Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma.
Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma. We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design. After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire. Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P < .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab. Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.


The retinoic acid-induced up-regulation of insulin-like growth factor 1 and 2 is associated with prolidase-dependent collagen synthesis in UVA-irradiated human dermal equivalents.
Ultraviolet (UV) A irradiation causes the degeneration of extracellular matrix in the skin dermis, mainly due to disrupted collagen homeostasis, resulting in the photo-aging of human skin. All-trans retinoic acid (ATRA) improves photo-aged human skin in vivo. Although the effects of ATRA on collagen synthesis and MMP regulation are well known, the effects of ATRA on other collagen homeostasis-associated genes have not been elucidated. This study was aimed to study the factors that are pharmacologically associated with the effect of ATRA on collagen homeostasis. The gene transcription profile of collagen homeostasis-associated genes was systematically evaluated in three-dimensional human dermal equivalents (HDEs) following UVA-irradiation and/or ATRA treatment. In addition to the expected changes in MMPs and collagen synthesis in HDEs in response to ATRA, prolidase, an important enzyme in the recycling of proline and hydroxyproline from degraded collagen molecules, was significantly decreased by UVA irradiation, and its down-regulation was antagonized by ATRA. Transfection with a prolidase-specific siRNA led to a significant decrease in procollagen synthesis in human fibroblasts. ATRA inhibited the UVA irradiation-induced decrease in prolidase activity through an insulin-like growth factor (IGF) receptor signaling pathway in HDEs. ARTA increased IGF1 and IGF2 production in HDEs, and neutralizing IGFs with anti-IGF antibodies abolished the effect of ATRA on proliase activity. These data demonstrate that ATRA regulates prolidase activity in HDEs via IGF receptor signaling, suggesting one of the pharmacological mechanisms by which improves photo-aged human skin.


[Primary location on non-Hodgkin's lymphoma in the jaw: a case study].
A rare case of primary non-Hodgkin's lymphoma (NHL) of the jaw is reported. Precise diagnosis of such primary manifestation of NHL may pose a diagnostic problem due to unspecific clinical and radiological findings as well as difficult interpretation of biopsy specimens. The prognosis is related to the clinical stage, tumour aggressiveness and response to treatment.


Optimal foraging and intraspecific diet differences in the lizard Cnemidophorus sexlineatus.
Previous studies have shown that adult and juvenile six-lined racerunners, Cnemidophorus sexlineatus, consume different sizes and taxa of arthropod prey. the purpose of this study was to determine if these differences could be explained in terms of energy cost and benefit parameters as related by the optimal diet model. Handling times and encounter rates with each of five categories of prey were determined by direct observation of lizard foraging behavior in the field. Energetic cost of search and energy content of prey were estimated from data in the literature. Mean values of all these parameters were used in the classic optimal diet model to determine which prey types yield the greatest rate of net energy gain for adult and juvenile racerunners. Grasshopper-like insects were the most valuable prey for adults, whereas plant and ground arthropods were the most valuable prey for juveniles. These findings correspond to the age-class specific diet differences.Each age-class adopts foraging tactics that increase the chance of finding the most valuable prey. Adult racerunners move hastily over a large area to find the relatively rare, but large and mobile grasshopper prey. Juveniles move much more slowly, and carefully investigate twigs and leaves to find smaller, cryptic plant and ground arthropods. However these foraging tactics do not preclude the taking of less valuable prey items, should they be encountered. This is because it is energetically better on average to eat the prey item rather than skipping it to search for better prey, except for the case of juvenile racerunners eating grasshoppers. That juvenile racerunners will attempt to capture and consume even very large grasshoppers is contrary to the expectations derived from the optimal diet model. This behavior may be the result of the foraging "rule of thumb" racerunners use to find their prey.


The use of sympathomimetic amines for the treatment of severe constipation refractory to conventional therapy--case report.
Sympathetic nervous system hypofunction has been found to be associated with motility disorders of the bowel, including gastroparesis, pseudointestinal obstruction, and esophageal motility disorders. These disorders respond to sympathomimetic amine therapy. The purpose of this study was to see if this therapy could be effective in treating pathological constipation. Dextroamphetamine sulfate 15 mg extended release capsules was prescribed to an 18-year-old young woman who had severe constipation with a bowel movement every two to three weeks and sometimes every five to six weeks who did not respond to standard therapy and where no definite etiology was determined. Two hours after her first dosage of the sympathomimetic amine, she had a bowel movement and has had regular bowel movements ever since. Sympathomimetic amine therapy seems to help severe constipation refractory to standard therapy.


Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells.
Immune suppression remains a consistent obstacle to successful anti-tumor immune responses. As tumors develop, they create a microenvironment that not only supports tumor growth and metastasis but also reduces potential adaptive immunity to tumor antigens. Among the many components of this tumor microenvironment is a population of dendritic cells which exert profound immune suppressive effects on T cells. In this review, we discuss our recent findings related to these tumor-associated dendritic cells and how targeting them may serve to generate more durable anti-tumor immune responses.


A comparison of the effects of flupentixol and relaxation on laboratory pain: an experimental study.
The present experiment compared the effects of flupentixol (0.5 mg) and relaxation on acute laboratory pain induced by pressure. Results showed that flupentixol, in general, did not have an analgetic effect, but rather a negative effect. Relaxation with specific training for the pain site did have pain-relieving properties, while an "unspecific relaxation" control procedure did not result in significant pain relief. Possible explanations for the unexpected negative effect of flupentixol are discussed.


Single-incision plus two-port robotic surgery for sigmoid colon cancer using the Senhance robotic system.
Informed by our experiences with reduced-port surgery for colorectal cancer, we performed the first single-incision plus two-port robotic sigmoidectomy for cancer with the Senhance robotic system. A 70-year-old woman presented to our department for the treatment of sigmoid colon cancer. We performed single-incision two-port robotic sigmoidectomy. A wound protector was inserted through a 3.0-cm transumbilical incision, a multiport access device was mounted on top of it, and then a camera port and a 5-mm assistant's port were placed in the multiport access device. Two extra ports were placed on the central line of the abdomen. Lymph node dissection around the inferior mesenteric artery and mobilization of the left-sided colon were completed without any perioperative complications. The total operative time was 204 minutes, and the console time was 113 minutes. The estimated blood loss was 75 mL. The patient was discharged on postoperative day 8 without any complications.


Identical 5S rRNA nucleotide sequence of Vibrio cholerae strains representing temporal, geographical, and ecological diversity.
Enzymatic determination of the nucleotide sequence of 5S rRNA prepared from a Vibrio cholerae non-O1 serovar isolated from a canal in Louisiana in 1978 revealed it to be identical to that of V. cholerae O1 isolated in 1905 from a pilgrim at the E1 Tor quarantine station. The two strains are associated with sharply contrasting habitats. Ranges of variation of 5 to 15% in procaryotic 5S rRNA sequences between species are typical; variation within species may be 2% or greater. Because the 5S rRNA sequences were identical, it is concluded that they have a common phylogenic origin.


Contribution of Increases in Late Systolic Ejection Volume to the Impact of Heart Rate on Central Arterial Pulse Pressure in a Community Sample.
A lower heart rate (HR) increases left ventricular (LV) ejection volume. Whether this contributes to the adverse effects of HR on central pulse pressure (PPc) through reservoir volume effects is uncertain. Using noninvasive central pressure, aortic velocity, and diameter measurements in the outflow tract (echocardiography), we assessed the role of LV ejection volume as a determinant of HR relations with PPc in 824 community participants. A lower HR was independently associated with both stroke volume (SV) (P < 0.001) and a shift in ejection volume from early (until the first systolic shoulder) to late (from first systolic shoulder to peak PP) systole (P < 0.05 to P < 0.005). Adjustments for LV end diastolic volume markedly diminished HR relations with SV and indexes of the shift in ejection volume to late systole. A lower HR was also independently associated with increases in forward traveling pressure waves (Pf) and PPc (P < 0.0001). However, adjustments for neither SV, nor indexes of a shift in ejection volume to late systole modified HR-Pf or PPc relations. This was despite relationships between indexes of a shift in ejection volume to late systole and both Pf and PPc (P < 0.0001). In contrast, adjustments for the increases in re-reflected and backward traveling wave pressures with a lower HR, eliminated HR-Pf and PPc relations. In contrast to current thought, a lower HR is not associated with increases in PPc through an impact of increases in late systolic ejection volume on aortic reservoir volume, but rather through increases in backward wave pressures.


Effect of glutaurine on vitamin A and prednisolone treated thymus cultures.
The hormone of the parathyroid gland, Glutaurine (gamma-L-glutamyl-taurine) exerts on rat thymus cultures an effect synergistic with vitamin A and antagonistic to prednisolone. When applied in itself, it increased the vitality and macrophage reaction of thymus cultures.


