Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression.
To analyze the clinical presentation and complications of varicella zoster virus (VZV) infection in children with rheumatic diseases treated with immunosuppressive medication such as biological disease-modifying antirheumatic drugs (bDMARDs) and/or conventional disease-modifying antirheumatic drugs (cDMARDs), and to analyze the therapeutic approach to VZV infections with respect to the concomitant immunosuppressive treatment. Retrospective multicenter study using the Swiss Pediatric Rheumatology registry. Children with rheumatic diseases followed in a Swiss center for pediatric rheumatology and treated with cDMARD and/or bDMARD with a clinical diagnosis of varicella or herpes zoster between January 2004 and December 2013 were included. Twenty-two patients were identified, of whom 20 were treated for juvenile idiopathic arthritis, 1 for a polyglandular autoimmune syndrome type III, and 1 for uveitis. Of these 22 patients, 16 had varicella and 6 had herpes zoster. Median age at VZV disease was 7.6 years (range 2 to 17 years), with 6.3 years (range 2 to 17 years) for those with varicella and 11.6 years (range 5 to 16 years) for those with herpes zoster. The median interval between start of immunosuppression and VZV disease was 14.1 months (range 1 to 63 months). Two patients had received varicella vaccine (1 dose each) prior to start of immunosuppression. Concomitant immunosuppressive therapy was methotrexate (MTX) monotherapy (n = 9) or bDMARD monotherapy (n = 2), or a combination of bDMARD with prednisone, MTX or Leflunomide (n = 11). Four patients experienced VZV related complications: cellulitis in 1 patient treated with MTX, and cellulitis, sepsis and cerebellitis in 3 patients treated with biological agents and MTX combination therapy. Six children were admitted to hospital (range of duration: 4 to 9 days) and 12 were treated with valaciclovir or aciclovir. The clinical course of varicella and herpes zoster in children under immunosuppression is variable, with 4 (18 %) of 22 children showing a complicated course. Thorough assessment of VZV disease and vaccination history and correct VZV vaccination according to national guidelines at diagnosis of a rheumatic autoimmune disease is essential to minimize VZV complications during a later immunosuppressive treatment.


Adrenomedullin: A vasoactive agent for sporadic and hereditary vascular cognitive impairment.
Adrenomedullin (AM) is an endogenous peptide mainly secreted from endothelial cells, which has multiple physiological actions such as anti-inflammation, vasodilation, vascular permeability regulation and angiogenesis. Blood AM levels are upregulated in a variety of pathological states including sepsis, severe COVID-19, acute ischemic stroke and vascular cognitive impairment with white matter changes, likely serving as a compensatory biological defense response against infection and ischemia. AM is currently being tested in clinical trials for ulcerative colitis, Crohn's disease, severe COVID-19 for its anti-inflammatory properties and in ischemic stroke for its additional angiogenic action. AM has been proposed as a therapeutic option for vascular cognitive impairment as its arteriogenic and angiogenic properties are thought to contribute to a slowing of cognitive decline in mice after chronic cerebral hypoperfusion. As AM promotes differentiation of oligodendrocyte precursor cells into mature oligodendrocytes under hypoxic conditions, AM could also be used in the treatment of CADASIL, where reduced oxygen delivery is thought to lead to the death of hypoxia-prone oligodendrocytes. AM therefore holds potential as an innovative therapeutic drug, which may regenerate blood vessels, while controlling inflammation in cerebrovascular diseases.


Evaluation of the BD Vacutainer Plus Urine C&S Preservative Tubes compared with nonpreservative urine samples stored at 4°C and room temperature.
The stability of urine specimens submitted for culture remains a challenge for many laboratories because of delays in specimen transport. We evaluated the usefulness of BD Vacutainer Plus Urine C&S Preservative Tube in ensuring specimen stability. Clinical urine specimens collected in sterile collection cups (n = 110) were plated onto sheep blood and MacConkey agar following standard laboratory procedures guidelines. Thereafter, specimens were divided into 3 storage conditions: nonpreservative, refrigerated; nonpreservative, room temperature (RT); BD Vacutainer Plus Urine C&S Preservative Tube, RT. For each sample type, additional cultures were set up at 2, 4, 24, and 48 hours. Initially, 18 specimens had no growth, 32 showed mixed skin flora, and 60 yielded at least 1 uropathogen. Increased colony counts of uropathogens were observed for nonpreserved urine samples stored at RT; these changes were statistically significant. Minor differences between refrigerated urine samples and BD Vacutainer Plus Urine C&S Preservative Tube samples were seen but were not statistically significant. The use of preservative-containing collection tubes is desirable to ensure specimen stability when prompt processing or refrigeration is not feasible.


Targeted Therapy for Melanomas Without BRAF V600 Mutations.
Modern therapy of advanced melanoma offers effective targeted therapeutic options in the form of BRAF plus MEK inhibition for patients with BRAF V600 mutations. For patients lacking these mutations, checkpoint inhibition remains the only first-line choice for treatment of metastatic disease. However, approximately half of patients do not respond to immunotherapy, requiring effective options for a second-line treatment. Advances in genetic profiling have found other possible target molecules, especially a wide array of rare non-V600 BRAF mutations which may respond to available targeted therapy.More information on the characteristics of such mutants is needed to further assess the efficacy of targeted therapies in the metastatic and adjuvant setting of advanced melanoma. Thus, it may be helpful to classify known BRAF mutations by their kinase activation status and dependence on alternative signaling pathways. While BRAF V600 mutations appear to have an overall more prominent role of kinase activity for tumor growth, non-V600 BRAF mutations show great differences in kinase activation and, hence, response to BRAF plus MEK inhibition. When BRAF-mutated melanomas rely on additional signaling molecules such as RAS for tumor growth, greater benefit may be expected from MEK inhibition than BRAF inhibition. In other cases, mutations of c-kit or NRAS may serve as important pharmacological targets in advanced melanoma. However, since benefit from currently available targeted therapies for non-V600 mutants is usually inferior regarding response and long-term outcome, checkpoint inhibitors remain the standard recommended first-line therapy for these patients.Herein, we review the current clinical data for characteristics and response to targeted therapy of melanomas lacking a V600 BRAF mutation.


Go the Distance: Reproductive Health Care for People with Sickle Cell Disease.
This overview of reproductive and sexual health care concerns for people with sickle cell disease (SCD) addresses clinical concerns that can be complex and are inherently multidisciplinary. Clinicians must be prepared to initiate reproductive health care discussions, as these intimate concerns may not be volunteered by patients. SCD is associated with delayed onset of puberty, sickle pain during menstruation, disease-specific contraceptive considerations, high-risk pregnancy, priapism, erectile dysfunction, and offspring who inherit a hemoglobinopathy trait from affected parents. Reproductive health considerations are underrecognized, undertreated, and understudied. They need attention in primary care and specialty SCD, urology, and obstetrics and gynecology clinics.


Pathogen-induced pH changes regulate the growth-defense balance in plants.
Environmental adaptation of organisms relies on fast perception and response to external signals, which lead to developmental changes. Plant cell growth is strongly dependent on cell wall remodeling. However, little is known about cell wall-related sensing of biotic stimuli and the downstream mechanisms that coordinate growth and defense responses. We generated genetically encoded pH sensors to determine absolute pH changes across the plasma membrane in response to biotic stress. A rapid apoplastic acidification by phosphorylation-based proton pump activation in response to the fungus Fusarium oxysporum immediately reduced cellulose synthesis and cell growth and, furthermore, had a direct influence on the pathogenicity of the fungus. In addition, pH seems to influence cellulose structure. All these effects were dependent on the COMPANION OF CELLULOSE SYNTHASE proteins that are thus at the nexus of plant growth and defense. Hence, our discoveries show a remarkable connection between plant biomass production, immunity, and pH control, and advance our ability to investigate the plant growth-defense balance.


Oxatomide. A review of its pharmacodynamic properties and therapeutic efficacy.
Oxatomide is an orally active H1-histamine receptor antagonist which, as appears to occur with some other antihistamines, also inhibits mast cell degranulation. Oxatomide has demonstrated response rates similar to those with other more established members of its drug class in a few studies of chronic urticaria and allergic rhinitis. Interestingly, some patients responding to oxatomide were said to be unresponsive to previously administered antihistamines. The effect of oxatomide was little different from placebo in clinical trials of bronchial asthma in adults. While somewhat more encouraging results have been reported in children with bronchial asthma when higher than presently recommended dosages were employed, and in follicular conjunctivitis, atopic dermatitis and food allergy, reports to date are largely preliminary in nature and additional well-controlled studies are needed to clarify the efficacy of oxatomide in such conditions. The drug has been generally well tolerated, but shares some of the familiar H1-histamine receptor antagonist side effects. As with other similarly acting drugs, the 2 primary side effects with oxatomide are drowsiness and weight gain. Thus, on the basis of present evidence, a trial with oxatomide seems a potentially useful alternative in patients with conditions known or thought to be allergic in nature, in whom more established treatments were ineffective or poorly tolerated.


A potential hybrid nanocomposite of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) and fullerene for bone tissue regeneration and sustained drug release against bone infections.
Developing a multifunctional biomaterial for bone filling and local antibiotic therapy is a complex challenge for bone tissue engineering. Hybrid nanocomposites of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) with nanohydroxyapatite (nHA), fullerene (C60), and vancomycin (VC) were produced by injection. Fullerene was successfully impregnated with VC, as seen in FTIR. The crystallinity degree of PHBHV was slightly reduced in the presence of C60 and VC (64.3 versus 60.8 %), due to the plasticizing effect of these particles. It also resulted in a decrease in the glass transition temperature (Tg), observed by differential scanning calorimetry (DSC). Dense PHBHV/nHA/C60/VC had a flexural elastic modulus 29 % higher than PHBHV, as a result of the good interface between PHBHV, C60, and nHA - particles of high elastic modulus. Dense disks released 25.03 ± 4.27 % of VC for 14 days, which demonstrated its potential to be an alternative treatment to bone infections. Porous scaffolds of PHBHV/nHA/C60/VC were 3D printed with a porosity of 50 % and porous size of 467 ± 70 μm, and had compression elastic modulus of 0.022 GPa, being a promising material to trabecular bone replacement. The plasticizing effect of C60 improved the printability of the material. The hybrid nanocomposite was non-cytotoxic and showed good ability in adhering macrophage cells.


