguinhos kit (EIE-Rec kit) developed by the Oswaldo Cruz Foundation, Brazil, to monitor cure of chagasic patients who were treated during the acute phase of T. cruzi infection. Treated patients were previously studied by parasitological and serological tests and classified as cured patients (CP) (n = 10), dissociated patients (DP) (n = 6), and noncured patients (NCP) (n = 6). When sera of these patients were assayed by EIE-Rec kit all sera from NCP and all sera from CP showed positive and negative reactions, respectively. These results were in full agreement with those obtained previously by the classical tests. Two DP showed a positive reaction; the remaining four displayed a negative reaction, similar to that observed in sera from nonchagasic (NCh) individuals, and could therefore be considered CP. Our results suggest that the EIE-Rec kit could be used to monitor the efficacy of Chagas' disease treatment.


PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.
PICK1 and ABP/GRIP bind to the AMPA receptor (AMPAR) GluR2 subunit C terminus. Transfer of the receptor from ABP/GRIP to PICK1, facilitated by GluR2 S880 phosphorylation, may initiate receptor trafficking. Here we report protein interactions that regulate these steps. The PICK1 BAR domain interacts intermolecularly with the ABP/GRIP linker II region and intramolecularly with the PICK1 PDZ domain. Binding of PKCalpha or GluR2 to the PICK1 PDZ domain disrupts the intramolecular interaction and facilitates the PICK1 BAR domain association with ABP/GRIP. Interference with the PICK1-ABP/GRIP interaction impairs S880 phosphorylation of GluR2 by PKC and decreases the constitutive surface expression of GluR2, the NMDA-induced endocytosis of GluR2, and recycling of internalized GluR2. We suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking.


Laboratory-confirmed, health care-associated bloodstream infections in Jordan: a matched cost and length of stay study.
No studies have been carried out in Jordan to examine length of stay (LOS) and extra cost associated with health care-associated bloodstream infections (HCABSIs). This study aims to estimate the extra LOS and cost associated with HCABSIs among adult hospitalized Jordanian patients. Five-year data were retrieved from 1 large university-affiliated hospital in Jordan. Matched case-control design was used in this study. Cases were determined based on confirmed positive blood culture after 48 hours of admission. Matching criteria were age (±5 years), gender, admission diagnosis, and LOS in comparison group equal to the LOS (±5%) before blood culture for the case group. Of the total 445 infected patients 125 (28.1%) were matched with uninfected patients. The mean LOS after infection for cases was 12.1 days (standard deviation [SD] = 17.2) compared with 8.3 (SD = 7.9) days for the controls (P = .02). The total mean inflation-adjusted charges for cases was M (mean) = US $7,426, SD = $7,252 compared with M = $3,274, SD = $4,209 for controls, P < .001. Using multiple regression modeling, LOS after acquiring HCABSIs, admission to critical care units, and being infected with HCABSIs were significant predictors of patients' total charges. Figures generated from this can be used to inform health care researchers, policy makers, and professionals about the impact of HCABSIs.


Sciatic nerve compression: diagnostic value of electromyography and computerized tomography.
A 54 year old man on long term anticoagulation (warfarin) treatment for prosthetic heart valve, developed sciatic nerve compression and femoral nerve dysfunction due to hematoma and edema in the gluteal muscles. Computerized tomography of the pelvis and electrodiagnostic studies helped in localizing and understanding the pathophysiology of the clinical signs and symptoms.


Plants, symbiosis and parasites: a calcium signalling connection.
A unique family of protein kinases has evolved with regulatory domains containing sequences that are related to Ca(2+)-binding EF-hands. In this family, the archetypal Ca(2+)-dependent protein kinases (CDPKs) have been found in plants and some protists, including the malarial parasite, Plasmodium falciparum. Recent genetic evidence has revealed isoform-specific functions for a CDPK that is essential for Plasmodium berghei gametogenesis, and for a related chimeric Ca(2+) and calmodulin-dependent protein kinase (CCaMK) that is essential to the formation of symbiotic nitrogen-fixing nodules in plants. In Arabidopsis thaliana, the analysis of 42 isoforms of CDPK and related kinases is expected to delineate Ca(2+) signalling pathways in all aspects of plant biology.


Protective effects of the combination Bifidobacterium longum plus lactoferrin against NSAID-induced enteropathy.
Nonsteroidal anti-inflammatory drugs can exert detrimental effects in the lower digestive tract. The aim of this study was to examine the protective effects of a combination of the probiotic Bifidobacterium longum BB536 (Bifidobacterium) with the prebiotic lactoferrin in a rat model of diclofenac-induced enteropathy. Enteropathy was induced in 40-wk-old male rats by intragastric diclofenac (4 mg/kg twice daily for 14 d). Lactoferrin (100 mg/kg twice daily), Bifidobacterium (2.5 × 106 CFU/rat twice daily) or their combination were administered 1 h before diclofenac. At the end of treatments, the ileum was processed for the evaluation of histologic damage, myeloperoxidase (MPO) and malondialdehyde (MDA) levels, as well as the expression of Toll-like receptors 2 and 4 (TLR-2/-4) and the activation of downstream signaling molecules (MyD88 and nuclear factor [NF]-κB p65). Blood hemoglobin and fecal calprotectin were also assessed. Diclofenac induced intestinal damage, along with increments of MPO and MDA, overexpression of TLR-2, TLR-4, MyD88, and NF-κB p65, increased fecal calprotectin and decreased blood hemoglobin levels. Lactoferrin or Bifidobacterium alone prevented diclofenac-induced enteric damage, and the changes in blood hemoglobin, MPO, MDA, fecal calprotectin, and NF-κB p65. Bifidobacterium, but not lactoferrin, decreased TLR-4 expression, although none of them affected MyD88 overexpression. TLR-2 expression was slightly enhanced by all treatments. The combined administration of lactoferrin and Bifidobacterium reduced further the intestinal damage, and restored MPO and blood hemoglobin levels. Diclofenac induced ileal mucosal lesions by activation of inflammatory and pro-oxidant mechanisms. These detrimental actions were prevented by the combination of lactoferrin with Bifidobacterium likely through the modulation of TLR-2/-4/NF-κB proinflammatory pathways.


Advantages and drawbacks of dexamethasone in glioblastoma multiforme.
The most widespread, malignant, and deadliest type of glial tumor is glioblastoma multiforme (GBM). Despite radiation, chemotherapy, and radical surgery, the median survival of afflicted individuals is about 12 months. Unfortunately, existing therapeutic interventions are abysmal. Dexamethasone (Dex), a synthetic glucocorticoid, has been used for many years to treat brain edema and inflammation caused by GBM. Several investigations have recently shown that Dex also exerts antitumoral effects against GBM. On the other hand, more recent disputed findings have questioned the long-held dogma of Dex treatment for GBM. Unfortunately, steroids are associated with various undesirable side effects, including severe immunosuppression and metabolic changes like hyperglycemia, which may impair the survival of GBM patients. Current ideas and concerns about Dex's effects on GBM cerebral edema, cell proliferation, migration, and its clinical outcomes were investigated in this study.


Effect of preozonation on the characteristic transformation of fulvic acid and its subsequent trichloromethane formation potential: presence or absence of bicarbonate.
The effects of bicarbonate on the characteristic transformation of fulvic acid (FA) and its subsequent trichloromethane formation potential (TCMFP) were investigated in the process of preozonation. Dissolved organic carbon (DOC) removal rate and the residual aqueous ozone concentration during preozonation were measured with different bicarbonate concentration. The presence of bicarbonate inhibited DOC removal and decreased TCMFP yields in the initial oxidation period. In order to explain these phenomena, the molecular weight (MW) distribution (<5, 5-10, 10-30, and >30 kDa) and corresponding TCMFP were investigated for FA and its subsequent oxidation products. Furthermore, transformation of molecular structure, based on MW distribution, was also characterized with Fourier transform infrared (FTIR) spectrum. Bicarbonate showed different inhibiting effects on TCMFP of organic species with different MW, and more significant TCMFP decrement was observed for the high MW fraction (>30 kDa) than for the low MW fractions. Preozonation led to obvious reduction on DOC and UV254 in most of MW fractions wherever bicarbonate was present or not, demonstrating that ozone contributed to both organics mineralization and structure variation, synchronously. As being indicated from the results of FTIR and gas chromatography-mass spectrometry, the functional groups such as alcohols, epoxides and phenols, the formation of which was promoted with hydroxyl radicals (.OH) and would be remarkably inhibited by bicarbonate, were responsible for the increment of TCM precursor's concentration during ozonation. Results of these studies confirmed low dosage bicarbonate affecting the ozonation pathways, influencing the intermediate species formation and impacting its subsequent TCMFP yields through inhibiting the .OH radicals reactions mainly occurred in high MW fractions.


