Simultaneous Electrochemical Detection of Dopamine and Uric Acid via Au@Cu-Metal Organic Framework.

The incorporation of noble metals with metal-organic frameworks (MOFs) are conducive to the simultaneous electrochemical detection of analytes owing to multiple accessible reaction sites. Herein, Au@Cu-metal organic framework (Au@Cu-MOF) is successfully synthesized and modified as a screen-printed carbon electrode (SPCE), which serves as an excellent electrocatalyst for the oxidation of dopamine (DA) and uric acid (UA). The sensor shows a linear range from 10 µM to 1000 µM, with sensitivity and detection limit of 0.231 µA µM-1 cm-2 and 3.40 µM for DA, and 0.275 µA µM-1 cm-2 and 10.36 µM for UA. Au@Cu-MOF could realize the individual and simultaneous electrochemical sensing of DA and UA, with distinguishable oxidation peak potentials. Moreover, it exhibits reproducibility, repeatability, and stability. Ultimately, the sensor provides an avenue for an ultrasensitive label-free electrochemical detection of DA and UA.

Acute Fever of Unknown Origin: A Presentation of West Nile Encephalitis.

INTRODUCTION: West Nile virus is an asymptomatic infection in most cases, but it can present with a rare complication of deadly neuroinvasive disease. CASE PRESENTATION: A 81-year-old White man presented with altered mental status and fever of unknown origin. After extensive workup, he was diagnosed with West Nile encephalitis based on positive serology, lumbar puncture, and clinical presentation. DISCUSSION: West Nile virus is a mosquito-borne RNA arbovirus that, in rare cases, can lead to encephalitis, which is a challenging diagnosis. There is no current treatment; however, a 5-day course of intravenous immunoglobulin seemed to show acute clinical improvement in both mentation and magnetic resonance imaging of the head and no long-term effects. CONCLUSION: We report this case to increase awareness among clinicians to include West Nile virus in the differential diagnosis of encephalitis with fever of unknown origin, particularly in endemic areas.

VerSe: A Vertebrae labelling and segmentation benchmark for multi-detector CT images.

Vertebral labelling and segmentation are two fundamental tasks in an automated spine processing pipeline. Reliable and accurate processing of spine images is expected to benefit clinical decision support systems for diagnosis, surgery planning, and population-based analysis of spine and bone health. However, designing automated algorithms for spine processing is challenging predominantly due to considerable variations in anatomy and acquisition protocols and due to a severe shortage of publicly available data. Addressing these limitations, the Large Scale Vertebrae Segmentation Challenge (VerSe) was organised in conjunction with the International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) in 2019 and 2020, with a call for algorithms tackling the labelling and segmentation of vertebrae. Two datasets containing a total of 374 multi-detector CT scans from 355 patients were prepared and 4505 vertebrae have individually been annotated at voxel level by a human-machine hybrid algorithm (https://osf.io/nqjyw/, https://osf.io/t98fz/). A total of 25 algorithms were benchmarked on these datasets. In this work, we present the results of this evaluation and further investigate the performance variation at the vertebra level, scan level, and different fields of view. We also evaluate the generalisability of the approaches to an implicit domain shift in data by evaluating the top-performing algorithms of one challenge iteration on data from the other iteration. The principal takeaway from VerSe: the performance of an algorithm in labelling and segmenting a spine scan hinges on its ability to correctly identify vertebrae in cases of rare anatomical variations. The VerSe content and code can be accessed at: https://github.com/anjany/verse.

Betaine supplementation to rats alleviates disturbances induced by high-fat diet: pleiotropic effects in model of type 2 diabetes.

Betaine is a biologically active compound exerting beneficial effects in the organism, however, the exact mechanisms underlying its action are not fully elucidated. The present study aimed to explore, whether betaine alleviates disorders induced by feeding rats a high-fat diet (HFD). Rats were divided into 3 groups: control, fed an HFD and fed an HFD and receiving betaine (2% water solution for 8 weeks). Betaine improved glucose tolerance, decreased blood levels of non-esterified fatty acids and prevented lipid accumulation in the skeletal muscle of rats on an HFD. Betaine reduced activities of blood alanine aminotransferase, blood levels of bilirubin and hepatic lipid content. Expression of fatty acid synthase in the liver and the skeletal muscle was decreased in response to feeding an HFD, and this effect was deepened by betaine in the muscle tissue. Hepatic and muscular expression of genes related to insulin signaling were unchanged in HFD-fed rats. Lipolysis stimulated by epinephrine (an adrenergic receptor agonist), forskolin (an activator of adenylate cyclase), dibutyryl-cAMP (an activator of protein kinase A) and DPCPX (an adenosine A1 receptor antagonist) was diminished in the adipocytes of rats fed an HFD, however, this effect was alleviated by betaine. Moreover, blood leptin levels in HFD-fed rats were elevated, whereas leptinemia have normalized by betaine supplementation. Betaine prevented the increase in expression of N-methyl D-aspartate receptors in the hippocampus and in the cerebral cortex. These results indicate that betaine positively affects the insulin-sensitive tissues: liver (hepatoprotective effects), skeletal muscle (reduced lipid accumulation) and adipose tissue (a rise in lipolysis), which is associated with improved insulin sensitivity. Betaine-induced prevention of hyperleptinemia indicates restoration of leptin action, and changes in the brain reveal neuroprotective properties. Our results show that betaine induces positive changes in HFD-fed rats, its action is pleiotropic and involves different tissues.

Management of chronic testicular pain due to thoracolumbar junction syndrome: A pilot study.

INTRODUCTION: Thoracolumbar dysfunction (TLD) had been evoked as a possible etiology of chronic testicular pain. Our study investigated the efficacy of osteopathic diagnosis and treatment of TLD in men with chronic testicular pain. METHODS: Patients suffering from testicular pain were examined for thoracolumbar dysfunction and enrolled in a prospective trial if they have both conditions. Following standardized examination, all patients were prescribed 1 to 3 osteopathic treatment sessions, usually at weekly interval. Treatment success was evaluated using the Visual Analog scale and durability was assessed by regular follow-up. Patient satisfaction was also assessed. Comparison of pain improvement was done using Wilcoxon matched-pairs signed-ranks test. Logistic regression was used to assess for risk factors of success. A P<0.001 was used for significance. RESULT: Out of 62 patients enrolled, 41 patients (median age 32 years, IQR 24-37) were suffering from chronic testicular pain and TLD. 37 of the 41 participants completed the treatment and follow-up according to the plan. Patients underwent a median of 2 osteopathic treatment sessions (range 1-3). Overall, pain disappeared completely in 25 patients (67.5%) and improvement was noted in 7 patients (18.9%). After initial improvement, two patients experienced relapse at their last visit (5.4%). Five patients (13.5%) had no improvement of their symptoms after osteopathic treatment. Statistically, improvement was significant with a P<0.001 and on logistic regression, site of pain and duration of pain were the sole predictors of failure. CONCLUSION: TLD is a pathology that should be considered in the differential diagnosis in patients with chronic testicular pain and osteopathic manipulation of the spine appears to be an effective treatment option.

A new pharmacokinetic model for 90Y-ibritumomab tiuxetan based on 3-dimensional dosimetry.

Monoclonal antibodies (mAbs) are key components in several therapies for cancer and inflammatory diseases but current knowledge of their clinical pharmacokinetics and distribution in human tissues remains incomplete. Consequently, optimal dosing and scheduling in clinics are affected. With sequential radiolabeled mAb-based imaging, radiation dosing in tissues/organs can be calculated to provide a better assessment of mAb concentrations in tissues. This is the first pharmacokinetic model of 90Y-Ibritumomab tiuxetan (90Y-IT) in humans to be described, based on three-dimensional (3D) dosimetry using single-photon emission computed-tomography coupled with computed-tomography. 19 patients with follicular lymphoma were treated initially with 90Y-IT in the FIZZ trial. Based on a compartmental approach individualising the vascular compartment within studied organs, this study proposes a reliable pharmacokinetic (PK) five-compartment model replacing the currently used two-compartment model and constitutes a new direction for further research. This model provides exchange constants between the different tissues, Area Under the Curve of 111In-IT in blood (AUC) and Mean Residence Time (MRT) that have not been reported so far for IT. Finally, the elimination process appears to occur in a compartment other than the liver or the spleen and suggests the metabolism of mAbs may take place mainly on the vascular compartment level.

Pharmacogenomics and chemical library screens reveal a novel SCFSKP2 inhibitor that overcomes Bortezomib resistance in multiple myeloma.

While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin ligase Skp1-Cullin-1-Skp2 (SCFSkp2) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCFSkp2 activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138+ cells isolated from BTZ-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138+ cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCFSkp2 complex, stabilized p27 and increased the number of annexin-V-positive cells after BTZ treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced BTZ-induced apoptosis. DT204 co-treatment with BTZ overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof of concept for rationally designed drug combinations that incorporate SCFSkp2 inhibitors to treat BTZ resistant disease.

Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib.

Although the therapeutic benefit of proteasome inhibition in multiple myeloma remains unchallenged, drug resistance inevitably emerges through mechanisms that remain elusive. Bortezomib provokes unwanted protein accumulation and the endoplasmic reticulum stress to activate the unfolded protein response (UPR) and autophagy as compensatory mechanisms that restore protein homeostasis. High-throughput screens to detect pharmacologics that modulated autophagy to enhance the anti-myeloma effect of bortezomib revealed metformin, a widely used antidiabetic agent with proven efficacy and limited adverse effects. Metformin co-treatment with bortezomib suppressed induction of the critical UPR effector glucose-regulated protein 78 (GRP78) to impair autophagosome formation and enhance apoptosis. Gene expression profiling of newly diagnosed myeloma patient tumors further correlated the hyperexpression of GRP78-encoding HSPA5 with reduced clinical response to bortezomib. The effect of bortezomib was enhanced with metformin co-treatment using myeloma patient tumor cells and the chemoresistant, stem cell-like side population that may contribute to disease recurrence. The relevance of the findings was confirmed in vivo as shown by metformin co-treatment with bortezomib that delayed the growth of myeloma xenotransplants. Taken together, our results suggest that metformin suppresses GRP78, a key driver of bortezomib-induced autophagy, and support the pharmacologic repositioning of metformin to enhance the anti-myeloma benefit of bortezomib.

Comparisons of dosimetric approaches for fractionated radioimmunotherapy of non-Hodgkin lymphoma.

AIM: The aim of this study was to compare different dosimetric approaches on therapy naïve patients enrolled in a multicentre fractionated radioimmunotherapy trial, to determine which methodological approach correlates with bone marrow toxicity. METHODS: Twenty-height non-Hodgkin lymphoma patients were treated with one or two fractions of 90Y-Ibritumomab-Tiuxetan (11.1 MBq/kg) 8 to 12 weeks apart in four different institutions. Quantitative imaging with 111In-Ibritumomab-Tiuxetan (185 MBq) was performed at 0, 1, 4 and 7 days after infusion, starting two weeks before the therapeutic administration. A whole-body (WB) CT scan was also acquired prior to the 111In-Ibritumomab injection, for attenuation correction purposes and was segmented to derive patient-specific organ masses. All dosimetry processing was centralized in a single institution. The first method (M_2D) was based on geometric mean WB scans, corrected for attenuation, scatter and organs superposition. The second method (M_2.5D) was based on the computed assisted matrix inversion approach and used segmented CT scans. The third method (M_3D) used iterative reconstruction of tomographic scans, corrected for attenuation, scatter and collimator response. Absorbed doses were estimated for lungs, liver, kidneys and spleen using MIRD S values adjusted for organ masses. Bone marrow (BM) absorbed doses were evaluated according to imaging methods (3) and compared to blood-based approaches. RESULTS: For some patients, organ masses such as liver or spleen significantly differed from male/female reference masses, whereas lungs and kidneys masses were relatively constant. Except for lungs, absorbed doses estimated by M_2D were higher than those from M_2.5D and these, in turn, were higher that those calculated from M_3D (Wilcoxon P<8.6e-4). Median organ absorbed dose estimates were equivalent for both fractions except for the spleen. In fact, spleen absorbed doses for the second fraction were lower than those for the first fraction, regardless of the approach. Possible explanations are that patient spleen masses were kept constant for analysis of both fractions and/or that spleen uptake was lowered after the first fraction. Estimation of BM absorbed doses from blood sampling was unable to predict platelet toxicity, but image-based methods performed better. Additionally, for most organs, the absorbed dose delivered by the first fraction could predict that delivered by the second fraction. CONCLUSION: These results confirm that different acquisition/processing protocols will lead to statistically different absorbed doses. Additionally, image-based dosimetric approaches are needed in order to correlate absorbed dose to bone marrow toxicity.

[Etology and treatment of community acquired pneumonia in children]. / Pneumonies communautaires chez l'enfant: étiologie et traitement.