Spawn predation and larval growth inhibition as mechanisms for niche separation in anurans.
We have investigated interspecific interactions between larvae of the 3 native British anurans, Rana temporaria, Bufo bufo and B. calamita in the field and in the laboratory. Over a 3 year period, predation of B. calamita spawn by the two competitively superior species accounted for only 0.3-3.0% of the total deposited in the dune pools of the study site. However, in ponds with marked niche overlap destruction of natterjack spawn was often 100%. Furthermore, growth rates of B. calamita larvae surviving to hatch were grossly inhibited when large numbers (>0.1 per l) of common frog or toad tadpoles were present. Overall survival to metamorphosis by the competitively inferior species was always negligible in these situations. These results were confirmed by experiments using caged larvae, and by movement of R. temporaria spawn between pools. Growth could be reduced to <25% of uninhibited controls, and time taken to achieve metamorphosis extended by at least 40% in the presence of larger larvae. Laboratory experiments confirmed that inhibitory effects of both R. temporaria and B. bufo larvae on growth by B. calamita tadpoles was demonstrable at tadpole densities comparable with those found in the field.


A pharmacist-led penicillin allergy de-labelling project within a preoperative assessment clinic: the low-hanging fruit is within reach.
Having a false penicillin-allergy label is linked to longer hospital stays and to an increased risk of Clostridioides difficile and meticillin-resistant Staphylococcus aureus infection. To assess a penicillin-allergy de-labelling tool designed for use by the non-allergist. Patients attending the surgical preoperative assessment clinic (POAC) at a large UK teaching hospital, who reported a penicillin allergy, were directly de-labelled by nursing or pharmacy staff, where appropriate. A penicillin-allergy de-labelling tool designed for use by the non-allergist was adapted and applied; nursing staff were provided with supporting information and education to enable removal of spurious labels. Antimicrobial pharmacists (AMPs) provided follow-up, cross-checked prophylactic antibiotics administered, interrogated clinical notes, and telephoned patients following their surgery, for details of any adverse reactions suffered. A total of 163 patients reporting a penicillin allergy were identified for intervention. Twenty-nine (17.8%) patients reported a penicillin-allergy history appropriate for direct de-labelling, of whom eight (27.6%) declined to consent. The remaining 21 patients (12.8%) were directly de-labelled, with 12 (7.4%) patients consenting during their POAC appointment; the remaining nine (5.5%) patients were consented and de-labelled after their surgery by an AMP. The POAC was identified as an appropriate location and time-point in the patient pathway to enable the direct removal of spurious penicillin-allergy labels prior to surgery. Results suggest that this could be undertaken by nursing staff, although support from AMPs enabled a greater number of patients to be de-labelled.


Heavy metal accumulation, biochemical and transcriptomic biomarkers in earthworms Eisenia andrei exposed to industrially contaminated soils from south-eastern Tunisia (Gabes Governorate).
Heavy metal pollution is causing harmful consequences on soil fertility, and earthworms are frequently employed as test organisms to evaluate the ecotoxicity of polluted soils. In this study, Eisenia andrei was exposed for 7 and 14 days to polymetallic contaminated soils collected from an industrial zone in the south-eastern Tunisia. Earthworm growth, heavy metal accumulation, genotoxicity, cytotoxicity, biochemical and transcriptional responses were determined. Results revealed a higher accumulation of heavy metals in earthworms after 14 than 7 days of soil exposure, a reduction in lysosomal membrane stability (LMS), besides an increase in micronuclei frequency (MN). Moreover, earthworm oxidative status was affected in terms of increases in malondialdehyde (MDA) and metallothionein (MTs) content, and enhancement of catalase (CAT) and glutathione-S-transferase (GST) activities. An inhibition of acetylcholinesterase (AChE) activity was also observed in treated earthworms, whereas transcriptional data demonstrated an up-regulation of cat, gst, mt, p21 and topoisomerase genes. Overall, these findings support the use of earthworms as suitable bioindicator species for pollution monitoring and assessment, advance our understanding of the interaction between heavy metals and earthworms, and provide valuable information about the harmful impact of biota exposure to naturally contaminated soils.


Systematic review and meta-analysis of histopathological factors influencing the risk of lymph node metastasis in early colorectal cancer.
Lymph node (LN) metastases are present in up to 17% of early colorectal cancers (pT1). Identification of associated histopathological factors would enable counselling of patients regarding this risk. Pubmed and Embase were employed utilizing the terms 'early colorectal cancer', 'lymph node metastasis', 'submucosal invasion', 'lymphovascular invasion', 'tumour budding' and 'histological differentiation'. Analysis was performed using REVIEW MANAGER 5.1. Twenty-three cohort studies including 4510 patients were analysed. There was a significantly higher risk of LN metastasis with a depth of submucosal invasion > 1 mm than with lesser degrees of penetration (OR 3.87, 95% CI 1.50-10.00, P = 0.005). Lymphovascular invasion was significantly associated with LN metastasis (OR 4.81, 95% CI 3.14-7.37, P < 0.00001). Poorly differentiated tumours had a higher risk of LN metastasis compared with well or moderately differentiated tumours (OR 5.60, 95% CI 2.90-10.82, P < 0.00001). Tumour budding was found to be significantly associated with LN metastasis (OR 7.74, 95% CI 4.47-13.39, P < 0.001). Meta-analysis of the current literature demonstrates that in early colorectal cancer a depth of submucosal invasion by the primary tumour of > 1 mm, lymphovascular invasion, poor differentiation and tumour budding are significantly associated with LN metastasis.


Fluorescence detection of dopamine based on the polyphenol oxidase-mimicking enzyme.
In this work, a novel fluorescent method for the detection of dopamine (DA) was developed based on a fluorescent nanocomposite (Pdots@AMP-Cu) with polyphenol oxidase activity. Pdots@AMP-Cu was first prepared by the composite of fluorescent polymer dots and coordination nanostructures of adenosine monophosphate (AMP) and Cu2+. The Pdots@AMP-Cu exhibited obvious red fluorescence emission (668 nm), as well as polyphenol oxidase activity by catalyzing the substrate 2,4-DP and 4-AP, and resulted in obvious changes of the solution color from colorless to red. A novel detection method for DA was then developed based on Pdots@AMP-Cu. It is observed that DA can be oxidized by Pdots@AMP-Cu to form eumelanin, and at the same time, the fluorescence of Pdots@AMP-Cu is efficiently quenched by eumelanin due to electron transfer. A good linear relationship was observed between the fluorescent intensity and DA concentration from 10 to 400 μM, and the limit of detection for DA was 4 μM. Moreover, the proposed method exhibited high selectivity toward common amino acids, ascorbic acid, uric acid, etc. And it could also be utilized for DA sensing in human serum samples with satisfactory recoveries. Graphical abstract.


Use of magnetic resonance imaging in diagnosing eosinophilic fasciitis. Report of two cases.
To determine the role of magnetic resonance imaging (MRI) in the diagnosis of eosinophilic fasciitis (EF), selection of appropriate biopsy site, and followup of treatment. MRI was used to examine 2 patients with EF at the time of their initial clinical presentation and after several months of treatment. T2-weighted axial, T2-weighted axial with fat saturation, and T1-weighted axial post-gadolinium with fat saturation scans at 1.5T were obtained. MRI demonstrated hyperintensity within the fascia. This defect resolved with treatment and clinical improvement. MRI is a useful noninvasive tool for diagnosing EF and for monitoring the effectiveness of therapy.


Kinetics of intravenous theophylline.
The pharmacokinetics of theophylline was studied in 6 normal, nonsmoking, adult male volunteers. A constant-rate intravenous infusion of 3.84 to 4.98 mg/kg of theophylline (as the ethylenediamine salt, aminophylline) was administered over 40 min. Serum theophylline concentrations were measured for 24 hr by means of a gas chromatographic method specific for theophylline. Within 30 min of an average intravenous dose of 4.4 mg/kg of theophylline, serum levels reached 10 microgram/ml. The highest serum level at the end of the infusion was 17 microgram/ml. The serum concentration-time data were fitted to a two-compartment open model and yielded a mean serum half-life (t1/2) of 11.02 hr, a value longer than those previously reported. Our results indicated that after the original loading dose of 4.4 mg/kg was infused for 40min, an immediate infusion rate of 1.40 mg/kg/hr (1.65 mg/kg/hr aminophylline) would be necessary to maintain a serum level of 10 microgram/ml.


Housing, feeding and management of calves and replacement heifers in Swedish dairy herds.
A questionnaire was sent to 1500 randomly selected dairy herds in Sweden, asking for general information about the herds, including routines from birth to first calving and also routines at breeding, calving and during the grazing period. Fifty-eight percent of the questionnaires were returned. The preweaned calves were kept in individual calf pens in 68% and in group housing systems in 28% of the herds. Pens with slatted floors were the main housing system for replacement heifers from weaning to breeding, and tie stalls from breeding to first calving. Whole milk was used in 44% and milk replacements in 42% of the herds. The calves received, as a median, 2.5 litres of milk per meal and 2 meals per day. The median age at weaning was 8 weeks. Age was the single most common criteria used for deciding both weaning and breeding time. The median age when the heifers were first turned out to pasture was 6 months. Prophylactic anthelmintic treatment was used by 65% of the herds. The most common diet for replacement heifers before calving was a combination of grain, hay and silage.


Teosin, a novel basic shell matrix protein from Hyriopsis cumingii induces calcium carbonate polycrystal formation.
In this study, a novel matrix protein (teosin) was isolated from Hyriopsis cumingii. Gene expression analysis showed that teosin is mainly expressed in the mantle and blood, and a hybridization signal was found in dorsal epithelial cells of the mantle pallial by in situ hybridization. Moreover, teosin expression during pearl formation indicated its participation in initial nacreous layer biomineralization, and suppressing teosin expression resulted in irregular crystal morphology and disordered arrangement in RNAi assay. In vitro crystallization assays indicated teosin could increase the size of calcite. By turning the sample stage about 15°, we got the high-resolution TEM images of the crystals' edges. This is a novel method to observe the crystal which is over 200 nm under TEM. In the control experiment group, the calcite show the character of long range order. The calcite induced by teosin were composed of nano-grains, and the polycrystal character were confirmed by EDS. These results suggested that teosin is involved in regulating crystal morphology regulation and inducing polycrystal formation during nacreous-layer formation.