Linking microbial community composition to farming pattern in selenium-enriched region: Potential role of microorganisms on Se geochemistry.
Selenium (Se) is an essential micronutrient for lives. Indigenous microbial communities play an important role on Se geochemistry in soils. In this study, the microbial community composition and functions of 53 soil samples were investigated using high-throughput sequencing. Samples were divided into 3 groups with different farming types based on the measured geochemical parameters and microbial functional structures. Results indicated that putative Se related bacteria Bacillus, Dyella, Paenibacillus, Burkholderia and Brevibacillus were dominant in dryland plantation soils which were characterized with higher available Se and low contents of H2O, total organic carbon (TOC), NH4+ and NO2-. In contrast, the putative denitrifier Pseudomonas dominated in flooded paddy soils with higher TOC, NO3- and organic Se, whereas genera Rhizobium, Nitrosospira, and Geobacter preferred woodland soils with higher oxidation-reduction potential (ORP), pH, NH4+ and Fe. Farming patterns resulted in distinct geochemical parameters including moisture, pH, ORP, TOC, and contents of soluble Fe, NO2- and NH4+, shaping the microbial communities, which in turn affected Se forms in soils. This study provides a valuable insight into understanding of Se biogeochemistry in soils and prospective strategy for Se-rich agriculture production.


Novel insights into redox system and the mechanism of redox regulation.
In view of the critical role of redox system in numerous physiological and pathophysiological processes, it is important to clearly understand the family members and regulatory mechanism of redox system. In this work, we will systematically review the current data detailing the reactive oxygen species (ROS), enzymatic and non-enzymatic antioxidants and redox sensitive transcription factors and we give a brief description of redox-mediated epigenetic and post-translational regulation. We propose that the redox system functions as a "Redox Chain", consisting of "ROS-generating Enzyme Chain", "Combined Antioxidant Chain" and "Transcription Factor Chain". We suggest that an individualized assessment of the redox status in the body should be conducted for the redox intervention of a patient. The strategy of intervention is to maintain redox homeostasis via either facilitation of ROS signaling or enhancement of antioxidant defense. These findings provide valuable new insights into redox system and open up new paths for the control of redox-related disorders.


The neuroprotective role and mechanisms of TERT in neurons with oxygen-glucose deprivation.
Telomerase reverse transcriptase (TERT) is reported to protect neurons from apoptosis induced by various stresses including hypoxia-ischemia (HI). However, the mechanisms by which TERT exerts its anti-apoptotic role in neurons with HI injury remain unclear. In this study, we examined the protective role and explored the possible mechanisms of TERT in neurons with HI injury in vitro. Primary cultured neurons were exposed to oxygen and glucose deprivation (OGD) for 3h followed by reperfusion to mimic HI injury in vivo. Plasmids containing TERT antisense, sense nucleotides, or mock were transduced into neurons at 48h before OGD. Expression and distribution of TERT were measured by immunofluorescence labeling and western blot. The expression of cleaved caspase 3 (CC3), Bcl-2 and Bax were detected by western blot. Neuronal apoptosis was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). The mitochondrial reactive oxygen species (ROS) were measured by MitoSOX Red staining. Fluorescent probe JC-1 was used to measure the mitochondrial membrane potential (ΔΨm). We found that TERT expression increased at 8h and peaked at 24h in neurons after OGD. CC3 expression and neuronal apoptosis were induced and peaked at 24h after OGD. TERT inhibition significantly increased CC3 expression and neuronal apoptosis after OGD treatment. Additionally, TERT inhibition decreased the expression ratio of Bcl-2/Bax, and enhanced ROS production and ΔΨm dissipation after OGD. These data suggest that TERT plays a neuroprotective role via anti-apoptosis in neurons after OGD. The underlying mechanisms may be associated with regulating Bcl-2/Bax expression ratio, attenuating ROS generation, and increasing mitochondrial membrane potential.


The Precision Oncology Program for Cancer of the Prostate (POPCaP) Network: A Veterans Affairs/Prostate Cancer Foundation Collaboration.
The promise of precision oncology only can be realized when genetic alterations are identified that can be lever-aged to improve response and minimize toxicity. Identifying those alterations as efficiently as possible and then giving patients access to targeted therapy and clinical study requires a comprehensive strategy across health care systems. The US Department of Veterans Affairs (VA) and Prostate Cancer Foundation have established a network of VA centers to help develop best practices for precision oncology for the treatment of veterans with advanced prostate cancer. This article describes the genesis and structure of this network and its potential for contributing to care and research in the VA and the health care system as a whole. The Precision Oncology Program for Cancer of the Prostate network and its partnership with VA clinical and research efforts is anticipated to provide important insights into barriers and solutions to the implementation of precision oncology for prostate cancer across the VA.


Thromboelastography detects inadequate response to abciximab therapy during stent-assisted cerebral aneurysm coil embolization complicated by stroke.
Thromboembolic stroke is the most common severe complication following coil embolization of intracerebral aneurysms, with a 5% incidence of permanent deficits. Despite heparin anticoagulation, rescue therapy with the platelet glycoprotein IIb/IIIa receptor antagonist abciximab may be required. However, we describe a failure of abciximab rescue therapy and discuss the importance of monitoring the variable individual response to abciximab. Two patients underwent stent-assisted cerebral aneurysm coil embolization complicated by thromboembolic stroke. In one patient, abciximab rescue therapy failed and was associated with a poor neurological outcome. Thromboelastography (TEG model 5000; Haemoscope, Skokie, IL) and platelet aggregometry suggested inadequate platelet inhibition, although other tests of platelet function suggested adequate inhibition. We describe a failure of regular-dose abciximab rescue therapy for thromboembolic stroke-complicating stent-assisted cerebral aneurysm coil embolization. The use of TEG to individualize abciximab dosing in this setting may improve patient outcome, as it tracks a pattern of coagulation consistent with the clinical picture.


Parents' experiences with health care transition of their adolescents and young adults with medically complex conditions: A scoping review.
Health care transition (HCT) has become increasingly important as adolescents and young adults (AYAs) with complex medical conditions now live well into adulthood but little attention has been given to parents of AYAs preparing for HCT. This scoping review aimed to identify and synthesize information on parental facilitators and barriers to health care transition readiness. English-language, peer-reviewed original studies focused on the parents' experience of HCT were included. Studies were excluded if AYAs were not anticipated to be independent or if AYAs had only mental health disorders. Parent-reported facilitators and barriers were identified in each study and then categorized to identify common themes. Themes related to parental facilitators included evidence of coordination between pediatric and adult levels of care, healthcare provider guidance for HCT, and parental awareness and acceptance of natural seasons of life. Themes related to parental barriers included relationship loss, loss of parental role, lack of knowledge and/or skills, and concerns related to the health care system in general. Common facilitators and barriers were found across studies, regardless of medical diagnosis. Relationships and role change figure prominently in parents' perceptions of the HCT experience and their readiness for their AYA children to transition. These findings suggest potential areas for future research inquiry as well as potential nursing interventions designed to aid parents through HCT.


Sadyovamana - An effective therapy in the management of Bell's palsy - A case report.
Bell's palsy or Facial nerve palsy is a condition that causes temporary weakness or paralysis of the muscles in the face. In Ayurveda, Ardita is a disease with functional disturbances affecting the Uthamanga (head) and stands close with the symptoms of Bell's palsy. This crippling disease has been elaborated by Ayurveda Acharyas Charaka, Susrutha and Vagbhata in their respective samhithas. It is narrated as one among the Asheeti Vata Vikaras (80 types of typical vata predominant diseases). This report is on a case study of 44 year old male patient who approached the Panchakarma OPD presenting with complaints of deviated face towards left side, difficulty in closing right eye and feeling of heaviness and swelling over right side of face for about 3 days. After relevant examinations and screening it was diagnosed as Bell's palsy. This disease though self-resolving some cases remain partially recovered and some may be left with major facial dysfunction. This patient was admitted at Govt. Ayurveda College, Tripunithura, Kerala, India for speedy recovery and complete resolution of this disease. Fourteen days of treatment primarily Sadyovamana followed with oral medications, pratimarsha nasya and physiotherapy were administered. The patient got complete recovery from all the symptoms of Ardita without any residual weakness or deformity within two weeks which is much early than the self-resolving period of 6 months. Being one among the aseetivatavikaras, Sadyovamana is the least practiced treatment for this condition. So in this report the scope of Sadyovamana in Bell's palsy management is discussed.


Intestinal Absorption of Isoalantolactone and Alantolactone, Two Sesquiterpene Lactones from Radix Inulae, Using Caco-2 Cells.
Isoalantolactone and alantolactone are the main sesquiterpene lactones in Radix Inulae (dried root of Inula helenium L. or I. racemosa Hook. F.), which is a frequently utilized herbal medicine. They also occur in several plants and have various pharmacologic effects. However, they have been found to have poor oral bioavailability in rats. To understand the intestinal absorptive characteristics of isoalantolactone and alantolactone as well specific influx and efflux transporters in their absorption. Bidirectional permeabilities of isoalantolactone and alantolactone were investigated across Caco-2 cell monolayers. Transport assays were performed using different concentrations of two lactones and specific inhibitors of ATP-binding cassette transporters and influx transporters. The absorption permeability of isoalantolactone and alantolactone was high at the tested concentrations (5, 20 and 80 μmol/l), and the major permeation mechanism of both lactones was found to be passive diffusion with active efflux mediated by multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). