Inhibition of photohemolysis induced by m-chloroperbenzoic acid by metal complexes with SOD-mimetic activity.
Red blood cells (RBCs) are probably the most common target through the damaging action of reactive oxygen species on the cells. The photohemolysis activity of m-chloroperbenzoic acid (CPBA) was concentration- and exposure time-dependent. Twenty minutes photo exposure time and 200 microm of CPBA concentration were optimum to study the effect of generated superoxide (O2-) and hydroxyl (*OH) radicals on RBCs. RBCs lysis photosensitized by CPBA was investigated in the presence of [(VL2O)(VL2H2O)]Cl6, [MnL2O]2Cl42H2O, [FeL2Cl2]Cl H2O, [CoL2Cl2]4H2O or [ZnL2Cl2]H2O respectively, where L is 2-methylaminopyridine, with SOD-mimetic activities with the aim of ascertaining their protective activity towards the photo induced cell damage. The decrease of photolytic activity caused by these complexes was concentration-dependent and the maximum percentage of protective activity was 75, 70, 68, 57 or 24% for [(VL2O)(VL2H2O)]Cl6, [MnL2O]2Cl4 2H2O, [FeL2Cl2]Cl H2O, [CoL2Cl2]4H2O or [ZnL2Cl2]H2O complex respectively, against the cell irradiated without addition of metal complexes. The comparison between the decrease of photolytic activity caused by these complexes and their SOD-mimetic activity of these metal complexes showed an appreciable correlation.


Solid-phase extraction of chloramphenicol with graphitized carbon black.
The sorption and desorption properties of graphitized carbon black (GCB) were evaluated for enrichment of highly polarizable chloramphenicol (CP) from biological fluids. The distribution of CP between GCB and water lay strongly toward GCB. Among the organic solvents examined, methanol gave the lowest adsorption coefficient. The optimum packing amount of GCB, and the optimum volume and flow-rate of the eluent were deduced from the breakthrough curve and methanol elution curve, respectively. The inner diameter of GCB extraction columns was chosen from the sorption efficiency curve obtained by plotting CP recovery against column inner diameter. The solid-phase extraction method using GCB was applied to the assay of CP in serum samples in the concentration range of 5 to 50 micrograms/ml.


Developing a national pharmaceutical research strategy in Lebanon: opportunities to bridge the gaps and reach the goals.
Pharmaceutical research can be structured into clear national strategies that optimize patient health and foster innovation. The objectives of this document are to assess the need for a national pharmaceutical research strategy based on the current situation in Lebanon, to identify the strengths and weaknesses of pharmaceutical research in Lebanon, and to suggest a pharmaceutical research strategy for Lebanon, including goals and objectives. In Lebanon, in the absence of a national health research policy, pharmaceutical research is conducted in academia or hospitals, although projects are the result of personal or team initiatives that should be organized to better serve the needs of the country. Many strengths of pharmaceutical research were identified, such as the pharmaceutical workforce and academics who are willing to contribute to research, while the implementation of the national pharmaceutical strategy represents an important opportunity to promote research. Among the weaknesses is the lack of research culture in some institutions and interinstitutional/interprofessional collaborations. Thus, the suggested strategy aims to structure pharmaceutical research in Lebanon, including the priorities towards which research is directed, the process by which research is conducted, and the workforce conducting research. It will mainly rely on the World Health Organization's interrelated goals (organization, priorities, capacity, standards, and translation). The implementation of the suggested pharmaceutical research strategy will only be achieved through the leadership of the pharmaceutical authorities and the collaboration of stakeholders.


Effects of immobilization on the isometric contractile properties of embryonic avian skeletal muscle.
Chicken embryos were chronically immobilized by applying a neuromuscular blocking agent, curare, to the chorioallantoic membrane from day 8 through day 16 of incubation to study the effects of a deficit in motor activity on the development of contractile properties of skeletal muscle. Compared with control embryos, spontaneous embryonic motor activity was depressed by 60 to 90% in the curare-treated animals during the treatment period. Growth of the posterior latissimus dorsi muscle, a fast-twitch muscle in the adult, was greatly affected by immobilization. The average blotted mass of the muscles from curare-treated 18- to 19-day embryos was approximately 20% of that from control embryos. The isometric contractile properties of posterior latissimus dorsi muscles isolated from control and curare-treated embryos were compared at 18 to 19 days of incubation. The times to peak tension and to one-half relaxation of the twitch and tetanic responses were significantly greater for the muscles from the immobilized embryos. The peak twitch and tetanic tensions, normalized for muscle cross-sectional area, were significantly less than control values for the muscles from curare-treated embryos. The maximal rate of tetanic tension production was, however, unaffected by immobilization. The results of this study demonstrate that the development of isometric contractile properties of embryonic skeletal muscle is significantly altered by an experimentally induced reduction of spontaneous motor activity. A disruption in the functional development of the sarcoplasmic reticulum following a similar decrease in motor activity, as reported by others, is discussed as a potential mechanism for the altered contractile properties of muscles from the curare-treated embryos.


A candidate vaccine composed of live nonpathogenic Iranian Lizard Leishmania mixed with Chitin microparticles protects mice against Leishmania major infection.
The protective effect of immunization using Iranian Lizard Leishmania (ILL) mixed with CpG oligodeoxynucleotides (CpG-ODN) was demonstrated in a previous study. Here, we report the effect of leishmanization using ILL mixed with chitin microparticles (CMPs) as an adjuvant against L. major infection in BALB/c mice. Briefly, 2 × 107 live ILL were mixed with 10 µg CMPs (<40 μm in size) (ILL+CMP) and were injected subcutaneously into the right footpad of BALB/c mice. Three control groups were included in the study and received ILL, chitin, and PBS respectively. Three weeks later, mice were challenged with 2 × 105 live L. majorEGFP promastigotes, which were inoculated into the left footpad. The infection course was monitored using footpad swelling measurement and in vivo imaging. Eleven weeks after the challenge, all mice were sacrificed and parasite burden was measured in the spleen and the draining lymph node using three different methods including real-time PCR, flow cytometry, and direct fluorescent microscopy. In addition, cytokines levels (IFN-γ and IL-10), and nitric oxide production were assayed in splenocytes. Mice immunized with ILL+CMP had a smaller footpad diameter in comparison to control groups and notably, no lesion was developed at the inoculation site. Additionally, in vivo imaging study revealed that there was no detectable fluorescence in the ILL+CMP group footpad by the end of the tenth week. This finding was confirmed by three methods used for parasite burden assays. Moreover, higher IFN-γ level was observed in mice immunized with ILL+CMP in comparison with other groups. On the other hand, nitric oxide concentration was higher in the ILL control group. ILL mixed with chitin microparticles is an effective vaccine against leishmaniasis in BALB/c mice. This vaccine is able to induce an adequate immune response to decrease the parasite burden and prevent lesion formation. Further studies are needed to evaluate long-lasting immunity, especially in experimental outbreed models.


No association of the SLC1A2 rs3794087 allele with risk for essential tremor in the Spanish population.
A recent genome-wide association study and other replication studies have suggested that the rs3794087 single nucleotide polymorphism in the solute carrier family 1 - glial affinity glutamate transporter-member 2 (SLC1A2) gene is associated with an increased risk for essential tremor (ET), and a replication study in an Asian cohort has shown a decreased risk for ET associated with the rs3794087T allele. We tried to replicate this association in a White Spanish population. We analyzed the distribution of allelic and genotypic frequencies of rs3794087 in 202 patients with familial ET and 308 healthy controls using a TaqMan-based quantitative PCR assay. Genotypic and allelic frequencies of rs3794087 did not differ significantly between patients with ET and controls and were unrelated with the age at onset of tremor or sex. Our study suggests that SLC1A2 rs3794087 is not associated with the risk for developing familial ET in the Spanish population, thus subtracting relevance to SLC1A2 rs3794087 as a risk biomarker for ET.


Light-responsive multillamellar vesicles in coumaric acid/alkyldimethylamine oxide binary systems: Effects of surfactant and hydrotrope structures.
Herein, we report a series of novel light-responsive multilamellar vesicles based on the surfactant/hydrotrope binary systems. The phase behaviors of alkyldimethylamine oxide (CmDMAO, m=10, 12, 14) and trans-coumaric acid (trans-CA) isomerides, including trans-ortho-coumaric acid (trans-OCA), trans-meta-coumaric acid (trans-MCA) and trans-para-coumaric acid (trans-PCA), show that the multilamellar vesicle (MLV) formation region is commonly presented in the trans-CA/CmDMAO systems except trans-PCA/C12DMAO. Moreover, the molecular structures of CmDMAO and trans-CA affect the multilamellar vesicle formation region significantly. Generally speaking, the bigger the m, the larger the MLV region. Various techniques such as rheology, polarized optical microscopy (POM), (1)H NMR, (2)H NMR, cryogen transmission electron microscopy (cryo-TEM) and freeze-fracture transmission electron microscopy (FF-TEM) are used to characterize the aggregate structures. The multilamellar vesicles can transform into a homogeneous and transparent micelle phase or a two-phase system in the trans-OCA/CmDMAO binary systems under UV light irradiation, which depends on the chain length of CmDMAO and the molar ratio of [trans-OCA]/[CmDMAO]. Specifically, the light-stimuli response of multilamellar vesicles in the trans-OCA/C12DMAO system is representatively studied in detail. UV-vis spectra and (1)H NMR measurements illustrate that the light-induced trans-OCA to cis-OCA isomerization is essential during the transitions and the light-induced two-phase formation is attributed to the enrichment of surfactants, because the trans-cis isomerization can not only strengthen the hydrophilicity of cis-OCA but also increase the steric hindrance between cis-OCA and C12DMAO, and thereby altering the morphology of aggregate and the rheological response of bulk phase significantly.


Risks of road injuries in patients with bipolar disorder and associations with drug treatments: A population-based matched cohort study.
Using a nation-wide, population-based dataset, we aimed to investigate the risk of road injury among individuals with bipolar disorder (BD) compared to individuals without BD. In addition, we investigated the putative moderating effects of prescription for lithium, anticonvulsants, antidepressants, and/or first- or second-generation antipsychotic agents on the association between BD and risk of road injury. As part of an16-year longitudinal cohort study, we compared the risk of road injuries among study subjects aged 16 and above with a diagnosis of BD, with ten age- and sex-matched sample of individuals without BD. Individuals were compared on measures of incidence on road injuries using medical claims data based on the ICD-9-CM codes: E800~807, E810~817, E819~830, E840~848. Time dependent Cox regression models were used to adjust for time-varying covariates such as age, and medication uses. Hazard ratios before and after adjusting for age, sex, other comorbidities, and drug use were calculated. 3953 people with BD were matched with 39,530 controls from general population. Adjusted hazard ratios revealed a 1.66-fold (95% CI 1.40-1.97) increase in risk of road injuries among bipolar subjects when compared to controls. Female gender, older age (i.e. over 80), residence in areas of highest levels of urbanization, and use of antidepressants were associated with a lower risk of road injuries. In this large, national, population-based cohort, BD was associated with an elevated risk of road injuries. However, prescriptions of antidepressants might help mitigate the foregoing risk.


Acupuncture for Patients with Chronic Spontaneous Urticaria: A Randomized, Sham-Controlled Pilot Trial.
To determine the feasibility of conducting a full-scale randomized controlled trial (RCT) and investigate the basic information and safety of acupuncture for patients with chronic spontaneous urticaria (CSU). A total of 80 participants with CSU from July 2018 to July 2019 were randomly assigned to receive active acupuncture (n=41) on a fixed prescription of acupoints or sham acupuncture (n=39) with superficial acupuncture on non-acupuncture points through the completely randomized design. Patients in both groups received 5 sessions per week for 2 weeks, and participants were followed for a further 2 weeks. Feasibility was assessed by recruitment and randomization rates, retention of participants, treatment protocol adherence, and the incidence of adverse events (AEs). The clinical primary outcome was the changes from baseline weekly urticaria activity scores (UAS7) after treatment at 2 weeks. Secondary outcomes included the Visual Analogue Scale (VAS) score of itching intensity, Dermatology Life Quality Index (DLQI), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA). A total of 80 participants were enrolled. The recruitment rate of 24.02%, randomization rate of 100%, a loss rate of 6.25%, and no obvious AEs were observed in either group. The decrease from baseline in the mean UAS7 total score at week 2 in the active acupuncture group was -8.63 (95%CI, -11.78 to -5.49) and -6.21 (95%CI, -9.43 to -2.98) in the sham acupuncture group for a between-group difference of -2.42 (95% CI, -6.93 to 2.07). The change in the DLQI, VAS of itching intensity, HAMA, and HAMD were a slightly better improvement trend in the active acupuncture group than the sham acupuncture group, but the between-group difference was not significant. Active acupuncture had a better improvement trend in alleviating symptoms, improving quality of life and regulating the mood of anxiety and depression in patients with CSU than sham acupuncture. (Registration Nos. AMCTR-ICR-18000190 and ChiCTR2100054776).


Effect of pH and temperature on fibrous structure formation of plant proteins during high-moisture extrusion processing.
This study investigated the effect of pH on fibrous structure formation (protein alignment) during high-moisture extrusion processing of gluten, rice protein, as well as pea protein concentrate, and isolate. The pH of the raw material was shifted to 5 and 7 in water suspension with an acid or base and freeze-dried, after which, conductivity, solubility, water-holding capacity, particle size, and pH were measured. The pH-shifted raw materials were extruded at various temperatures (95-160 °C) and the extrudates were analysed for protein alignment (macro and microstructure), tensile strength, free thiol groups, and cooking properties. In general, all raw materials generated fibrous structure at lower temperatures (115-140 °C) at pH 7 than at pH 5 (135-160 °C). Higher pH and temperature values led to an increased tensile strength and pronounced protein alignment. No such unambiguous link could be observed between the raw material properties and enhanced structure formation. This study showed that the structure formation of the extrudate can be positively influenced by increasing the pH of the raw material, which facilitates the plant protein structuring into appealing meat analogue products.


Isolated convergence-retraction nystagmus secondary to intralesional haemorrhage of a pineal cyst: an easily missed neurological finding with potentially life-threatening consequences.
This case report describes a patient who presented to the emergency department with intermittent visual disturbance and was found to have convergence-retraction nystagmus. This occurred in the setting of supratherapeutic anticoagulation on warfarin for an aortic dissection graft repair. Urgent imaging demonstrated haemorrhagic transformation of a previously identified incidental pineal cyst. After close monitoring given the risk of secondary hydrocephalus, the patient was discharged in stable condition with symptom resolution and without any further significant complications. This case report highlights the importance of identifying subtle clinical findings and the risk of secondary haemorrhage of pineal cysts when on anticoagulation. While the risk of secondary hydrocephalus is a significant concern, clinically stable patients can be followed without need for neurosurgical intervention.


A 29-year-old with gunshot wound to the spine.
A mobile intensive care unit (MICU) was dispatched to transport a critically injured patient with a gunshot wound to the spine from a community hospital to a level I trauma center. The patient transported suffered from a gunshot wound to the left posterior midthoracic region. The patient experienced transient traumatic cardiac arrest before transfer. The MICU crew arrived at the emergency department and found the patient intubated and with a chest tube. Fluid resuscitation was continued, and the patient was transported. At the level I trauma center, the patient was admitted in critical condition. The patient was declared brain-dead on postinjury day 8. Spinal immobilization in penetrating trauma is a controversial topic. This patient met the historic clinical indication for spinal immobilization. The patient's injuries included multiple cervical vertebrae fractures and spinal cord disruption from the penetrating projectile, with the bullet remaining in the patient. Interfacility management by the MICU crew was focused on adequate ventilations and immobilization while continuing to address the patient's shock state. Penetrating injuries to the spinal cord can be devastating. Being aware of the pathophysiology of penetrating spinal injuries, along with current evidence-based practice, will assist providers in making sound clinical decisions for their patients.


[Bilateral papilledema: prospective study of fifty patients].
In this prospective study, we report fifty consecutive cases of bilateral papilledema without neurosurgical or obvious ophthalmologic etiology, referred to our institution between January 2005 and March 2007. Lumbar puncture with opening CSF pressure measurement distinguished two groups of patients: Group 1 (n=39) with and Group 2 (n=11) without intracranial hypertension. In Group 1, 9/39 patients presented secondary intracranial hypertension mainly due to cerebral venous thrombosis. In 30 patients, after complete investigations, a diagnosis of idiopathic intracranial hypertension was made: as commonly reported, patients were predominantly overweight (96.7% with body mass index>25kg/m2) young (mean age=27.6 years) and women (96.7%). Eleven patients with intracranial hypertension had no headaches. In Group 2, the most common diagnosis was bilateral non-arteritic anterior ischemic optic neuropathy, but rare causes have been identified.


A bedside ultrasound protocol to the measurement of the systemic vascular resistances: Preliminary results in the patients with sepsis.
The use of the ultrasound (US) bedside examination is increasing for the detailed evaluation of the hemodynamic parameters, allowing the physicians to set the appropriate therapeutic strategies with greater precision. The aim of this study is to evaluate the hemodynamic parameters (the cardiac output or CO, the central venous pressure or CVP and the systemic vascular resistance or SVR) in the patients with sepsis, by using a bedside US approach. We consecutively enrolled n.82 patients of S.Andrea Hospital (n.47 with sepsis and n.35 without sepsis), examining the hemodynamic parameters by a bedside US evaluation. The incidence of sepsis was more than 50% of cases. The patients with sepsis presented higher comorbidity and polypharmacy (p < 0.01, p < 0.001), with increased creatinine (p < 0.001) and consequent esteemed glomerular filtration rate (p < 0.01), C-reactive protein (p < 0.01), SOFA (Sepsis-related Organ Failure Assessment) score (p < 1.58×10-7) and reduced SVR (p < 0.05). The SOFA score was inversely related to the SVR (p < 0.05). To our best knowledge, this is the first study with a bedside US protocol to measure SVR, beyond the abdominal and cardiac qualitative evaluation.


A gas chromatographic-mass spectrometric assay for nine hydroxyphenolic acids in uremic serum.
A mass fragmentographic method for the determination of m-hydroxybenzoic acid, p-hydroxybenzoic acid, o-hydroxyphenylacetic acid, m-hydroxyphenylacetic acid, p-hydroxyphenylacetic acid, vanillic acid, p-hydroxymandelic acid, homovanillic acid and vanilmandelic acid in uremic serum is described. The hydroxyphenolic acids were extracted from one ml of serum ultrafiltrate. After trimethylsilylation, the extract was analyzed by a gas chromatograph-mass spectrometer. Concentrations of nine hydroxyphenolic acids are higher in uremic serum. In particular, p-hydroxybenzoic acid and p-hydroxyphenylacetic acid are markedly increased in uremic serum. The influence of hemodialysis on the hydroxyphenolic acids was studied by quantitating the acids before and after hemodialysis.


In-line electrochemical reagent generation coupled to a flow injection biamperometric system for the determination of sulfite in beverage samples.
This work reports an in-line electrochemical reagent generation coupled to a flow injection biamperometric procedure for the determination of SO3(2-). The method was based on a redox reaction between the I3(-) and SO3(2-) ions, after the diffusion of SO2 through a gas diffusion chamber. Under optimum experimental conditions, a linear response ranging from 1.0 to 12.0 mg L(-1) (R=0.9999 and n=7), a detection and quantification limit estimated at 0.26 and 0.86 mg L(-1), respectively, a standard deviation relative of 0.4% (n=10) for a reference solution of 4.0 mg L(-1) SO3(2-) and sampling throughput for 40 determinations per hour were achieved. Addition and recovery tests with juice and wine samples were performed resulting in a range between 92% and 110%. There were no significant differences at a 95% confidence level in the analysis of eight samples when comparing the new method with a reference procedure.


Contrast-enhanced ultrasound: a comprehensive review of safety in children.
Contrast-enhanced ultrasound (CEUS) has been increasingly used in pediatric radiology practice worldwide. For nearly two decades, CEUS applications have been performed with the off-label use of gas-containing second-generation ultrasound contrast agents (UCAs). Since 2016, the United States Food and Drug Administration (FDA) has approved the UCA Lumason for three pediatric indications: the evaluation of focal liver lesions and echocardiography via intravenous administration and the assessment of vesicoureteral reflux via intravesical application (contrast-enhanced voiding urosonography, ceVUS). Prior to the FDA approval of Lumason, numerous studies with the use of second-generation UCAs had been conducted in adults and children. Comprehensive protocols for clinical safety evaluations have demonstrated the highly favorable safety profile of UCA for intravenous, intravesical and other intracavitary uses. The safety data on CEUS continue to accumulate as this imaging modality is increasingly utilized in clinical settings worldwide. As of August 2021, 57 pediatric-only original research studies encompassing a total of 4,518 children with 4,906 intravenous CEUS examinations had been published. As in adults, there were a few adverse events; the majority of these were non-serious, although very rarely serious anaphylactic reactions were reported. In the published pediatric-only intravenous CEUS studies included in our analysis, the overall incidence rate of serious adverse events was 0.22% (10/4,518) of children and 0.20% (10/4,906) of all CEUS examinations. Non-serious adverse events from the intravenous CEUS were observed in 1.20% (54/4,518) of children and 1.10% (54/4,906) of CEUS examinations. During the same time period, 31 studies with the intravesical use of UCA were conducted in 12,362 children. A few non-serious adverse events were encountered (0.31%; 38/12,362), but these were most likely attributable to the bladder catheterization rather than the UCA. Other developing clinical applications of UCA in children, including intracavitary and intralymphatic, are ongoing. To date, no serious adverse events have been reported with these applications. This article reviews the existing pediatric CEUS literature and provides an overview of safety-related information reported from UCA uses in children.


Anti-TMV activity and mode of action of three alkaloids isolated from Chelidonium majus.
Plant viral diseases are difficult to control and have caused serious damage to the agricultural industry. Recently, botanical biopesticides characterized by environment friendly, safe to non-target organism and not as susceptible to produce drug resistance, have exhibited great potential to be developed as antiviral agents. To screen the natural products with antiviral effect, three alkaloids possessed anti-tobacco mosaic virus (TMV) activity were isolated from Chelidonium majus and the modes of action were investigated. The anti-TMV effect of crude extracts at 10 mg mL-1 was 51.73%. Bioassay-guided fractionation and isolation of the compounds with anti-TMV activity were performed on the methanol extract of C. majus yielding three bioactive alkaloids namely: chelerythrine (1), chelidonine (2), and sanguinarine (3). The results of bioassay showed that chelerythrine exhibited great inactivation, proliferation inhibition and protection effects against TMV at 0.5 mg mL-1 with the efficiency of 72.67%, 77.52% and 59.34%, respectively. Chelidonine at 0.1 mg mL-1 can provide 54.90% and 64.45% inhibitions on TMV through inducing resistance in two kinds of tobacco. Sanguinarine showed a weaker protection for resisting TMV in comparison to chelerythrine and chelidonine. Chelerythrine and chelidonine displayed significant inhibitions on TMV with different modes of action. These results provided important evidence that the extracts in C. majus might be a potential source of new drugs in controlling virus disease agriculturally.


Efficacy and safety of Chinese herbal for carotid atherosclerosis: A protocol for systematic review and network meta-analysis.
Carotid atherosclerosis (CAS) can cause acute events such as myocardial infarction and stroke, seriously injuring human health. There are some shortcomings for statins and surgical in the treatment of CAS. Research has proved that Chinese herbal shows its unique advantages with the multichannel and multitarget treatment strategy. As a result, we propose this study to evaluate the efficacy and safety of Chinese herbal in the treatment of CAS. We will retrieve the relevant databases to collect the studies of Chinese herbal treatment of CAS up to July 2021. The retrieval language is limited to Chinese and English. Researchers will be responsible for screening studies and extracting data, and use STATA16.0 and WinBUGS1.4.3 for data analysis. We will conduct a bias risk assessment based on the Cochrane Collaboration's bias risk assessment tool and use the grading of recommendations assessment development and evaluation tool to assess the confidence of cumulative evidence. The study will evaluate the efficacy and safety of Chinese herbal in the treatment of carotid atherosclerosis. The study will offer more evidence for the treatment of CAS with Chinese herbal and expand the selection range of clinicians. INPLASY2021100112.


Ultrasensitivity by molecular titration in spatially propagating enzymatic reactions.
Delineating design principles of biological systems by reconstitution of purified components offers a platform to gauge the influence of critical physicochemical parameters on minimal biological systems of reduced complexity. Here we unravel the effect of strong reversible inhibitors on the spatiotemporal propagation of enzymatic reactions in a confined environment in vitro. We use micropatterned, enzyme-laden agarose gels which are stamped on polyacrylamide films containing immobilized substrates and reversible inhibitors. Quantitative fluorescence imaging combined with detailed numerical simulations of the reaction-diffusion process reveal that a shallow gradient of enzyme is converted into a steep product gradient by addition of strong inhibitors, consistent with a mathematical model of molecular titration. The results confirm that ultrasensitive and threshold effects at the molecular level can convert a graded input signal to a steep spatial response at macroscopic length scales.


Human DNA (cytosine-5)methyltransferase selectively methylates duplex DNA containing mispairs.
The presence of the C.C mispair in a defined duplex oligodeoxynucleotide enhanced its capacity to serve as a substrate for highly purified human DNA methyltransferase. Analysis of tritiated reaction products showed that the C.C mispair acted as a "methylation acceptor" in that it was itself rapidly methylated. The m5C.G base pair also enhanced the capacity of the oligodeoxynucleotide to serve as a substrate for the enzyme. However, this complementary base pair was found to act as a "methylation director". That is, the presence of the m5C in one strand induced the enzyme to rapidly methylate at the cytosine residue on the opposite strand in an adjacent C.G base pair.


Salvage reimplantation in patient with local recurrent prostate carcinoma after brachytherapy with three dimensional computed tomography-guided permanent pararectal implant.
Thirty-one [31] patients with local recurrent or residual adenocarcinoma of the prostate, with no evidence of distant metastases, were treated with second permanent implant using a stereotactic three dimensional system and posterior pararectal CT-guided method. All patients had extensive under local anesthesia or IV sedation pararectal CT-guided biopsy of the prostate and seminal vesicles. All patients except one had 3 month neoadjuvant androgen ablation prior to salvage reimplantation. Twenty [20] of these patients had local recurrence in the prostate and eleven [11] patients had seminal vesicle invasion which was not diagnosed nor treated with the initial brachytherapy. In addition, the patients had PSA failure or local palpable disease, "cold spots" with CT imaging or areas of dosage less than 80% of the prescribed dose with DVH (dose volume histogram). Initial prescribed dose was 120 Gy with (103)Pd loose seeds in 26 patients and 144 Gy with (125)I loose seeds in 5 patients. For the reimplant the dosage in the recurrent site was 100-144 Gy with (125)I seeds in strand in 24 patients (77%) and 100-120 Gy with (103)Pd loose seeds in 7 patients (23%). The preference of (125)I seeds in the second treatment was because only (125)I in strand was available at the time of the reimplant. Eleven [11] patients had second implant twelve to twenty-four months after the initial implant and 20 patients had after twenty-five to eighty-seven months and median follow-up was thirty months. A high level of biochemical control (87%) was achieved in all of these patients who are recognized as high risk due to local recurrence. Four [4] patients experienced grade 2 or 3 GI or GU complications and two [2] patients experienced grade 4 GI complications. Patients with local recurrent prostate cancer following initial brachytherapy including those with seminal vesicle invasion can be successfully treated with pararectal stereotactic CT-guided reimplantation. Assessment of seminal vesicle status is an essential part of staging for local recurrence.


A High Separation Factor for 165Er from Ho for Targeted Radionuclide Therapy.
Background: Radionuclides emitting Auger electrons (AEs) with low (0.02-50 keV) energy, short (0.0007-40 µm) range, and high (1-10 keV/µm) linear energy transfer may have an important role in the targeted radionuclide therapy of metastatic and disseminated disease. Erbium-165 is a pure AE-emitting radionuclide that is chemically matched to clinical therapeutic radionuclide 177Lu, making it a useful tool for fundamental studies on the biological effects of AEs. This work develops new biomedical cyclotron irradiation and radiochemical isolation methods to produce 165Er suitable for targeted radionuclide therapeutic studies and characterizes a new such agent targeting prostate-specific membrane antigen. Methods: Biomedical cyclotrons proton-irradiated spot-welded Ho(m) targets to produce 165Er, which was isolated via cation exchange chromatography (AG 50W-X8, 200-400 mesh, 20 mL) using alpha-hydroxyisobutyrate (70 mM, pH 4.7) followed by LN2 (20-50 µm, 1.3 mL) and bDGA (50-100 µm, 0.2 mL) extraction chromatography. The purified 165Er was radiolabeled with standard radiometal chelators and used to produce and characterize a new AE-emitting radiopharmaceutical, [165Er]PSMA-617. Results: Irradiation of 80-180 mg natHo targets with 40 µA of 11-12.5 MeV protons produced 165Er at 20-30 MBq·µA-1·h-1. The 4.9 ± 0.7 h radiochemical isolation yielded 165Er in 0.01 M HCl (400 µL) with decay-corrected (DC) yield of 64 ± 2% and a Ho/165Er separation factor of (2.8 ± 1.1) · 105. Radiolabeling experiments synthesized [165Er]PSMA-617 at DC molar activities of 37-130 GBq·µmol-1. Conclusions: A 2 h biomedical cyclotron irradiation and 5 h radiochemical separation produced GBq-scale 165Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutics. This will enable fundamental radiation biology experiments of pure AE-emitting therapeutic radiopharmaceuticals such as [165Er]PSMA-617, which will be used to understand the impact of AEs in PSMA-targeted radionuclide therapy of prostate cancer.


Antitumor activity of antiestrogenic phenylindoles on experimental prostate tumors.
Two antiestrogenic phenylindoles (D 16726 and D 15413) were tested for their prostatic tumor-inhibiting activity. Both compounds exerted a strong inhibitory effect on prostate and seminal vesicle weight of intact rats and mice comparable to that of diethylstilbestrol. Their estrogenic properties, however, are much lower than those of DES. Therefore, there is no direct correlation between estrogenic potency and inhibition of accessory sex organ weights. The tumor-inhibiting activity of D 16726 and D 15413 on the androgen-dependent R 3327 Dunning prostatic carcinoma and the human prostatic tumor PC 82 implanted in nude mice equals that of castration or of diethylstilbestrol. Both 2-phenylindoles had good affinities for estrogen receptors from calf uterine and R 3327 tumor cytosol, but no affinities for androgen and progesterone receptors. As these 2-phenylindoles have much lower estrogenic properties than diethylstilbestrol, they may also have low side-effects, and can therefore be of interest for the therapy of the prostatic carcinoma.