Tigecycline in febrile neutropenic patients with haematological malignancies: a retrospective case documentation in four university hospitals.
Tigecycline (TGC) is a first-in-class glycylcycline with an expanded spectrum of activity. Although TGC has not been prospectively studied in febrile neutropenia (FN), we observed that occasionally critically ill neutropenic patients unresponsive to other antibiotics were treated with TGC in our departments. The aim of our study was to analyse effectiveness and toxicity of TGC in FN. Data of infectious episodes treated with TGC were retrospectively collected. Baseline data of patients, haematological malignancy, infection and adverse events were documented. Success was defined as defervescence (≥7 days) in the absence of any sign of persistent infection. Data of 35 patients with haematological malignancies and FN were evaluated. Median duration of neutropenia was 25 days (range 6-69 days). The type of infection was pneumonia in 24 patients, four microbiologically documented infections, three clinically documented infections and four with fever of unknown origin. The TGC was administered after a median of two (range 1-5) prior antibiotic regimens. Treatment was successful in 15 (43 %) patients. In patients with prolonged neutropenia (≥28 days), response was significantly lower (13 vs. 79 %; p =0.001). Eight (23 %) patients died during the fever episode. Grade 3-4 toxicity occurred in five (14 %) patients. Our results showed promising response rates to TGC and very low toxicity rates compared to the generally low response rate of third-line antibiotic therapies, indicating that TGC may be a successful alternative for salvage treatment of febrile neutropenia, but further study is needed.


Changes in the Pneumococcal Vaccine Serotypes in Adult Noninvasive Pneumonia after the Introduction of Pneumococcal Conjugate Vaccination for Children.
Although the incidence of invasive pneumococcal infections in children has decreased since the introduction of pneumococcal conjugate vaccines (PCVs), the appearance of serotype replacements has continued to increase. We examined the frequency of serotype replacements in adult cases of pneumococcal pneumonia. Furthermore, the transition in the coverage of vaccine serotypes (VTs) to non-VTs (NVTs) was also examined. We investigated all confirmed cases of pneumococcal pneumonia in 303 adult patients admitted to Yamagata Saisei Hospital between April 2006 and March 2015. Pneumococcal serotypes were determined by testing for a specific type of antiserum using the capsular swelling method. Chi-square tests were used to compare patient characteristics. Annually, the number of admitted patients ranged from 24 to 43, with most of them being men (64.7% of the total patient cohort). Although many cases involved some underlying conditions, the rate of pneumococcal vaccination remained low. The average rate of multigeneration housing was high (37.6%). The rates of pneumococcal vaccine coverage declined since 2013 (7-valent PCV (PCV7), 18.5%; PCV13, 59.3%; and 23-pneumococcal polysaccharide vaccine (PPSV23), 66.7%) and were <50% for each vaccine (PCV7, 4.7%; PCV13, 32.6%; and PPSV23, 48.8%) in 2015. In addition, the VTs were replaced with NVTs in 2015 (48.8% vs. 51.2%). The frequency of NVTs in adult pneumococcal pneumonia increased in 2013, with the frequency exceeding that of the vaccine forms in 2015. Regular PCV vaccination of children and multigeneration housing seem to be associated with this reversed trend.


The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs.
In model organisms, chemical mutagenesis provides a powerful alternative to natural, polygenic variation (for example, quantitative trait loci (QTLs)) for identifying functional pathways and complex disease genes. Despite recent progress in QTLs, we expect that mutagenesis is will ultimately prove more effective because the prospects of gene identification are high and every gene affecting a trait is potentially a target.


Simplified Point-of-Care Full SARS-CoV-2 Genome Sequencing Using Nanopore Technology.
The scale of the ongoing SARS-CoV-2 pandemic warrants the urgent establishment of a global decentralized surveillance system to recognize local outbreaks and the emergence of novel variants of concern. Among available deep-sequencing technologies, nanopore-sequencing could be an important cornerstone, as it is mobile, scalable, and cost-effective. Therefore, streamlined nanopore-sequencing protocols need to be developed and optimized for SARS-CoV-2 variants identification. We adapted and simplified existing workflows using the 'midnight' 1200 bp amplicon split primer sets for PCR, which produce tiled overlapping amplicons covering almost the entire SARS-CoV-2 genome. Subsequently, we applied Oxford Nanopore Rapid Barcoding and the portable MinION Mk1C sequencer combined with the interARTIC bioinformatics pipeline. We tested a simplified and less time-consuming workflow using SARS-CoV-2-positive specimens from clinical routine and identified the CT value as a useful pre-analytical parameter, which may help to decrease sequencing failures rates. Complete pipeline duration was approx. 7 h for one specimen and approx. 11 h for 12 multiplexed barcoded specimens. The adapted protocol contains fewer processing steps and can be completely conducted within one working day. Diagnostic CT values deduced from qPCR standardization experiments can act as principal criteria for specimen selection. As a guideline, SARS-CoV-2 genome copy numbers lower than 4 × 106 were associated with a coverage threshold below 20-fold and incompletely assembled SARS-CoV-2 genomes. Thus, based on the described thermocycler/chemistry combination, we recommend CT values of ~26 or lower to achieve full and high-quality SARS-CoV-2 (+)RNA genome coverage.


Cysticercosis & Heart: A Systematic Review.
Cysticercosis is a parasitic tissue infection caused by larval cysts of the tapeworm Taenia solium. These larval cysts infect brain, muscle, or other tissue, and are a major cause of adult-onset seizures in most low-income countries with tropical climate. Prevalence it's around 50 million people. Although cardiovascular system is not the most affected, this disease can also be associated with multiple and randomly distributed cysts in the subpericardium, subendocardium and myocardium in up to 25% of infected patients. Most cardiac cysticercosis' cases are asymptomatic, but it can manifest with ventricular arrhythmias and conduction disorders. Area Covered: The "Neglected Tropical Diseases and other Infectious Diseases affecting the Heart" (NET-Heart project) is an initiative by the Emerging Leaders group of the Interamerican Society of Cardiology to systematically review all these endemic conditions affecting the heart. A systematic review was conducted following preferred reporting items for systematic review and meta-analysis guidelines and including articles published in MEDLINE, ScienceDirect, PubMed and LILACS databases. A total of 41 papers were included in this review. Expert Opinion: In the areas of greatest prevalence, unhealthiness and poverty favor the development of this disease, which highlights the need to establish global health policies that reduce morbidity and mortality, economic losses of the affected population, and health costs related to hospitalizations for cardiovascular involvement. Authors provide an algorithm to evaluate the possibility of Cysticercosis' cardiovascular complications.


[Molecular genetic analysis of the X-chromosomal nuclear envelope attachment region in nurse cells of the malaria mosquitoes Anopheles messeae Fall].
DNA of the X-chromosomal nuclear envelope attachment region was isolated from malaria mosquito Anopheles messeae Fall. nurse cells by chromosome microdissection. A DNA library of the region was constructed using a plasmid vector. DNA sequencing revealed gene fragments, tandem repeats, and a great variety of transposable elements (TEs). The X-chromosomal nuclear envelope attachment region was concluded to correspond in molecular organization and cytogenetics to diffuse intercalary heterochromatin.


New photoluminescent iodoargentates with bisimidazole derivatives as countercations.
In this article, three bisimidazole derivatives (1,4-bis(2-ethylimidazol-1-yl)butane, L1; 4,4'-di(1H-imidazol-1-yl)-1,1'-biphenyl, L2'; and 1,3-bis(2-ethylimidazol-1-yl)propane, L3) were employed to solvothermally react with AgI in an acidic environment, creating three new 1-D chained iodoargentates [H(L1)][Ag5I6]·DMF (DMF = N,N'-dimethylformamide) 1, [L2][Ag3I5] (L22+ = 4,4'-di(1H-imidazol-1-ium)-1,1'-biphenyl) 2, and [H2(L3)][Ag2I4] 3. L22+ in 2 originated from the in situ N-alkylation of L2' with the CH3OH solvent. X-ray single-crystal diffraction analysis reveals that (i) in 1, Ag+ and I- aggregate to form a 1-D tube-like iodoargentate, which exhibits the same topology as the carbon tube; (ii) the chain structure of the iodoargentate in 2 is based on a kind of trinuclear Ag-I cluster, which can be viewed as a segment of the classical cubic M4I4 cluster; (iii) the chain structure of the iodoargentate in 3 is simple, which can be described as a linear arrangement of the AgI4 tetrahedra by sharing edges. The photoluminescence analysis reveals that at 77 K, (i) 1 and 2 emit strong yellow light with ms-grade photoluminescence lifetimes (5.460 ms for 1, 6.931 ms for 2); (ii) 3 possesses photochromic luminescence properties. Upon excitation at 254 nm, it emits blue-green light, whereas upon excitation at 365 nm, it emits yellow light.


Plumbagin: A Potential Candidate for Future Research and Development.
Plumbagin has gained a lot of attention in research due to its various therapeutic actions. It is a secondary metabolite obtained from different plant families, such as Plumbaginaceae, Droseraceae, and Ebenceae. Various studies on plumbagin have revealed that it is a natural gift for mankind in treating chronic diseases, like cancer, diabetes, malaria, bacterial infection, and controlling cardiovascular disease. However, there are several challenges in developing plumbagin as a therapeutic agent. The first and foremost is its limited solubility and oral bioavailability. The second limitation is its toxicity. Plumbagin has a narrow therapeutic window, and literature reveals that the compound has moderate toxicity in animals. However, data are insufficient to prove that plumbagin is unsafe for humans. Despite the many therapeutic benefits of plumbagin, it remains unexploited for mankind. Thus, a systematic review of its toxicity, pharmacology, and safety is required to be performed. This review work signifies the depth of therapeutic applications proven via research, its different modes of isolation and separation of chemical constituents, and its modification. A thorough review of promising therapeutic targets via docking studies is also presented. Different methods used to quantify plumbagin from the plant are reviewed. An overview of attempts to design novel formulations which could enhance its bioavailability is also presented. The review paper will help the scientist to exploit the drug to its optimum, which will help to overcome the challenges faced during its design and developmental stages.


Invasive sinus aspergillosis in apparently immunocompetent hosts.
to describe the clinical, microbiological and pathological features of invasive sinus aspergillosis affecting immunocompetent hosts, and to identify the risk factors for mortality. we report three apparently immunocompetent patients with invasive sinus aspergillosis, and review all cases reported in the English literature since 1987, the year in which the triazole antifungal agents were introduced. twenty-nine patients (including three of our own) were identified. The presenting symptoms were non-specific and indistinguishable from viral, bacterial or allergic causes of sinusitis. The findings on computed tomography scan were also non-specific, and histopathology and culture of sinus tissue biopsy had low yield. These factors, along with the mistaken impression that Aspergillus can only affect immunocompromised hosts, frequently delayed the diagnosis. Fifty-nine percent of patients either failed therapy or died. The following factors were associated with a poor prognosis: delayed diagnosis, intracranial extension of infection, and histopathology demonstrating hyphal invasion of blood vessel or tissue. Complete surgical extirpation was the key element of successful therapy; antifungal agents played an adjunctive role. invasive sinus aspergillosis carries high morbidity and mortality, even in immunocompetent hosts. To improve outcome, the diagnosis must be recognized early, before the organism can invade the central nervous system or vascular structures. Aggressive surgical resection of the infected areas is of utmost importance in the management of this infection.