In children under 5 years, most lower respiratory tract infections are caused by viruses and do not require antibiotics. This is true for almost all episodes of bronchitis and bronchiolitis but also for the majority of pneumonias. Atypical pneumonias due to Mycoplasma pneumoniae or Chlamydia pneumoniae predominate in older children while Streptococcus pneumoniae remains by far the most common cause of bacterial pneumonia. Diagnosis of pneumonia itself can be difficult and relies on a combination of clinical judgement and radiological and laboratory investigations. In real-life situations, etiologic agents are rarely identified, an issue further complicated by the possibility of mixed infections particularly in hospitalised children. Since viruses are often the sole cause of pneumonia in childhood, it is appropriate not to treat every child with antibiotics. However, when a bacterial origin can not be excluded, antibiotics efficient on Streptococcus pneumoniae are to be prescribed. Amoxicillin is the first choice empirical antibiotic treatment, having a higher efficacy on poorly sensitive pneumococcus than cephalosporins. Macrolides are indicated for the treatment of atypical pneumonia. Current immunisation strategies have decreased the number of bacterial pneumonias. However, there is some evidence that among hospitalised children the rate of complicated pneumonias is increasing with an emerging role of Streptococcus pneumoniae serotype 1, which is not covered in the 7-valent vaccine.

Human schistosomiasis in Puerto Rico: reduced prevalence rate and absence of Biomphalaria glabrata.

A combined epidemiologic and malacologic survey of schistosomiasis in Puerto Rico was carried out in areas where previous surveys had reported the prevalence of the disease. This limited survey, with 495 persons examined, found a low prevalence (0.6%) of Schistosoma mansoni infections. The infections were restricted to three people more than 36 years of age. No infections were detected in children 16 years of age or less, and this cohort comprised 57.8% of the study group. Malacologic surveys of the four streams, 10 rivers, and eight lakes throughout the island revealed the absence of intermediate host Biomphalaria glabrata and the presence of Thiara granifera, a competitive species of B. glabrata and the predatory snail Marisa cornuarietis. We believe that the absence of B. glabrata is the primary reason for the sustained reduction in the prevalence of schistosomiasis in Puerto Rico.

Comparison of three methods for determining aflatoxins in melon seeds.

The suitability of 3 methods for determining aflatoxins in melon seeds was examined. The first 2 are the Contaminants Branch (CB) method and the Best Foods (BF) method, both official methods for determining aflatoxins in peanuts and peanut products. The third method, the modified CB method-Rapid Modification of the Cottonseed (CB-RCS-Mod) method, devised in this work, was derived by combining steps from the CB method and the Rapid Modification of the Cottonseed method. The CB method was superior to the other 2 methods for quantitation of aflatoxins. It gave better recoveries and cleaner extracts that exhibit less fluorescent interference for thin-layer chromatography (TLC) than the BF method. Also, its solvent efficiency was better than that of the CB-RCS-Mod method. With the CB method, recoveries from spiked samples were 85.0% for aflatoxin B1 and 90.0% for aflatoxin B2. Recoveries of G aflatoxins were more variable, averaging 90.0% for aflatoxin G1 and 72.5% for aflatoxin G2. Total aflatoxin recovery was 86.5% for the CB method. At a low aflatoxin contamination level (8 micrograms B1/kg sample), aflatoxin B1 was detectable by the CB method but not by the BF method. Detection of aflatoxins in BF method sample extracts by TLC was not improved by the use of chloroform-acetone-water (88 + 12 + 1), benzene-ethanol-water, or ether-methanol-water (96 + 3 + 1) in place of the standard chloroform-acetone (88 + 12) developer. Use of ether-methanol-water (96 + 3 + 1) for detecting aflatoxins by TLC in the CB method extracts increased interference compared with the standard chloroform-acetone (88 + 12) developer.

First record of Angiostrongylus cantonensis (Chen, 1935) (Nematoda: Metastrongylidae) in the Dominican Republic.

Rats, Rattus norvegicus, trapped in some sections (barrios) of the city of Santo Domingo, the capital of the Dominican Republic showed that 5 of them from two barrios harbored the nematode Angiostrongylus cantonensis in the pulmonary artery. Macerated and digested terrestrial snails, Subulina octona, collected from the backyards of houses where the rats were trapped contained L2 and L3 larvae of the nematode. The morphology of the adult worms and the larvae was consistent with that described for A. cantonensis in the literature. This is the first report of this Oriental and Western Pacific nematode in the Dominican Republic and the fourth in the Americas. Gastrointestinal hemorrhage, a rare symptom due to another species, the American A. costaricensis, which occurs in mesenteric arterioles of rodents and humans, is in the recent literature; the patient was a 41-year old Dominican. Thus the Dominican Republic is the first country in the Western Hemisphere to have the two species of Angiostrongylus.

The influence of selected environmental parameters on the toxicity of Bayluscide to Schistosoma mansoni miracidia.