Dietary supplementation with antioxidants. Is there a case for exceeding the recommended dietary allowance?
The containment of damaging oxygen species by antioxidant nutrients has led to the speculation that the RDA for these specific nutrients may be overly low. Among these nutrients are vitamin E, vitamin C, and to a lesser extent beta-carotene and selenium. Evidence for the role of these nutrients in cancer and heart disease is evaluated. The case is presented for an increase of two-fold for the vitamin C RDA and between three and five-fold for vitamin E; for establishing 15 mg as the RDA for beta-carotene; for no change in the vitamin A RDA; and for further study on selenium.


Cancer-biomarkers associated with sex hormone receptors and recent therapeutic advancements: a comprehensive review.
Hormones and its regulation plays vital role in causing breast, prostate, ovarian and endometrial cancers collectively known as hormone-sensitive cancers. This review discusses the various functions of the sex hormones and the biological pathways involved in causing hormone-associated cancer under differential regulation. We have also attempted to explore the biomarkers associated with the cancers and the current therapeutic availability to treat such cancers. Among various sex hormones such as estrogen, progesterone and androgen, estrogen the female sex hormone and its receptor had a major contribution in causing cancer and hence are considered a predominant target in treating the associated cancers. Other hormones and receptors such a androgen, progesterone, and their respective receptors were also reported to have a significant correlation in causing cancers. Apart from these receptors certain enzymes that act as precursors or as promoters are also targeted for treatment strategies. The drugs commonly used belong to the selective drug classes such as selective estrogen receptor modulators and selective progesterone receptor modulators. In the case of androgen regulation androgen deprivation therapies are practiced. It is also suggested that the use of natural substances to treat cancer could prevent resistance and reduce side effects. Identification of significant targets and the discovery of many efficient drugs shall be possible in the future with better understanding of hormone regulation and its influence on cancer causative mechanisms.


Screening for total ergot alkaloids in rye flour by planar solid phase extraction-fluorescence detection and mass spectrometry.
The analysis of ergot alkaloids is generally performed by high-performance liquid chromatography (HPLC) coupled to fluorescence detection (FLD) or mass selective detection. As for monitoring only the sum of ergot alkaloids is relevant, a fast and easy screening method for the determination of the total alkaloid content was developed using planar solid phase extraction (pSPE). Applying pSPE, recently introduced for pesticide residue analysis in fruits and vegetables (Oellig and Schwack, 2011) and tea (Oellig and Schwack, 2012), all ergot alkaloids are concentrated in a target zone followed by detection as the sum. The herein presented method includes an ammonium acetate buffered extraction step, followed by a fast liquid-liquid partitioning pre-cleaning before pSPE is performed on high-performance thin-layer chromatography (HPTLC) amino plates with a single methanol development to separate the ergot alkaloids from the remaining matrix and to collect them in a single zone. For quantitation, the native fluorescence was used after dipping the plate in n-hexane/paraffin solution for fluorescence enhancement. Limits of detection and quantitation of 0.07 and 0.24 mg/kg rye, respectively, expressed as ergocristine, were well below the currently applied quality criterion limit for rye. Near-100% recoveries were obtained at relevant spiking levels for different rye flour samples. Hence, the fast pSPE-FLD is an efficient and reliable method to screen for the total ergot alkaloid content in rye and a rapid alternative to the HPLC determination of individual alkaloids and to summing them up. HPTLC-MS additionally enables the identification of the ergot alkaloid composition by a single mass spectrum, when utilized as a fingerprint, offering an easy differentiation of Secale cornutum from different origins.


Clinical and hemodynamic effects of the new dilator drug molsidomine.
The effects of a single 2 mg oral dose of molsidomine were assessed with treadmill multistage exercise testing in six men with stable angina. A double-blind, placebo-controlled protocol was used, with exercise to the point when anginal pain forced the patient to stop. Exercise was undertaken before and at 1/2, 1 1/2, 4, and 6 hours after drug administration. Molsidomine improved exercise performance, with the best antianginal effect at 1 1/2 hours after administration, when the mean times to limiting angina were approximately 6 3/4 minutes with placebo and 11 1/2 minutes with molsidomine (p less than 0.05). The corresponding energy expenditures were 33.8 and 77.6 mets, an increase of 130% with the active drug. Intra-arterial blood pressure recording verified that molsidomine had a vasodilator hemodynamic profile, and the immediate postexercise rate-pressure product 1 1/2 hours after molsidomine treatment was 232 mm Hg/min X 10(-2), compared with 183 mm Hg/min X 10(-2) after administration of placebo (NS). Side effects of molsidomine were limited to headache in two patients.


Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: relevance to systemic vasculitis.
There is a breakdown of tolerance to neutrophil components during systemic vasculitis, which is marked by autoantibodies and T cells with specificity for proteinase 3 or myeloperoxidase, expressed on the surface of apoptotic neutrophils. This study was undertaken to investigate the effects of human apoptotic and necrotic neutrophils on human dendritic cell (DC) phenotype and ability to stimulate allogeneic T cell proliferation. DCs were generated from human peripheral blood mononuclear cells and allowed to interact with human apoptotic and necrotic neutrophils in the presence or absence of tumor necrosis factor alpha (TNFalpha). Effects on DC phenotype and ability to stimulate T cell proliferation were observed. Immature DCs engulfed apoptotic and necrotic neutrophils, resulting in up-regulation of CD83 and class II major histocompatibility complex molecules, but down-regulation of CD40, CD80, and CD86, and a decreased ability to stimulate T cell proliferation. When TNFalpha was added in combination with apoptotic neutrophils, the inhibitory effects were overcome to some extent. Our results suggest that DC uptake of apoptotic or necrotic neutrophils alone does not shift the immune response from tolerance to autoimmunity in systemic vasculitis. However, cytokines found at sites of inflammation in vasculitis patients may act as maturation factors for DCs, and in combination with apoptotic neutrophils, may lead to an autoimmune phenotype.


Linear IgM dermatosis of pregnancy.
An intensely pruritic dermatosis that occurred in a woman during the third trimester of pregnancy is described. The clinical manifestations included red follicular papules symmetrically distributed on the skin of the forearms, abdomen, thighs, and legs. The histopathologic findings were not specific. However, immunopathologic examination revealed dense linear deposition of IgM in the dermoepidermal junction. The eruption and the immunopathologic findings disappeared at the end of the puerperium. This dermatosis differs from previously described specific dermatoses of pregnancy because of the clinical appearance and the immunopathologic findings. Thus we propose the term linear IgM dermatosis of pregnancy.


Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.
Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer. An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies. Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione sulfate and elevation of progesterone suggest inhibition of 17-hydroxylase and 21-hydroxylase activities by sorafenib.


The molecular ontogeny of follicular lymphoma: gene mutations succeeding the BCL2 translocation define common precursor cells.
Relapsed follicular lymphoma (FL) can arise from common progenitor cells (CPCs). Conceptually, CPC-defining mutations are somatic alterations shared by the initial and relapsed tumours, mostly B-cell leukaemia/lymphoma 2 (BCL2)/immunoglobulin heavy locus (IGH) translocations and other recurrent gene mutations. Through complementary approaches for highly sensitive mutation detection, we do not find CPC-defining mutations in highly purified BCL2/IGH-negative haematopoietic progenitor cells in clinical remission samples from three patients with relapsed FL. Instead, we find cells harbouring the same BCL2/IGH translocation but lacking CREB binding protein (CREBBP), lysine methyltransferase 2D (KMT2D) and other recurrent gene mutations. Thus, (i) the BCL2/IGH translocation can precede CPC-defining mutations in human FL, and (ii) BCL2/IGH-translocated cells can persist in clinical remission.


Increased sympathetic drive during the onset of hypertension in conscious Cyp1a1-Ren2 rats.
Despite advances in our understanding concerning the pathology of hypertension, the mechanisms that underpin the origin of hypertension remain to be fully elucidated. This enigma is, at least in part, due to inherent limitations of various animal models of hypertension. Here, we show the genetically modified Cyp1a1-Ren2 rat model, in which the onset and severity of angiotensin II-dependent hypertension can be tightly controlled, as an effective model for investigating increased sympathetic drive for the onset of hypertension. Cyp1a1-Ren2 rats were surgically prepared with radiotelemetric transmitters for the continuous measurement of arterial blood pressure (ABP). ABP was recorded in freely moving rats that were fed with either normal rat chow or a diet containing indole-3-carbinol (0.225% w/w) for 7 days to induce hypertension. Structural morphology of and endothelial NO synthase (eNOS) protein expression in heart and/or vascular tissue were analyzed. Sympathetic tone was estimated using spectral analysis of heart rate variability. The progressive induction of hypertension over 7 days was matched with a parallel increase in sympathetic tone. By day 7 of hypertension, eNOS expression in the mesenteric artery was elevated. However, the elevated ABP, sympathetic tone, and eNOS had not elicited gross morphological remodeling of the heart or vasculature. Importantly, both the increase in sympathetic tone and overexpression of eNOS within the vasculature were reversed when ABP was returned to normal. We conclude that the Cyp1a1-Ren2 rat provides an effective model for investigating specific adverse and transient changes in central sympathetic modulation of arterial blood pressure during the early onset of angiotensin-dependent hypertension.