[Surgical therapeutic concept of immune thyropathy].
73 patients with Graves' disease, surgically treated from 1975-1986, were investigated retrospectively. 43 patients, treated by subtotal thyroidectomy (Enderlen-Hotz) and a bilateral thyroid remnant of a total of about 8-12 g, were compared with 30 patients, treated by a modified subtotal thyroidectomy leaving a unilateral thyroid remnant of about 4-8 g, with respect to preoperative duration of disease, indications for surgical treatment, weight of resected specimens, operative complications and postoperative thyroid function. Surgical complications were similar in both groups. After subtotal thyroidectomy 14/43 patients (33%) displayed either recurrent hyperthyroidism (9/43, 21%) or local recurrence of Graves' goiter (3/43, 7%) or both (2/43, 5%). The modified subtotal resected group showed no recurrences of the disease. After subtotal thyroidectomy 11 patients were euthyroid without thyroid medication (26%) compared to only two patients (7%) after the modified procedure of subtotal thyroid resection. To prevent recurrences of goiter as well as hyperthyroidism and, on the other hand, to achieve euthyroid function postoperatively without need for thyroid replacement therapy, subtotal thyroidectomy with a small thyroid remnant of about 4-8 g is recommended for all patients with large goiter and a chronic recurrent course of the disease or with iodine induced thyrotoxicosis. Patients with non-recurrent Graves' disease but large goiter probably benefit from subtotal thyroidectomy with a larger thyroid remnant of about 8-12 g.


The Fully Oxidized State of the Glutamate Coordinated O2-Tolerant [NiFe]-Hydrogenase Shows a Ni(III)/Fe(III) Open-Shell Singlet Ground State.
The oxygen tolerance of the [NiFe]-hydrogenase from H. thermoluteolus was recently assigned to originate from an unusual coordination sphere of the active site nickel atom (Shomura et al. Science 2017, 357, 928-932, 10.1126/science.aan4497). In the oxidized state, a terminal cysteine residue is displaced by a bidentate coordinating nearby Glu32 and thus moves to occupy a third μ-cysteine bridging position. Spectral features of the oxidized state were assigned to originate from a closed-shell Ni(IV)/Fe(II) state (Kulka-Peschke et al. J. Am. Chem. Soc. 2022, 144, 17022-17032, 10.1021/jacs.2c06400). Such a high-valent nickel oxidation state is unprecedented in biological systems. The spectral properties and the coordination sphere of that [NiFe]-hydrogenase can, however, also be rationalized by an energetically lower broken-symmetry Ni(III)/Fe(III) state of the active site which was not considered. In this open-shell singlet, the ligand-mediated antiferromagnetic spin-coupling leads to an overall S = 0 spin state with evenly distributed spin densities over the metal atoms. Experiments are suggested that may clarify the final assignment of redox states.


Rapid eye movement (REM) sleep homeostatic regulatory processes in the rat: changes in the sleep-wake stages and electroencephalographic power spectra.
The aim of this study was to elucidate physiological processes that are involved in the homeostatic regulation of REM sleep. Adult rats were chronically instrumented with sleep-wake recording electrodes. Following post-surgical recovery, rats were habituated extensively for freely moving polygraphic recording conditions. On the first experimental recording day (baseline day, BLD), polygraphic signs of undisturbed sleep-wake activities were recorded for 4 h (between 11:00 AM and 3:00 PM). During the second experimental recording day (REM sleep deprivation day, RDD), rats were selectively deprived of REM sleep for the first 2 h and then allowed to have normal sleep-wake for the following 2 h. The results demonstrated that during the first 2 h, compared to BLD, RDD recordings exhibited 87.80% less time in REM sleep and 16% more time in non-REM (NREM) sleep. The total percentages of wakefulness remained comparable between the BLD and RDD. During the RDD, the mean number of REM sleep episodes was much higher than in the BLD, indicating increased REM sleep drive. Electroencephalographic (EEG) power spectral analysis revealed that selective REM sleep deprivation increased delta power but decreased theta power during the residual REM sleep. During the last 2 h, after REM sleep deprivation, rats spent 51% more time in REM sleep compared to the BLD. Also during this period, the number of REM sleep episodes with the shortest (5-30 s) and longest (>120 s) duration increased during the RDD. These findings suggest that the REM sleep homeostatic process involves increased delta- and decreased theta-frequency wave activities in the cortical EEG.


Structural defects in chronic peritoneal dialysis catheters contributing to peritonitis.
Recurrent peritonitis remains a critical problem in patients treated with continuous ambulatory peritoneal dialysis. 3 case histories are presented documenting an association between catheter defects and peritonitis. Illustrative defects are shown. Improved awareness of the hazard and better catheter design may reduce the risks of peritonitis.


Sequential insertion of multiple I-SceI recognition sites at designed loci of the Bacillus subtilis 168 genome.
Bacillus subtilis 168 is the only bacterium-based host serving for the cloning of giant DNA above 1.000 kbp. As rapid verification of the genome structure is crucial during the cloning process, six of 18-base sequence recognized by endonuclease I-SceI were sequentially created in the B. subtilis 168 genome. The established method and materials should be of use for other B. subtilis derivatives.


Developmental expression of APEX nuclease, a multifunctional DNA repair enzyme, in mouse brains.
Expression of the mammalian major apurinic/apyrimidinic (AP) endonuclease (designated as APEX nuclease, or HAP1, APE or Ref-1 gene product) during mouse brain development was investigated by in situ and northern blot hybridizations. The enzyme is known to be a redox factor (Ref-1) stimulating DNA binding activity of AP-1 binding proteins such as Fos and Jun as well as a multifunctional DNA repair enzyme having 5' AP endonuclease, DNA 3' repair diesterase, 3'-5' exonuclease and DNA 3'-phosphatase activities. In the embryonic and postnatal development, APEX mRNA was expressed at high levels in the proliferative zone of various brain regions, with showing temporal and spatial changes. Its expression decreased in association with brain development to the basal expression level which was observed even in adulthood, with the exception of its expression in the hippocampal formation. The growth-dependent expression of APEX gene suggests that it has some roles on cell proliferation and/or differentiation in developmental brain. Its expression on the hippocampal formation became significant from postnatal day 7 and then increased. The pyramidal and granule cell layers expressed it at a higher level than most other brain regions at postnatal day 21. The developmental change of APEX gene expression was not necessarily associated with the changes of expression of c-fos and c-jun genes measured by northern blot hybridization. However, the present results suggested that APEX/Ref-1 gene product can interact with AP-1 binding proteins in brain, especially in the hippocampal formation, to regulate some brain functions by redox-activation.


Trends in the Physical Medicine and Rehabilitation Match: Analysis of NRMP Data from 2007 to 2018.
We provide an updated analysis of data about U.S. Physical Medicine and Rehabilitation (PM&R) residency program applicants collected by the National Resident Matching Program (NRMP). Analyze trends within NRMP data for PM&R residency match rates, compare matched to unmatched applicants, and compare PM&R applicants to other medical specialties. Secondary analysis of NRMP data. NRMP data set. Residency program applicants who participated in the NRMP Match, 2007 to 2018. Not applicable. Number of applicants, match rates, difference in characteristics including rank order list (ROL), U.S. Medical Licensing Examination (USMLE) Step 1 and Step 2 Clinical Knowledge (CK) scores, publications, Alpha Omega Alpha (AOA) status, PhD degree, and experiences in research, volunteer, and work. Number of applicants and residency positions increased from 2007 to 2018. Length of ROL increased and was longer for matched compared to unmatched applicants, with maximum mean difference of 7.4 in 2016 (95% confidence interval [CI] 5.6-9.2). Matched U.S. Allopathic Seniors had higher USMLE scores compared to unmatched, with a mean difference of 12.7 for Step 1 (95% CI 8.3-17.0) and 12.6 (95% CI 8.6-16.6) for Step 2 CK (P < .001). Number of publications and volunteer experiences were higher for matched U.S. Allopathic Seniors (0.64, 95% CI 0.09-1.2 and 1.5, 95% CI 0.65-2.3, respectively). PM&R USMLE Step 1 and 2 CK scores increased at a significantly faster rate than for all other specialties, with estimated rate differences of 0.46 (95% CI 0.21-0.71) and 0.69 (95% CI 0.45-0.93) points per year, respectively. PM&R residency has become more competitive. USMLE Step 1 and 2 CK scores have outpaced the inflation of scores in other specialties. ROL length has increased, suggesting more ranked programs to successfully match. These analyses update our knowledge about PM&R residency applicants and suggest surrogate markers for a successful match.


Modulation of Treg cells/T effector function by GITR signaling is context-dependent.
Treg cells express high levels of the glucocorticoid-induced tumor necrosis factor-related receptor (GITR), while resting conventional T (Tconv) cells express low levels that are increased upon activation. Manipulation of GITR/GITR-Ligand (GITR-L) interactions results in enhancement of immune responses, but it remains unclear whether this enhancement is secondary to costimulation of Tconv cells or to reversal of Treg-cell-mediated suppression. Here, we used a nondepleting Fc-GITR-L and combinations of WT and GITR KO Treg cells and Tconv cells to reexamine the effects of GITR stimulation on each subpopulation in both unmanipulated mice and mice with inflammatory bowel disease. Treatment of mice with Fc-GITR-L resulted in significant expansion of Treg cells and a modest expansion of Tconv cells. When RAG KO mice were reconstituted with Tconv cells alone, GITR-L resulted in Tconv-cell expansion and severe inflammatory bowel disease. The protective effect of Treg cells was lost in the presence of Fc-GITR-L, secondary to death of the Treg cells. When RAG KO mice were reconstituted with Treg cells alone, the transferred cells expanded normally, and Fc-GITR-L treatment resulted in a loss of Foxp3 expression, but the ex-Treg cells did not cause any pathology. The effects of GITR activation are complex and depend on the host environment and the activation state of the Treg cells and T effector cells.