Laboratory studies were conducted to investigate the influence of selected environmental parameters on the toxicity of Bayluscide to Schistosoma mansoni miracidia. Test results indicated that temperature, pH, hardness and salinity of the water exerted profound effects on miracidial survival and that the miracidicidal action of bayluscide was highly influenced by these factors. In summary, this chemical was found to be more effective in killing the miracidia of S. mansoni in waters of higher temperatures, lower values of pH (acidic waters), lower degrees of hardness (soft waters) and lower levels of salt (freshwaters). The implications of such studies in the control of schistosomiasis transmission are addressed.

Toxicity evaluation of Bayluscide and malathion to three developmental stages of freshwater snails.

Laboratory studies were conducted to assess the conditions under which the use of malathion in ricelands of Cameroon may impact the transmission of schistosomiasis. Helisoma trivolvis and Biomphalaria havanensis were selected as test organisms due to the lack of intermediate snail hosts in the U.S. Using Bayluscide as a reference molluscicidal compound, malathion was tested against snail eggs, juveniles, and adults. Snail eggs were more susceptible to Bayluscide and malathion than juvenile snails which in turn were more susceptible than adult snails. A Bayluscide concentration of 0.200 mg/L caused 100% mortality to adults of both snail species after 24 h exposure. This relatively high toxicity of Bayluscide to freshwater snails is one of the reasons why it has been recommended by the World Health Organization as the molluscicide of choice for control of schistosome-bearing snails. The concentrations of malathion resulting in 100% kill of adult snails after 24 h exposure were 1,200 mg/L for H. trivolvis and 500 mg/L for B. havanensis. After 48 h exposure, these concentrations were reduced to 500 mg/L and 300 mg/L, respectively. Therefore it is expected that the use of malathion for insect control in ricelands of Cameroon may affect the survival of freshwater snails including the intermediate hosts of bilharziasis.

Toxicity evaluation of ammonium sulphate and urea to three developmental stages of freshwater snails.

Studies were performed to evaluate the toxic effects of ammonium sulphate and urea (chemical fertilizers currently applied in ricelands of Cameroon) against eggs, juveniles, and adults of two species of freshwater snails (Helisoma trivolvis and Biomphalaria havanensis). Results obtained from ammonium sulphate tests indicated 24-h LC50 values of 558 mg/L and 669 mg/L for eggs; 393 mg/L and 526 mg/L for juveniles, and 701 mg/L and 657 mg/L for adults of H. trivolvis and B. havanensis, respectively. Similar analysis with urea revealed LC50 values of 14,241 mg/L and 13,532 mg/L for eggs; 18,255 mg/L and 24,504 mg/L for juveniles and 30,060 mg/L and 26,024 mg/L for adults of H. trivolvis and B. havanensis, respectively. Following 48 h exposure, the concentrations of ammonium sulphate killing 100% of snails were 1,250 mg/L and 1,000 mg/L for the adults of H. trivolvis and of B. havanensis, respectively. Those of urea were computed to be 25,000 mg/L for H. trivolvis and 35,000 mg/L for B. havanensis. In rice culture in Cameroon, these fertilizers are applied at doses of 100 kg/ha (ammonium sulphate) and of 150 kg/ha (urea); hence, the above found concentrations lethal to snails appeared to be 10 to 13 times (ammonium sulphate) and to be 165 to 235 times (urea) higher assuming an average water depth of 10 cm in these ricefields. Therefore, the use of ammonium sulphate and urea as chemical fertilizers in ricelands of the Republic of Cameroon might adversely affect the survival of freshwater snails only in the case of spills or of stressful environmental conditions. Under normal laboratory conditions, both chemicals show a low molluscicidal activity with urea being about 25 to 35 times less potent than ammonium sulphate.

Displacement of Biomphalaria glabrata by Thiara granifera under natural conditions in the Dominican Republic.

After a study of the population dynamics of Biomphalaria glabrata snails in several breeding places in the Dominican Republic, the snail Thiara granifera was introduced in some B. glabrata habitats. T. granifera became established in one point in one habitat in the town of Quisqueya, in the east of the country. Around this point of establishment 6 points were selected in order to observe the population dynamics of both species of snails and the chemical and biological characteristics at each point. Four of these points already harbored B. glabrata. One control point was selected also harboring B. glabrata. After 14 months of observations, the results showed that T. granifera was competing with and displacing B. glabrata. This competition does not seem to be competition for food or vital space. Rather, B. glabrata avoids the presence of T. granifera and moves away to new areas, and this is possibly due to a chemical substance(s) secreted by T. granifera or by physical contact with the large number of individuals of T. granifera.