Compounds with NO Inhibitory Effect from the Rattan Stems of Sinomenium acutum, a Kind of Chinese Folk Medicine for Treating Rheumatoid Arthritis.
Three new alkaloids (1-3), one new diphenyl ether (4) and fifteen known alkaloids (5-19) were isolated from the rattan stems of Sinomenium acutum. Comprehensive analyses of HR-ESI-MS, 1D (1 H and 13 C), 2D-NMR (1 H-1 H COSY, HSQC, HMBC, NOESY), circular dichroism (CD), UV and IR revealed the structures and absolute configurations of these new compounds. The structures of other compounds were determined by comparison of their 1 H and 13 C-NMR data with previous literature reports. By measuring the amount of NO produced, the anti-inflammatory properties of the isolated compounds were studied. The results showed that compounds 4 and 5 had strong NO inhibitory activity.


Reappraisal of the options for colorectal cancer screening in England.
The aim was to use newly available data to estimate the cost effectiveness and endoscopy requirements of screening options for colorectal cancer (CRC) to inform screening policy in England. A state transition model simulated the life experience of a cohort of individuals in the general population of England with normal colon/rectal epithelium through to the development of adenomas and CRC and subsequent death. CRC natural history model parameters and screening test characteristics were estimated simultaneously by a process of model calibration. This process was fitted to observed data on CRC incidence in the absence of screening, data from existing screening programmes, and data from the UK flexible sigmoidoscopy (FS) screening trial. The costs, effects and resource impact were evaluated for a range of screening options involving the guaiac or immunochemical faecal occult blood test (gFOBT/iFOBT) and FS. The model suggests that screening strategies involving FS or iFOBT may produce additional benefits compared with the current policy of biennial gFOBT for 60-74-year-olds. The age at which a single FS screen results in the greatest quality-adjusted life year gain was 55, with similar gains for ages between 52 and 58. Strategies which combined FS and iFOBT showed further benefits and improved economic outcomes. Strategies which combine different screening modalities may provide greater clinical and economic benefits. The collection of comprehensive screening data using a uniform format will enable comparative analysis across screening programmes in different countries, will improve our understanding of the disease and will allow identification of optimal screening modalities.


Crosstalk between cdk5 and MEK-ERK signalling upon opioid receptor stimulation leads to upregulation of activator p25 and MEK1 inhibition in rat brain.
Cyclin-dependent kinase 5 (cdk5) participates in opioid receptor signalling through complex molecular mechanisms. The acute effects of selective μ-(fentanyl) and δ-(SNC-80) opioid receptor agonists, as well as the chronic effects of morphine (the prototypic opiate agonist mainly acting at μ-receptors), modulating cdk5 and activators p35/p25 and their interactions with neurotoxic/apoptotic factors, dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) and extracellular signal-regulated kinase (ERK) were quantified (Western Blot analyses) in the rat corpus striatum and/or cerebral cortex. To assess the involved mechanisms, MDL28170 was used to inhibit calpain activity and SL327 to disrupt MEK (ERK kinase)-ERK activation. Acute fentanyl (0.1mg/kg) and SNC-80 (10mg/kg) induced rapid (7-60 min) 2- to 4-fold increases of p25 content, without induction of cdk5/p25 pro-apoptotic c-Jun NH(2)-terminal protein kinase or aberrant cleavage of poly(ADP-ribose)-polymerase-1, a hallmark of apoptosis. In contrast, fentanyl and SNC-80 stimulated cdk5-mediated p-Thr75 DARPP-32 (+116-166%; PKA inhibition) and p-Thr286 MEK1 (+21-82%; MEK inactivation), and this latter effect resulted in uncoupling of MEK to ERK signals. Calpain inhibition with MDL28170 (cleavage of p35 to p25) attenuated fentanyl-induced p25 accumulation (-57%), but not the stimulation of p-Thr286 MEK1 or p-Thr75 DARPP-32. MEK-ERK inhibition with SL327 fully prevented fentanyl-induced p25 upregulation. Notably, chronic morphine treatment (10-100mg/kg for 6 days) also increased p25 content and p25/p35 ratio (and activated/inactivated MEK1) in rat brain cortex, which indicated that p25 upregulation persisted under the sustained stimulation of μ-opioid receptors. The results demonstrate that the acute stimulation of opioid receptors leads to upregulation of p25 activator through a MEK-ERK and calpain-dependent pathway, and to disruption of MEK-ERK signalling by a cdk5/p35-induced MEK1 inhibition. Moreover, the effects induced by the sustained stimulation of μ-receptors with morphine suggest the participation of cdk5/p25 complex in opiate-induced long-term neuroplasticity.


Cooperative transformation of murine fibroblast NIH3T3 cells by hepatitis C virus core protein and hepatitis B virus X protein.
Co-infection with hepatitis B virus (HBV) and hepatitis C Virus (HCV) is associated with increased frequency in the development of hepatocellular carcinoma (HCC). Here, we demonstrated that HBV X protein (HBx) and HCV core cooperate to transform mouse fibroblast NIH3T3 cells. They additively stimulated cell growth, especially in the absence of serum growth factors. In addition, co-expression of HBx and HCV core had additive effects on the induction of anchorage-independent cell growth as well as on the secretion of matrix metalloproteases, which may contribute to increased metastatic potential. Furthermore, the cells expressing both viral proteins exhibited higher tumorigenicity, as demonstrated in athymic nude mice.


[Syndrome of hypocalсiuric hypercalcemia. Is it rare? Two clinical cases in an outpatient clinic].
Hypocalciuric hypercalcemia syndrome (familial hypocalciuric hypercalcemia, FHH) is an inherited condition based on dysfunction of the calcium receptor or its associated partner proteins. Recent evidence suggests that the prevalence of this condition may be comparable to that of primary hyperparathyroidism. Clinical manifestations of FHH are usually absent; however the classic symptoms of hypercalcemia may be present in some cases. Timely differential diagnosis of FHH avoids unnecessary and expensive instrumental examination, as well as ineffective treatment. The clinical cases presented in this publication demonstrate the unjustified difficulties in this issue and the necessity to raise the awareness of physicians about the familial hypocalciuric hypercalcemia.


Monitoring the patient response as an alternative to commercial negative quality control in infectious serology.
Traditional internal quality control schemes for qualitative infectious serology mostly rely on the use of commercial positive and negative quality control materials. However, with respect to the negative control, target values provided by the manufacturer are often poorly defined and non-commutability of the commercial materials further complicates correct interpretation of control results. An alternative quality control procedure using the median patient seronegative response is presented. Daily patient median responses were calculated for our Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody and HIV antigen/antibody test systems. Because of the low prevalence of these viruses in our area, most patient responses are negative. A minimum of 5 patient samples per day was required to generate a stable daily median. Control limits were calculated and daily patient medians were plotted against commercial quality control results. Commercial negative controls and daily patient medians mostly behaved in the same way. Nevertheless, for the Hepatitis B surface antigen test, patient medians frequently exceeded the calculated control limit in contrast to commercial quality controls. This confirms that target ranges provided by the manufacturer are not always adequate. Moreover, an important matrix-related interference occurred on our HIV antigen/antibody test system and correct interpretation was only possible using daily patient median results. Monitoring the daily patient median response can be a valuable alternative to traditional commercial negative quality control. It's easy to perform, cost-free, provides additional information with respect to matrix effects and allows for the establishment of well-defined control limits.


Association between sleeping hours and cardiometabolic risk factors for metabolic syndrome in a Saudi Arabian population.
Epidemiological and molecular studies have shown that sleep duration is associated with metabolic syndrome (MtS), a disease that is on the rise in the Kingdom of Saudi Arabia. We aim to investigate the association between sleep duration and selected cardiometabolic risk factors of MtS in a Saudi Arabian population. Secondary care was given to the participants. There were 2 participating centres, shopping malls in North and South Jeddah, Saudi Arabia. We recruited 2686 participants over a 1-year study period. Participants were selected based on their willingness. The only criterion for exclusion was living in the area (North or South Jeddah) for less than 15 years. Participants were measured for blood sugar levels, blood pressure and body mass index. All participants were asked to fill out a questionnaire. There was a positive association between longer sleep duration and obesity, hypertension and hyperglycaemia. The adjusted ORs for obesity, hypertension and hyperglycaemia were 1.54 (95% CI 1.20 to 1.98), 1.89 (95% CI 1.45 to 2.48) and 1.59 (95% CI 1.19 to 2.13), respectively, in participants sleeping >8 h/night, as compared with those sleeping 7 h. The positive associations between longer sleep duration, defined as sleeping >7 h, and the disease status, did not differ from other risk factors such as physical activity and nutrition. This is the first epidemiological study reporting on the association between sleep duration and cardiometabolic risk factors of MtS in a Saudi Arabian population. Sleep durations of 8 h or greater were found to be associated with all 3 cardiometabolic risk factors: obesity, hypertension and hyperglycaemia, and this relationship was not confounded by quality of nutrition or physical activity levels.