Electrically Driven Reversible Phase Changes in Layered In2 Se3 Crystalline Film.
An unconventional phase-change memory (PCM) made of In2 Se3 , which utilizes reversible phase changes between a low-resistance crystalline β phase and a high-resistance crystalline γ phase is reported for the first time. Using a PCM with a layered crystalline film exfoliated from In2 Se3 crystals on a graphene bottom electrode, it is shown that SET/RESET programmed states form via the formation/annihilation of periodic van der Waals' (vdW) gaps (i.e., virtual vacancy layers) in the stack of atomic layers and the concurrent reconfiguration of In and Se atoms across the layers. From density functional theory calculations, β and γ phases, characterized by octahedral bonding with vdW gaps and tetrahedral bonding without vdW gaps, respectively, are shown to have energy bandgap value of 0.78 and 1.86 eV, consistent with a metal-to-insulator transition accompanying the β-to-γ phase change. The monolithic In2 Se3 layered film reported here provides a novel means to achieving a PCM based on melting-free, low-entropy phase changes in contrast with the GeTe-Sb2 Te3 superlattice film adopted in interfacial phase-change memory.


Re-imagining the UN Committee on World Food Security.
This article argues that the United Nations Committee on World Food Security can and must serve as a space for catalyzing and strengthening public interest-oriented food systems governance grounded in the human rights framework. This would necessarily entail confronting the fragmentation of governance and erasure of accountability promoted by corporate designed multi-stakeholderism, and democratizing multilateralism through genuine participation of rights holders, public scrutiny and participatory science. Pivotal to this endeavor is arresting the growing corporate influence in governance mechanisms and reorienting them towards reinvigorating relationships among people, communities and governments.


An in vitro study on the effects of isoprinosine on immune responses in cancer patients.
The in vitro effects of ISO on the immune responses of cancer patients were investigated. Forty seven patients with primary tumors (26 lung carcinoma, 14 breast adenocarcinoma, 7 melanoma) were studied. Concanavalin A (ConA)-induced lymphocyte proliferation, natural killer cell (NK) activity, and monocyte chemotaxis were measured. In 40 of the 47 patients (85%), ConA-induced lymphocyte proliferation was depressed; NK activity was depressed in 32 (68%), and monocyte chemotaxis was found to be depressed in 36 (77%). For in vitro studies, an optimum concentration of ISO (100 micrograms/ml per 10(6) cells) was used to treat peripheral blood mononuclear cells. In the presence of ISO, all three parameters were restored to normal or near normal levels in those that were depressed. Under these preincubation conditions in vitro treatment of mononuclear cells from the peripheral blood of normal individuals with ISO had no effect on their activities in the three assays. Similar effects on these three immune parameters were observed when 24 h supernatants obtained from patients' mononuclear cells pretreated with ISO were employed in these assays.


Further studies of mode of action of lipolytic enzymes.
Pancreatic lipase and phospholipase A2 have been shown by the monomolecular film technique to be progressively inactivated when adsorbed at the interface of their respective substrates. This inactivation is faster for lipase than for phospholipase. It is also enhanced by low film pressures and film transfer. The use of radioactive phospholipase and lipase samples offered the possibility to measure the amount of enzyme adsorbed at a monomolecular film with a reasonable accuracy. This adsorption was found to be relatively slow under the conditions of the assays. The main conclusion drawn from these data is that the enzyme kinetics in presence of a substrate film, and probably also under bulk conditions, is controlled by an adsorption flux responsible for an initial lag period and an inactivation flux tending to decrease the reaction rate. The kinetics are linear only when both fluxes equilibrate.


Periareolar techniques for mammary reduction and elevation.
Between June 1990 and June 1992 we carried out 56 breast operations: 18 reductions, 32 mastopexies, and 6 implant changes. The surgical techniques used in all cases basically consisted of three phases: the periareolar incision, the creation of the superior pedicle with two medial and lateral flaps, and the "anchoring," crossed by both flaps in order to hold up the mammary gland. The diameter of the "doughnut" of skin that we had to deepidermize varied between 5 and 15 cm, thus raising the nipple-areola complex by as much as 10 cm. The volume of tissue removed from the hypertrophic breast ranged from 70 to 520 g. In 24 of the 32 mastopexies, the use of a silicone implant was necessary in order to provide greater volume, texture, and better mammary contour. In these cases the size of the prostheses varied between 120 and 300 cc. All patients completed the postop followup in the normal way. Only three patients suffered a slight dehiscence of the periareolar suture, which was solved within a few days of the operation by means of a Friedreich. The periareolar cutaneous pleats and the hardness of the breast gradually disappeared, as predicted, within a period of 3-4 months; afterward the breast looked perfectly natural.


The selective mGlu2/3 receptor antagonist LY341495 exacerbates behavioral signs of morphine withdrawal and morphine-withdrawal-induced activation of locus coeruleus neurons.
Previous research has demonstrated that mGlu2/3 agonists can decrease many behavioral signs and the activation of locus coeruleus (LC) neurons observed during morphine withdrawal. However, it is not known if mGlu2/3 receptors are activated during morphine withdrawal by endogenous glutamate. Therefore, we investigated the effect of a novel metabotropic glutamate 2, 3 (mGlu2/3) receptor antagonist (LY341495) on naltrexone-precipitated behavioral signs of morphine withdrawal and withdrawal-induced activation of LC neurons. Three levels of severity of morphine withdrawal (mild, moderate, and strong) were operationally defined by varying the exposure to morphine. Pretreatment with LY341495 (1 mg/kg, s.c.) had no affect on behavioral signs at the mild level of withdrawal, but significantly increased behavioral signs at the moderate level of withdrawal. At the strong level of withdrawal, 3 and 10 mg/kg, but not 1 mg/kg, LY341495 significantly increased the behavioral signs of withdrawal. In in vivo recordings from anesthetized rats, pretreatment with 1 mg/kg LY341495 did not affect the morphine-withdrawal-induced activation of LC neurons at the mild level of withdrawal. At the moderate level of withdrawal, 1 and 10 mg/kg LY341495 did not affect morphine-withdrawal-induced activation of LC neurons. At the strong level of withdrawal, both 1 and 10 mg/kg LY341495 significantly increased morphine-withdrawal-induced activation of LC neurons. These results indicate that endogenous activation of mGlu2/3 receptors during morphine withdrawal acts to reduce the severity of morphine withdrawal and demonstrates that mGlu2/3 receptors are activated under a physiologically relevant, pathological condition.


The use of QT interval to determine pacing rate: early clinical experience.
Despite the current availability of physiologic pacing systems, there remain distinct disadvantages associated with their operation. Although in theory the atrial synchronous pacemaker (VDD or DDD) is the ideal system, in practice it performs satisfactorily over a very limited range of heart rates in a limited number of individuals. We describe the TX system which incorporates ventricular pacing and is driven by T wave sensing determined by the QT interval. This pacemaker can distinguish between physiologic and pathologic tachycardias while providing an almost unlimited rate response even in the presence of an unresponsive atrium.


Effect of DNA binding on geminate CO recombination kinetics in CO-sensing transcription factor CooA.
Carbon monoxide oxidation activator (CooA) proteins are heme-based CO-sensing transcription factors. Here we study the ultrafast dynamics of geminate CO rebinding in two CooA homologues, Rhodospirillum rubrum (RrCooA) and Carboxydothermus hydrogenoformans (ChCooA). The effects of DNA binding and the truncation of the DNA-binding domain on the CO geminate recombination kinetics were specifically investigated. The CO rebinding kinetics in these CooA complexes take place on ultrafast time scales but remain non-exponential over many decades in time. We show that this non-exponential kinetic response is due to a quenched enthalpic barrier distribution resulting from a distribution of heme geometries that is frozen or slowly evolving on the time scale of CO rebinding. We also show that, upon CO binding, the distal pocket of the heme in the CooA proteins relaxes to form a very efficient hydrophobic trap for CO. DNA binding further tightens the narrow distal pocket and slightly weakens the iron-proximal histidine bond. Comparison of the CO rebinding kinetics of RrCooA, truncated RrCooA, and DNA-bound RrCooA proteins reveals that the uncomplexed and inherently flexible DNA-binding domain adds additional structural heterogeneity to the heme doming coordinate. When CooA forms a complex with DNA, the flexibility of the DNA-binding domain decreases, and the distribution of the conformations available in the heme domain becomes restricted. The kinetic studies also offer insights into how the architecture of the heme environment can tune entropic barriers in order to control the geminate recombination of CO in heme proteins, whereas spin selection rules play a minor or non-existent role.


Extracellular Vesicles: Investigating the Pathophysiology of Diabetes-Associated Hypertension and Diabetic Nephropathy.
Extracellular vesicles (EVs) include exosomes, microvesicles, and apoptotic bodies. EVs are released by all cell types and are found in biological fluids including plasma and urine. Urinary extracellular vesicles (uEVs) are a mixed population of EVs that comprise small EVs that are filtered and excreted, EVs secreted by tubular epithelial cells, and EVs released from the bladder, urethra, and prostate. The packaged cargo within uEVs includes bioactive molecules such as metabolites, lipids, proteins, mRNAs, and miRNAs. These molecules are involved in intercellular communication, elicit changes in intracellular signaling pathways, and play a role in the pathogenesis of various diseases including diabetes-associated hypertension and diabetic nephropathy. uEVs represent a rich source of biomarkers, prognosis markers, and can be loaded with small-molecule drugs as a vehicle for delivery.


Isolated central sleep apnea in type I Chiari malformation: improvement after surgery.
Sleep apnea is a rare but well-known clinical feature of disorders of the craniocervical junction. It may be obstructive or central in nature, and rarely presents without other neurological symptoms. We report the cases of two children, presenting with isolated central sleep apnea leading to a diagnosis of type I Chiari malformation. Surgical treatment resulted in a dramatic improvement in respiratory parameters during sleep, both clinically and on polysomnography. We discuss this uncommon presentation of type I Chiari malformation and suggest that it be considered in the differential diagnosis of central sleep apnea in children, as posterior fossa decompression may lead to significant clinical improvement.


[Molecular mechanism of diabetic retinopathy: role of advanced glycation end products(AGEs) and their receptor (RAGE) in the pathogenesis of diabetic retinopathy].
There is a growing body of evidence that advanced glycation end product-receptor(AGE-RAGE) interaction elicits oxidative stress generation, thus indicating that it is involved in the pathogenesis of diabetic retinopathy. Inhibition of AGE formation or blockade of the downstream RAGE signaling is a promising therapeutic strategy for treatment of patients with diabetic retinopathy.