Effects of obstructive sleep apnea on myocardial injury and dysfunction: a review focused on the molecular mechanisms of intermittent hypoxia.
Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH) and is strongly associated with adverse cardiovascular outcomes. Myocardial injury and dysfunction have been commonly observed in clinical practice, particularly in patients with severe OSA. However, the underlying mechanisms remain obscure. In this review, we summarized the molecular mechanisms by which IH impact on myocardial injury and dysfunction. In brief, IH-induced cardiomyocyte death proceeds through the regulation of multiple biological processes, including differentially expressed transcription factors, alternative epigenetic programs, and altered post-translational modification. Besides cell death, various cardiomyocyte injuries, such as endoplasmic reticulum stress, occurs with IH. In addition to the direct effects on cardiomyocytes, IH has been found to deteriorate myocardial blood and energy supply by affecting the microvascular structure and disrupting glucose and lipid metabolism. For better diagnosis and treatment of OSA, further studies on the molecular mechanisms of IH-induced myocardial injury and dysfunction are essential.


Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.
Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.


Heterogeneity of immune defects in three children with a chronic active Epstein-Barr virus infection.
Three children, all girls, showed long-lasting clinical and serologic evidence of chronic active Epstein-Barr virus (EBV) infection. Extremely high serum titers of IgG- and IgA-type VCA antibodies and EA antibodies were present, whereas EBNA antibody titers were in the range of those found in seropositive individuals. All three patients repeatedly showed the presence of nonspecific pokeweed mitogen (PWM)-activatable suppressor cells in the peripheral blood. The analysis of EBV-specific cytotoxic T cells showed that one patient exhibited normal cytotoxicity, whereas a second patient demonstrated no EBV-specific cytotoxicity together with unusually high levels of virus-infected B cells in the blood and lymph node. The third patient repeatedly showed refractoriness of the circulating B cells to EBV infection, probably on the basis of some developmental defect. It was concluded that each patient has his or her own peculiar defect in the virus-host balance, indicating that heterogeneity may underlie the syndrome of chronic active EBV infection in humans.


IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice.
Primary hyperparathyroidism (PHPT) is a common cause of bone loss that is modeled by continuous PTH (cPTH) infusion. Here we show that the inflammatory cytokine IL-17A is upregulated by PHPT in humans and cPTH in mice. In humans, IL-17A is normalized by parathyroidectomy. In mice, treatment with anti-IL-17A antibody and silencing of IL-17A receptor IL-17RA prevent cPTH-induced osteocytic and osteoblastic RANKL production and bone loss. Mechanistically, cPTH stimulates conventional T cell production of TNFα (TNF), which increases the differentiation of IL-17A-producing Th17 cells via TNF receptor 1 (TNFR1) signaling in CD4(+) cells. Moreover, cPTH enhances the sensitivity of naive CD4(+) cells to TNF via GαS/cAMP/Ca(2+) signaling. Accordingly, conditional deletion of GαS in CD4(+) cells and treatment with the calcium channel blocker diltiazem prevents Th17 cell expansion and blocks cPTH-induced bone loss. Neutralization of IL-17A and calcium channel blockers may thus represent novel therapeutic strategies for hyperparathyroidism.


Minimal clinically important differences of oral health-related quality of life after removable partial denture treatments.
This study aimed to determine the minimal clinically important difference (MID) of the oral health-related quality of life (OHRQoL) in removable partial dentures (RPDs) wearers, using the oral health impact profile (OHIP). In this study, RPD patients were asked to complete the OHIP and self-reported oral health (SROH) questionnaires before the treatment and 3 months after the RPD treatment. The Wilcoxon signed ranked test compared the pre- and post-treatment status and the Spearman correlation analysis evaluated the relationship between the pre- and post- treatment change scores of the OHIP and SROH. The median OHIP change score in a subgroup that showed minimum SROH improvement was determined as the MID. Of the 277 participants, 248 (89.5 %) completed the pre-and post- treatment evaluations. SROH and OHIP scores showed significant improvements after RPD treatment (P < 0.05). The OHIP change scores showed significant moderate correlations with the SROH change scores (P < 0.05). The MIDs for the summary scores of OHIP-49, 20, 14, and 5 versions were 14, 7, 3, and 2 points, respectively. An additional 2-3 points were assigned to the four dimensions (oral function, orofacial pain, orofacial appearance, and psychological impact). An OHIP change of more than 14 points (OHIP-49), 7 points (OHIP-20), 3 points (OHIP-14), 2 points (OHIP-5) and 2-3 points (4 dimensions) was considered clinically meaningful in RPD treatments. The proposed MID scores could be used as a benchmark for clinical decision making, interpretation of RPD treatment effects on OHRQoL, and sample size calculations in clinical trials.


Estrogens, androgens, and EGF receptor expression in gastric carcinoma induced by N-methyl-N'-nitro-N-nitrosoguanidine.
Complex and conflicting relationships between epidermal growth factor (EGF), estrogens (E), androgens (A), and related receptors (EGF-R, E-R, A-R) have been reported in different biological situations associated with cell proliferation. There is also evidence that EGF and sex hormone receptors may be involved in normal and neoplastic growth of the gastrointestinal mucosa. In this study, we investigated the behavior of EGF receptors and sex hormone and related receptors, during N-methyl-N'-nitro-N-nitrosoguanidine (NG)-induced gastric carcinogenesis in Sprague-Dawley male rats. Four groups of 15 rats each (10 NG-treated and five controls) were sacrificed after 1, 20, 30, and 40 weeks of treatment. Gastric tissue from each rat was processed for receptor status (number and affinity) and proliferative activity. A significant and progressive decrease of A-R and EGF-R was observed starting from the 20th week, while no change of E-R occurred throughout the experiment. Cell proliferation in the gastric mucosa of NG-treated rats increased after 30 weeks of treatment. These data indicate that NG treatment is able to modify the receptor status of gastric mucosa in rats.


Post-transplant diabetes mellitus in lung transplant recipients: incidence and risk factors.
Post-transplant diabetes mellitus (PTDM) is a common and potentially serious complication after solid organ transplantation. There are only a few data, however, about the incidence of DM in patients undergoing lung transplantation. The medical records of 119 consecutive patients who underwent lung transplantation from 1998 to September 2004 were reviewed. Patients were divided in three groups according to their diabetes status, including pre-transplant DM, the PTDM group and those without DM. Patient records and all laboratory data were reviewed and the clinical course of diabetes was monitored. All recipients were treated with tacrolimus based regimen. Mean follow-up for all patients was 25+/-10. Twenty-three patients had DM in the pre-lung transplantation (LTX) DM group. PTDM developed in 34 of the remaining 96 patients (35.4%) with an incidence of 20%, 23% after 6 months and 12 months post-transplant. No significant difference was noted between 12 and 24 months post-LTX. The patients who developed DM were older (57+/-15 vs 53+/-13 years, p=0.009), had increased BMI (26+/-5 vs 24+/-4, p=0.0001), shorter time from diagnosis to LTX (21+/-13 vs 28+/-18 months, p=0.007) more cytomegalovirus infection and more acute rejection and hyperglycemia in the first month after LTX. Four patients died in the PTDM group compared to nine patients in the no-DM group (12% vs 14%; p=0.72). Post-transplant diabetes is a common complication in lung transplant patients receiving tacrolimus-based immunosuppression. The risk for developing PTDM is greatest among older recipients, those obese, and among recipients with more rejections episodes.


Incidence of apparent life-threatening events and post-neonatal risk factors.
Even though a standard clinical definition for an apparent life-threatening event (ALTE) was established more than two decades ago, the specific International Classification of Disease (ICD) code was firstly included only in 2012. This study estimated the incidence of ALTEs in Northern Italy, together with features and risk factors. We used the Lombardy Region Hospital Discharge Records (HDR) database to estimate the cumulative incidence for ALTE during 2002-2006 and drew up a risk profile by comparing cases with and without ALTE who were followed in infancy. There were 246 infants registered in the HDR with ALTE putative diagnostic codes, suggesting a cumulative incidence of 4.1 per 1000 live births in the study area. Of the 148 cases with clinical co-morbidities, 31% had gastroesophageal reflux and 7% had acute respiratory infections. We analysed follow-up data from 15 ALTE cases and 1619 healthy infants and found that the significant risk factors were gastroesophageal reflux and a family history of sudden death. We established the regional incidence of ALTE and found risk factors in infants considered healthy in the first week of life and without pathological perinatal conditions. The systematic use of the specific ALTE ICD code (R68.13, ICD-10-CM) and common knowledge about ALTE diagnostic guidelines are clearly needed.


Defluviimonas denitrificans gen. nov., sp. nov., and Pararhodobacter aggregans gen. nov., sp. nov., non-phototrophic Rhodobacteraceae from the biofilter of a marine aquaculture.
Three Gram-negative bacterial strains were isolated from the biofilter of a recirculating marine aquaculture. They were non-pigmented rods, mesophiles, moderately halophilic, and showed chemo-organoheterotrophic growth on various sugars, fatty acids, and amino acids, with oxygen as electron acceptor; strains D9-3(T) and D11-58 were in addition able to denitrify. Phototrophic or fermentative growth could not be demonstrated. Phylogenetic analysis of the 16S rRNA gene sequences placed D9-3(T) and D11-58, and D1-19(T) on two distinct branches within the alpha-3 proteobacterial Rhodobacteraceae, affiliated with, but clearly separate from, the genera Rhodobacter, Rhodovulum, and Rhodobaca. Based on morphological, physiological, and 16S rRNA-based phylogenetic characteristics, the isolated strains are proposed as new species of two novel genera, Defluviimonas denitrificans gen. nov., sp. nov. (type strain D9-3(T)=DSM 18921(T)=ATCC BAA-1447(T); additional strain D11-58=DSM19039=ATCC BAA-1448) and Pararhodobacter aggregans gen. nov., sp. nov (type strain D1-19(T)=DSM 18938(T)=ATCC BAA-1446(T)).