A Cap for Every Occasion: Alternative eIF4F Complexes.
The eukaryotic translation initiation factor 4F (eIF4F) has become essentially synonymous with 5' cap-dependent mRNA translation. Recent studies demonstrate that cells assemble variants of eIF4F to produce adaptive, cap-dependent translatomes during physiological conditions that inhibit eIF4F. These findings challenge us to reassess classical perceptions of cellular translational pathways.


Shigellosis in men who have sex with men: an overlooked opportunity to counsel with pre-exposure prophylaxis for HIV.
In the absence of other epidemiological exposures, shigellosis in men who have sex with men (MSM) suggests engagement in high-risk sexual encounters. Infection and diagnosis of shigellosis in MSM presents a potentially overlooked opportunity to discuss the availability of pre-exposure prophylaxis medications to prevent incident HIV infections.


Performance of hand-held whole-breast ultrasound based on BI-RADS in women with mammographically negative dense breast.
To assess the performance of breast ultrasound based on BI-RADS final assessment categories in women with mammographically negative dense breast. Of 3,820 cases with mammographically negative dense breast and subsequent hand-held bilateral whole-breast ultrasound, a total of 1,507 cases in 1,046 women who had biopsy or at least 2-year follow-up ultrasound constituted the basis of this retrospective study. Cancer rate of each sonographic BI-RADS category was determined and medical audit was performed separately in screening-general, screening-treated, and diagnostic group. A total of 43 cases (2.9%) were confirmed as malignancy. Cancer rate among BI-RADS categories was significantly different (p < 0.0001). Among three groups, the cancer rate was significantly different (p < 0.0001) and the highest in diagnostic group (15.8%, 22 of 139). Abnormal interpretation rate, PPV of biopsy performed, cancer detection rate, and rate of early stage cancer, and the size of invasive cancer were significantly different among three groups and the highest in diagnostic group. Regarding cancer characteristics, the proportion of advanced cancer was the highest in diagnostic group. Breast ultrasound based on BI-RADS as an adjunctive to negative mammography can be useful for predicting malignancy in women with dense breast.


Contemporary use of cardiovascular risk reduction strategies in type 2 diabetes. Insights from the diabetes collaborative registry.
Cardiovascular disease remains the primary source of morbidity and mortality in type 2 diabetes (T2D). We characterized the change over time in the use of evidence-based therapies to reduce cardiovascular risk in US patients with T2D. Data from a longitudinal outpatient diabetes registry were used to calculate the prescription of SGLT2i or GLP-1RA over time and among those with high-risk comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], chronic kidney disease [CKD]) and a diabetes cardiovascular composite score (DCCS; calculated as: #eligible medications prescribed/#eligible medications x 100 for SGLT2i, GLP-1RA, statin, antiplatelet/anticoagulant therapy, ACEi/ARB/ARNI). Scores ranged from 0% to 100% (higher=more optimal care). Among 1,001,542 outpatients from 391 US sites, 51.7% patients had ASVCD, 17.7% HF, and 23.0% CKD. The percentage of patients prescribed an SGLT2i or GLP-1RA increased over time (7.3% in 2013 to 28.8% in 2019), and 18.3% of patients with ASCVD, HF, or CKD were on at least one of these medications at last follow-up vs 25.5% of patients without any of these comorbidities. Mean DCCS was 54±36%; 54±25% in patients with ASCVD, HF, or CKD vs 52±50% in patients without any of these comorbidities (P<0.001 for both). In a hierarchical linear model, male sex, and a diagnosis of CKD were independently associated with higher DCCS whereas a diagnosis of HF or ASCVD was associated with a lower DCCS. In a large, contemporary cohort of patients with T2D, we found improvement in the use of SGLT2i and GLP-1RA but unexpectedly lower use in patients with ASCVD, heart failure, and CKD, highlighting a treatment-risk paradox. Further education is needed to shift the understanding of these medications as tools for glucose-lowering to cardiovascular risk reduction and to improve their implementation in clinical practice.


Endoscopic approach to orbital apex lesions.
To examine the role of transnasal and transantral endoscopic surgical approaches in the management of apical orbital lesions. Retrospective case series. Three patients underwent combined orbital and endoscopic surgery for treatment of apical orbital lesions. In two of these patients, the orbital apex was decompressed, which resulted in visual recovery. Using endoscopic approaches to the posterior orbit and orbital apex allowed better visualization, with minimal manipulation of tissues in an area where surgical access is limited. Apical orbital lesion management benefits from a multidisciplinary and individualized plan. Endoscopic approaches can be used to improve visualization and access to a difficult surgical area. They also allow extra instrumentation to be used through the relatively capacious paranasal sinuses. These advantages may obviate lateral orbitotomy in some situations. Although endoscopic techniques are useful for biopsy, debulking, and removal of orbital apex lesions, they may be more difficult to apply to an intraconal lesion at the orbital apex.


Evaluation of the non-auditory responses in individuals with auditory brainstem implant.
After auditory brainstem implant (ABI) surgery, stimulation of certain cranial nerves may result in a non-auditory response, and the electrodes that stimulate these nerves may be deactivated. The goals of this study are to compare the number of active electrodes in the initial activation and the last fitting, to investigate non-auditory response types and their frequency as a result of non-auditory stimulation, to compare the placements of deactivated electrodes as a result of non-auditory stimulation in the initial activation and the last fitting. The computer software system was used to perform a retrospective analysis of the fitting data of 69 ABI users who underwent auditory brainstem implant surgery between January 1997 and January 2019. The non-auditory response types, deactive electrodes, and the positioning of the deactive electrodes horizontally and vertically were recorded in these users during the initial activation and the last fitting. There was no statistically significant difference between the number of active electrodes in the initial activation and the last fitting. The proportion of the users with deactive electrodes in the initial activation and the last fitting was not statistically significant different. In the horizontal and vertical placement classification, the placement of the deactive electrodes was not statistically different between initial activation and last fitting. The most common type of non-auditory response was facial nerve stimulation at the initial activation and no auditory perception at the last fitting. According to the difference between the number of active and deactive electrodes in the initial activation and the last fitting, as well as the auditory and non-auditory responses, it was found that the ABI users were statistically different between the initial activation and the last fitting. The results of this study show that not only auditory but also non-auditory responses occur in most ABI users. In addition, to the best of our knowledge, this study is the first to examine the frequencies of non-auditory response types, and the placement of the electrodes that cause these responses according to horizontal and vertical classifications.


Unsymmetrically-Substituted 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione Scaffold-A Useful Tool for Bioactive Molecules Design.
Unsymmetrically N-substituted and N,N'-disubstituted 5,12-dihydrodibenzo [b,f][1,4]diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation or acylation agents, expanding the structural diversity and possible applications of synthesized molecules. The extension of developed method resulted in the synthesis of novel: tricyclic 5,10-dihydrobenzo[b]thieno[3,4-f][1,4]diazocine-4,11-dione scaffold and fused pentacyclic framework possessing two benzodiazocine rings within its structure. Additionally, the unprecedented rearrangement of 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-diones to 2-(2-aminophenyl)isoindoline-1,3-diones was observed under the basic conditions in the presence of sodium hydride for secondary dilactams. The structures of nine synthesized products have been established by single-crystal X-ray diffraction analysis. Detailed crystallographic analysis of the investigated tri- and pentacyclic systems has shed more light on their structural features. One cell line derived from non-cancerous cells (EUFA30-human fibroblasts) and three tumor cells (U87-human primary glioblastoma, HeLa-cervix adenocarcinoma, BICR18-laryngeal squamous cell carcinoma) were used to determine the cytotoxic effect of the newly synthesized compounds. Although these compounds showed a relatively weak cytotoxic effect, the framework obtained for 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione could serve as a convenient privilege structure for the design and development of novel bioactive molecules suitable for drug design, development and optimization programs.