Accumulation of hydrocarbon in a patient with adrenoleukodystrophy.
The lipid composition of tissues from a patient with adrenoleukodystrophy was examined. Cholesterol esters of both brain and adrenal tissues contained increased proportions of fatty acids longer than C22 in agreement with previous reports. During this study, thin-layer chromatographic analysis of the neutral lipid fraction from the cerebral white matter and the adrenal gland revealed an unknown spot, which was identified as hydrocarbon of n-alkanes (CnH2n + 2, n = 16-33) by means of gas-liquid chromatography and gas chromatography/mass spectrometry. There may be a relationship between the accumulation of hydrocarbons and the change in fatty acid metabolism that is the fundamental disorder of ALD, as: (1) the fatty acids abnormally accumulated in cerebral white matter and adrenal gland coincided in chain length (i.e. C24-C26) with the main peaks of n-alkane in the same tissues, and (2) an abnormal accumulation of n-alkanes occurred in the diseased tissues where cholesterol esters with very long chain fatty acids were markedly increased.


[Cellular immunity in 18 cirrhotic African carriers of hepatitis B virus surface antigen (HBsAg)].
The cell mediated immunity has been studied by 3 different tests on a population including 32 african patients with cirrhosis; amongst those, 18 were HBs Ag carriers and 14 were Hbs Ag-. In those 2 groups, the intradermal tuberculin test and the DNCB cutaneous test showed a striking imminutary deficiency in half cases. The lymphoblastic transformation induced by PHA gave less striking results.


Effect of octanoate on blood-brain barrier permeability using L-dopa as a marker.
Short-chain fatty acid injection into animals produces coma, seizures, and hyperventilation. One mechanism of coma production may be through alterations in membrane permeability characteristics. The SPG histofluorescence technique was used to evaluate changes in blood-brain barrier permeability to injected L-dopa in rats after intraperitoneal injections of the short-chain fatty acid, sodium octanoate. Diffusion of intravascular fluorescence was observed around brain capillaries in the octanoate-injected rats suggesting an alteration in capillary permeability to L-dopa. Diffusion of fluorescence around neuronal cell bodies and brain fiber tracts was also seen after treatment with octanoate. These findings suggest that octanoate may also alter neuronal membrane function.


Taste and olfaction in human obesity.
Earlier studies have shown differences between normal weight and obese humans in responsivity to external and internal stimuli. This study shows that normal weight and obese subjects do not differ in hedonic response to sucrose (taste) and benzaldehyde (odor). However, a perceptual typing of individuals based upon hedonic response is possible for both gustatory and olfactory processes. Ratings of pleasantness for the sweet taste of sucrose appear to generalize to the food-related odor of bitter almonds. The method of magnitude estimation as applied to the study of taste and olfaction in man may reveal relationship between changes in internal state and hedonic behavior.


Contraception: the changing needs of women throughout the reproductive years.
The contraceptive needs of women often change as they get older. Dinah Gould discusses the reasons behind this and reviews the different methods of contraception currently available.


A pipeline to evaluate the discrepant interactions between typical nitrogenous disinfection byproduct haloacetonitriles and human hemoglobin.
To evaluate the interaction between haloacetonitriles (HANs) and human hemoglobin (Hb), a pipeline was established based on fluorescence spectra, mass spectra and molecular docking. Fluorescence spectra analysis showed the fluorescence of Hb was statically quenched by HANs in the sequence of TCAN > DBAN > DCAN > IAN > BAN > CAN. HANs could combine to multiple surface sites of Hb accounting for "hydrogen bonds" and "van der Waals forces". The high-resolution mass spectra analysis for Hb with and without HANs further confirmed the formation of multiple HAN-Hb complexes with different conversion rates. With the assistance of MOE molecule docking, the potential combination sites and related interactions parameters between HANs and Hb were filtrated. By analyzing the correlations between the candidate interactions parameters and fluorescence quenching constants/MS conversion rates, the combination sites of HANs were fixed at Asp126 (α1/α2), Lys127 (α1/α2) in the form of "hydrogen bonds" X → Asp126 (α1/α2), N → Lys127 (α1/α2). In this way, the potential interactions between HANs and Hb were effectively evaluated.


Formulation of a geldanamycin prodrug in mPEG-b-PCL micelles greatly enhances tolerability and pharmacokinetics in rats.
Geldanamycin (GA) and its analogues inhibit heat shock protein 90 (Hsp90) and have shown significant antitumor activity in vivo; however, clinical development of GA has been hampered by its poor solubility and severe hepatotoxicity. More soluble analogues, such as 17-DMAG and 17-AAG, are easier to formulate, and have progressed through early clinical trials. However the large volume of distribution and systemic toxicity associated with these analogues may limit their distribution into tumors, thereby severely reducing efficacy and increasing non-specific toxicities. We have evaluated a formulation of a lipophilic GA prodrug, 17'GAC(16)Br encapsulated in methoxy-capped poly(ethylene glycol)-block-poly(epsilon-caprolactone) (mPEG-b-PCL) micelles, by comparing it to free 17-DMAG at 10 mg/kg in rats. mPEG-b-PCL micelles reported herein demonstrated substantial sustained release and conversion of 17'GAC(16)Br into 17'GAOH at significantly greater levels in all tissues analyzed compared to the free drug, allowing for a 72-fold enhancement in the AUC, a 21-fold decrease in V(d), an 11-fold decrease in CL(tot), and a 2-fold and 7-fold enhancement in the overall MRT of 17'GAC(16)Br and 17'GAOH, respectively. Importantly, the micellar formulation exhibited lower systemic toxicity than 17-DMAG, with a MTD >200 mg/kg and a 2000-fold enhancement in the AUC. 17'GAC(16)Br in micelles were poorly cleared renally, in contrast to 17-DMAG and 17'GAOH, but showed preferential accumulation and prodrug conversion in reticuloendothelial organs of normal animals. Overall, the data indicate that this nanocarrier system is a promising alternative to the current 17-DMAG formulation and offers excellent potential for further pre-clinical and clinical cancer studies.


[Dislocation of the tendon of the ulnar extensor muscle of the wrist. Important differential diagnosis of ulnar wrist pain].
Undefined pain of the ulnar wrist often poses diagnostic and therapeutic problems for the physician. Without proof of a definite cause, the diagnosis of damage to the triangular discus is frequently given.


Association Between the Risk for Cardiovascular Events and Antiviral Treatment for Herpes Zoster.
Cardiovascular risk increases following herpes zoster. We investigated whether treatment with antiviral agents, steroids, and common cardiovascular medications was associated with the risk of postherpetic cardiovascular events. This was a nationwide population-based, retrospective, cohort study using the National Health Insurance Service health claims data in Korea. We included patients with a first-ever diagnosis of herpes zoster in 2003-2014 and no prior cardiovascular event. The primary outcome was the occurrence of composites of myocardial infarction (International Statistical Classification of Diseases, Tenth Revision, code I21) and stroke (codes I60-I63) since the herpes zoster. We analyzed the exposure (intravenous or oral administration) to antiviral agents, steroids, antithrombotics, and statins within ±7 days from the index date of herpes zoster diagnosis. Follow-up was performed until occurrence of the primary outcome, death, or 31 December 2015, whichever came first. Of 84 993 patients with herpes zoster, the proportions of patients who received the treatment with antiviral agents, steroids, antithrombotics, and statins were 90.5%, 48.0%, 9.1%, and 7.9%, respectively. During the mean (standard deviation) follow-up period of 5.4 (3.1) years, 1523 patients experienced the primary outcome. Multivariate Cox regression analysis demonstrated that treatment with antiviral agents (adjusted hazard ratio, 0.82; 95% confidence interval, .71-.95) and statins (0.71; .59-.85) were significantly associated with the lower risk of primary outcome. Use of antithrombotics and steroids were not associated with the risk. After herpes zoster, treatment with antiviral agents was significantly associated with lower risk of cardiovascular events. We need more information on the cardiovascular protective role of herpes zoster treatments.


lncRNA PART1 Promotes Breast Cancer Cell Progression by Directly Targeting miR-4516.
Breast cancer is a serious threat to human health. It is meaningful to study the pathogenesis of breast cancer. lncRNAs have been found to play vital roles in numerous biological processes including development, immunology and cancer. qRT-PCR was performed to examine the expressions of PART1 and miR-4516. CCK-8 assay, colony formation assay and transwell assay were used to examine the progression of breast cancer cells. In this study, we showed that lncRNA PART1 was highly expressed in breast cancer cells. Knockdown of PART1 induced decreased proliferation, invasion and migration of breast cancer cells. Moreover, we found that PART1 can bind to miR-4516 directly. We also found that inhibition of miR-4516 could rescue the decreased proliferation, migration and invasion of breast cancer cells induced by knockdown of PART1. lncRNA PART1 and miR-4516 were proven to be involved in the progression of many cancers. However, the roles of lncRNA PART1 and miR-4516 in the regulation of breast cancer remain unknown. Here, we demonstrated that PART1 can bind to miR-4516 to decrease the expression of miR-4516 and promote the development of breast cancer.


Absence of experimental evidence of a delta-shock in the system phenetole and 4-tert-butylphenol on Zorbax 300SB-C18.
We investigate the system consisting of phenetole (PNT) and 4-tert-butylphenol (TBP) in methanol-water (63:37 v:v) on a Zorbax 300SB-C18 column by characterising single component isotherms, by performing a large number of binary experiments of different types and by describing the experiments through simulations carried out using a novel, rather powerful competitive adsorption isotherm, that we call the generalized bi-Langmuir isotherm. This system is of great interest because it was previously reported to yield a new type of transition in nonlinear chromatography, the so-called delta-shock. Such transition had been discovered earlier through a theoretical analysis and confirmed by detailed simulations. The initial aim of this work was to reach a satisfactory agreement between delta-shock experiments and corresponding numerical simulations. In the course of this work however, a number of inconsistencies in the interpretation of the previous experimental results were highlighted and explained. This led to a new experimental campaign, which is reported here and has allowed to reach two important conclusions: (1) The binary system PNT-TBP mentioned above does not exhibit a delta-shock; the spike in the UV profile, which has previously been interpreted as an experimental evidence of the delta-shock, results from liquid-liquid phase separation within the chromatographic column. (2) The same system exhibits a rather peculiar behavior in breakthrough and displacement experiments, which could be well described using the generalized bi-Langmuir isotherm.


Drug-Polymer Solubility Determination: A New Thermodynamic Model Free from Lattice Theory Assumptions.
Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. The new thermodynamic model presented combines DSC analysis and application of Hess's law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.


Evaluation of ImmunoCard STAT test and ELISA versus light microscopy in diagnosis of giardiasis and cryptosporidiosis.
This study was designed to evaluate ImmunoCard STAT Cryptosporidium/Giardia rapid assay and ELISA copro-antigen assays in detecting Giardia lamblia and Cryptosporidium species in fecal samples in comparison to microscopy. Both ImmunoCard STAT and ELISA assays were evaluated with 90 stool specimens that were tested by the standard ova and parasite examination including staining with both iron hematoxylin stain and modified Ziehl Neelson stains. Counting the number of Giardia cysts and Cryptosporidia oocysts in the positive stool samples was done in order to quantify the lower limit of parasite number that was able to be detected by all included assays. Both ImmunoCard STAT and ELISA assays were compared on the basis of the attributes which are number of detected cases, sensitivity, specificity, time required for the procedure and screening, ease of performance and interpretation, and cost. Microscopic examination revealed that 13.3% of the samples were positive for Giardia and 2.2% for Cryptosporidium. By ELISA, 16.7% of the samples were infected with Giardia and 3.3% with Cryptosporidium, while by ImmunoCard STAT, 17.8 and 4.45% of the samples were positive for Giardia and Cryptosporidium, respectively. There is no statistically significant difference between the results of ELISA and ImmunoCard STAT assays. The lowest concentration detected in the stool samples was 10.50 ± 1.05 Giardia cysts and 2.83 ± 1.72 Cryptosporidium oocysts. The ImmunoCard STAT was extremely easy to read, thus requiring much less time, but its cost was much higher than ELISA. We concluded that although the overall ranking of both assays was high, the ImmunoCard STAT rapid assay was a more desirable test despite its higher cost.


Impaired cytokine production by bone marrow stromal cells of immunodeficient mice.
The aetiology of the bone marrow suppression in HIV-infected patients is unknown. We have demonstrated previously that the ability of bone marrow cells, derived from mice made immunodeficient by infection with the retrovirus LP-BM5, to establish long-term stromal cultures is impaired. In this study we determined the ability of bone marrow stromal cells from these immunodeficient mice to produce cytokines important in haemopoiesis. Neither SCF, IL-3, GM-CSF nor TNF alpha were found in conditioned media of long-term bone marrow cultures (LTBMC) of normal or MAIDS mice. We failed to detect mRNA for TNF or IL-1 alpha, by reverse transcription polymerase chain reaction (RT-PCR), in cultures derived from either normal or immunodeficient mice. Steady-state levels of transcripts for IL-6 were equal in cells from normal and MAIDS mice. Steady-state levels of mRNA for TGF beta 1, a known inhibitor of haemopoiesis, were decreased in cultures derived from MAIDS mice at late stages of infection. The mRNA level of the multipotent haemopoietic regulator stem cell factor was also decreased in MAIDS cultures as compared with normals. Transcripts encoding the transmembrane form of the growth factor were almost absent. Addition of soluble GM-CSF and SCF only transiently increased the production of CFUs (BFUE and CFU-G/M) in MAIDS LTBMC. These findings suggest that derangements in cytokine production in stromal cells of immunodeficient mice may contribute to the suppression of haemopoiesis observed in this disease. One mechanism of HIV-induced depression of haemopoiesis may be via alterations of the haemopoietic microenvironment.


Synthesis of chiral sulfinate esters by asymmetric condensation.
Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores1-3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centres, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide, have started to attract attention. The diversity and complexity of these sulfur stereogenic centres have the potential to expand the chemical space for drug discovery6-10. However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here we report straightforward access to enantioenriched sulfinate esters via asymmetric condensation of prochiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification11,12 of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres.


Durable complete response is achieved by balloon-occluded transcatheter arterial chemoembolization for hepatocellular carcinoma.
In 2013 and 2014, the development of microcatheters with balloons for the 4-Fr system and new embolization materials provided various options for transarterial chemoembolization (TACE), expanding the range of treatment strategies. At our hospital, balloon-occluded TACE (B-TACE), conventional TACE (C-TACE), and drug-eluting bead TACE (DEB-TACE) have been actively performed for hepatocellular carcinoma (HCC). This study compared the local recurrence-free (LRF) periods of nodules with complete necrosis (TE4) obtained using each treatment method by extracting the nodules evaluated as complete response by the modified Response Evaluation Criteria in Solid Tumors. We performed 580 TACE procedures between June 2013 and April 2019. Among them, 58 HCC nodules in 43 patients, 33 nodules in 30 patients, and 45 nodules in 25 patients were evaluated as having complete necrosis after C-TACE, DEB-TACE, and B-TACE, respectively. The time to local recurrence for each nodule was defined as the LRF period, and the quality of TE4 for each TACE was examined. Factors related to overall survival and the LRF period were determined by univariate and multivariate analyses, and overall survival and the LRF period were analyzed using the Kaplan-Meier method. Multivariate analysis of the LRF period showed that B-TACE was an independent factor. The median LRF periods were 39.3, 13, and 9.1 months for B-TACE, C-TACE, and DEB-TACE, respectively. Moreover, B-TACE had a significantly longer LRF period than C-TACE and DEB-TACE. Conclusion: There was no significant difference between C-TACE and DEB-TACE. The LRF period of nodules with TE4 was the longest with B-TACE, suggesting that B-TACE should be used to achieve a radical cure in patients with HCC.


Hybrids obtained by protoplast fusion with a salt-tolerant yeast.
An industrial strain of Saccharomyces cerevisiae was fused with an osmotolerant yeast, Debaryomyces hansenii, to obtain hybrids having increased tolerance to elevated salt concentrations. The hybrids were intermediate to parent species in production of ethanol and polyols.


Treatment of hyperdivergent growth pattern and anterior open bite with posterior metallic bite planes.
In the present paper, the authors analyze the effect of the "Swallowing Occlusal Contact Intercept Appliance" (SOCIA) in treatment of children with hyperdivergent Class II malocclusion. This functional appliance has no intra-oral anchorage, but induces a continuous periodontal, muscular, and articular stimulation. Twenty-six patients with hyperdivergent growth and class II malocclusion were selected and treated with SOCIA appliance. Cephalometric analysis was performed before treatment (T1) and immediately after the treatment (T2). After 24 months treatment authors observed a modification of maxillary growth with a reduction of the divergence with an increase of the posterior facial height, a modification of condylar inclination and forward position of the a hyoid. No modifications was observed about the ANB angle. After treatment the open bite was resolved with a reduction of the inclination of the upper incisors. SOCIA is a reliable functional appliance in growing age patients with a hyperdivergent pattern growth, anterior open bite and class II molar malocclusion.


Nonlinear optical response spatial self-phase modulation in MoTe2: correlations between χ(3) and mobility or effective mass.
We report on an unambiguous observation of the third-order nonlinear optical effect, spatial self-phase modulation (SSPM), in a MoTe2 dispersion. The values of the third-order nonlinear optical coefficients effectively for one-layer MoTe2, χone-layer(3), are obtained through the SSPM method at excitation wavelengths 473, 532, 750, and 801 nm, respectively. The wind-chime model is used to explain the ring formation time. The wavelength dependence of χone-layer(3) compares well with the photo-absorption spectra. Significantly, we find a correlation between χ(3) and the carrier mobility μ or effective mass m*, which again further supports the laser-induced ac electron coherence in 2D materials.


Individual Response to Radiation of Individuals with Neurofibromatosis Type I: Role of the ATM Protein and Influence of Statins and Bisphosphonates.
Neurofibromatosis type 1 (NF1) is a disease characterized by high occurrence of benign and malignant brain tumours and caused by mutations of the neurofibromin protein. While there is an increasing evidence that NF1 is associated with radiosensitivity and radiosusceptibility, few studies have dealt with the molecular and cellular radiation response of cells from individuals with NF1. Here, we examined the ATM-dependent signalling and repair pathways of the DNA double-strand breaks (DSB), the key-damage induced by ionizing radiation, in skin fibroblast cell lines from 43 individuals with NF1. Ten minutes after X-rays irradiation, quiescent NF1 fibroblasts showed abnormally low rate of recognized DSB reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones. Irradiated NF1 fibroblasts also presented a delayed radiation-induced nucleoshuttling of the ATM kinase (RIANS), potentially due to a specific binding of ATM to the mutated neurofibromin in cytoplasm. Lastly, NF1 fibroblasts showed abnormally high MRE11 nuclease activity suggesting a high genomic instability after irradiation. A combination of bisphosphonates and statins complemented these impairments by accelerating the RIANS, increasing the yield of recognized DSB and reducing genomic instability. Data from NF1 fibroblasts exposed to radiation in radiotherapy and CT scan conditions confirmed that NF1 belongs to the group of syndromes associated with radiosensitivity and radiosusceptibility.


Do preoperative endoscopic interventions predict symptom recurrence or reintervention after peroral endoscopic myotomy?
Studies assessing outcomes of patients undergoing peroral endoscopic myotomy (POEM) after botulinum injection or dilation have had various results with respect to failure, although this has not been differentiated between lack of clinical response and recurrence. We hypothesize that patients with previous endoscopic intervention(s) are more likely to recur than treatment-naïve patients. This is a retrospective cohort study of patients that underwent POEM for achalasia at a single tertiary care center between 2011 and 2022. Patients were excluded if they had previous myotomy (POEM or Heller). The remaining patients were stratified into treatment-naïve patients (TN), those with previous botulinum injection (BTX), those with previous dilatation (BD), and those with both previous endoscopic interventions (BOTH). Primary outcome was recurrence indicated by clinical symptoms or need for repeat endoscopic intervention or surgery after originally having clinical resolution (Eckardt ≤ 3). Multivariate logistic regression using preoperative and intraoperative factors was completed to assess odds of recurrence. A total of 164 patients were included in the analysis, 90 TN, 34 BD, 28 BTX, and 12 BOTH. There were no other significant differences in demographics or in preoperative Eckardt score (p = 0.53). There was no difference in the proportion of patients that had postoperative manometry (p = 0.74), symptom recurrence (p = 0.59), surgical intervention (p = 0.16). BTX (14.3%) and BOTH (16.7%) patients had a higher rate of repeat endoscopic intervention than BD and TN patients (5.9% and 1.1%). In the logistic regression analysis, there was no association among the BTX, BD, or BOTH groups compared to the TN group. No odds ratios achieved statistical significance. There were no increased likelihood of recurrence with botulinum injection or dilatation prior to POEM, implying that they are similarly good candidates compared to treatment-naïve patients.


