The state of the art in breast imaging using the Twente Photoacoustic Mammoscope: results from 31 measurements on malignancies.
Photoacoustic mammography is potentially an ideal technique, however, the amount of patient data is limited. To further our understanding of the in vivo performance of the method and to guide further research and development, we imaged 33 breast malignancies using the research system - the Twente Photoacoustic Mammoscope (PAM). Thirty-one patients participated in this retrospective, observational study. The study and informed consent procedure were approved by the local ethics committee. PAM uses 1,064 nm light for excitation with a planar, 588-element, 1-MHz ultrasound array for detection. Photoacoustic lesion visibility and appearance were compared with conventional imaging (x-ray mammography and ultrasonography) findings, histopathology and patient demographics. Of 33 malignancies 32 were visualized with high contrast and good co-localization with conventional imaging. The contrast of the detected malignancies was independent of radiographic breast density, and size estimation was reasonably good with an average 28 % deviation from histology. However, the presence of contrast areas outside the malignant region is suggestive for low specificity of the current system. Statistical analyses did not reveal any further relationship between PAM results and patient demographics nor lesion characteristics. The results confirm the high potential of photoacoustic mammography in future breast care. • Photoacoustic breast imaging visualizes malignancies with high imaging contrast. • Photoacoustic lesion contrast is independent of the mammographically estimated breast density. • No clear relationship exists between photoacoustic characteristics and lesion type, grade, etc. • Photoacoustic specificity to breast cancer from some cases is not yet optimal.


Manganese-induced α-synuclein overexpression promotes the accumulation of dysfunctional synaptic vesicles and hippocampal synaptotoxicity by suppressing Rab26-dependent autophagy in presynaptic neurons.
Manganese (Mn) overexposure induces learning and memory impairments in mice by disrupting the functions of synapses and synaptic vesicles (SVs) in the hippocampus, which is associated with α-synuclein (α-Syn) overexpression. Rab26-dependent autophagy is a key signaling step required for impaired SV clearance; however, it is unclear whether Mn-induced α-Syn overexpression is linked to dysregulated Rab26-dependent autophagy in presynaptic neurons. In this study, we developed manganism models in male C57BL/6 mice and hippocampal primary neurons to observe the associations between Mn-induced α-Syn overexpression and impaired SV accumulation. The results of the in vivo experiments showed that 100 and 200 μmol/kg Mn exposure significantly impaired memory and synaptic plasticity in the mice, which was related to the accumulation of impaired SVs in the hippocampus. Consistent with the in vivo outcomes, the level of in vitro injured SVs in the 50 and 100 μmol/L Mn-exposed neuron group were higher than that in the control group. Moreover, 100 μmol/L Mn suppressed the initiation of Rab26-dependent autophagy at the synapse. Then, we transfected neurons with LV-α-Syn short hairpin RNA (shRNA) and exposed the neurons to Mn for an additional 24 h. Surprisingly, the area of colocalization between Rab26 and Atg16L1 and the expression level of LC3II-positive SVs were both higher in Mn-exposed LV-α-Syn shRNA-transfected neurons than those in Mn-treated normal or Mn-treated LV-scrambled shRNA-transfected neurons. Thus, Mn-induced α-Syn overexpression was responsible for the dysregulation of Rab26-dependent autophagy, thereby promoting the accumulation of injured SVs, and causing synaptotoxicity and cognitive and memory deficits in mice.


Virus removal from water by a portable water treatment device.
Few portable point-of-use (POU) devices are available for treatment of water by recreational enthusiasts who may obtain water from untreated sources (rivers, lakes, etc.). This study evaluated a POU device containing a structure matrix capable of removing viruses from water without the use of a disinfectant. The unit was evaluated for the removal of poliovirus type 1, rotavirus SA-11, human norovirus, and a wide range of different coliphages exhibiting different isoelectric points, sizes, and shapes. The removal of all virus types tested exceeded 99.99%. The tested unit complied with the criteria guidelines for virus removal under the US Environmental Protection Agency's "Guide Standard and Protocol for Testing of Microbiological Water Purifiers."


Sources of Ca2+ for contraction of the heart tube of Tenebrio molitor (Coleoptera: Tenebrionidae).
Insect and vertebrate hearts share the ability to generate spontaneously their rhythmic electrical activity, which triggers the fluid-propelling mechanical activity. Although insects have been used as models in studies on the impact of genetic alterations on cardiac function, there is surprisingly little information on the generation of the inotropic activity in their hearts. The main goal of this study was to investigate the sources of Ca2+ for contraction in Tenebrio molitor hearts perfused in situ, in which inotropic activity was assessed by the systolic variation of the cardiac luminal diameter. Increasing the pacing rate from 1.0 to 2.5 Hz depressed contraction amplitude and accelerated relaxation. To avoid inotropic interference of variations in spontaneous rate, which have been shown to occur in insect heart during maneuvers that affect Ca2+ cycling, experiments were performed under electrical pacing at near-physiological rates. Raising the extracellular Ca2+ concentration from 0.5 to 8 mM increased contraction amplitude in a manner sensitive to L-type Ca2+ channel blockade by D600. Inotropic depression was observed after treatment with caffeine or thapsigargin, which impair Ca2+ accumulation by the sarcoplasmic reticulum (SR). D600, but not inhibition of the sarcolemmal Na+/Ca2+ exchanger by KB-R7943, further depressed inotropic activity in thapsigargin-treated hearts. From these results, it is possible to conclude that in T. molitor heart, as in vertebrates: (a) inotropic and lusitropic activities are modulated by the heart rate; and (b) Ca2+ availability for contraction depends on both Ca2+ influx via L-type channels and Ca2+ release from the SR.


Monolithic molecularly imprinted polymer for sulfamethoxazole and molecular recognition properties in aqueous mobile phase.
A monolithic molecularly imprinted polymer (monolithic MIP) for sulfamethoxazole (SMO) was prepared by in situ polymerization method as the HPLC stationary phase. By optimizing the polymerization conditions, the monolithic MIP showed highly specific recognition for the template SMO over its three structurally related analogs. As shown by SEM and the pore size distribution profile, the resultant MIP monolith showed a main pore diameter of 594 nm and a large specific surface area of 124 m2 g(-1), this allowed the mobile phase to flow through the column with low backpressure. Furthermore, the recognition abilities of the monolithic MIP in aqueous and organic media were studied. The results exhibited that the monolithic MIP possessed excellent recognition ability in aqueous media. Hydrophobic interactions, in addition to shape recognition, were the dominant effect for recognition in the mobile phase with high water content. Moreover, the binding sites and the dissociation constant were also determined by frontal chromatography as 122 micromol g(-1) and 1.88 x 10(-5)mol L(-1), respectively, which demonstrated that the obtained SMO-MIP monolith had a high binding capacity and strong affinity ability to the template molecule. Furthermore, the resultant SMO-MIP monolith was used as HPLC column directly to determine the SMO contents in three kinds of pharmaceutical tablets with the optimized aqueous mobile phase.


The Romberg sign, unilateral vestibulopathy, cerebrovascular risk factors, and long-term mortality in dizzy patients.
Describe the relationship between unsteadiness, canal paresis, cerebrovascular risk factors, and long-term mortality in patients examined for dizziness of suspected vestibular origin. Observational cohort with prospective collection of survival data. University clinic neurotological unit. Consecutive patients aged 18-75 years examined in the period 1992-2004 for dizziness of suspected vestibular origin. Overall survival. Standardized mortality ratio (SMR). Factors: Unsteadiness, canal paresis, age, sex, patient-reported diabetes, hypertension, heart disease, stroke, or TIA/minor stroke. Patients were classified as steady or unsteady based on static posturography at baseline compared to normative values. The study included 1,561 patients with mean age 48 years and 60 % females. Mean follow-up was 22 years. Unsteadiness was associated with higher age, heart disease, diabetes, hypertension, and cerebrovascular dizziness. There were 336 deaths over 31,335 person-years (SMR 0.96; 95 % confidence interval: 0.86-1.07). Canal paresis was not related to unsteadiness (chi square: p = 0.46) or to mortality (unadjusted Cox hazard ratio: 1.04, 95% CI: 0.80-1.34). Unsteadiness was an independent predictor of mortality (adjusted Cox hazard ratio: 1.44, 95% CI: 1.14-1.82). Unsteadiness measured by static posturography is associated with higher age, known cerebrovascular risk factors, and with increased long-term mortality, but not with canal paresis in patients evaluated for dizziness. The study highlights the importance of evaluating patients with conspicuous postural instability for non-vestibular causes.


Family-based association study of early growth response gene 3 with child bipolar I disorder.
The risk for relapse of child bipolar I disorder (BP-I) is highly correlated with environmental factors. Immediate early genes of the early growth response (EGR) gene family are activated at high levels in the brain in response to environmental events, including stress, and mediate numerous neurobiological processes that have been associated with mental illness risk. The objective of this study is to evaluate whether single nucleotide polymorphisms (SNPs) in EGR genes are associated with the risk to develop child bipolar I disorder. To investigate whether EGR genes may influence susceptibility to child bipolar I disorder (BP-I), we used Family Based Association Tests to examine whether SNPs in each of the EGR genes were associated with illness in 49 families. Two SNPs in EGR3 displayed nominally significant associations with child BP-I (p=0.027 and p=0.028); though neither was statistically significant following correction for multiple comparisons. Haplotype association analysis indicated that these SNPs are in linkage disequilibrium (LD). None of the SNPs tested in EGR1, EGR2, or EGR4 was associated with child BP-I. This study was limited by small sample size, which resulted in it being underpowered to detect a significant association after correction for multiple comparisons. Our study revealed a preliminary finding suggesting that EGR3, a gene that translates environmental stimuli into long-term changes in the brain, warrants further investigation for association with risk for child BP-I disorder in a larger sample. Such studies may help reveal mechanisms by which environment can interact with genetic predisposition to influence this severe mental illness.