Specific prebiotics in a formula for infants with Phenylketonuria.
This exploratory study investigated the influence of adding a patented, specific mixture of prebiotic oligosaccharides (scGOS/lcFOS [9:1 ratio], Danone Research) to a protein substitute suitable for infants with Phenylketonuria (PKU); PKU Anamix Infant (Nutricia). This was an 8-week open-label, single-arm, pilot intervention study in 9 infants (8-week median age) diagnosed with PKU. On study entry, infants were prescribed PKU Anamix Infant to replace an infant phenylalanine-free protein substitute without prebiotics (IPS). Blood phenylalanine concentrations were monitored and stool samples analyzed for pH/bacterial groups. PKU Anamix infant was well tolerated and accepted with no adverse events reported. Overall, plasma phenylalanine and tyrosine concentrations were maintained within target ranges throughout the study (120-360 μmol/l phenylalanine, 30-100 μmol/l tyrosine). All infants exhibited microbiota dominated by bifidobacteria (median 58.97% at Week 8), although no statistically significant change from baseline was observed at study endpoint. No infants showed abnormally high levels of Clostridium histolyticum/lituseburense or potentially pathogenic enterobacteriaceae at any point during the study. A significant reduction in median stool pH versus baseline was observed at Week 4 (pH reduced from 6.79 to 5.83), but this significance was not present at Week 8 (pH = 6.61). PKU Anamix Infant maintains phenylalanine control in line with established IPS without prebiotics and maintains levels of bifidobacteria and lowers stool pH. In exclusively breast-fed infants the latter two factors have been associated with a reduced risk of infection and may be of particular importance in infants with PKU.


Type of physical activity goal influences participation in healthy midlife women.
Regular physical activity can help to prevent cardiovascular disease in women. Understanding midlife women's exercise goals could offer insight into their motivational facilitators and barriers, and assist in the development of better primary prevention strategies for this population. We sought to investigate the relationship between midlife women's physical activity goals and their physical activity participation over time. A random sample of healthy, midlife women (40-60 years of age) was selected to participate in a longitudinal study (n = 156). This study fit a linear mixed model to the data to investigate the fixed effects of physical activity goals on physical activity participation, controlling for Body Mass Index (BMI) and Social Support. Mediational analyses were conducted to investigate whether commitment and planning mediated these results. There were significant differences between participants with distinct types of goals on physical activity participation over time (i.e., baseline, 1 month, and 1 year postbaseline), controlling for the effects of BMI and Social Support. Participants with Weight Loss and Health Benefits goals participated in significantly less physical activity than those with Sense of Well-being and Stress Reduction goals. Commitment and Planning each mediated the relationship between participant goals and their physical activity participation. These data suggest having physical activity goals that aim to decrease weight or benefit health may not bode well for healthy midlife women who desire to sustain physically active lives. Instead, health care providers and health promotion specialists might better facilitate long-term participation among healthy women if they emphasize physical activity as a means to enhance their quality of life.


Sensitized supervisors--a key to preserving nonunion status.
Properly selected, trained, sensitive supervisory personnel are the private, nonprofit hospital's first line of defense against attempts by unions to organize employees. Successful front line supervisors administer rules fairly, transmit information accurately, and strive for good human relations.


Verification of the turn at positions 22 and 23 of the beta-amyloid fibrils with Italian mutation using solid-state NMR.
The aggregation of 42-mer amyloid beta (Abeta42) plays a central role in the pathogenesis of Alzheimer's disease. Our recent research on proline mutagenesis of Abeta42 suggested that the formation of a turn structure at positions 22 and 23 could play a crucial role in its aggregative ability and neurotoxicity. Since E22K-Abeta42 (Italian mutation) aggregated more rapidly and with more potent neurotoxicity than wild-type Abeta42, the tertiary structure at positions 21-24 of E22K-Abeta42 fibrils was analyzed by solid-state NMR using dipolar-assisted rotational resonance (DARR) to identify the 'malignant' conformation of Abeta42. Two sets of chemical shifts for Asp-23 were observed in a ratio of about 2.6:1. The 2D DARR spectra at the mixing time of 500 ms suggested that the side chains of Asp-23 and Val-24 in the major conformer, and those of Lys-22 and Asp-23 in the minor conformer could be located on the same side, respectively. These data support the presence of a turn structure at positions 22 and 23 in E22K-Abeta42 fibrils. The formation of a salt bridge between Lys-22 and Asp-23 in the minor conformer might be a reason why E22K-Abeta42 is more pathogenic than wild-type Abeta42.


The extent of non-adherence in a large AIDS clinical trial using plasma dideoxynucleoside concentrations as a marker.
To assess adherence to study medications in an AIDS clinical trial, to evaluate whether study participants adhered to only one component of a multidrug regimen ('differential adherence'), and to determine whether there was evidence of non-uniform adherence to study medications among treatment groups. This was a substudy of AIDS Clinical Trials Group protocol 175, a large, double-blind, randomized study of monotherapy versus combination dideoxynucleoside therapy. Participants were required to adhere to a complex regimen of zidovudine, zalcitabine and didanosine, or their matching placebos. Between October 1992 and January 1994, study sites were selected at random, and a 1-week period was designated during which study participants attending routine clinic visits provided a blood sample and dosing history. Participants were not informed of the purpose of the substudy. Adherence was assessed using plasma drug concentrations and defined by the presence of detectable drug in a plasma sample obtained within a specified analysis window. Of 722 plasma samples analyzed, approximately 75% contained detectable concentrations of the assigned drugs and 5-14.5% contained no detectable drugs. Approximately 7 and 13% of samples from participants assigned to monotherapy arms contained non-prescribed dideoxynucleosides, and 14 and 19% assigned to combination therapies contained only one drug. Various non-adherence behaviors were observed, including patterns of underdosing and taking non-prescribed drugs. Non-adherence was moderate but uniform amongst the treatment groups and may have contributed to a marginal reduction in the power of the primary intent-to-treat analysis to detect differences in efficacy amongst the assigned treatments.


Ventral pallidal injections of a mu antagonist block the development of behavioral sensitization to systemic morphine.
Acute activation of opioid receptors in the ventral pallidum increases motor behaviors in rats. The present study was designed to investigate the possibility that the ventral pallidum influences motor responses induced by chronic opiate treatments and to examine the receptors that may be involved in such an effect. For five consecutive days, ambulations were quantified after rats received once-daily intraperitoneal (i.p.) injections of morphine (10 mg/kg) or saline following bilateral intra-ventral pallidal injections of either saline (0.5 microl/hemisphere), the mu antagonist CTOP (2. 1 microg/0.5microl/hemisphere), or the D1 antagonist SCH23390 (0.25 microg/0.5microl/hemisphere). Behavioral sensitization to an acute morphine challenge (10 mg/kg i.p.) was assessed 72 h after terminating the repeated treatment regimen. Rats who repeatedly received the intra-ventral pallidal saline + i.p. morphine exhibited increases in ambulations during the chronic treatment protocol and this effect was greatly enhanced (i.e., sensitized) following the post withdrawal acute morphine challenge. Rats repeatedly treated with intra-ventral pallidal CTOP + i.p. morphine did not display a motor response either during the chronic treatment regime or to the acute morphine challenge; an effect not seen when CTOP was injected into brain structures located dorsal to the ventral pallidum. The rats repeatedly treated with intra-ventral pallidal injections of SCH23390 + i.p. morphine demonstrated a motor response during the chronic protocol but the magnitude of this response was not significantly enhanced by the acute morphine challenge. These results demonstrate that: 1) mu opioid and D1-like dopamine receptors in the ventral pallidum influence the increase in locomotion that occurs during repeated morphine treatments; and 2) mu opioid (but not D1) receptors in the ventral pallidum are important in the postwithdrawal sensitized response to morphine. Such observations indicate that the ventral pallidum plays a critical role in morphine-induced behavioral sensitization.


Lumbar vertebral canal stenosis due to marked bone overgrowth after routine hemilaminectomy in a dog.
Bone overgrowth after decompressive surgery for lumbar stenosis resulting in recurrence of neurological signs has not been reported in veterinary literature. However, there are few cases described in human medicine. A 13-month-old entire female dog, a crossbreed between a Springer Spaniel and a Border Collie, weighing 24 kg, was referred with a 5-day history of progressive spastic paraplegia, indicative of a T3-L3 myelopathy. Magnetic resonance (MR) imaging revealed a right-sided L2-L3 compressive extradural lesion, compatible with epidural haemorrhage, which was confirmed by histopathology. The lesion was approached via right-sided L2-L3 hemilaminectomy and was successfully removed. One-year postoperatively the dog re-presented with pelvic limb ataxia. MR and computed tomography (CT) images demonstrated excessive vertebral bone formation affecting the right articular processes, ventral aspect of the spinous process of L2-L3, and contiguous vertebral laminae, causing spinal cord compression. Revision surgery was performed, and histopathology revealed normal or reactive osseous tissue with a possible chondroid metaplasia and endochondral ossification, failing to identify a definitive reason for the bone overgrowth. Nine-month postoperatively, imaging studies showed a similar vertebral overgrowth, resulting in minimal spinal cord compression. The patient remained stable with mild proprioceptive ataxia up until the last follow-up 18 months post-revision surgery. This is the first report in the veterinary literature of bone overgrowth after lumbar hemilaminectomy which resulted in neurological deficits and required a revision decompressive surgery.


Distal metaphyseal ulnar-shortening osteotomy: surgical technique.
Ulnar impaction is a common condition encountered by hand surgeons. Historically, treatment of this condition has been with wafer resection of the distal ulna, by either open or arthroscopic means, or diaphyseal ulnar shortening osteotomy; however, both of these have the potential for prolonged recovery or a need for additional procedures. Wafer procedures, whether done by open or arthroscopic techniques, can result in hemarthrosis, and diaphyseal osteotomies can require hardware removal. Recently, Slade and Gillon described a technique of ulnar shortening in the osteochondral region of the ulnar head, which offers advantages over previously used techniques. The purpose of this manuscript is to describe this technique, as well as pearls and pitfalls associated with the procedure. To more accurately describe the location of the osteotomy, we have changed the name of the procedure from Dr. Slade's original description to distal metaphyseal ulnar-shortening osteotomy.