Association between ADAM33 S2 and ST+4 polymorphisms and susceptibility to asthma: a meta-analysis.
The aim of this study was to determine whether ADAM33 (a disintegrin and metalloproteinase domain 33) polymorphisms confer susceptibility to asthma in different populations. We performed a meta-analysis on the association between the ADAM33 S2, ST+4, F+1, S1, and V4 polymorphisms and asthma. Thirteen studies in ten reports, which included 4942 patients and 7933 controls, were available for the meta-analysis. Meta-analysis stratified by ethnicity indicated an association between the ADAM33 S2 2 allele and asthma in Europeans (OR=0.912, 95% CI=0.851-0.977, p=0.009). Meta-analysis revealed an association between asthma and the ADAM33 ST+4 2 allele (OR=0.783, 95% CI=0.762-0.999, p=0.048). Stratification by ethnicity indicated an association between the ADAM33 ST+4 polymorphism and asthma in Asians. Stratification by age indicated an association between the ADAM33 ST+4 2 allele and asthma in adults (OR=0.863, 95% CI=0.782-0.964, p=0.008). However, no association was found between asthma and the ADAM33 F+1, S1, and V4 polymorphisms. This meta-analysis demonstrates that the ADAM33 S2 polymorphism confers susceptibility to asthma in Europeans and the ADAM33 ST+4 polymorphism is associated with asthma in Asians and adults.


Normative childhood EMG gait patterns.
The population characteristics of the linear envelopes of the electromyograms measured from seven lower extremity muscles in children were studied during locomotion. The variability and changes in pattern with respect to walking speed and age were investigated using statistical properties and analysis of variance of the envelopes. All muscles studied showed changes in their patterns that were associated with different walking speeds. Some changes concerned the relative intensity of existing phases of activity whereas others concerned the existence of additional phases of activity. The most remarkable trend was that all envelopes tended to have more consistent patterns as speed increased. With regard to age, within the span of 4-11 years, only the two thigh muscles studied demonstrated appreciable differences.


Pomalidomide plus dexamethasone for patients with relapsed or refractory multiple myeloma: Final results of the non-interventional study POSEIDON and comparison with the pivotal phase 3 clinical trials.
Prognosis of patients with multiple myeloma (MM) who have relapsed on or become refractory to immunomodulators and bortezomib is poor, and treatment options are limited. While pomalidomide plus low-dose dexamethasone (POM/DEX) has demonstrated efficacy in clinical trials, real-world evidence is scarce. POSEIDON was a prospective non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of POM/DEX in patients with relapsed or refractory MM (R/RMM) pretreated with at least two prior therapy lines including both lenalidomide and bortezomib in real world in Germany. Patients received POM/DEX according to physicians' choice. Data were analyzed descriptively. Between 2014 and 2017, 151 patients were enrolled, 144 patients with a median of three prior therapy lines qualified for effectiveness analysis. Median age was 73.2 years. Median progression-free and overall survival were 6.3 months [95% confidence interval (CI) 5.2, 8.6] and 12.9 months [95% CI 10.6, 15.1]. Most frequent grade 3/4 adverse events were leukopenia (8.2%), pneumonia (7.5%) and anemia (5.5%). QoL was maintained after start of POM/DEX. The results of POSEIDON support the effectiveness and safety of POM/DEX in R/RMM patients pretreated with lenalidomide and bortezomib and highlight the clinical value of the POM/DEX regimen in the real-world setting. Registered at clinicaltrials.gov (NCT02075996).


Hemoglobin Athens-Georgia [alpha 2 beta 2 40(C6)Arg----Lys] in association with beta 0-thalassemia in Tunisia.
We describe an Hb Athens-Georgia (Hb A-Ga)/beta 0-thalassemia compound heterozygosity, found in a Tunisian patient. Oxygen binding studies of red cell suspensions of this patient, containing approximately 95% Hb A-Ga, revealed an almost normal oxygen affinity. Nevertheless, dilute solutions of Hb A-Ga showed an increased overall oxygen affinity and decreased heme-heme interaction. This could be explained by a tetrameric hemoglobin with normal oxygen binding properties but with increased dissociation into monomers or dimers, as a consequence of a structural abnormality within the alpha 1 beta 2 interface. Such an interpretation would explain the increased oxygen affinity reported in previous studies performed on heterozygous Hb A/Hb A-Ga patients.


Expression of GATA6 in the human and mouse central nervous system.
The mammalian GATA family of transcription factors comprises of 6 members that are involved in diverse roles. The expression profile of GATA6 has been poorly defined in the central nervous system (CNS). In this report, we identify GATA6 expression in the normal mouse and human CNS, using Northern blot analyses, immunohistochemistry (IHC), and immunofluorescence (IF). GATA6 is expressed as a 2.2 kb transcript in the adult mouse brain and several regions of the adult human brain. Furthermore, cellular characterization demonstrates GATA6 nuclear expression in neurons, astrocytes, choroids plexus epithelium, and endothelial cells.


Blood-borne factors possibly associated with post-operative nausea and vomiting: an explorative study in women after breast cancer surgery.
The pathophysiology behind post-operative nausea and vomiting (PONV) is still not fully understood, especially with respect to gender. According to PONV risk scores, female gender is the strongest predictor for PONV. The risk for PONV after general anaesthesia for breast cancer surgery is 50-80%. The aim of the present explorative study was to identify blood-borne factors that might be associated with the development of PONV in women undergoing breast cancer surgery as a basis for further studies. Fifty patients were enrolled prospectively in the study. A standardized sevoflurane-based anaesthetic was used. Blood samples for the analysis of vasopressin, gastrin, cholecystokinin, epinephrine, norepinephrine, dopamine, serotonin, platelet count and blood glucose were taken at six pre-determined time points peri-operatively, and PONV was assessed during 24 h. PONV was found in 27 of 47 patients completing the study. Patients with PONV had a larger variability of the platelet count (P = 0.001), a reduced platelet count on the first post-operative day (P = 0.02) and a less pronounced relationship between the platelet count and whole blood serotonin (P = 0.004) compared with non-PONV patients. A lack of a decrease in epinephrine levels in response to the induction of anaesthesia (P = 0.03) and increased levels of vasopressin (P < 0.001), epinephrine (P = 0.005) and blood glucose (P = 0.004) were observed in the early post-operative period in PONV patients. Three different platelet-associated factors and an altered epinephrine pattern were found to be associated with the occurrence of PONV after breast cancer surgery.


Breast-feeding knowledge and practices among mothers in Manisa, Turkey.
to determine breast-feeding knowledge and practices among mothers before and after an educational intervention on breast feeding. cross-sectional, descriptive study using a face-to-face questionnaire. Manisa Maternity and Children's Hospital, which has Baby Friendly status. 158 women in the early postpartum period. 10.8% of women were not aware that they should offer colostrum to their babies. Only 43.7% of women commenced breast feeding within the first 30 minutes of giving birth. Prior to receiving the educational intervention, 55.7% of mothers knew how often they should feed their baby, 48.7% knew that they should breast feed their baby for two years together with additional food, although 55.1% of women did not know how to hold their breast during a feed. The mean pre-test score was 9.9 (SD 2.4; range 3-13), and the mean post-test score was 12.6 (SD 0.8; range 9-13). The difference between the mean pre- and post-test scores was statistically significant (paired t = 15.3, df = 157, P < 0.001). given the integral role of breast feeding in improving overall community health, regular breast-feeding counselling should be offered, particularly during the pregnancy and early postpartum period.


Iron status of adolescent girls from two boarding schools in southern Benin.
Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world, particularly in developing countries. Blood samples and a qualitative FFQ on Fe- and vitamin C-rich foods were obtained in 180 adolescent girls aged 12 to 17 years living in two boarding schools from south Benin. ID, defined as serum ferritin either 73 micromol/l or transferrin saturation<20%, was found in 32% of subjects. Anaemia (Hb<120 g/l) was found in 51% of adolescents, while 24% suffered from iron-deficiency anaemia (IDA) (ID and Hb<20 g/l). After adjusting for confounding factors (age, mother's and father's occupation, household size) in a logistic regression equation, subjects having a low meat consumption (beef, mutton, pork) (<4 times/week) were more than twice as likely to suffer from ID (OR=2.43; 95% CI 1.72, 3.35; P=0.04). Adolescents consuming less fruits (<4 times/week) also had a higher likelihood of suffering from ID (OR=1.53; 95% CI 1.31, 2.80; P=0.03). Finally, subjects whose meat consumption was low were twice as likely to suffer from IDA (OR=2.24; 95% CI 1.01, 4.96; P=0.04). The prevalence of ID represents an important health problem in these Beninese adolescent girls. A higher consumption of Fe-rich foods and of promoters of Fe absorption (meat factor and vitamin C) is recommended to prevent ID deficiency in these subjects.