The impact of long-term conditions and comorbidity patterns on COVID-19 infection and hospitalisation: a cohort study.
Older adults are usually more vulnerable to COVID-19 infections; however, little is known about which comorbidity patterns are related to a higher probability of COVID-19 infection. This study investigated the role of long-term conditions or comorbidity patterns on COVID-19 infection and related hospitalisations. This study included 4,428 individuals from Waves 8 (2016-2017) and 9 (2018-2019) of the English Longitudinal Study of Ageing (ELSA), who also participated in the ELSA COVID-19 Substudy in 2020. Comorbidity patterns of chronic conditions were identified using an agglomerative hierarchical clustering method. The relationships between comorbidity patterns or long-term conditions and COVID-19 related outcomes were examined using multivariable logistic regression. Among a representative sample of community-dwelling older adults in England, those with cardiovascular disease (CVD) and complex comorbidities had an almost double risk of COVID-19 infection (OR=1.87, 95% CI=1.42-2.46) but not of COVID-19 related hospitalisation. A similar pattern was observed for the heterogeneous comorbidities cluster (OR=1.56, 95% CI=1.24-1.96). The individual investigations of long-term conditions with COVID-19 infection highlighted primary associations with CVD (OR=1.46, 95% CI=1.23-1.74), lung diseases (OR=1.40, 95% CI=1.17-1.69), psychiatric conditions (OR=1.40, 95% CI=1.16-1.68), retinopathy/eye diseases (OR=1.39, 95% CI=1.18-1.64), and arthritis (OR=1.27, 95% CI=1.09-1.48). In contrast, metabolic disorders and diagnosed diabetes were not associated with any COVID-19 outcomes. This study provides novel insights into the comorbidity patterns that are more vulnerable to COVID-19 infections and highlights the importance of CVD and complex comorbidities.These findings facilitate crucial new evidence for appropriate screening measures and tailored interventions for older adults in the ongoing global outbreak.


SAR110894, a potent histamine H₃-receptor antagonist, displays procognitive effects in rodents.
SAR110894 is a novel histamine H₃-R ligand, displaying high and selective affinity for human, rat or mouse H₃-Rs. SAR110894 is a potent H₃-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H₃-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β₂₅₋₃₅ in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.


[Response to antitumoral agents of a human medulloblastoma implanted into the chorioallantoic membrane of a chick embryo].
In a previous study the authors have reported on a correlation between the effects of drugs on gliomas grown in the eggs and in the nude mice, and in this study, they have observed the antineoplastic effects of ACNU or combined chemotherapy (CAP-cyclophosphamide, adriamycin, cisplatin) against a medulloblastoma applied onto the chorioallantoic membrane (CAM) of a chick embryo. In this model, ACNU was thought to be ineffective because of an intracerebral dissemination that occurred in spite of the administration of ACNU. ACNU also proved ineffective against the medulloblastoma that grew on the CAM. There seemed to be correlation between the results of this test and the clinical course of this model. Thus this sensitivity test is thought to be useful in the screening of drugs against gliomas.


The chin.
The aesthetic aspects of the chin necessitate its evaluation in the context of the nose, mouth, and, to a lesser extent, the neck. Functional consideration must be given to the dental occlusion and the perioral muscular sphincter, and planning should acknowledge the sociologic implications of a strong versus a weak chin. After thorough skeletal and soft-tissue examination, the appropriate type of surgical intervention can be selected. Among the various procedures, chin implant remains the most commonly used, but the osteotomy offers the greatest flexibility, reliability, and potential for significant modification of chin form.


Presumptive subarticular stress reactions of the knee: MRI detection and association with meniscal tear patterns.
MRI detects subchondral marrow findings in painful knees which bear resemblance to spontaneous osteonecrosis of the knee (SONK). Gathering evidence suggests that the primary or predominant pathogenesis of these lesions is physical stress. This study analyzes the patient characteristics and meniscal pathology associated with these lesions-herein referred to as "presumptive subarticular stress related" (PSSR) lesions. All patients were scanned using a standardized imaging protocol. The criterion for a PSSR lesion was a subchondral marrow edema pattern encompassing a more focal, low-signal zone adjacent to or contiguous with the subchondral cortex. Patients were identified using an electronic database search of cases reported by one experienced musculoskeletal radiologist. Twenty-five PSSR lesions were identified among 1948 MRI evaluations of the knee. Twenty-one PSSR lesions occurred in the medial compartment, and four occurred in the lateral compartment. There was no sex predilection. Patients with PSSR lesions were older than other patients undergoing MRI evaluation (mean 66 years versus 52 years, P<0.001). Meniscal tears occurred more commonly in cases with PSSR lesions than in the group as a whole (76% versus 45%, P<0.001). Radial and posterior root tears were more common in knees with PSSR lesions than in other knees with meniscal tears (53% versus 26%, P<0.01). PSSR lesions are associated with meniscal tears and, more specifically, with meniscal tear patterns that dramatically increase contact forces across the knee joint. This observation supports the hypothesis that mechanical stress is important in the pathogenesis of these subarticular lesions that are detected by MRI.


Optimization of 2-aminothiazole derivatives as CCR4 antagonists.
A series of 2-aminothiazole-derived antagonists of the CCR4 receptor has been synthesized and their affinity for the receptor evaluated using a [(125)I]TARC (CCL17) displacement assay. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent, orally bioavailable antagonists.


Diagnosis and treatment of acute inflammatory sacroiliitis in pregnant or post-partum women: a systematic review of the current literature.
The aim of the present study is to systematically review the current literature about diagnosis and treatment of acute inflammatory sacroiliitis in pregnant or post-partum women. A systematic search was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data about clinical presentation, diagnosis methods and treatment strategies were retrieved from included studies and reported in a table. After screening, five studies on 34 women were included; they were all affected by acute inflammatory sacroiliitis. Clinical examination and magnetic resonance imaging were used to confirm diagnosis. In four studies, patients were treated with ultrasound-guided sacroiliac injections of steroids and local anesthetics, while one study used only manual mobilization. Clinical scores improved in all patients. Ultrasound-guided injections proved to be a safe and effective strategy for inflammatory sacroiliitis treatment during pregnancy or post-partum.


The Lavender Fertilized Anterior Cruciate Ligament Reconstruction: A Quadriceps Tendon All-Inside Reconstruction Fertilized With Bone Marrow Concentrate, Demineralized Bone Matrix, and Autograft Bone.
The use of biologics in sports medicine is increasing rapidly. Bone marrow concentrate has recently increased in popularity because it includes mesenchymal stem cells which, combined with AlloSync Pure, could lead to better incorporation and healing. The mixture of bone marrow concentrate and Allosync Pure can be used in anterior cruciate ligament reconstruction. We recently expanded on this approach with the addition of saving the host bone normally lost from tunnel reaming, using the GraftNet. After harvesting the autograft bone, we combine it with the AlloSync Pure and bone marrow concentrate. In this Technical Note, we show how this unique biologic composite is obtained and then added back into the tunnels on both the femur and tibia during a quadriceps tendon autograft all-inside anterior cruciate ligament reconstruction.


Sensitivity of chronic myeloid leukemia hemopoietic progenitors to PTT-119 in combination with human recombinant interferon alpha and gamma.
PTT-119, a new synthetic alkylating compound, has shown a marked "in vitro" inhibitory effect on chronic myeloid leukemia (CML) granulo-monocytic precursors (CFU-GM) at doses greater than 5 micrograms/ml. Based on previous experiences of synergistic associations between alkylating drugs and biological modifiers, we tested the effects of low doses of PTT-119 (from 0.1 to 1 microgram/ml) in concert with alpha, gamma, or alpha + gamma interferons and compared to IFNs alone, in order to investigate an alternative choice for treatment of CML patients in chronic phase. Our results showed a significantly higher CFU-GM cloning inhibition after addition of 100 or 1,000 U/ml of alpha IFN to 0.1 microgram/ml PTT-119 (from 39.6% +/- 26.6 SD to 80.7% +/- 10 SD and 91.5% +/- 8 SD, respectively), while gamma IFN resulted in only a slight increase in colony growth inhibition when compared to the drug used alone. The association of alpha plus gamma IFN coupled with PTT-119 treatment did not significantly improve the results observed after exposure of leukemic progenitors to PTT-119 and alpha IFN alone. We conclude that a combined treatment with PTT-119 and IFN is probably worth testing both for purging methods before autologous bone marrow transplantation and for in vivo administration in chronic myeloid leukemia.


Development of N-ferrocenyl(benzoyl)amino-acid esters stationary phase for high performance liquid chromatography.
A new stationary phase for high-performance liquid chromatography was prepared by covalently bonding N-ferrocenyl(benzoyl)amino-acid esters (L(1)) onto silica gel using 3-aminopropyltriethoxysilane as coupling reagent. The structure of new material was characterized by infrared spectroscopy, elemental analysis and thermogravimetric analysis. The chromatographic behavior of the phase was illustrated in reversed-phase (RP) and normal-phase (NP) modes using polycyclic aromatic hydrocarbons (PAHs), aromatics positional isomers, amines, 5-nitroimidazoles, organophosphorus pesticides and phenols as probes. Multiple mechanisms including hydrophobic, hydrogen bonding, π-π, dipole-dipole, charge-transfer and acid-base equilibrium interactions are involved. Thus, multi-interaction mechanisms and mixed-mode separation of the new phase can very likely guarantee its excellent chromatographic performance for the analysis of complex samples. The L(1) AminoSil column was successfully employed for the analysis of organophosphorus pesticides in vegetable.


Dorsal skin necrosis secondary to a solar-induced thermal burn in a brown-coated dachshund.
A 5-year-old neutered male brown dachshund dog was presented for a large dorsal cutaneous burn that occurred following direct sunlight exposure outdoors in high ambient temperatures. Although burns are quite common in dogs, full-thickness solar-induced radiation burns are less common and have not been previously reported in animals without a black hair coat.


Inhibition of xenograft tumor growth in mice by gold nanoparticle-assisted delivery of short hairpin RNAs against Mcl-1L.
A prerequisite for the therapeutic use of small RNAs is the development of a method that can deliver them into animals. Previous studies have shown the capability of functionalized gold nanoparticles to serve as a general platform for loading and delivering DNA oligonucleotides and short hairpin RNAs (shRNAs) into cultured human cells. Here, we report the ability of the gold nanoparticle-assisted gene delivery system (AuNP-GDS) to deliver shRNA to a xenograft tumor in a mouse model. AuNP-GDS delivery of in vitro synthesized shRNA targeted to the Mcl-1L gene knocked down levels of Mcl-1L mRNA and protein by ~36% and ~26%, respectively, which were sufficient to induce apoptosis of the xenograft tumor cells and consequently inhibited the development of the tumor. We demonstrated that our lego-like AuNP-GDS, which can easily load and deliver shRNAs targeted to any gene of interest into living systems, can deliver shRNAs into xenograft tumors, leading to antitumor activity in an animal model.


[Non-specific aortic arteritis with abdominal aortic coarctation].
The paper reports a lethal case of rupture of the 1st and 2nd lumbar arteries with formation of abdominal wall hematoma. Besides this, the unusual suprarenal site of the aorta coarctation was found.


Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.
Astrocytes, often considered as secondary responders to neurodegeneration, are emerging as primary drivers of brain disease. Here we show that mitochondrial DNA depletion in astrocytes affects their primary cilium, the signaling organelle of a cell. The progressive oxidative phosphorylation deficiency in astrocytes induces FOXJ1 and RFX transcription factors, known as master regulators of motile ciliogenesis. Consequently, a robust gene expression program involving motile cilia components and multiciliated cell differentiation factors are induced. While the affected astrocytes still retain a single cilium, these organelles elongate and become remarkably distorted. The data suggest that chronic activation of the mitochondrial integrated stress response (ISRmt) in astrocytes drives anabolic metabolism and promotes ciliary elongation. Collectively, our evidence indicates that an active signaling axis involving mitochondria and primary cilia exists and that ciliary signaling is part of ISRmt in astrocytes. We propose that metabolic ciliopathy is a novel pathomechanism for mitochondria-related neurodegenerative diseases.


Sentinel Lymph Node Biopsy in Thin Cutaneous Melanoma: A Systematic Review and Meta-Analysis.
Most patients with melanoma have a thin (≤1.00 mm) lesion. There is uncertainty as to which patients with thin melanoma should undergo sentinel lymph node (SN) biopsy. We sought to quantify the proportion of SN metastases in patients with thin melanoma and to determine the pooled effect of high-risk features of the primary lesion on SN positivity. Published literature between 1980 and 2015 was searched and critically appraised. Primary outcome was the proportion of SN metastases in patients with thin cutaneous melanoma. Secondary outcomes included the effect of high-risk pathological features of the primary lesion on the proportion of SN metastases. Summary measures were estimated by Mantel-Haenszel method using random effects meta-analyses. Sixty studies (10,928 patients) met the criteria for inclusion. Pooled SN positivity was 4.5 % [95 % confidence interval (CI) 3.8-5.2 %]. Predictors of a positive SN were: thickness ≥0.75 mm [adjusted odds ratio (AOR) 1.90 (95 % CI 1.08-3.34); with a likelihood of SN metastases of 8.8 % (95 % CI 6.4-11.2 %)]; Clark level IV/V [AOR 2.24 (95 % CI 1.23-4.08); with a likelihood of 7.3 % (95 % CI 6.2-8.4 %)]; ≥1 mitoses/mm2 [AOR 6.64 (95 % CI 2.77-15.88); pooled likelihood 8.8 % (95 % CI 6.2-11.4 %)]; and the presence of microsatellites [unadjusted OR 6.94 (95 % CI 2.13-22.60); likelihood 26.6 % (95 % CI 4.3-48.9 %)]. The pooled proportion of SN metastases in thin melanoma is 4.5 %. Thickness ≥0.75 mm, Clark level IV/V, mitoses, and microsatellites significantly increased the odds of SN positivity and should prompt strong consideration of SN biopsy.


Purification, photoaffinity labeling, and characterization of a single enzyme for 6-sulfation of both chondroitin sulfate and keratan sulfate.
A soluble sulfotransferase that could 6-sulfate both chondroitin sulfate and corneal keratan sulfate was purified 27,500-fold using a sequence of affinity chromatographic steps with heparin-Sepharose, wheat germ agglutinin-agarose, and 3',5'-ADP-agarose. The essentially pure enzyme had a specific activity 40 times greater than the most purified chondroitin 6-sulfotransferase previously reported and exhibited a single sharp Coomassie Blue-stained and a heavy silver-stained protein band of 75 kDa on SDS-polyacrylamide gel electrophoresis. Chromatography of the purified enzyme on Sephacryl demonstrated a size of 150 kDa, which indicated that the native enzyme exists as a dimer. In addition to 6-sulfation of nonsulfated GalNAc, the purified serum enzyme had the ability to sulfate GalNAc 4-sulfate residues to give GalNAc 4,6-disulfate residues. The purified enzyme exhibited a Km of 40 microM for adenosine 3'-phosphate 5'-phosphosulfate when either chondroitin sulfate or corneal keratan sulfate were used as the acceptors. Use of both chondroitin sulfate and keratan sulfate in the same experiment demonstrated mutual competition, establishing that the sulfation of these substrates is by the same enzyme. Photoaffinity labeling of the purified enzyme with 2-azidoadenosine 3',5'-di[5'-32P]phosphate occurred only with the 75-kDa protein, confirming that this is the chondroitin 6-sulfotransferase/keratan sulfotransferase.


Ecological drivers switch from bottom-up to top-down during model microbial community successions.
Bottom-up selection has an important role in microbial community assembly but is unable to account for all observed variance. Other processes like top-down selection (e.g., predation) may be partially responsible for the unexplained variance. However, top-down processes and their interaction with bottom-up selective pressures often remain unexplored. We utilised an in situ marine biofilm model system to test the effects of bottom-up (i.e., substrate properties) and top-down (i.e., large predator exclusion via 100 µm mesh) selective pressures on community assembly over time (56 days). Prokaryotic and eukaryotic community compositions were monitored using 16 S and 18 S rRNA gene amplicon sequencing. Higher compositional variance was explained by growth substrate in early successional stages, but as biofilms mature, top-down predation becomes progressively more important. Wooden substrates promoted heterotrophic growth, whereas inert substrates' (i.e., plastic, glass, tile) lack of degradable material selected for autotrophs. Early wood communities contained more mixotrophs and heterotrophs (e.g., the total abundance of Proteobacteria and Euglenozoa was 34% and 41% greater within wood compared to inert substrates). Inert substrates instead showed twice the autotrophic abundance (e.g., cyanobacteria and ochrophyta made up 37% and 10% more of the total abundance within inert substrates than in wood). Late native (non-enclosed) communities were mostly dominated by autotrophs across all substrates, whereas high heterotrophic abundance characterised enclosed communities. Late communities were primarily under top-down control, where large predators successively pruned heterotrophs. Integrating a top-down control increased explainable variance by 7-52%, leading to increased understanding of the underlying ecological processes guiding multitrophic community assembly and successional dynamics.


Molecular Association of Glia Maturation Factor with the Autophagic Machinery in Rat Dopaminergic Neurons: a Role for Endoplasmic Reticulum Stress and MAPK Activation.
Parkinson's disease (PD) is one of the several neurodegenerative diseases where accumulation of aggregated proteins like α-synuclein occurs. Dysfunction in autophagy leading to this protein build-up and subsequent dopaminergic neurodegeneration may be one of the causes of PD. The mechanisms that impair autophagy remain poorly understood. 1-Methyl-4-phenylpiridium ion (MPP+) is a neurotoxin that induces experimental PD in vitro. Our studies have shown that glia maturation factor (GMF), a brain-localized inflammatory protein, induces dopaminergic neurodegeneration in PD and that suppression of GMF prevents MPP+-induced loss of dopaminergic neurons. In the present study, we demonstrate a molecular action of GMF on the autophagic machinery resulting in dopaminergic neuronal loss and propose GMF-mediated autophagic dysfunction as one of the contributing factors in PD progression. Using dopaminergic N27 neurons, primary neurons from wild type (WT), and GMF-deficient (GMF-KO) mice, we show that GMF and MPP+ enhanced expression of MAPKs increased the mammalian target of rapamycin (mTOR) activation and endoplasmic reticulum stress markers such as phospho-eukaryotic translation initiation factor 2 alpha kinase 3 (p-PERK) and inositol-requiring enzyme 1α (IRE1α). Further, GMF and MPP+ reduced Beclin 1, focal adhesion kinase (FAK) family-interacting protein of 200 kD (FIP200), and autophagy-related proteins (ATGs) 3, 5, 7, 16L, and 12. The combined results demonstrate that GMF affects autophagy through autophagosome formation with significantly reduced lysosomal-associated membrane protein 1/2, and the number of autophagic acidic vesicles. Using primary neurons, we show that MPP+ treatment leads to differential expression and localization of p62/sequestosome and in GMF-KO neurons, there was a marked increase in p62 staining implying autophagy deficiency with very little co-localization of α-synuclein and p62 as compared with WT neurons. Collectively, this study provides a bidirectional role for GMF in executing dopaminergic neuronal death mediated by autophagy that is relevant to PD.


Rasch analysis of anxiety scales in Parkinson's disease.
Anxiety is a common non-motor symptom in Parkinson's disease (PD). This study analyzed the measurement properties of three frequently used anxiety scales in PD: the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HARS), and the Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A). The Rasch model was applied to a multicenter international cohort of 342 patients and assessed the following aspects: fit to the Rasch model, unidimensionality, reliability, response category ordering, item local independence, differential item functioning, and scale targeting. In their original form, the BAI, HARS, and HADS-A, did not fit the Rasch model. A good fit to the Rasch model was only found after significant modifications, including rescoring some items and deleting those failing to fit the model. For the BAI and HADS-A, these adjustments resulted in unidimensionality. The HARS was not unidimensional and separate analyses were performed for its psychic and somatic subscales. Whereas the somatic anxiety subscale fit the Rasch model, this was achieved for the psychic anxiety subscale after modifications. None of the currently used anxiety scales display satisfactory measurement properties for assessing anxiety in PD. The results suggest the need to develop a new disease-specific scale for measuring anxiety in PD.


Mouse vanin-1 is cytoprotective for islet beta cells and regulates the development of type 1 diabetes.
Islet cell death is a key initiating and perpetuating event in type 1 diabetes and involves both immune-mediated and endogenous mechanisms. The epithelial pantetheinase vanin-1 is proinflammatory and cytoprotective via cysteamine release in some tissues. We investigated the impact of a vanin-1 deficiency on islet death and type 1 diabetes incidence. Vanin-1-deficient mice were produced and tested in drug-induced and autoimmune diabetes models. The contribution of vanin-1 to islet survival versus immune responses was evaluated using lymphocyte transfer and islet culture experiments. The vanin-1/cysteamine pathway contributes to the protection of islet beta cells from streptozotocin-induced death in vitro and in vivo. Furthermore, vanin-1-deficient NOD mice showed a significant aggravation of diabetes, which depended upon loss of vanin-1 expression by host tissues. This increased islet fragility was accompanied by greater CD4+ insulitis without impairment of regulatory cells. Addition of cystamine, the product of pantetheinase activity, protected islets in vitro and compensated for vanin-1 deficiency in vivo. This study unravels a major cytoprotective role of cysteamine for islet cells and suggests that modulation of pantetheinase activity may offer alternative strategies to maintain islet cell homeostasis.


Characterization of new IgG lambda myeloma plasma cell line (EJM): a further tool in the investigation of the biology of multiple myeloma.
A new IgG lambda myeloma plasma cell line known as EJM was established from a peritoneal effusion from a patient with extramedullary myeloma. The EJM cells have a plasmablastic morphology with abundant rough endoplasmic reticulum and grow in liquid culture with a doubling time of 72 h and a labelling index of 36%. In addition to cytoplasmic IgG lambda, the cells are positive for CD9, 20, 32, 38, 44, 54, 71, 78, MHC Class II DR, DP and DQ. Studies on the control of the cell line proliferation by cytokines have demonstrated stimulation with interleukin 6. In contrast interferon alpha produces marked inhibition of proliferation in doses of greater than 100 units/ml. The culture conditions and the importance of accessory cells and cytokines in supporting myeloma plasma cell growth in vitro are discussed.


Amino-catalyzed fragmentation characteristics of polyamides containing N-methylpyrrole and N-methylimidazole by electrospray negative ionization mass spectrometry.
Different negative fragmentations of synthesized polyamides containing N-methylpyrrole and N-methylimidazole were analyzed by electrospray ionization tandem mass spectrometry with low-energy collision-induced dissociation. An interesting rearrangement derived from amino catalysis of N-methylimidazole was observed. The observation is useful for the study of the correlations between the sequences of polyamides and their mass fragmentation pathways.


A clinical nomogram and heat map for assessing survival in patients with stage I non-small cell lung cancer after complete resection.
Assessing the prognosis of patients with early-stage non-small cell lung cancer (NSCLC) has become a major clinical issue. This study aimed to devise an effective clinical nomogram and heat map for assessing the survival of patients with stage I NSCLC receiving complete resection. Nomograms were established based on a retrospective study of 654 patients with stage I NSCLC who underwent radical resection at Sun Yat-Sen University Cancer Center between January 2009 and December 2014. The concordance index (C-index) and calibration curve were used to measure the accuracy and discriminative ability of the final nomogram. Heat maps were constructed with prognostic factors and survival probabilities. Survival curves were depicted using the Kaplan-Meier method, and the log-rank test was used to determine significance. Patients were classified into low- and high-risk subgroups using recursive partitioning analysis based on nomogram scores. In univariate and multivariate analyses, the independent factors for overall survival (OS) and disease-free survival (DFS) were age, sex, tumor size, and visceral pleural invasion, which were all selected in the nomogram. The C-indices of the nomogram for predicting OS and DFS were 0.694 [95% confidence interval (CI) 0.651-0.737] and 0.653 (95% CI 0.61-0.696), respectively. The calibration curves for OS and DFS probabilities showed a good agreement between the nomogram prediction and actual observation. A heat map was generated using the above independent factors for OS and DFS. High-risk patients had shorter OS [hazard ratio (HR) = 3.535, 95% CI 2.444-5.113, p < 0.001] and DFS (HR = 2.607, 95% CI 1.922-3.537, p < 0.001) than low-risk patients. We established a prognostic nomogram and heat map that can be useful for evaluating survival in patients with stage I NSCLC after complete resection. The tools resulted in more accurate prediction and may guide clinicians in making treatment decisions.


T cell factor 1 is required for group 2 innate lymphoid cell generation.
Group 2 innate lymphoid cells (ILC2) are innate lymphocytes that confer protective type 2 immunity during helminth infection and are also involved in allergic airway inflammation. Here we report that ILC2 development required T cell factor 1 (TCF-1, the product of the Tcf7 gene), a transcription factor also implicated in T cell lineage specification. Tcf7(-/-) mice lack ILC2, and were unable to mount ILC2-mediated innate type 2 immune responses. Forced expression of TCF-1 in bone marrow progenitors partially bypassed the requirement for Notch signaling in the generation of ILC2 in vivo. TCF-1 acted through both GATA-3-dependent and GATA-3-independent pathways to promote the generation of ILC2. These results are reminiscent of the critical roles of TCF-1 in early T cell development. Hence, transcription factors that underlie early steps of T cell development are also implicated in the development of innate lymphoid cells.


Zambia cervical cancer control program resource mapping - Leveraging support to achieve the 90-70-90 elimination target.
Zambia has one of the highest incidence and mortality rates of cervical cancer at 65.5 and 43.4 per 100 000 respectively. In line with efforts of the cervical cancer elimination strategy the Zambia national cervical cancer sub-committee undertook a resource mapping exercise of projected spending on the prevention and control program. The aim was to elicit the available resources over a prospective 4-year period and compare it to the projected costs. A 4-step approach was used for this activity. This included creation of tool adapted for the local program, orientation of stakeholders to the tool, population of the tool by stakeholders and collation, comparison and reporting of submitted data. Comparative analysis to the cervical cancer control costing report 2019-2023 was conducted. Fifty-nine percent of resources in the stipulated period were allocated to prevention efforts. Isolated with diagnostic, treatment and palliation (14 %) the prevention allocation increased to 81 %. Community and stakeholder engagement was 5 % whilst technical assistance and health information were 12 % and 9 % respectively. The dispensation to research was the lowest at 0.7 %. For health system levels, secondary and primary levels were projected at 40 % and 12 % respectively following the central allotment of 45 %. Community and stakeholder engagement took up 3 %. The secondary prevention to tertiary intervention ratio was 4:1 in the projection compared to approximately 2:1 in the actual budgeted costs for the same period, showing a two-fold discordance. To achieve the accelerated elimination of cervical cancer as a public health problem policy cohesiveness is necessary. This can be facilitated with continuous stakeholder involvement in planning, implementation and review. In order to accelerate the elimination of cervical cancer as a public health problem policy cohesiveness is vital and this can be achieved by continuous stakeholder involvement in planning, implementation and review.


TransDIR: Deformable imaging registration network based on transformer to improve the feature extraction ability.
Imaging registration has a significant contribution to guide and support physicians in the process of decision-making for diagnosis, prognosis, and treatment. However, existing registration methods based on the convolutional neural network cannot extract global features effectively, which significantly influences registration performance. Moreover, the smoothness of the displacement vector field (DVF) fails to be ensured due to the miss folding penalty. In order to capture abundant global information as well as local information, we have proposed a novel 3D deformable image registration network based on Transformer (TransDIR). In the encoding phase, the transformer with the atrous reduction attention block is designed to capture the long-distance dependencies that are crucial for extracting global information. A zero-padding position encoder is embedded into the transformer to capture the local information. In the decoding phase, an up-sampling module based on an attention mechanism is designed to increase the significance of ROIs. Because of adding folding penalty term into loss function, the smoothness of DVF is improved. Finally, we carried out experiments on OASIS, LPBA40, MGH10, and MM-WHS open datasets to validate the effectiveness of TransDIR. Compared with LapIRN, the DSC score is improved by 1.1% and 0.9% on OASIS and LPBA40, separately. In addition, compared with VoxelMorph, the DSC score is improved by 2.8% on the basis of the folding index decreased by hundreds of times on MM-WHS. The results show that the TransDIR achieves robust registration and promising generalizability compared with LapIRN and VoxelMorph.


Foetal surgery for spina bifida.
In utero repair of open spina bifida or myelomeningocele (MMC) is now performed in selected patients and presents an additional alternative to obstetricians and neonatologists counselling expectant mothers carrying a foetus with MMC. Early foetal intervention may improve neurologic outcomes and reduce the hindbrain herniation associated with the Arnold-Chiari II malformation in open spina bifida. These changes may improve long-term neurologic function and limit requirements for shunt placements and other surgical interventions. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in utero intervention. A prospective, randomized clinical trial is planned comparing prenatal MMC repair with postnatal repair.


Strategies for quality management in clinical microbiology.
Quality assessment and performance improvement are important management functions that add value to information and services produced by the clinical microbiology laboratory. Analytical quality control procedures are well standardized, and in many cases regulated. Whereas preanalytical and postanalytical factors have considerable impact on quality, performance assessment and improvement in this area have received less consideration. This article describes an approach to quality management of the total testing process in clinical microbiology, including interdisciplinary participation, specimen quality, test use, result use, turnaround time, information quality, user perceptions, and benchmarking.


Identification and susceptibility to multipurpose disinfectant solutions of bacteria isolated from contact lens storage cases of patients with corneal infiltrative events.
Corneal infiltrative events (CIEs) are being reported with increasing frequency in lens wearers and may be related to specific multipurpose disinfecting solution (MPDS), contact lens type or bacterial bio-burden. Here, the efficacy of MPDS's against bacteria from contact lens storage cases (CLSC) of patients with CIEs was investigated. Eighteen CLSC from patients with CIEs were cultured. All reported using the same MPDS based on PQ-1+Aldox+nonanoyl-EDTA prior to experiencing CIEs. Bacteria were identified and tested for sensitivity to MPDS-1 and three other MPSDs. 16/18 CLSC (89%) contained bacterial counts of ≥10(4)-10(8)/mL. Achromobacter spp. was most frequently identified and was found in 11/18 cases (61%). This was followed by 4/18 (22%) Stenotrophomonas maltophilia, 3/18 (17%) Serratia marcescens, 3/18 (17%) Delftia spp., 2/18 (11%) Elizabethkingia spp., 2/18 (11%) Chryseobacterium indologenes and 1/18 Sphingobacterium spiritivorum. Acanthamoeba was not isolated. All of the Achromobacter strains were resistant to MPDS-1 with <1log10 kill up to 14 days exposure and the solution also showed reduced efficacy against the other isolates at the manufacturer's recommended disinfection time of 6h. Two strains of S. maltophilia and Delftia spp. grew in the solution over 14 days. Factors responsible for causing adverse events such as CIEs in contact lens wearers remain unclear. However, the presence of significant bio-burden in the contact lens storage case and lens may initiate an immunological response resulting in CIEs either directly or through the release of endotoxins (e.g. lipopolysaccharides) from the bacterial outer cell membrane.


Surveillance of antimicrobial resistant Shiga toxin-producing E. coli O157:H7 in England, 2016-2020.
Shiga toxin-producing Escherichia coli (STEC) O157:H7 are zoonotic pathogens and transmission to humans occurs via contaminated food or contact with infected animals. The aim of this study was to describe the frequency, and distribution across the phylogeny, of antimicrobial resistance (AMR) determinants in STEC O157:H7 isolated from human cases in England. Short-read whole-genome sequencing data from 1473 isolates of STEC O157:H7 from all seven sub-lineages (Ia-Ic, IIa-IIc and I/II) were mapped to genes known to confer phenotypic resistance to 10 different classes of antibiotic. Long-read sequencing was used to determine the location and genomic architecture of the AMR determinants within phylogenetic clusters exhibiting multidrug resistance. Overall, 216/1473 (14.7%) isolates had at least one AMR determinant, although the proportion of isolates exhibiting AMR varied by sub-lineage. The highest proportion of AMR determinants were detected in sub-lineages Ib (28/64, 43.7%), I/II (18/51, 35.3%) and IIc (122/440, 27.7%). In all sub-lineages, the most commonly detected AMR determinants conferred resistance to the aminoglycosides, tetracyclines and sulphonamides, while AMR determinants conferring resistance to fluroquinolones, macrolides and third-generation cephalosporins were rarely detected. Long-read sequencing analysis showed that the AMR determinants were co-located on the chromosome in sub-lineages Ib and lineage I/II, whereas those associated with sub-lineage IIc were encoded on the chromosome and/or large plasmids. AMR genes were unevenly distributed across the different sub-lineages of STEC O157:H7 and between different clades within the same sub-lineage. Long-read sequencing facilitates tracking the transmission of AMR at the pathogen and mobile genetic element level.


Septo-hippocampal relationships during EEG theta rhythm.
The firing pattern of 96 neuron in the medial septal nucleus (MSN) and diagonal band of Broca (DBB) and their functional relationships with hippocampal theta generators were investigated in rats during physostigmine-induced hippocampal theta rhythm (theta). Three types of discharge were found. (a) Type 1 (74%), in rhythmic bursts phase-locked with theta. (b) Type 2 (19%), non-rhythmic but phase-related to theta. (c) Type 3 (7%), unrelated to theta and non-rhythmic. Three sub-patterns of type 1 discharges were found. (1) Type 1A (56%), with regular bursts at high intraburst rates. (2) Type 1B (11%), with short bursts, or a single spike per theta cycle, and long interburst silent intervals. (3) Type 1C (6%), without clearly separate bursts, but with a rate modulation related to theta. Electrical stimulation of structures projecting to MSN-DBB or hippocampus tended to determine a constant poststimulus phase of theta and type 1 unit activity (i.e., reset). Our findings are in agreement with the hypothesis that MSN-DBB type 1 cells function as the theta "pacemaker', type 1A probably being the most influential in generating theta. Type 1B may be local interneurons and type 1C may receive rhythmic information from both septal and hippocampal neurons. Type 2 cells, although non-rhythmic, carry information of theta rhythmicity. Stimulus effects suggest that hippocampal theta reset is generated in the MSN-DBB.


Correlation between inhibitory effect on platelet aggregation and disposition of sulfinpyrazone and its metabolites in rabbits. Part II: Multiple dose study.
In a crossover study rabbits were given perorally sulfinpyrazone (SO) and the sulfide metabolite (S) every 24 h for 5 days on separate occasions and inhibition of aggregation was measured. The results showed: the dosage regimen is effective if the minimum effective concentration of S is defined to be between 0.5-1.0 microgram ml-1, and the repeated dosing did not cause changes in disposition kinetics except that the terminal half-life of S was reduced after dosing with S. No significant accumulations in trough concentration and inhibition of aggregation were observed. The results obtained in this study could provide some useful information for design of dosage regimen and blood level monitoring for humans.


A review of factors associated with unprotected sex among adult women in the United States.
To provide an updated review of research since 2005 on factors associated with unprotected sex among women in the United States. PubMed, CINAHL, and PsychINFO were searched from January 2006 through April 2011 using the terms unsafe sex, sexual risk taking, contraception, contraception behavior, birth control, condoms, and condom utilization. Inclusion criteria included studies written in English on adult women in the United States age ≥ 18. Forty-five publications met inclusion criteria. All factors associated with engagement in unprotected sex are presented. Unprotected sex has been associated with increasing age, being married, establishment of trust, recent experience of intimate partner violence, contraceptive side effects, infrequent sexual intercourse, and decreased arousal and pleasure due to contraceptive use. Religion, depression, history of abortion, number of children, having children, and number of pregnancies have not been associated with unprotected sex in recent studies. Several other variables have been studied with mixed results, possibly due to differences in research methods and sample characteristics. More research is needed to elucidate the impact of cultural factors, relationship factors, attitude to pregnancy and motherhood, and reproductive coercion on prevention of pregnancy and sexually transmitted infections. Nurses can lead research on these topics and implement evidence-based practice based on study findings.


Minimax estimation of the integral of a power of a density.
We construct an estimator of ∫fp (z) dz, based on a random sample of size n from a density f on the unit cube in ℝ d . This estimator achieves the minimax rate for f known to belong to a multiple of the unit ball in a Hölder space of order α, where α ≤ d/4. We are mostly interested in the case that the power p is larger than 2 and/or the dimension d is large.


Reality orientation therapy: a study investigating the value of this therapy in the rehabilitation of elderly people.
The Leeds Technique for Therapy with the Aged is described and evaluated. The purpose of the study was two-fold--to evaluate the therapy itself, and to examine it as a possible extra incentive for nurses working with the aged. Forty-six elderly patients were included in the study. Fourteen took part in a pilot study. Later, in a more carefully controlled investigation, the remaining 32 patients were divided into two groups, one of experimental subjects and one of control subjects. Improvement was assessed using the Clifton Assessment Schedule (CAS) and the Stockton Geriatric Rating Scale (SGRS). Twenty-five of the 30 experimental subjects improved and 10 were discharged. Eight of the 16 control subjects improved, but none was discharged.


Pancreatic acinar cell carcinoma--literature review and case report of a 56-year-old man presenting with abdominal pain.
We present a case of acinar cell carcinoma of the pancreas (ACC) with metastasis to the liver in a patient who presented with complaints abdominal pain. The presentation, diagnosis, and management of a 56-year-old man with ACC are discussed here. Imaging with computerized tomography (CT) in particular is crucial in the diagnosis, which can identify the primary lesion as well as metastases. ACC should be considered in the differential as a source of abdominal, epigastric, or back pain with imaging that is suggestive of the diagnosis as prompt recognition and initiation of treatment is paramount in the overall prognosis.


Peritoneal drainage is associated with higher survival rates for necrotizing enterocolitis in premature, extremely low birth weight infants.
To evaluate peritoneal drainage (PD) and laparotomy ± resection/ostomy (LAP) as initial approaches to the surgical management of necrotizing enterocolitis (NEC) in premature, extremely low birth weight (ELBW) infants. Kids' Inpatient Database (2003-2012) was searched for cases of NEC (International Classification of Diseases, ninth revision, Clinical Modification [ICD-9-CM] 777.5x) in premature (<37 weeks), extremely low birth weight (<1000 g) infants. Infants were admitted at <28 days of life. Propensity score (PS)-matched analyses were performed, using end points of hospital mortality, length of stay (LOS), and cost of hospitalization. Cases were matched 1:1 on 48 confounding variables (demographic, clinical, and hospital characteristics and 39 comorbidities). On PS-matched comparison, PD had higher survival versus LAP, P = 0.0009. LOS and cost were higher for PD versus LAP, P < 0.003. Survival rates did not differ between PD + LAP and PD-only treatments. LOS and cost were higher for PD + LAP versus PD-only, P < 0.02. PD + LAP infants had higher survival versus LAP, P = 0.0193. LOS and cost were higher for PD + LAP, P < 0.005. A risk-adjusted PS-matched analysis of operative management in premature, ELBW infants with NEC found higher survival rates associated with PD placement versus LAP, whether PD was used as definitive treatment or with subsequent LAP even after controlling for potential contributors to selection bias (i.e., stability influencing management preference).


The type 2 anti-Müllerian hormone receptor has splice variants that are dominant-negative inhibitors.
Anti-Müllerian hormone (AMH) has both paracrine and hormonal actions that occur at different AMH concentrations, and in cells with different densities of its specific receptor (Amhr2). This diversity is not explained by canonical AMH signaling. We report that Amhr2 has two splice variants: Amhr2Δ2 (AMH binding site) and Amhr2Δ9/10 (kinase domain). Both spliced variants inhibit AMH signaling in a reporter assay. The mRNA for the spliced variants was relatively less abundant than Amhr2 mRNA in all tissues. This suggests that the physiological function(s) of the receptor variants may be restricted to specific cellular/subcellular sites and/or to the transport of AMH.


A micromethod for the isolation of drugs from blood using amberlite XAD-2.
The extraction of drugs from small blood samples (1 ml or less) for subsequent quantitative determination is described. Isolation was carried out by adsorption of the drugs to Amberlite XAD-2 resin utilizing a batch procedure that enabled the simultaneous extraction of up to 200 samples in approx. 5 hours. A new desorption technique yielded extracts of high purity that could be used directly for gas chromatographic or radioimmunological determinations, even if hemolyzed or putrid blood was to be examined. The following 26 substances were quantitated after addition to postmortem blood speciments at concentrations of 1-10 microgram/ml: tilidine, diphenhydramine, dibenzepine, imipramine, chlorpromazine, amphetamine, pentazocine, phenacetin, methaqualone, meprobamate, parathion, diazepam, digoxin, beta-methyldigoxin, carbromal, glutethimide, amobarbital, pentobarbital, cyclobarbital, phenobarbital, diphenylhydantoin, carbutamide, tolbutamide, glycodiazin, tolazamide and chlorpropamide. Thereby recoveries of 60-100% could be achieved. The reproducibility of the procedure was satisfactory as demonstrated by coefficients of variation of 3.7-8%.


Syndecan proteoglycans and cell adhesion.
It is now becoming clear that a family of transmembrane proteoglycans, the syndecans, have important roles in cell adhesion. They participate through binding of matrix ligand to their glycosaminoglycan chains, clustering, and the induction of signaling cascades to modify the internal microfilament organization. Syndecans can modulate the type of adhesive responses induced by other matrix ligand-receptor interactions, such as those involving the integrins, and so contribute to the control of cell morphology, adhesion and migration.


Intra-ponto-mesencephalic recording of binaural interaction in human brain-stem auditory evoked potentials.
Brain-stem auditory evoked potentials (BAEPs) were recorded at intraparenchymatous sites along a ponto-mesencephalic stereotactic penetration path in a patient with the rare condition of a ponto-medullary lesion which required biopsy but did not grossly alter scalp BAEPs. Click stimuli were applied either monaurally (with contralateral masking noise against acoustic cross-talk; conditions 'R,' 'L') or binaurally (condition 'RL'). A binaural interaction trace ('BI') was derived by subtracting the sum of the monaural from the binaural responses: BI = (RL)-(R + L). Despite failure to obtain significant BI components above noise level for scalp BAEPs, at the lower pons clearly discernible, multiphasic BI activity could be recorded beginning at the peak latency of scalp wave III and extending over approximately the next 4 msec. Its amplitude rapidly fell off with distance toward more rostral, mesencephalic recording sites. In relation to this positive finding, the equivocality among some of the previous studies on the detection of BI components in human scalp BAEPs is tentatively rephrased in terms mainly of a low signal-to-noise ratio and of functional peculiarities introduced by the respective stimulation protocols.


Distribution and evolution of chitinase genes in Streptomyces species: involvement of gene-duplication and domain-deletion.
Streptomyces coelicolor A3(2) possesses nine genes for family 18 chitinases and two for family 19, showing high multiplicity. By hybridization analyses, distribution of those chitinase genes was investigated in six other Streptomyces species covering the whole phylogenetic range based on 16S rDNA sequences. All strains showed high-multiplicity of chitinase genes, like S. coelicolor A3(2). The phylogeny and gene organization of the family 18 chitinase genes cloned from Streptomyces species so far were then analyzed to investigate the gene evolution. It was concluded that Streptomyces already possessed a variety of chitinase genes prior to branching into many species, and that the ancestral genes of chiA and chiB have been generated by gene-duplication. In the course of the analyses, evidence that the chi30 and chi40 genes of S. thermoviolaceus were derived from their corresponding original chitinase genes by losing gene parts for substrate-binding domains and fibronectin type III-like domains was obtained. It was thus shown that gene-duplication and domain-deletion were implicated in generating the high diversity and multiplicity of chitinase genes in Streptomyces species.


Protective efficacy of dietary natural antioxidants on microplastic particles-induced histopathological lesions in African catfish (Clarias gariepinus).
Microplastic particles (MPs) are a common environmental pollutant easily ingested by fish in aquaculture. The current study evaluated the protective efficacies of some antioxidant, e.g., lycopene, citric acid, and chlorella, against the toxic effects of MP ingestion by Clarias gariepinus using histopathological biomarkers. Five experimental groups were established, a control group receiving only a standard diet, a group exposed to 500 mg/kg MP concomitant with the standard diet, and three antioxidant groups exposed to MPs plus either lycopene (500 mg/kg), citric acid (30 g/kg), or chlorella (50 g/kg) in the standard diet. After 15 days, fish were sacrificed for histological and histochemical examinations. Histological analysis of the kidney for group 2 (fed 500 mg/kg MPs alone) revealed distributed tissue dissociation, regional glomerular hypertrophy or shrinkage, melanomacrophage accumulation, and expansion of Bowman's space, while liver tissue exhibited dilation and rupture of the central vein wall, hemorrhage, cytoplasmic vacuolation, and cellular necrosis or apoptosis. Fish exposed to MPs also exhibited connective tissue fiber accumulation around renal blood vessels, renal tubules, the central hepatic vein, hepatic blood sinusoids, and serosal, muscle, and submucosal layers of the intestine. In addition, MP exposure reduced carbohydrate (mainly glycogen) contents in the brush borders and basement membranes of renal tubules, glomeruli, and intestinal tissues as well as in the cytoplasm of hepatocytes. These signs of renal, hepatic, and intestinal histopathology were fully or partially reversed by dietary lycopene, chlorella, or citric acid. Enhancing dietary antioxidants is an effective strategy for preventing MP toxicity in Clarias gariepinus in aquaculture.


Effect of foot shock stress on the interferon-gamma production of murine intestinal intraepithelial lymphocytes.
To investigate the effect of stress on interferon (IFN)-gamma production by intestinal intraepithelial lymphocytes (IEL), we exposed male C3H/HeN mice to electric foot shock for 30 min a day for 5 consecutive days. Immediately after the final foot shock stress, IEL from small intestine were isolated by Percoll density gradient. The stress induced a marked suppression of IFN-gamma production by IEL stimulated with immobilized anti-CD3 mAb and a marked decrease in the proportion of IFN-gamma-producing CD3+ IEL or alphabetaTCR+ IEL stimulated with PMA+ionomycin. The alphabetaTCR+ subset was the major cause of stress-induced suppression of IFN-gamma production by IEL. Glucocorticoid induced the suppression of IFN-gamma production by IEL in vitro, which was reversed by mifepristone (RU486), a glucocorticoid receptor antagonist. In vivo administration of RU486 reversed the stress-induced suppression of IFN-gamma production by IEL. In conclusion, repeated foot shock stress suppressed IFN-gamma production of IEL by stress-induced elevation of endogenous glucocorticoid. Substantial suppression of the alphabetaTCR+ subset was the major cause of the suppression.


Transplant social worker and donor financial assistance to increase living donor kidney transplants among African Americans: The TALKS Study, a randomized comparative effectiveness trial.
Lack of donors hinders living donor kidney transplantation (LDKT) for African Americans. We studied the effectiveness of a transplant social worker intervention (TALK SWI) alone or paired with living donor financial assistance to activate African Americans' potential living kidney donors. African Americans (N = 300) on the transplant waiting list were randomly assigned to usual care; TALK SWI; or TALK SWI plus Living Donor Financial Assistance. We quantified differences in live kidney donor activation (composite rate of live donor inquiries, completed new live donor evaluations, or live kidney donation) after 12 months. Participants' mean age was 52 years, 56% were male, and 43% had annual household income less than $40,000. Most previously pursued LDKT. Participants were highly satisfied with TALK social workers, but they rarely utilized Financial Assistance. After 12 months, few (n = 39, 13%) participants had a new donor activation event (35 [12%] new donor inquiries; 17 [6%] new donor evaluations; 4 [1%] LDKT). There were no group differences in donor activation events (subdistribution hazard ratio [95% CI]: 1.09 [0.51-2.30] for TALK SWI and 0.92 [0.42-2.02] for TALK SWI plus Financial Assistance compared to Usual Care, p = 91). Alternative interventions to increase LDKT for African Americans on the waiting list may be needed. Trial registration: ClinicalTrials.gov (NCT02369354).


Usefulness of minimal luminal coronary area determined by intravascular ultrasound to predict functional significance in stable and unstable angina pectoris.
Little is known about the intravascular ultrasound (IVUS) minimal lumen area (MLA) criteria and their accuracy in lesion subsets assorted according to vessel type, lesion location, vessel size, and clinical settings. We therefore assessed the accuracy of subgroup-specific cut-off values in predicting fractional flow reserve (FFR) <0.80. In total 692 consecutive patients with 784 coronary lesions were assessed by IVUS and FFR before intervention. All patients had ≥1 target vessel with a de novo lesion (30% to 90% diameter stenosis). For prediction of FFR <0.80 in the group overall, the best cut-off value of MLA was 2.4 mm(2) (sensitivity 84% and specificity 63%). Overall diagnostic accuracy was only 69%. In the subgroup analysis, the MLA cutoff was 2.4 mm(2) for the left anterior descending coronary artery, 1.6 mm(2) for the left circumflex coronary artery, and 2.4 mm(2) for the right coronary artery. By lesion location, the optimal cutoff was 2.6 mm(2) for proximal, 2.3 mm(2) for mid, and 1.9 mm(2) for distal segments. Furthermore, the cutoffs were 3.2 mm(2) in lesions with a larger RLD >3.5 mm and 1.9 mm(2) in lesions with a smaller RLD <2.75 mm. Nevertheless, diagnostic accuracies of all subgroup-specific criteria were <80%. In conclusion, because IVUS-measured MLA is only 1 of many factors affecting coronary flow hemodynamics, even subgroup-specific criteria were inaccurate in identifying ischemia-inducible stenosis. In conclusion, direct functional assessment is therefore essential in guiding treatment strategies for coronary lesions.


5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by mu-opiate receptor activation.
Activation of 5-hydroxytryptamine-2A receptors increases the frequency of excitatory postsynaptic currents through a focal action at apical, but not basilar, dendrites of neocortical layer V pyramidal cells. Since mu-, delta- and kappa-opiate receptors are known to inhibit depolarization-induced glutamate release in cerebrocortical slices, we examined the opiate receptor subtype(s) that suppress(es) 5-hydroxytryptamine-induced excitatory postsynaptic currents in the medial prefrontal cortex and whether this suppression was occurring through a presynaptic or a postsynaptic mechanism. Only opioid agonists that act upon mu-receptors (i.e. [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin, the endogenous mu-selective agonist endomorphin-1 and the non-selective opioid agonist [Met]enkephalin) suppressed 5-hydroxytryptamine-induced excitatory postsynaptic currents. The delta-agonist [D-phen(2,5)]enkephalin and the kappa-agonist U50,488 were ineffective. Only the selective mu-antagonist CTOP blocked the suppressant effect of enkephalin, while the selective delta-antagonist naltrindole and the selective kappa-antagonist norbinaltorphimine were ineffective. Since the 5-hydroxytryptamine-induced excitatory postsynaptic currents are mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type excitatory amino acid receptors, the failure of mu-agonists to either block postsynaptic AMPA responses or induce outward currents in layer V pyramidal cells suggest that mu-agonists are acting at a presynaptic site to block 5-hydroxytryptamine-induced excitatory postsynaptic currents. Strikingly, a regional selectivity in the suppressant effect of mu-receptor activation on 5-hydroxytryptamine-induced excitatory postsynaptic currents exists, as 300 nM [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin suppressed 5-hydroxytryptamine-induced excitatory postsynaptic currents in the medial prefrontal cortex by nearly 100%, while in the frontoparietal cortex 1 microM [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin suppressed 5-hydroxytryptamine-induced excitatory postsynaptic currents by only 58%. This is the first demonstration of a previously unsuspected physiological interaction between 5-hydroxytryptamine-2A and mu-opiate receptors and may be relevant to the relationship between these receptors and both mood and psychotic disorders.