Neural substrates of sexual arousal in heterosexual males: event-related fMRI investigation.
Sexual behavior is an important role for the survival of species. The advancement of brain imaging methods has enabled the understanding of the brain mechanism related to sexual arousal. The previous studies on the brain mechanism related to sexual arousal have mostly conducted on block design paradigm. Despite its requirement for stricter experimental control, the event-related paradigm is known to be more efficient in detecting instant emotional and cognitive responses. The paradigm also enables the observation of hemodynamic responses through time. Therefore, this study used the event-related fMRI to examine the brain activation in various areas associated with sexual arousal as well as changes in hemodynamic responses with time. Strong activations were observed in the various areas associated with sexual arousal comprised of various factors: (1) activation areas related to cognitive factors: the occipital lobe and parietal lobe; (2) activation areas related to emotional factors: the thalamus and amygdala; (3) activation areas related to motivational factors: the anterior cingulate gyrus, orbitofrontal cortex, and insula; and (4) activation areas related to physiological factors: the precentral gyrus, putamen, and globus pallidus. We also identified the activation of the putamen and globus pallidus that were not well observed in previous block design studies. In the result of the hemodynamic response, the neural activity in those areas showed more transient aspects of the hemodynamic responses relative to the neural activity of other areas. These results suggested that the event-related paradigm is better at detecting the neural activity of the brain regions, which tend to appear suddenly, but disappear soon.


Quenching of long lifetime emitting fluorophores with paramagnetic molecules.
In this work, we have studied quenching of the fluorescence of two well-known oxygen probes, 1-pyrene butyric acid (PBA) and tris(2,2'-bipyridine)ruthenium ([Ru(bpy)(3)](2+)) by reactive oxygen species (superoxide anion, nitric oxide derivative, hydrogen peroxide) and by the O(2) molecule. Both, time-resolved and steady state fluorescence measurements were performed in solution (ethanol, dimethyl sufoxide, water) and in micelles of Sodium Dodecyl Sulfate that serve as a model for membrane-containing biological structures. We have found that only the free radicals and O(2) can actively quench for the two probes, but not the diamagnetic H(2)O(2). Our data correspond to the classical Stern-Volmer equation. H(2)O(2) has an effect only at high molar concentrations (>0.1 M). In contrast, effective concentrations of free radicals and O(2) that lead to quenching are in millimolar range. In conclusion, our methods allows for detecting global ROS that are small free radicals without interference from the reactive hydroxyl radical. Our data suggest that the method can be used for the quantification of ROS in individual living cells based on the measurement of fluorescence lifetime of those probes.


Sexuality in Huntington's disease.
Sexuality and partnership have an important influence on the quality of life of patients with chronic disorders. There are just a few studies in literature about sexuality in Huntington's disease which conclude that up to 85% men and up to 75% of women experience high levels of sexual problems, most of them having prevalent symptoms of a hypoactive sexual disorder but also increased sexual interest and paraphilia were found. There is no evidence that sexual dysfunction is mainly a specific symptom of HD and may be associated with the specific brain lesion itself or if it is chiefly related to the psychosocial factors caused by the steadily worsening of the disease. Further studies should focus on asymptomatic patients to explore sexual changes preceding neurological and motor symptoms and should incorporate partners to objectify sexual distinctive features. Investigations on the context of sexual dysfunction with depression, irritability and dementia symptoms are needed to better understand reasons for sexual changes in HD. Treatment options for HD patients with sexual disorder are only reported sporadically, guidelines can only be obtained from non-HD patients and further research is needed.


Development of the First Potential Nonpeptidic Positron Emission Tomography Tracer for the Imaging of CCR2 Receptors.
Herein we report the design and synthesis of a series of highly selective CCR2 antagonists as 18 F-labeled PET tracers. The derivatives were evaluated extensively for their off-target profile at 48 different targets. The most potent and selective candidate was applied in vivo in a biodistribution study, demonstrating a promising profile for further preclinical development. This compound represents the first potential nonpeptidic PET tracer for the imaging of CCR2 receptors.


Understanding engagement behaviors and rapport building in tobacco cessation telephone counseling: An analysis of audio-recorded counseling calls.
Though telephone counseling is a modality commonly used to promote health behavior change, including tobacco cessation, specific counselor and participant behaviors that indicate engagement and therapeutic alliance remain poorly characterized in the literature. We sought to explore smokers' and counselors' engagement and rapport-building behaviors in telephone counseling for smoking cessation and patterns of these behaviors by smokers' psychiatric symptoms. The study team transcribed, audio-recorded tobacco cessation counseling calls for the presence of engagement and rapport-building behaviors among recently hospitalized participants enrolled in a smoking cessation randomized controlled trial (RCT). The study used baseline data from the RCT to explore frequencies of counselors' and smokers' behaviors among smokers who had reported more (vs. fewer) symptoms of depression (PHQ8 ≥ 10) or anxiety (GAD7 ≥ 10) at study entry. Participants (n = 37) were mostly female (23/37), White (26/37), with a median age of 58. At study entry while hospitalized, moderate-to-severe symptoms of depression (18/37) and anxiety (22/37) were common. Participant-led engagement behaviors included referencing past quit attempts, asking questions, elaborating response to yes/no questions, expressing commitment to behavior change, and assigning importance to nonautomated calls. Counselor-led behaviors included building off prior interaction, empathy, normalizing challenges, reframing and summarizing, validating achievements, and expressing shared experience. Both participants and counselors engaged via general discussion and humor. Participant-led engagement behaviors appeared more often in call transcripts among patients with higher baseline depression and anxiety symptoms compared to those with lower symptom scores. This study classified participant-led, counselor-led, and shared engagement behaviors during tobacco cessation counseling calls. Increased engagement via telephone counseling may be important for individuals with psychiatric symptoms identified at the start of treatment.


Biotech nanocellulose: A review on progress in product design and today's state of technical and medical applications.
Biotech nanocellulose (bacterial nanocellulose, BNC) is a high potential natural polymer. Moreover, it is the only cellulose type that can be produced biotechnologically using microorganisms resulting in hydrogels with high purity, high mechanical strength and an interconnecting micropore system. Recently, the subject of intensive research is to influence this biosynthesis to create function-determining properties. This review reports on the progress in product design and today's state of technical and medical applications. A novel, dynamic, template-based technology, called Mobile Matrix Reservoir Technology (MMR Tech), is highlighted. Thereby, shape, dimensions, surface properties, and nanonetwork structures can be designed in a process-controlled manner. The formed multilayer materials open up new applications in medicine and technology. Especially medical materials for cardiovascular and visceral surgery, and drug delivery systems are developed. The effective production of layer-structured composites and coatings are important for potential applications in the electronics, paper, food and packaging technologies.


A rare case of anomalous origin of the left main coronary artery in an adult patient.
Anomalous origin of left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly that causes a left-to-right shunt via the coronary system, resulting in coronary steal. We report an unusual case of a healthy 48 years-old patient presenting with dyspnea on exertion and mild chest pain who underwent surgical correction of this rare anomaly. Multiple procedures have been proposed in adults with ALCAPA. Although re-implantation of the left main coronary artery (LMCA) to the aorta remains the most physiological correction for this anomaly, the combination of LMCA ligation and coronary artery bypass grafting provides a dual coronary flow system and is preferable when re-implantation is impossible.


An effective model of blood flow in capillary beds.
In this article we derive applicable expressions for the macroscopic compliance and resistance of microvascular networks. This work yields a lumped-parameter model to describe the hemodynamics of capillary beds. Our derivation takes into account the multiscale nature of capillary networks, the influence of blood volume and pressure on the effective resistance and compliance, as well as, the nonlinear interdependence between these two properties. As a result, we obtain a simple and useful model to study hypotensive and hypertensive phenomena. We include two implementations of our theory: (i) pulmonary hypertension where the flow resistance is predicted as a function of pulmonary vascular tone. We derive from first-principles the inverse proportional relation between resistance and compliance of the pulmonary tree, which explains why the RC factor remains nearly constant across a population with increasing severity of pulmonary hypertension. (ii) The critical closing pressure in pulmonary hypotension where the flow rate dramatically decreases due to the partial collapse of the capillary bed. In both cases, the results from our proposed model compare accurately with experimental data.


Cell-cell interaction modulates neuroectodermal specification of embryonic stem cells.
The controlled differentiation of embryonic stem (ES) cells is of utmost interest to their clinical, biotechnological, and basic science use. Many investigators have combinatorially assessed the role of specific soluble factors and extracellular matrices in guiding ES cell fate, yet the interaction between neighboring cells in these heterogeneous cultures has been poorly defined due to a lack of conventional tools to specifically uncouple these variables. Herein, we explored the role of cell-cell interactions during neuroectodermal specification of ES cells using a microfabricated cell pair array. We tracked differentiation events in situ, using an ES cell line expressing green fluorescent protein (GFP) under the regulation of the Sox1 gene promoter, an early marker of neuroectodermal germ cell commitment in the adult forebrain. We observed that a previously specified Sox1-GFP+ cell could induce the specification of an undifferentiated ES cell. This induction was modulated by the two cells being in contact and was dependent on the age of previously specified cell prior to coculture. A screen of candidate cell adhesion molecules revealed that the expression of connexin (Cx)-43 correlated with the age-dependent effect of cell contact in cell pair experiments. ES cells deficient in Cx-43 showed aberrant neuroectodermal specification and lineage commitment, highlighting the importance of gap junctional signaling in the development of this germ layer. Moreover, this study demonstrates the integration of microscale culture techniques to explore the biology of ES cells and gain insight into relevant developmental processes otherwise undefined due to bulk culture methods.


Thermoregulation in three species of Afrotropical subterranean mole-rats (Rodentia: Bathyergidae) from Zambia and Angola and scaling within the genus Cryptomys.
The thermoregulatory characteristics of three species of Cryptomys from Zambia and Angola are examined and, together with published data on four other species of Cryptomys from southern Africa, used to determine whether scaling occurs in this genus of subterranean rodents. The thermoregulatory properties of acclimated giant Zambian mole-rats, Cryptomys mechowi ([Formula: see text]=267 g), Angolan mole-rats, Cryptomys bocagei ([Formula: see text]=94 g) and Zambian common mole-rats Cryptomys hottentotus amatus ([Formula: see text]=77 g) are as follows. Mean resting metabolic rates (RMRs) within the respective thermoneutral zones were 0.60±0.08 cm3 O2 g-1 h-1 (n=12) for C. mechowi; 0.74±0.06 cm3 O2 g-1 h-1 (n=8) for C. bocagei and 0.63±0.06 cm3O2 g-1 h-1 (n=21) for C. h. amatus. The thermoneutral zones (TNZs) of all three species are narrow: 29-30°C for C. mechowi; 31.5-32.5°C for C. bocagei and 28-32° C for C. h. amatus. The increase in mean RMR at the lowest temperatures tested (15° C for C. mechowi, 18° C for C. bocagei and C. h. amatus) was 2.35, 2.2 and 3.82 times their RMR in the TNZ respectively. Body temperatures are low, 34±0.53° C (n=24) for C. mechowi, 33.7±0.32° C (n=20) for C. bocagei and 33.8±0.43° C (n=40) for C. h amatus. At the lower limit of thermoneutrality, conductances are 0.09±0.01 cm3 O2 g-1 h-1 °C-1 (n=30) in C. mechowi; 0.12±0.01 cm3 O2 g-1 h-1 °C-1 (n=20) in C. bocagei and 0.12±0.03 cm3 O2 g-1 h-1 °C-1 (n=32) in C. h. amatus. The range in mean body mass among the seven species of Cryptomys examined for scaling was 60 g (C. darlingi) to 267 g (C. mechowi). There is no clear relationship between RMR within the TNZ and body mass. The resultant relationship is represented by the power curve RMR=2.45 mass-0.259.


Safety, efficacy and prognostic analyses of sunitinib in the post-marketing surveillance study of Japanese patients with gastrointestinal stromal tumor.
This study was conducted to expand the sunitinib safety database in Japanese imatinib-resistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. No unexpected safety issues occurred. Grade ≥ 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16-24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7-24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88-94). Higher relative dose intensity (≥70 vs. <70%) during the first 6 weeks and better Eastern Cooperative Oncology Group performance status (0 vs. ≥1) were associated with longer progression-free survival (24.0 vs. 20.1 weeks; P = 0.011; and 24.1 vs. 16.9 weeks; P < 0.001) and higher 24-week overall survival rate (94 vs. 83%; P < 0.001; and 96 vs. 83%; P < 0.001). Increased progression-free survival and overall survival rates were associated with specific adverse events. Cox proportional hazard modeling adjusted for relative dose intensity and performance status established hand-foot syndrome (hazard ratio = 0.636; 95% confidence interval, 0.456-0.888) and leukopenia (hazard ratio = 0.683; 95% confidence interval, 0.492-0.948) occurring within 12 weeks were significantly correlated with increased progression-free survival. Sunitinib showed good efficacy and tolerable safety. Factors associated with greater efficacy were relative dose intensity, performance status and specific early adverse events.


How international are the editorial boards in the field of hand research? A cross-sectional study of leading subspecialty hand journals.
Although low- and middle-income countries (LMIC) have great disease burden, but the lack of studies from LMIC have been shown in several fields. Multiple researchers from LMIC perceive editorial bias against their studies. Editorial board members (EBMs) from LMIC are under-represented across many medical journals. It is still unclear whether this phenomenon exists in the field of hand research. The purpose of this study was to investigate the composition of EBMs in leading subspecialty hand journals, and to reveal the international representation of EBMs in the field of hand research. This cross-sectional study included seven leading subspecialty hand journals. The EBMs were obtained from the journals' websites. The country affiliations of EBMs were categorized based on their locations and economy status. The composition of EBMs was investigated. There were 211 EBMs in the seven journals. A total of 185 EBMs (87.7%) were affiliated with high-income countries (HIC), 18 (8.5%) with upper middle-income countries, and 8 (3.8%) with lower middle-income countries. None EBMs were affiliated with low income countries. The EBMs were affiliated with 30 countries. The biggest number of EBMs were affiliated with the USA 74 (35.07%), followed by the United Kingdom (45, 21.33%), and France (13, 6.16%). Most of EBMs were based in Europe and Central Asia (86, 40.8%) and North America (81, 38.4%). The EBMs of leading subspecialty hand journals are dominated by HIC with a very low representation of LMIC. There is a need to make the editorial boards more international in the field of hand research.


Protocol for a randomized controlled trial of the Enhanced Smoking Cessation Approach to Promote Empowerment (ESCAPE) digitalized intervention to promote lung health in high-risk individuals who smoke.
Low dose computed tomography (LDCT) is an effective screening test to decrease lung cancer deaths. Lung cancer screening may be a teachable moment helping people who smoke to quit, which may result in increased benefit of screening. Innovative strategies are needed to engage high-risk individuals in learning about LDCT screening. More precise methods such as polygenic risk scores quantify genetic predisposition to tobacco use, and optimize lung health interventions. We present the ESCAPE (Enhanced Smoking Cessation Approach to Promote Empowerment) protocol. This study will test a smoking cessation intervention using personal stories and a lung cancer screening decision-aide compared to standard care (brief advice, referral to a quit line, and a lung cancer screening decision-aide), examine the relationship between a polygenic risk score and smoking abstinence, and describe perceptions about integration of genomic information into smoking cessation treatment. A randomized controlled trial followed by a sequential explanatory mixed methods approach will compare the efficacy of the interventions. Interviews will add insight into the use of genomic information and risk perceptions to tailor smoking cessation treatment. Two-hundred and fifty individuals will be recruited from primary care, community-based organizations, mailing lists and through social media. Data will be collected at baseline, 1, 3 and 6-months. The primary outcomes are 7-day point prevalence smoking abstinence and stage of lung cancer screening at 6-months. The results from this study will provide information to refine the ESCAPE intervention and facilitate integration of precision health into future lung health interventions. Clinical trial registration number: NCT0469129T.


Incidence of Pneumocystis Jiroveci Pneumonia in Patients With ANCA-Associated Vasculitis Initiating Therapy With Rituximab or Cyclophosphamide.
This manuscript assesses the incidence of Pneumocystis jiroveci pneumonia (PJP) among patients receiving contemporary treatment regimens for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and adverse events associated with PJP prophylaxis. Incident users of rituximab or cyclophosphamide for AAV were identified in the TriNetX electronic health records database from 2011 to 2022. The incidence rates (IRs) of PJP in the first 6 months of induction therapy with rituximab and/or cyclophosphamide and during postinduction maintenance therapy with rituximab were calculated. Cox proportional hazard models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) for the risk of adverse events commonly associated with PJP prophylaxis. We identified 1,461 AAV cases who received induction therapy with rituximab (69.7%), cyclophosphamide (18.9%), or both (11.4%). Prophylaxis prescribed within 30 days of induction included trimethoprim-sulfamethoxazole (30.7%), atovaquone (5.4%), dapsone (3.8%), and pentamidine (0.8%). During induction therapy, 10 cases of PJP were identified (IR 15.0 cases per 1,000 patient-years); no deaths occurred. In adjusted analyses, those who received prophylaxis had a higher risk of leukopenia (HR 3.1; 95% CI 1.1-8.6), rash (HR 1.9; 95% CI 1.0-3.6), and nephropathy (HR 2.6; 95% CI 1.3-5.1) than those who did not. During rituximab maintenance therapy (n = 709), five cases of PJP were identified (IR 2.1 cases per 1,000 person-years), one of whom died during the hospitalization associated with a PJP diagnosis. Rates of PJP in patients with AAV were lower than previously observed, and few cases occurred during rituximab maintenance therapy. PJP prophylaxis was associated with adverse events.


Characterization and sexual dimorphic expression of Cytochrome P450 genes in the hypothalamic-pituitary-gonad axis of yellow catfish.
Yellow catfish (Pelteobagrus fulvidraco) is an important freshwater fish species in China. In particular, an all-male population has been commercially produced for the males grow faster than females. However, the molecular mechanisms underlying sexual dimorphism of body size and sex differentiation are still unclear in yellow catfish. This study attempts to characterize and analyze the expression of Cytochrome P450 (CYP) family members that have been shown to play an important role in sex differentiation and metabolism in teleosts. A total of 25 CYP genes were identified from our transcriptomes by 454 pyrosequencing and Solexa sequencing, including 17 genes with complete open reading frame (ORF). Phylogenetic analyses were conducted to compare these genes with their counterparts from other teleosts. In the tissues of hypothalamic-pituitary-gonad (HPG) axis, most of the genes were expressed at uniform level in both sexes. However, multiple CYP genes displayed sexual dimorphic expression, such as cyp2AD, cyp4b, cyp8a, cyp11b2, cyp17a and cyp27a expressed at higher level in testis than in ovary, whereas cyp2g, cyp7a, cyp8b, cyp19a1a and cyp26a expressed at higher level in ovary than in testis. The expression response of six CYP genes in ovary was also assessed after 17α-methyltestosterone (MT) treatment. Testis-biased expressed cyp11b2 and cyp17a were significantly up-regulated, while cyp11a and cyp19a1a were reduced in ovary after MT treatment. Our work is helpful for understanding molecular evolution of CYP genes in vertebrates and the mechanism of sexual dimorphism in teleosts.


Differences in Rate of Gestational Diabetes Between Active Duty and Non-active Duty Beneficiaries at a Military Treatment Facility.
Gestational diabetes mellitus (GDM) affects approximately 1-14% of all pregnancies in the United States and has significant maternal and neonatal consequences. Developing GDM can increase a patient's risk of developing overt diabetes in the future which may impact a soldier's readiness. The purpose of this study is to compare the incidence of GDM in active duty females compared with civilian dependents. This retrospective cohort analysis was performed at a military medical center with IRB approval. Active duty and dependent status women who delivered between June 1, 2014 and April 30, 2015 were identified along with incidence of GDM. Sample size calculation determined a need for 391 women in each group to observe a 5% difference in rate of GDM with a power of 80%. Chi-squared analysis was used to compare rates of GDM. Rates of GDM were similar between the two cohorts (active duty = 9.95%, dependent = 9.72%, P = .91). Age, gravidity, and prepregnancy BMI were also similar between groups. The rate of diet-controlled GDM were different between the two cohorts (active duty = 53.8%, dependent = 34.2%, P = .02). This study highlights active duty females have similar rates of GDM as dependents. Gestational diabetes mellitus is known to affect short- and long-term maternal and neonatal outcomes and can impact a soldier's readiness. Further research is required to determine the long-term impact of GDM in active duty females and best practices to decrease rates of GDM in the military population.