The 'knee' pattern in spirometry flow-volume curves in children: Does it relate to tracheomalacia?
There is little data on patterns of spirometry curves in children with tracheomalacia but convex inflection on flow-volume curves (identified as the 'knee') is thought to represent tracheomalacia. To determine (a) the prevalence of tracheomalacia in children with the 'knee' pattern on spirometry, and (b) whether spirometry parameters and visual characteristics of the 'knee' can identify presence/absence or severity of tracheomalacia. We reviewed the spirometry undertaken at Queensland Children's Hospital between 2016 and 2019 and retrieved spirometry with the 'knee' pattern in the flow-volume curves. Flexible bronchoscopy videos of these children were reviewed for tracheomalacia diagnosis and severity in a blinded manner. We also evaluated several 'knee' characteristics (onset of inflection, angle of inflection, a scoop before plateau, plateau progression), spirometry parameters and tracheomalacia severity. Of the 78 children with the 'knee', 51 (65.4%) had tracheomalacia. Spirometry values were significantly lower in those with tracheomalacia, compared to those without (predicted FEV1 = 86.1% vs 99.9%, FVC = 95.1% vs 104%, FEF25-75% = 68.6% vs 89.6%, all p < 0.02). A scoop before plateau was significantly associated with tracheomalacia (66.7% vs 40.7%, p = 0.03). There was no significant difference in spirometry parameters or the 'knee' characteristics between children with mild versus moderate-to-severe tracheomalacia. Most but not all children with the 'knee' pattern have flexible bronchoscopy-defined tracheomalacia. Those with tracheomalacia had lower spirometry values and the presence of a scoop before plateau was the most characteristic feature. A prospective longitudinal study is required to determine the diagnostic value of spirometry flow-volume curve characteristics in children.


Transumbilical flexible endoscopic cholecystectomy in humans: first feasibility study using a hybrid technique.
Natural-orifice transluminal endoscopic surgery (NOTES) procedures have been tested using numerous approaches, mainly in animals. In humans, only cholecystectomy has been assessed, using a combined transvaginal and transumbilical approach. We present another variant of a hybrid technique for cholecystectomy, namely the combination of a flexible transumbilical double-channel endoscope and a 3-mm rigid transcutaneous trocar placed in the left hypochondrium for liver retraction. The procedure was attempted in 10 well-selected young patients (M : F = 4 : 6, mean age 29.5 years). Instruments used through the two working channels of the endoscope were either a grasping forceps or snare for grasping and pulling and a hot-biopsy forceps for cold and hot preparation and dissection. Endoclips were used for cystic duct and artery closure. Postoperative analgesia consisted of one intravenous dose of analgesic, followed by oral administration for one further day. Follow-up visits were scheduled at 7 days, 30 days, 90 days, and 6 months. In 4 of the 10 cases the operation had to be converted to conventional laparoscopic cholecystectomy due to difficulty in dissection (in 2 cases) or uncontrollable hemorrhage (2 cases). The mean operating time was 148 minutes. Of the 6 cases in which the procedure was finished by the new approach, cystic artery bleeding occurred in 1 and was successfully clipped. One further patient had a postoperative cystic duct leak with a bilioma, successfully treated by endoscopic retrograde cholangiopancreatography with stenting. Five of the six patients reported themselves as satisfied at 3- or 6-month follow-up. So far, our endoscope-based transumbilical cholecystectomy technique has not yielded satisfactory results in humans. Further instrument and accessory improvements may increase both success rate and acceptance. Scarless surgery without the inherent risks of a transluminal approach may then become feasible.


Chronic demyelinating neuropathy with anti-myelin-associated glycoprotein antibody without any detectable M-protein.
Previous case reports and studies have shown that anti-myelin-associated glycoprotein (MAG) antibody can be detected in patients with polyneuropathy without any detectable M-protein. Nevertheless, the frequency of and related factors have not yet been adequately investigated. The objectives of this study are to examine the prevalence of anti-MAG antibody in patients with demyelinating neuropathy without M-protein and to determine their clinical characteristics. From January, 2004, to September, 2016, consecutive patients with chronic demyelinating neuropathy were recruited. Anti-MAG antibody presence was tested at the first evaluation. We determined the prevalence of anti-MAG antibody without M-protein among included patients and evaluated the clinical characteristics. A total of 44 patients were included in the present study (12 women; median age at first visit 60 years [interquartile range 47-67 years]; median duration between onset and first visit 9 months [3-26 months]). M-protein was found in eight patients (18%) at the first evaluation. Anti-MAG antibody was present in 2 of remaining 36 (5.6 [95% confidence interval 0-13.0] %) patients without M-protein. Patients with anti-MAG antibody exhibited slowly progressive and distal dominant neuropathy with elevated serum IgM levels and refractory to immunotherapy. There were no differences in clinical features between patients having anti-MAG antibody without M-protein, and those with M-protein. One patient with the anti-MAG antibody showed a delayed appearance of M-protein during a 4-year follow-up after diagnosis. The prevalence of the anti-MAG antibody in chronic demyelinating neuropathy without any detectable M-protein was 5.6%. Anti-MAG antibody may be detectable earlier than M-protein.


Axillary meristem initiation-a way to branch out.
Plants differ from most animals in their retained ability to initiate new cycles of growth and development, which relies on the establishment and activity of branch meristems. In seed plants, branching is achieved by axillary meristems, which are established in the axil of each leaf base and develop into lateral branches. Research into axillary meristem initiation has identified transcription factors and phytohormones as key regulators. Based on these findings, a mechanistic framework for understanding axillary meristem initiation has emerged. Taking recent research into account, we discuss mechanisms underlying stem cell fate regulation that enable axillary meristem formation.


[Enteritis cystica profunda].
Enteritis cystica profunda is a rare and benign disease defined as the invagination of the intestinal epithelium into the submucosa and more profound layers of intestinal wall leading to the formation of mucin-filled cystic spaces. We reported the case of a 45-year-old female, suffering from a Crohn's disease, with a Koenig's syndrome, diarrhea, abdominal pain and weight loss. The colonoscopy and the abdominopelvic scan showed a terminal ileal stenosis, with parietal calcifications. A surgical ileocecal resection was decided. Gross examination of the ileocecal resection showed a thickening of the ileal wall, with many mucin-filled cysts measuring 1mm to 2cm, with some calcifications. The ileal mucosa was ulcerated, and showed a stenotic sector extending over 3cm. Histological examination showed acute ulcerated ileitis lesions, with chronic ileitis lesions and stenosis, compatible with the known diagnosis of Crohn's disease. There were also many cysts into the ileal wall. They were lined with a regular ileal epithelium. The cysts contained mucus, with some calcifications. Some cysts were ruptured, with extravasation of mucus within the wall. Cystica profunda can be found anywhere along the digestive tract. The physiopathology is not yet well understood, but it seems to be favored by chronic aggression of the intestinal wall. This pathology most often coexists with Crohn's disease. The main differential diagnosis is mucinous adenocarcinoma. Cystica profunda does not require any specific treatment.


Chemiluminescence quenching capacity as a surrogate for total organic carbon in wastewater.
Total organic carbon (TOC) is a valuable indicator to evaluate the degree of organic pollution in wastewater. Real-time analysis of TOC in wastewater can allow the wastewater treatment plants to manage the treatment process efficiently, avoid violations of the discharge regulations, and eliminate overtreatment. However, traditional methods for TOC determination are time-consuming. Benefitting from the rapid generation of SO4•- in the iron(II)-activated peroxymonosulfate (Fe(II)/PMS) system and the high reactivity of SO4•- towards naproxen as a chemiluminescence (CL) probe, a surrogate for TOC based on the determination of CL quenching capacity (CLQC) of organics in the Fe(II)/PMS-naproxen system was developed. According to the derived equation by considering both non-fluorescent and fluorescent quenching, the CLQC of organics in the Fe(II)/PMS-naproxen system was highly dependent on their TOC, making it to be a potential surrogate for TOC. The interferences of ubiquitous inorganic ions in wastewater on the determination of CLQC were leveled by adjusting electrical conductivity and adding mercury ions. Finally, the feasibility of CLQC as a surrogate for TOC in two real wastewaters containing different concentrations of inorganic anions was confirmed. This work can provide a TOC value within several seconds by determining the CLQC of wastewater with Fe(II)/PMS-naproxen system.


Dermatologic manifestations of underlying infectious disease among illicit injection-drug users.
Drug use patterns and serious bloodborne infections commonly have dermatologic manifestations among illicit injection-drug users (IDUs). To assess how self-reported skin conditions of IDUs may correlate with underlying infectious diseases after adjustment for drug use patterns. Prospective analysis of factors associated with self-reports of skin rashes, cellulitis, oral lesions, and lymphadenopathy obtained from 1,065 IDUs enrolled in a large cohort study. Variables potentially associated with each outcome were evaluated using multivariate generalized estimating equations. In multivariate analyses, drug use patterns were associated with cellulitis, whereas human immunodeficiency virus (HIV) infection and hepatitis C (HCV) were not. HCV infection was independently associated with skin rashes (odds ratio [OR] 1.85; 95% CI 1.17-2.94). HIV infection was independently associated with lymphadenopathy (OR 2.00; 95% CI 1.52-2.63), skin rash (OR 2.12; 95% CI 1.57-2.86), and oral lesions (OR 14.95; 95% CI 9.41-23.76). Self-reports of IDUs, which could easily be obtained as part of a functional inquiry in a clinical setting, correlate with specific drug use patterns and underlying bloodborne infections.


New approaches to human facial morphology using automatic quantification of the relative positions of the orbital and nasal apertures.
The purpose of this study was to define and quantify the relative positions of the orbital and nasal apertures in the human face. The material consisted of 44 skulls (32 males, 12 females). For each skull, an image of the projection of the face was captured perpendicular to the palatal plane, using a CCD camera. The orbital and nasal apertures were segmented and characterized using classical image analysis procedures. New quantitative parameters were automatically determined from the centres of area of the facial apertures, and from horizontal and vertical lines of reference. Sexual differences were only significant for orbital height, nasal height, and orbitonasal height. A medio-lateral orbitonasal overlap, as well as a vertical orbitonasal overlap, existed in all individuals; the vertical overlap was always much more marked than the medio-lateral overlap. Significant proportions of the human face were also demonstrated: on average, the interorbital breadth corresponded to a fifth of the biorbital breadth, and thus to half of the mean orbital breadth; the nasal breadth corresponded to one fourth of the biorbital breadth, and the vertical orbitonasal overlap to one fourth of the orbitonasal height. Some instructive significant correlations were observed between these new parameters. The applications of the present methodology seem of great potential interest in anthropology and clinical biometry.