Tumour blood vessel normalisation by prolyl hydroxylase inhibitor repaired sensitivity to chemotherapy in a tumour mouse model.
Blood vessels are important tissue structures that deliver oxygen and nutrition. In tumour tissue, abnormal blood vessels, which are hyperpermeable and immature, are often formed; these tissues also have irregular vascularisation and intravasation. This situation leads to hypoperfusion in tumour tissue along with low oxygen and nutrition depletion; this is also called the tumour microenvironment and is characterised by hypoxia, depleted nutrition, low pH and high interstitial pressure. This environment induces resistance to anticancer drugs, which causes an increase in anticancer drug doses, leading to increased side effects. We hypothesised that normalised tumour blood vessels would improve tumour tissue perfusion, resupply nutrition and re-oxygenate the tumour tissue. Chemotherapy would then be more effective and cause a decrease in anticancer drug doses. Here we report a neovascularisation-inducing drug that improved tumour vascular abnormalities, such as low blood flow, blood leakage and abnormal vessel structure. These results could lead to not only an increased chemo-sensitivity and tissue-drug distribution but also an up-regulated efficiency for cancer chemotherapy. This suggests that tumour blood vessel normalisation therapy accompanied by angiogenesis may be a novel strategy for cancer therapy.


Betahistine alleviates benign paroxysmal positional vertigo (BPPV) through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway.
Betahistine is a clinical medication for the treatment of benign paroxysmal positional vertigo (BPPV). Otolin, a secreted glycoprotein with a C-terminal globular domain homologous to the immune complement C1q, has been identified as a biomarker for BPPV. However, the role of complement C1q/TNF-related proteins (CTRPs) with a C-terminal globular domain in BPPV is unclear, so we explored the change of CTRPs in betahistine treated BPPV. We treated BPPV patients with Betahistine (12 mg/time, 3 times/day) for 4 weeks and observed the clinical efficacy and the expression of CTRP family members in BPPV patients. Then, we constructed a vertigo mice model of vestibular dysfunction with gentamicin (150 mg/Kg) and a BPPV model of Slc26a4loop/loop mutant mice. Adenoviral vectors for CTRP expression vector and small interfering RNA were injected via the intratympanic injection into mice and detected the expression of CTRP family members, phosphorylation levels of ERK and AKT and the expression of PPARγ. In addition, we treated mice of vestibular dysfunction with Betahistine (10 mg/Kg) and/or ERK inhibitor of SCH772984 (12 mg/Kg) and/or and PPARγ antagonist GW9662 (1 mg/Kg) for 15 days, and evaluated the accuracy of air righting reflex, the time of contact righting reflex and the scores of head tilt and swimming behavior. After treatment with Betahistine, the residual dizziness duration and the score of the evaluation were reduced, and the expression of CTRP1, 3, 6, 9 and 12 were significantly increased in BPPV patients. We also found that Betahistine improved the accuracy of air righting reflex, reduced the time of contact righting reflex and the scores of head tilt and swimming behavior in gentamicin-treated mice and Slc26a4loop/loop mutant mice. The expression levels of CTRP1, 3, 6, 9 and 12, phosphorylation levels of ERK and AKT, and PPARγ expression were significantly increased, and the scores of head tilt and swimming behavior were decreased in vestibular dysfunction mice with overexpression of CTRPs. Silencing CTRPs has the opposite effect. SCH772984 reversed the effect of Betahistine in mice with vestibular dysfunction. Betahistine alleviates BPPV through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway.


Developmental switch of S-layer protein synthesis in Bacillus anthracis.
Adjustment of the synthesis of abundant protein to the requirements of the cell involves processes critical to the minimization of energy expenditure. The regulation of S-layer genes might be a good model for such processes because expression must be controlled, such that the encoded proteins exactly cover the surface of the bacterium. Bacillus anthracis has two S-layer genes, sap and eag, encoding the S-layer proteins Sap and EA1 respectively. We report that the production and surface localization of Sap and EA1 are under developmental control, suggesting that an exponential phase 'Sap layer' is subsequently replaced by a stationary phase 'EA1 layer'. This switch is controlled at the transcriptional level: sap is most certainly transcribed by RNA polymerase containing sigmaA, whereas eag expression depends on sigmaH. More importantly, Sap is required for the temporal control of eag, and EA1 is involved in strict feedback regulation of eag. This control may be direct because both S-layer proteins bind, in vitro, the eag promoter, specifically suggesting that they might act as transcriptional repressors.


Early visual processing is enhanced in the midluteal phase of the menstrual cycle.
Event-related potential (ERP) studies have revealed an early attentional bias in processing unpleasant emotional images in women. Recent neuroimaging data suggests there are significant differences in cortical emotional processing according to menstrual phase. This study examined the impact of menstrual phase on visual emotional processing in women compared to men. ERPs were recorded from 28 early follicular women, 29 midluteal women, and 27 men while they completed a passive viewing task of neutral and low- and high- arousing pleasant and unpleasant images. There was a significant effect of menstrual phase in early visual processing, as midluteal women displayed significantly greater P1 amplitude at occipital regions to all visual images compared to men. Both midluteal and early follicular women displayed larger N1 amplitudes than men (although this only reached significance for the midluteal group) to the visual images. No sex or menstrual phase differences were apparent in later N2, P3, or LPP. A condition effect demonstrated greater P3 and LPP amplitude to highly-arousing unpleasant images relative to all other stimuli conditions. These results indicate that women have greater early automatic visual processing compared to men, and suggests that this effect is particularly strong in women in the midluteal phase at the earliest stage of visual attention processing. Our findings highlight the importance of considering menstrual phase when examining sex differences in the cortical processing of visual stimuli.


Molecular investigation of zoonotic intracellular bacteria in Chilean bats.
Intracellular pathogens were investigated for the first time in 55 Chilean bats belonging to six species. Using a conventional PCR protocol targeting a fragment of the ITS region, 21 bats (38 %) were positive for DNA of Bartonella sp. Molecular characterization of fragments of the gltA, rpoB and fstZ genes and subsequent phylogenetic analysis indicated the presence of diverse genotypes related to Bartonella from bats worldwide. DNA from C. burnetii was investigated using a real-time PCR (qPCR) protocol targeting the IS1111 gene and yielded positive results for 5 individuals (9%), being the first report of C. burnetii in wildlife in Chile. All bats were negative for Rickettsia sp., evaluated by qPCR for the gltA gene, confirming that bats do not act as important reservoirs for Rickettsia. This preliminary survey calls for more comprehensive studies on the epidemiology of these agents, including larger sample sizes, the evaluation of potential transmission routes and spillover potential.


[Ex vivo confocal laser scanning microscopy for melanocytic lesions and autoimmune diseases].
Ex vivo confocal laser scanning microscopy (CLSM) enables bedside histology and offers the surgeon a direct intraoperative tissue examination. To determine whether this innovative, ultra-fast diagnostic tool can be expanded beyond nonmelanoma skin cancer, particularly basal cell carcinoma, to other indications including melanocytic lesions and autoimmune diseases. Review of literature and summary of the current knowledge and experience of the use of ex vivo CLSM in melanocytic lesions and in autoimmune diseases. Up to date experience of the use of ex vivo CLSM in melanocytic lesions and in autoimmune diseases is limited but promising. Current knowledge on melanocytic lesions in ex vivo CLSM and their examples together with classic ex vivo CLSM features are presented. Previous results on the use of ex vivo CLSM in autoimmune dermatoses are presented, and future application possibilities of ex vivo CLSM are discussed. The method is particularly suitable for the rapid examination of basal cell carcinomas during Mohs surgery but could also be used in the future for the intraoperative examination of melanocytic and autoimmune skin lesions.


Validation and application of the pneumonia prognosis index to nursing home residents with pneumonia.
To evaluate the predictability of a pneumonia prognosis index in nursing home residents with pneumonia and to use the index to account for acute severity of pneumonia before comparing the short-term outcome of residents with pneumonia treated with intravenous antibiotic therapy in two different settings: an inpatient geriatrics unit and a nursing home A retrospective chart review of 158 episodes of nursing home-acquired pneumonia treated initially with intravenous antibiotics; 100 episodes were treated in an inpatient acute geriatrics service (AGS), and 58 were treated completely in a nursing home (Nursing Home group) The AGS is a 20-bed unit within a 400-bed, public, university-affiliated hospital. The Nursing Home group consisted of residents of two nonproprietary nursing homes. Nursing home residents with radiographically proven pneumonia who had at least one of the following signs/symptoms: cough, fever, purulent sputum, respiratory rate > or = 25 per minute, localized auscultatory findings, or pleuritic pain. The pneumonia prognosis index was calculated for each resident at the time of diagnosis of pneumonia; the index has been validated as a predictor of hospital outcome in patients with community-acquired pneumonia and is also considered a measure of acute severity of pneumonia. Status (alive or dead) of each resident at 30 days after diagnosis was the major dependent variable Mean (+/-SD) duration of antibiotic therapy for the Nursing Home group (10.7+/-4.5 days) was not significantly different from that of the AGS group (9.6+/-3.4 days; P = .26). The pneumonia prognosis index stratified the 158 episodes of pneumonia into low- and high-risk groups for 30-day mortality; the mortality rates in each risk strata were not significantly different from those reported in the original derivation and validation studies of the index. In addition, the distribution of episodes among the risk strata of the index was not significantly different for the two study groups, which was an indication that the two groups were similar in terms of acute severity of pneumonia. Thirty-day mortality was not significantly different between the two groups: AGS, 21% and Nursing Home, 24.1% (P = .66). The pneumonia prognosis index seems to have the same capability for predicting the outcome in nursing home residents with pneumonia as in residents with community-acquired pneumonia. The index is also a measure of acute pneumonia severity. Nursing home residents with pneumonia, even those who are most acutely ill, can be treated successfully with intravenous therapy in the nursing home; their 30-day mortality was no different than that of those with the same acute severity of illness who were admitted to a hospital for treatment.


Aberrations in the microbiome of cyanobacteria from a tropical estuary polluted by heavy metals.
The effect of heavy metal pollution on the microbiome of cyanobacteria in Cochin estuary (CE) on the southwest coast of India is reported in the study. Statistically significant difference in heavy metal concentration was observed between water, suspended particulate matter (SPM) and sediment. The Zn, Cd, Cu, Ni and Cr were 2-6 times higher in the SPM compared with the sediment, while Pb was 10 to 25 times higher. Although nearly 60% of the species diversity of microbiome was common between cyanobacteria enriched from the upstream (S1S) and downstream (S11B), there was a difference in the major groups of heterotrophic bacterial associates. Proteobacteria was the dominant phylum (>80%) in S1S, while it was second only (27.5%) after Planctomycetes (37.4%) in S11B. The results of the current study indicate that the pollution can influence an ecosystem at the micro-niche level.


Associations of HDL subclasses and lipid content with complement proteins over the menopause transition: The SWAN HDL ancillary study: HDL and complement proteins in women.
The menopause transition (MT) could trigger low-grade chronic inflammation which may modify high-density lipoproteins (HDL) and lead to additional inflammatory responses contributing to atherosclerosis development. To test whether complement proteins C3 and C4 increase around the final menstrual period (FMP), and whether changes in HDL subclasses and lipid content associate with C3 and C4 levels over time in midlife women. The study included 471 women (at baseline: age 50.2(2.7) years; 87.3% pre or peri-menopausal) who had nuclear magnetic resonance spectroscopy HDL subclasses, lipid content, and C3 and C4 measured up to 5 times over the MT. Adjusted annual changes in C3 and C4 varied by time segments relative to FMP with significant increases, steeper for C3, only observed within 1 year before to 2 years after the FMP. Greater decreases in large HDL particles (HDL-P), HDL size, and HDL-phospholipids, and greater increases in small HDL-P and HDL-Triglycerides were associated with higher C3 and C4 over time, although associations with C4 were weaker than those with C3. Complement proteins C3 and C4 significantly rise around menopause with C3 showing the steepest rise. Changes in HDL subclasses, overall size, and lipid content, over the MT may play a role in modulating inflammation responses known to be related to atherosclerosis. These results raise the possibility that novel therapeutic agents focusing on HDL might contribute to CVD protection by modulating inflammation.


Kinetics of cytokines and PMN-E in thoracoscopic esophagectomy.
Perioperative increases in the levels of cytokines and polymorphonuclear leukocyte elastase (PMN-E) have been shown to be related to degree of surgical trauma. We measured the changes in levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and PMN-E in the perioperative period in patients undergoing thoracoscopic esophagectomy (n = 15) and conventional transthoracic esophagectomy (n = 15) for thoracic esophageal cancer. Both IL-6 and IL-8 increased markedly immediately after transthoracic esophagectomy and thereafter, but only a slight increase was observed after the thoracoscopic procedure (IL-6: p = 0.047; IL-8: p = 0.03). A difference was also seen in the pattern of changes in PMN-E. Levels of PMN-E increased immediately after transthoracic esophagectomy and continued to be high up to the 3rd postoperative day, but they remained low after the thoracoscopic procedure and showed no increase (p <lt; 0.01). These results suggest that, compared with transthoracic esophagectomy, thoracoscopic esophagectomy results in less production of cytokines and PMN-E and thus causes less surgical trauma.


Recovery of non-specific cholinesterase activity in sensory corpuscles of mouse toe skin after irreversible inhibition of this enzyme and cold injury.
Mouse digital corpuscles, located in the dermal papillae of toe pad skin, consist of the sensory axon terminals enveloped by the cytoplasmic processes of Schwann-derived cells forming the so-called inner core. The inner core cells are capable to synthetize nCHE molecules which are released into the interlamellar spaces filled by the basal lamina, collagenous microfibrils, and amorphous matrix. In the present study, the histochemical detection of the nCHE activity was investigated in the sensory corpuscles after sciatic and saphenous nerve transections and subsequent application of irreversible nCHE inhibitor (iso-OMPA) or cryo-treatment of toe pad skin. The recovery of the nCHE reaction product in both intact and denervated corpuscles revealed the resynthesis of the nCHE molecules by the inner core cells without assistance of sensory terminals, as well. The cellular constituents of corpuscles were degraded while extracellular matrix appeared to be undamaged after freezing injury. The molecules of nCHE attached to the extracellular matrix components disappeared in coincidence with the disintegration of Schwann-derived cells. After about 5 d of survival, the Schwann cells exhibiting the nCHE reactivity migrated through the basal lamina tubes as guidance of regrowing axons or alone. After 7 d from the treatment, immature Schwann cells marked by the nCHE reaction product occupied the scaffolds of old damaged sensory corpuscles. During further days of surviving, the Schwann cells entering the extracellular matrix of degraded corpuscles were differentiated to the inner core cells. The re-differentiation of the Schwann cells into the inner core cells was observed not only in the presence but also in the absence of sensory terminals. These findings suggest certain trophic independence of inner core cells upon sensory terminals in the sensory corpuscles of adult animals.


Piriform Rim Asymmetry in Unilateral Cleft Lip and Palate Patients Before Orthognathic Surgery.
Complete unilateral cleft lip and palate (UCLP) creates a continuity defect on the nasal floor, which contributes to nasal asymmetry. Traditionally, piriform rim symmetry has been evaluated by comparing cleft and noncleft sides. No study has compared the magnitude of perinasal asymmetry in UCLP patients with a control group of patients without clefts. To address the following question: In UCLP patients, whose alveolar clefts are reconstructed with alveolar bone grafts (ABGs), is the magnitude of remaining piriform rim asymmetry similar to that of patients without UCLP? This is a retrospective cohort study that used the cone beam computed tomography of UCLP and non-UCLP patients to evaluate the piriform rim symmetry. The sample was derived from patients who presented for orthognathic surgery between January 2015 and December 2022. To be included, patients had to have a maxillary deficiency. The cleft group had ABG performed with symphyseal bone harvest and bone morphogenetic protein application. Patients were excluded from the control group if they had clinical asymmetry and nasal septum deviation. Patients from the UCLP group were excluded if they failed the first attempt of ABG or had a syndrome. Preorthognathic cone beam computed tomography was used to measure the distance from the inferior and lateral aspects of the piriform rim to reference lines. UCLP status grouped as present or absent (control). The magnitude of piriform rim asymmetry defined as the millimetric distance from the inferior and lateral aspects of the piriform rim to reference lines. The covariates were age, sex, tissue thickness at the level of the alar base, and turbinate size. Welch's two-sample t-test was utilized to compare means. A level of significance of 5% (P < .05) was used for all analyses. To analyze the reliability of the measurements intraexaminer and interexaminer errors were tested using the Weir method. A total of 60 patients were included, 30 in each group. The mean age of UCLP patients was 16.76 (range 13 to 25), and the control group was 17 (range 13 to 25), P = .71. The UCLP group had 12 girls, and the control had 18 girls (P = .12). In the UCLP group, the mean discrepancy between affected and unaffected sides at the inferior aspect of the piriform rim was 3.9 mm (range 0.9 to 7 mm, P < .01), and in the control group the discrepancy between right and left sides was 0.1 mm (0-2.1 mm, P = .87). The mean discrepancy between affected and unaffected sides at the lateral aspect of the piriform rim was 3.6 mm (range 0.7 to 7.6 mm, P < .01) in the UCLP group, and in the control group the discrepancy between right and left sides was 0.1 mm (range 0.1 to 5.8 mm, P = .78) in the control group. The mean alar base soft tissue thickness discrepancy was 3.1 mm (range 0.9 to 7.9 mm, P < .01) in the UCLP group and 0 mm (range -1.8 to 1.9 mm, P = .97) in the control group. The mean difference in the turbinate area in the UCLP group was 314 mm2 (range 797 to 2,898) and in the control group 35 mm2 (range 702 to 2,302) (P = .19). ABG with symphyseal bone and bone morphogenetic protein was not able to provide the same level of piriform symmetry observed in patients without a cleft. Alar base tissue was thicker on the cleft side, and the turbinate size demonstrated greater variability in the UCLP patients.


Quantum dots induced monocyte chemotactic protein-1 expression via MyD88-dependent Toll-like receptor signaling pathways in macrophages.
Quantum dots (QDs) are nano-sized semiconductors. Previously, intratracheal instillation of QD705s induces persistent inflammation in mouse lungs. In our present study, QD705-COOH and QD705-PEG activated NF-κB and increased monocyte chemotactic protein-1 (MCP-1) expression in macrophages RAW264.7 via MyD88 dependent Toll-like receptor (TLR) signaling pathways. MyD88 is an adapter protein for most TLRs to activate NF-κB. Silencing expression of MyD88 or p65 with siRNA or co-treatment with a NF-κB inhibitor tremendously abolished QD705s-induced NF-κB activity and MCP-1 expression. The involved TLRs might locate either on the cell surface or inside of cells. Co-treatment with a TLR4 inhibitor completely prevented MCP-1 induction by QD705-PEG. Nevertheless, QD705-COOH readily entered cells, and co-treatment with either inhibitors of endocytosis or intracellular TLRs prevented MCP-1 induction. These findings indicate that, depending on their surface modification, OD705s activate MyD88 dependent-TLRs at the surface or inside of the cells, which is an important mechanism for nanoparticles-induced inflammatory responses. But other MyD88-independent pathways may also involve in these responses.


Tumour necrosis factor-alpha-mediated human polymeric immunoglobulin receptor expression is regulated by both mitogen-activated protein kinase and phosphatidylinositol-3-kinase in HT-29 cell line.
Human polymeric immunoglobulin receptor (pIgR) is present on the surface of glandular epithelium, and it plays a crucial role in the mucosal immune defence. pIgR expression in HT-29 cells is up-regulated by one of the proinflammatory cytokines, tumour necrosis factor (TNF)-alpha. However, the mechanism used by the TNF-alpha-mediated signalling pathway has not been examined exclusively. To elucidate this mechanism in detail, HT-29 cells were cotreated with TNF-alpha and mitogen-activated protein kinase kinase (MAPKK, also called MEK1) inhibitor, PD98059, and the amount of free secretory component (SC) secreted into the culture medium was measured. The amount of free SC stimulated by TNF-alpha was increased by addition of PD98059. This up-regulation occurred at the transcriptional level. The amount of SC was also up-regulated by addition of TNF-alpha with U0126, an inhibitor of MEK1 and MEK2. Nuclear factor (NF)-kappaB activity and NF-kappaB binding to the kappaB2 site localized upstream of the pIgR gene did not change after coincubation of HT-29 cells with TNF-alpha and PD98059. The expression level of pIgR by TNF-alpha was decreased by LY294002, an inhibitor of phosphatidylinositol-3-kinase (PI3K), at the transcriptional level. Extracellular signal-regulated kinase (ERK)1/2 phosphorylation and NF-kappaB binding to the kappaB2 site were not affected by LY294002 treatment. These data suggest that TNF-alpha-mediated pIgR expression is negatively regulated by ERK pathway, which is independent of NF-kappaB. In addition, decrease of SC production by Ly294002 suggests that the presence of PI3K mediated regulation of SC production.


Global Positioning System-Derived Workload Metrics and Injury Risk in Team-Based Field Sports: A Systematic Review.
To evaluate the current literature regarding the utility of global positioning system (GPS)-derived workload metrics in determining musculoskeletal injury risk in team-based field-sport athletes. PubMed entries from January 2009 through May 2019 were searched using terms related to GPS, player workload, injury risk, and team-based field sports. Only studies that used GPS metrics and had injury as the main outcome variable were included. Total distance, high-speed running, and acute : chronic workload ratios were the most common GPS metrics analyzed, with the most frequent sports being soccer, rugby, and Australian rules football. Many distinct workload metrics were associated with increased injury risk in individual studies performed in particular sport circumstances; however, the body of evidence was inconclusive as to whether any specific metrics could consistently predict injury risk across multiple team-based field sports. Our results were inconclusive in determining if any GPS-derived workload metrics were associated with an increased injury risk. This conclusion is due to a myriad of factors, including differences in injury definitions, workload metrics, and statistical analyses across individual studies.


Elevated serum beta-2-microglobulin--a prognostic marker for development of AIDS among patients with persistent generalized lymphadenopathy.
For evaluation of its prognostic value, the level of serum beta-2-microglobulin was determined in early serum samples from 88 patients with persistent generalized lymphadenopathy in a prospective longitudinal study. Patients with serum beta-2-microglobulin greater than 2.6 mg/l were found to have a significantly higher risk of developing AIDS earlier when compared to patients with a lower level (p less than 0.001).


Mapping evidence on HIV status awareness among key and vulnerable populations in sub-Sahara Africa: a scoping review protocol.
Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) continue to be a major public health issue, especially in sub-Sahara Africa (SSA). Literature shows significant HIV status awareness, testing, and treatment have generally improved among the population since the inception of the UNAIDS 90:90:90 programme. Despite this, it is possible literature gaps exist that require future research to inform in-country programmes to improve the gains post-UNAIDS 90:90:90 programme. This study, therefore, aims to synthesize literature and describe the evidence on HIV status awareness among key and vulnerable populations in SSA focusing on the first UNAIDS 90 since it is essential for treatment initiation. This systematic scoping review will be guided by the framework proposed by Arksey and O'Malley and improved by Levac and colleagues. Literature searches will be conducted in PubMed, SCOPUS, CINAHL, Google Scholar, and Science Direct from 2016 to 2020. A snowball approach will also be used to search for relevant articles from the reference of all included studies. This study will include both published and grey literature, articles that include HIV key and vulnerable populations, HIV status awareness, and evidence from SSA countries. Two reviewers will independently conduct the abstract and full-text article screening as well as pilot the data extraction form. Thematic content analysis and a summary of the themes and sub-themes will be reported narratively. The evidence that will be provided by this study may be useful to inform in-country programmes to improve the gains made post-UNAIDS 90:90:90 programme from 2021 onwards. This study also anticipates identifying literature gaps to guide researchers interested in this field of study in the future. Peer review journals, policy briefs, and conference platforms will be used to disseminate this study's findings.


Human platelets do not express tissue factor.
The controversy about the expression of tissue factor (TF) in platelet after de novo synthesis prevail despite many groups recognize that platelet isolation, assays and reagents, particularly non-specific antibodies, may account for the diversity. In this study the potential of TF expression was evaluated using immune-purified human platelets and employing a very sensitive and highly specific TF activity assay. Isolated platelets in plasma anti-coagulated with Fragmin were subjected to stimulation by LPS plus PMA, IgG antibody or TRAP and tested for TF activity. Platelets stimulated with LPS plus PMA for 4 hours expressed trace amounts of TF like activity (PCA), not inhibited by anti-TF antibody (0.2±0.1 mU/ml blood). Platelets, not immune-adsorbed to remove monocytes, showed significant TF activity (2.0±0.9 mU/ml blood) that was nearly abolished by anti-TF antibody. IgG antibody from patient with lupus anticoagulant failed to enhance the trace amount of PCA as compared to the control in contrast to high TF activity induced in monocytes (0.4±0.1 mU/ml blood versus 27.5±10.5 mU/10(6) cells) showing that activation of complement is not mediating TF expression. Platelet subjected to TRAP activation for 10 min possessed only trace amounts of PCA that was not inhibited by anti-TF antibody and slightly enhanced by anti-TFPI antibody. It is concluded that platelets free of monocytes do not express TF activity when stimulated by LPS or activated complement factors, implying no role for Toll like receptor (TLR4) as suggested recently. There is no evidence of TF activity associated with platelets as a result of rapid and dynamic process.


Seeking optimization of LT4 treatment in patients with differentiated thyroid cancer.
Levothyroxine sodium (LT4) is the mainstay treatment to replace thyroid hormonal production in thyroidectomized patients, but, depending on the aggressiveness of the cancer and on the risk of recurrence, patients with differentiated thyroid cancer may also be treated in a TSH-suppressive or semi-suppressive mode. The pathophysiological rationale for this LT4 treatment stems from the role of TSH, considered to be a growth factor for follicular cells, potentially inducing initiation or progression of follicular cell-derived thyroid cancer. Therefore, accurate tailoring of treatment, taking into account both patient characteristics (age and comorbidities) and risk of persistent/recurrent disease, is highly recommended. Furthermore, adjustments to traditional LT4 treatment should be made in thyroidectomized patients due to the lack of thyroidal contribution to whole body triiodothyronine (T3) concentration. Since LT4 exhibits a narrow therapeutic index and the side effects of over- and under-treatment could be deleterious, particularly in this category of patients, caution is required in dose individualization, in the mode of ingestion, and in potential pharmacological and other types of interference as well. Our aim was to analyze the current knowledge concerning LT4 dose requirements in patients with thyroid cancer according to different therapeutic approaches, taking into account a number of factors causing interference with LT4 efficacy. Specific mention is also made about the use of the novel LT4 formulations.