Comparison of atmospheric concentrations of currently used pesticides between urban and rural areas during intensive application period in Alsace (France) by using XAD-2® based passive samplers.
XAD-2® passive samplers (PAS) have been exposed simultaneously for 14 days on two sites, one rural and one urban, situated in Alsace (East of France) during intensive pesticides application in agriculture (between March and September). PAS have been extracted and analyzed for current-used pesticides and lindane with an analytical method coupling accelerated solvent extraction (ASE), solid-phase microextraction (SPME) and GC/MS/MS. Results show the detection of pesticides is linked to the period of application and spatial and temporal variabilities can be observed with these PAS during the selected sampling period. The spatial and temporal variability is comparable to the one previously observed by comparing data obtained with PAS with data from Hi.-Vol. samplers in an urban area. Sampling rates were calculated for some pesticides and values are comparable to the data already available in the literature. From these sampling rates, concentrations in ng m-3 of pesticides in PAS have been calculated and are in the same order of magnitude as those obtained with Hi.Vol. sampling during the same period of time.


Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading.
Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics.


P1 deficiency in shiverer myelin is expressed by Schwann cells in shiverer dystrophic normal mouse chimaera nerves.
The myelin basic protein (P1) deficiency in shiverer myelin is expressed in shiverer reversible normal mouse chimaera nerves. Chimaera examined with immunocytochemical techniques have revealed populations of both densely labeled and unreacting myelinated Schwann cells. Single axons can innervate both Schwann cell types, demonstrating that the expression of P1 in Schwann cell myelin is unrelated to the shiverer or normal genotype of the neuron. The coexistence of both Schwann cell types in single nerves indicates that multiple progenitor Schwann cells are allocated to developing nerves and the mosaic patterns expressed further suggest that such cells tend to proliferate relatively small coherent clones of Schwann cells.


Inversionless amplification by anisotropic molecules.
Switching from opaque via transparent to a strongly amplifying state is shown to be possible for molecular media without a change in the noninverted population of their energy levels.


Green plants as intelligent organisms.
Intelligent behaviour, even in humans, is an aspect of complex adaptive behaviour that provides a capacity for problem solving. This article assesses whether plants have a capacity to solve problems and, therefore, could be classified as intelligent organisms. The complex molecular network that is found in every plant cell and underpins plant behaviour is described. The problems that many plants face and that need solution are briefly outlined, and some of the kinds of behaviour used to solve these problems are discussed. A simple way of comparing plant intelligence between two genotypes is illustrated and some of the objections raised against the idea of plant intelligence are considered but discarded. It is concluded that plants exhibit the simple forms of behaviour that neuroscientists describe as basic intelligence.


Long-Term Improvement in Liver Function Following Transjugular Intrahepatic Portosystemic Shunt in Patients With Budd-Chiari Syndrome.
Transjugular intrahepatic portosystemic shunt (TIPS) relieves hepatic venous obstruction in Budd-Chiari syndrome (BCS), but the effect on liver function is unclear, particularly outside the immediate post-treatment period. This study aims to evaluate the long-term impact of TIPS on liver function and outcomes in BCS patients. Twenty patients with BCS who underwent TIPS from 1999 to 2018 were included. Demographic data and clinical data at the time of TIPS procedure, 6 months, 12 months, 2 years, 5 years, and 10 years post-TIPS were collected. There were 13 (13/20, 65%) women and 7 (7/20, 35%) men with a mean age at the time of TIPS of 42.6 ± 12.8 years. The median time from BCS diagnosis to TIPS was 41 (IQR: 4-165) days. The number of patients with severe ascites decreased significantly from 10/17 (58.8%) at the time of TIPS, to 1/16 (7.7%), 1/13 (7.7%), 2/16 (12.5%), 1/14 (7.1%), and 0/8 (0%) at 6 months, 12 months, 2 years, 5 years and 10 years post-TIPS, respectively. 4/20 (20%) patients developed new hepatic encephalopathy post-TIPS procedure. Child-Pugh score significantly decreased from a score of 9.4 ± 1.8 pre-TIPS to 7.6 ± 1.8 at 6 months, 7.4 ± 1.5 at 12 months, 7.3 ± 1.6 at 2 years, 6.8 ± 1.5 at 5 years, and 6.4 ± 0.7 at 10 years post-TIPS. Fifteen (15/20, 75%) patients required TIPS revision including 4 (4/15, 26.7%) within 30 days, 2 (2/15, 13.3% within 1 month to 1 year, and 9 (9/15, 60%) at more than 1 year. Eight (8/20, 40%) patients underwent liver transplantation (LT) at median time of 7.3 (IQR 3.2-12.9) years after TIPS. TIPS placement for BCS results in sustained resolution of symptoms and improved liver function. Despite the frequent need for revisions, the long-term durability of TIPS can forgo the need for LT in the majority of patients.


Simian virus 40 DNA extracted from infected cells with sodium deoxycholate no longer reflects its in vivo superhelix density.
When simian virus 40 DNA is extracted from infected cells with low concentrations of sodium deoxycholate, which selectively extract non-encapsidated simian virus 40 DNA, the DNA has a lower average number of superhelical turns than the DNA extracted from purified viral particles. During extraction, a partial deproteinization of the DNA by a concentration of detergent that did not inactivate a nicking-closing activity led to the removal of some superhelical turns. The DNA extracted in this way no longer reflected its in vivo number of superhelical turns.


Demonstration of a direct effect of inhibitors of the degradation of receptor-bound human choriogonadotropin on the steroidogenic pathway.
Results presented in the previous paper (Ascoli, M., and Puett, D. (1978) J. Biol. Chem. 253, 7832--7838) show that the degradation of receptor-bound 125I-labeled human choriogonadotropin can be inhibited by chloroquine, protease inhibitors, and metabolic inhibitors. These compounds were also shown to inhibit gonadotropin-stimulated steroidogenesis. It is reported herein that these inhibitors also block the stimulation of steroidogenesis by both cholera toxin and 8-Br-adenosine 3':5'-monophosphate, thus showing that they are not specific for the hormonal stimuli. These results, taken together with previous observations that show that NH2Cl can block hormone degradation without inhibiting hormone-stimulated steroidogenesis, strongly suggest that the degradation of choriogonadotropin is not required for its stimulatory action on progesterone production.


Insulin resistance and associated factors in patients with Type 1 Diabetes.
To assess the presence of insulin resistance (IR) in patients with type 1 diabetes (T1DM) according to the estimated glucose disposal rate formula (eGDR) and the insulin sensitivity score (ISS) and to estimate the correlation between these two measures and identify the clinical and laboratory markers related to IR. Cross-sectional study of adults with T1DM (n = 135). The results of the formulas that estimate IR were separated into quartiles and correlated with demographic data, clinical characteristics and laboratory parameters. We analyzed the total and regional adiposity by dual-energy X-ray absorptiometry and skin fold thickness measurements. Two thirds of the patients were overweight or obese. A moderate correlation was found between eGDR and ISS (r = 0.612). The results of both formulas were positively correlated with BMI (r = -0.373 eGDR and r = -0.721 ISS), thoracic-abdominal fat (r = -0.484 eGDR and r = -0.758 ISS), waist/height ratio (r = -0.537 eGDR and r = -0.779 ISS), subscapular skinfold (mm) (r = -0.356 eGDR and r = -0.569 ISS), total dose insulin IU/lean mass (kg) (r = -0.279 eGDR and r = -0.398 ISS), age (years) (r = -0.495 eGDR and r = -0.190 ISS) and diabetes duration (years) (r = -0.428 eGDR and r = -0.187 ISS). A moderate agreement (Kappa 0.226) was observed between the 1st quartile of results determined by the formulas in 10.4% of the patients, but the 4th quartile presented a strong correlation (Kappa 0.679). The individuals with IR that were classified in the 1st quartile by the ISS formula had a higher chance of presenting with acanthosis nigricans (OR = 5.58, 95% CI =1.46-21.3). The correlations found in this study indicate the possibility of using clinical and laboratory data to estimate IR in patients with TDM1. The detection of IR in T1DM patients may allow early intervention and possibly impact on future diabetes complications.


Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for seminoma: Limitations of surgical intervention after first-line chemotherapy.
Patients with relapsed seminoma after first-line chemotherapy can be treated with salvage chemotherapy or postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). Based on prior experience, surgical management can have worse efficacy and increased morbidity compared to nonseminomatous germ cell tumor. Our aim was to characterize the surgical efficacy and difficulty in highly selected patients with residual disease after first-line chemotherapy. The Indiana University testis cancer database was queried to identify men who underwent PC-RPLND for seminoma between January 2011 and December 2021. Included patients underwent first-line chemotherapy and had evidence of retroperitoneal disease progression. We identified 889 patients that underwent PC-RPLND, of which only 14 patients were operated on for seminoma. One patient was excluded for lack of follow-up. Out of 13 patients, only 3 patients were disease free with surgery only. Median follow up time was 29.9 months (interquartile ranges : 22.6-53.7). Two patients died of disease. The remaining 8 patients were treated successfully with salvage chemotherapy. During PC-RPLND, 4 patients required nephrectomy, 1 patient required an aortic graft, 2 patients required a partial ureterectomy, and 3 patients required partial or complete caval resection. The decision between salvage chemotherapy and PC-RPLND as second-line therapy can be challenging. Salvage chemotherapy is effective but is associated with short and long-term morbidity. Surgical efficacy in this setting seems to be limited, but careful selection of patients may lead to surgical success without affecting the ability to receive any systemic salvage therapies if necessary or causing life-threating morbidity.


Overexpression, purification, crystallization and preliminary X-ray crystal analysis of Bacillus pallidusD-arabinose isomerase.
D-Arabinose isomerase catalyzes the isomerization of D-arabinose to D-ribulose. Bacillus pallidus D-arabinose isomerase has broad substrate specificity and can catalyze the isomerization of D-arabinose, L-fucose, L-xylose, L-galactose and D-altrose. Recombinant B. pallidus D-arabinose isomerase was overexpressed, purified and crystallized. A crystal of the enzyme was obtained by the sitting-drop method at room temperature and belonged to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 144.9, b = 127.9, c = 109.5 A. Diffraction data were collected to 2.3 A resolution.