X-ray photoelectron spectroscopic and electrochemical impedance spectroscopic analysis of RuO2-Ta2O5 thick film pH sensors.
The paper reports on investigation of the pH sensing mechanism of thick film RuO2-Ta2O5 sensors by using X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS). Interdigitated conductimetric pH sensors were screen printed on alumina substrates. The microstructure and elemental composition of the films were examined by scanning electron microscopy and energy dispersive spectroscopy. The XPS studies revealed the presence of Ru ions at different oxidation states and the surface hydroxylation of the sensing layer increasing with increasing pH. The EIS analysis carried out in the frequency range 10 Hz-2 MHz showed that the electrical parameters of the sensitive electrodes in the low frequency range were distinctly dependent on pH. The charge transfer and ionic exchange occurring at metal oxide-solution interface were indicated as processes responsible for the sensing mechanism of thick film RuO2-Ta2O5 pH sensors.


SKY1 and IXR1 interactions, their effects on cisplatin and spermine resistance in Saccharomyces cerevisiae.
The yeast Saccharomyces cerevisiae has been previously used as a model eukaryotic system to identify genes related to drug resistance. Deletion of the IXR1 gene increases resistance to cisplatin, and deletion of the SKY1 gene increases resistance to cisplatin and spermine. Three S. cerevisiae strains and their derivatives, carrying single Δixr1 and Δsky1 and double Δixr1Δsky1 deletions, were compared in terms of resistance against these compounds. We found that the effects of these deletions are highly dependent on the genetic background of the selected strains. These results are valuable in the selection of yeast strains to be used in genetic screenings of compounds with putative pharmacological interest.


Investigation of the effects of cephalosporin antibiotics on glutathione S-transferase activity in different tissues of rats in vivo conditions in order to drug development research.
Glutathione S-transferases are multifunctional enzymes for the cellular defense against xenobiotics and provide protection for organism. In this study, the inhibition effects of some antibiotics were investigated against GST obtained from albino-rats kidney, liver, and heart tissues. Ninety-six albino-rats were randomly divided into 16 groups (n:6). The first four groups were control groups that were administrated blank enjection and decapitated at 1-7 h. The other groups were administrated the antibiotics. In all tissues, GST activity was increased in antibiotics groups at 1st and 3rd hours compared to control groups, while it began to fall at 5th and 7th hours (p < .05). In kidney tissues, it was lower than the same control group the cefuroxime and cefoperazone groups at 7th hours (p < .05). In addition, almost all antibiotic groups of kidney tissues had higher GST activity at all hours than those of control groups, but it was higher only at 5th hours in heart tissues (p < .05).


Translation and evaluation of psychometric properties of the Persian version of the Hypertension Self-Care Activity Level Effects (H-SCALE).
Hypertension is a major cause of cardiovascular disease and premature death worldwide. Managing hypertension through self-care practices is considered one of the most effective strategies. However, to accurately assess the self-care status of individuals with hypertension, a valid and reliable tool is necessary. This study aimed to evaluate the psychometric properties of the Persian version of the Hypertension Self-Care Activity Level Effects Questionnaire. Present methodological study was conducted on 218 patients with hypertension visiting the Clinic of Qom educational and medical centers. Subjects were selected with convenience sampling. Data were collected using the H-SCALE, and a demographic questionnaire. The translation was done from the recommended backward-forward method according to the WHO protocol. After that, face and content validity were applied, along with construct validity involving a comparison of known groups and confirmatory factor analysis. To test reliability, Cronbach's alpha was used. Data analysis was performed by SPSS and smart-PLS software. The factor loadings of the self-care behaviors questionnaire were significant in all constructs, and were higher than 0.5 except for three items. The known-groups method showed that the self-care score of patients with controlled blood pressure was significantly higher than those with uncontrolled blood pressure. The extent of average variance extracted (AVE) of the majority of the constructs in the questionnaire was greater than 0.5 and, the composite reliability was greater than the AVE, indicating a good convergent validity. The divergent validity of the questionnaire was confirmed using the Fornell-Larcker criterion and the heterotrait-monotrait ratio (HTMT). Cronbach's alpha coefficient, combined reliability, and communalities index were optimal. According to research findings, the Persian version of the questionnaire has good validity and reliability that can be used as a tool to measure the level of self-care of hypertension by health care providers.


Reduced M2 macrophages and adventitia collagen dampen the structural integrity of blood blister-like aneurysms and induce preoperative rerupture.
Blood blister-like aneurysms (BBAs) are extremely rare aneurysms. They are predisposed to preoperative rerupture with a high case-fatality rate. Here, we attempt to interrogate the distinct clinicopathology and the histological basis underlying its clinical rerupture. Three middle meningeal arteries, 11 BBA (5 reruptured, 6 non-rerupture) and 19 saccular aneurysm samples were obtained for histopathological investigation. Three reruptured BBAs, 3 non-reruptured BBAs and 6 saccular (3 ruptured, 3 unruptured) aneurysms were obtained for quantitative flow cytometry analysis. Compared with true saccular aneurysms, the BBA aneurysm wall lacks arterial stroma cells including CD31+ endothelial cells and α-SMA + smooth muscle cells. Only fibroblasts and adventitial collagen were observed in the BBA aneurysm wall. Meanwhile, BBAs were enriched with infiltrated inflammatory cells, especially polarized macrophages. Based on the rerupture status, those reruptured BBAs showed drastically reduced fibroblasts and adventitia collagen. Moreover, M2-polarized macrophages were observed dominant in BBAs and exhibit repairing cellular functions based on their interplays with arterial fibroblasts. Reduced M2 macrophages and arterial tissue repairing modulation may be responsible for the decreasing collagen synthesis and fibrosis repairment, which potentially dampens the aneurysm integrity and induces BBA aneurysm reruputre. BBAs poses histopathological features of occult pseudoaneurysms or dissecting aneurysms. Reduced M2 macrophages and adventitia collagen may dampen the structural integrity of BBAs and induce preoperative rerupture.


[Transpatellar refixation of acute quadriceps tendon ruptures close to the proximal patella pole using FiberWire].
Reconstruction of the extensor mechanism of the knee joint by stable suture of the quadriceps tendon. Early functional treatment. Acute or partial disruption of the quadriceps tendon close to the proximal patella pole with loss of extensor function of the knee joint. Open rupture of the quadriceps tendon with extended soft-tissue damage and high risk of or ongoing inflammation until healing of the soft tissues. Chronic quadriceps tendon rupture. Ruptures at the musculotendinous junction. Supine positioning of the patient on a standard operating table with the knee in 30 degrees of flexion. Securing of the proximal tendon stump with two Bunnell sutures using no. 2 Fiber-Wire (Arthrex GmbH, Karlsfeld/Munich, Germany). Creation of a transverse, central trough in the superior pole of the patella. Transosseous refixation of the quadriceps tendon through longitudinal transpatellar drill holes. Intraoperative evaluation of the stability of the suture at 60 degrees of flexion. Repair of the retinacula with multiple interrupted sutures. Partial weight bearing (15-25 kg) for 6 weeks. Knee orthesis for 6 weeks, with increase of the initially allowed flexion of 30 degrees every 2 weeks by another 30 degrees . Initially, continuous passive motion (CPM) and passive movement exercises up to 60 degrees of flexion. After discharge from hospital, outpatient physical therapy with prone active flexion exercises. At the beginning of the 5th week, start with active and passive extension of the knee joint. From the 7th week on, full weight bearing is allowed and coordinative and strengthening exercises should be commenced. Sport activities can gradually be taken up after 3 months. Early diagnosis, timely surgical repair and early functional treatment are important for the outcome of quadriceps tendon ruptures. With the presented method, ruptures close to the upper patella pole can be treated. The majority of quadriceps tendon ruptures takes place in this area since the avascular zone found here predisposes to degenerative changes.


Crystallographic analysis of ribulose 1,5-bisphosphate carboxylase from spinach at 2.4 A resolution. Subunit interactions and active site.
The X-ray structure of the quaternary complex of ribulose 1,5-bisphosphate carboxylase/oxygenase from spinach with CO2, Mg2+ and a reaction-intermediate analogue (CABP) has been determined and refined at 2.4 A resolution. Cyclic non-crystallographic symmetry averaging around the molecular 4-fold axis and phase combination were used to improve the initial multiple isomorphous replacement phases. A model composed of one large subunit and one small subunit was built in the resulting electron density map, which was of excellent quality. Application of the local symmetry gave an initial model of the L8S8 molecule with a crystallographic R-value of 0.43. Refinement of this initial model was performed by a combination of conventional least-squares energy refinement and molecular dynamics simulation using the XPLOR program. Three rounds of refinement, interspersed with manual rebuilding at the graphics display, resulted in a model containing all of the 123 amino acid residues in the small subunit, and 467 of the 475 residues in the large subunit. The R-value for this model is 0.24, with relatively small deviations from ideal stereochemistry. Subunit interactions in the L8S8 molecule have been analysed and are described. The interface areas between the subunits are extensive, and bury almost half of the accessible surface areas of both the large and the small subunit. A number of conserved interaction areas that may be of functional significance have been identified and are described, and biochemical and mutagenesis data are discussed in the structural framework of the model.


The functioning of cytochrome b in the electron transport to furmarate in Propionibacterium freudenreichii and Propionibacterium pentosaceum.
Fumarase-free electron particles from Propionibacterium freudenreichii and P. pentosaceum were prepared by discontinuous sucrose gradient centrifugation, and the influence of 2-n-heptyl-4-hydroxy-quinoline-N-oxide (HQNO) and ultraviolet irradiation on the reduction of menaquinone and cytochrome b with L-lactate or glycerol-3-phosphate and the reoxidation by fumarate was studied. In the presence of HQNO the steady state reduction level of menaquinone during fumarate reduction was increased whereas the steady state reduction level of cytochrome b was decreased as compared with the reduction levels measured in the absence of HQNO. The steady state reduction level of menaquinone during electron transport to fumarate was not influenced by ultraviolet irradiation and the steady state reduction level of cytochrome b was decreased at increasing irradiation times. The data indicate that cytochrome b is involved in the electron transport to fumarate.


Two-year carbohydrate metabolism studies in women using a norethindrone or levonorgestrel triphasic oral contraceptive.
Carbohydrate metabolism was prospectively studied in 28 women using triphasic oral contraceptives (TOC) for two years. They were tested using a 100-gram oral glucose tolerance test with measurements of plasma glucose and insulin levels during the three-hour test. The women were randomly assigned to either a norethindrone-containing TOC or a levonorgestrel-containing TOC. Both types of drugs contained the estrogen ethinyl estradiol. No significant changes were noted in the norethindrone TOC group. The levonorgestrel TOC two-year test had a significant elevation of the 0.5- and 2-hour plasma glucose values and the fasting insulin value. These data show that the two triphasic oral contraceptive preparations affect carbohydrate metabolism differently.


Comparison of compliance with care procedures performed by orthokeratology wearers and their parents and factors affecting compliance.
To compare the levels of compliance with care routines of orthokeratology (ortho-k) wearers and their parents and to identify factors affecting compliance in a hospital setting in Chengdu, China. Patients who had worn ortho-k lenses for at least one month were invited to participate in a survey on compliance. Wearers or their parents were required to complete a questionnaire to determine their compliance with hand hygiene, ortho-k lenses and accessory care procedures. A total of 200 wearers, 78 male wearers and 122 female wearers, median age 12 (range 8-18) years were enrolled. Except for use of lens solution, the percentage of participants reporting total compliance with all procedures did not differ significantly between lens wearers and their parents. However, compliance for some items was significantly higher when performed by parents p < 0.001-0.01). 'Eye care practitioner provided instructions' was a significant protective factor for most procedures (p < 0.001-0.04). Age and sex were significant risk factors for some items (p < 0.001-0.04; p = 0.03-0.04, respectively), with girls having higher compliance than boys. 'Parental supervision' was a significant protective factor for some items (p = 0.02-0.04) when wearers performed the procedures themselves. When parents performed lens care procedures, only 'eye care practitioner provided instructions' was a significant variable (p = 0.001-0.04). Some degree of non-compliance was noted in the majority of ortho-k wearers, particularly for the care of the lens case and suction holder. Compliance with care of some items was higher when performed by parents. Regular reinforcement of care procedures by practitioners is important, especially for older and male lens wearers. Parental supervision is necessary when children perform lens care procedures themselves, even for older wearers.


Leveraging National Germplasm Collections to Determine Significantly Associated Categorical Traits in Crops: Upland and Pima Cotton as a Case Study.
Observable qualitative traits are relatively stable across environments and are commonly used to evaluate crop genetic diversity. Recently, molecular markers have largely superseded describing phenotypes in diversity surveys. However, qualitative descriptors are useful in cataloging germplasm collections and for describing new germplasm in patents, publications, and/or the Plant Variety Protection (PVP) system. This research focused on the comparative analysis of standardized cotton traits as represented within the National Cotton Germplasm Collection (NCGC). The cotton traits are named by 'descriptors' that have non-numerical sub-categories (descriptor states) reflecting the details of how each trait manifests or is absent in the plant. We statistically assessed selected accessions from three major groups of Gossypium as defined by the NCGC curator: (1) "Stoneville accessions (SA)," containing mainly Upland cotton (Gossypium hirsutum) cultivars; (2) "Texas accessions (TEX)," containing mainly G. hirsutum landraces; and (3) Gossypium barbadense (Gb), containing cultivars or landraces of Pima cotton (Gossypium barbadense). For 33 cotton descriptors we: (a) revealed distributions of character states for each descriptor within each group; (b) analyzed bivariate associations between paired descriptors; and (c) clustered accessions based on their descriptors. The fewest significant associations between descriptors occurred in the SA dataset, likely reflecting extensive breeding for cultivar development. In contrast, the TEX and Gb datasets showed a higher number of significant associations between descriptors, likely correlating with less impact from breeding efforts. Three significant bivariate associations were identified for all three groups, bract nectaries:boll nectaries, leaf hair:stem hair, and lint color:seed fuzz color. Unsupervised clustering analysis recapitulated the species labels for about 97% of the accessions. Unexpected clustering results indicated accessions that may benefit from potential further investigation. In the future, the significant associations between standardized descriptors can be used by curators to determine whether new exotic/unusual accessions most closely resemble Upland or Pima cotton. In addition, the study shows how existing descriptors for large germplasm datasets can be useful to inform downstream goals in breeding and research, such as identifying rare individuals with specific trait combinations and targeting breakdown of remaining trait associations through breeding, thus demonstrating the utility of the analytical methods employed in categorizing germplasm diversity within the collection.


Functionalized magnetic PAMAM dendrimer as an efficient nanocatalyst for a new synthetic strategy of xanthene pigments.
A green protocol has been developed for preparation of the wide variety of colored xanthene derivatives using a new efficient magnetic solid acid catalyst bearing polyamidoamine dendrimer moiety as a nanoscopic compound. Dendrimers, highly symmetric molecules around a core and 3D spherical morphology, show interesting traits based on their functionalized groups on the branched surface. They can be designed to provide water soluble structures or pseudo-active sites of biomolecules. The catalyst was assembled via a polyamidoamine dendrimer immobilized on the surface of γ-Fe2O3 followed by the sulfonylation of the amine groups by chlorosulfonic acid resulting in γ-Fe2O3@PAMAM-SO3H. Herein, PAMAM dendrimer with repeating amine/amide branches as catchable sites of sulfonic acid groups was introduced as transformer of homogeneous to heterogeneous acidic catalysts. The physicochemical properties of synthesized catalyst were studied using by FT-IR, FE-SEM, XRD, VSM, EDS, TGA/DTG, and TEM. Finally, the catalytic activity of γ-Fe2O3@PAMAM-SO3H was evaluated for the preparation of xanthene derivatives via a one-pot, three components reaction of aromatic aldehydes with i) β-naphthol, ii) cyclic 1,3-dicarbonyl, iii) β-naphthol and cyclic 1,3-dicarbonyl compounds, iv) 2-hydroxy-1,4-naphthoquinone, leading to the eco-riendly preparation of the target compounds in good to excellent yields. The catalyst could be easily recycled for at least five consecutive runs without significant loss in its catalytic activity.


Engineering nanoparticle toolkits for mRNA delivery.
The concept of using mRNA to produce its own medicine in situ in the body makes it an ideal drug candidate, holding great potential to revolutionize the way we approach medicine. The unique characteristics of mRNA, as well as its customizable biomedical functions, call for the rational design of delivery systems to protect and transport mRNA molecules. In this review, a nanoparticle toolkit is presented for the development of mRNA-based therapeutics from a drug delivery perspective. Nano-delivery systems derived from either natural systems or chemical synthesis, in the nature of organic or inorganic materials, are summarised. Delivery strategies in controlling the tissue targeting and mRNA release, as well as the role of nanoparticles in building and boosting the activity of mRNA drugs, have also been introduced. In the end, our insights into the clinical and translational development of mRNA nano-drugs are presented.


Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study.
Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC-MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: β = 0.19 (0.09, 0.28); DMS: β = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: β = 0.15 (0.08, 0.23); DMS: β = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: β = 0.16 (0.08, 0.25); DMS: β = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.


The pharmacokinetics of cefuroxime after intravenous injection.
Cefuroxime, a new cephalosporin antibiotic which is stable to most beta-lactamases produced by gram-negative bacteria, was given by bolus intravenous injection to six volunteers in doses of 500 mg and 750 mg. The concentrations of cefuroxime in serum and urine were measured at pre-determined times after injection and the data analysed by a two-compartment open system model. A serum concentration of 8 microgram/ml was exceeded for 100.3 min (+/- 18.3) after a 500 mg dose and for 144.5 min (+/- 19.8) after 750 mg. The ultimate serum half-life was 1.1 h. Excretion of cefuroxime in the urine was almost complete in 24 h, the clearance being 150 ml/min/1.73m2. About 45% was excreted through the renal tubules. The injections were well tolerated and no changes in haematological or biochemical values were seen. The resulting data are compared with those published for some other cephalosporins. It is concluded that the favourable pharmacokinetics, especially the high concentrations of unbound cefuroxime in the serum, are likely to aid effective therapy of human infection caused by sensitive bacteria.


Subcritical hydrothermal pretreatment of olive mill solid waste for biofuel production.
The hydrothermal pretreatment of olive mill solid waste amended with 0.6M organic acids was studied at temperatures between 100 and 170°C. Acetic and formic acids which are endogenous intermediates of hemiacetyl splitting at subcritical conditions were tested. Formic acid, with smaller molecular size and lower pKa, was found to be more effective than acetic in the entire range of temperatures tested. Yield of enzymatic hydrolysis was significantly enhanced (>2 folds) at temperatures above 140°C. Concentration of aldehyde byproducts in the medium increased with temperature and pressure and addition of organic acids, however, the highest concentration detected (ca 1g/L) did not surpass values reported as inhibitory of sugars fermentation to ethanol by either yeast or bacteria. Aldehyde production was more affected by temperature than by acid addition. Concluding, addition of formic acid to hydrothermal pretreatment at relatively mild temperatures (140-170°C) and pressure (10-13 atm) improved saccharification yield while saving energy.


Pharmacokinetic study of baicalein after oral administration in monkeys.
Baicalein, a flavonoid originally isolated from the root of Scutellaria baicalensis Georgi, has numerous pharmacological activities. Up to now, several studies regarding the pharmacokinetic profiles of baicalein have been described, while there is no such study reported in monkey, the species which is more similar to human. The purpose of this study was to investigate the pharmacokinetic profiles of baicalein after oral administration in monkeys. After orally administrating three doses of baicalein in monkeys, multi-peaks of the plasma concentration-time curves were observed and the non-linear pharmacokinetics for baicalein and its metabolite baicalin were found at doses of 50-500mg/kg. In order to calculate the absolute bioavailability, the intravenous pharmacokinetic study was also carried out after intravenous administration of 10mg/kg baicalein. The absolute bioavailability of baicalein in different doses was ranged from 13.1% to 23.0%. In this study, baicalein and baicalin were determined by LC-MS method. The chromatographic separation was performed on Agilent Poroshell 120 SB-C18 column (2.7μm, 2.1×50mm). Baicalein and baicalin were detected by single quadrupole mass spectrometer equipment with electrospray ionization interface with the selected ion monitoring mode. The assay was linear for both baicalein and baicalin with the correlation coefficients>0.99. The intra- and inter-day precisions for baicalein and baicalin were all less than 15% by relative standard deviation. The analytes were stable during samples storage and handling, and no matrix effects were observed. The method we developed in this study was sensitive, precise, stable and producible.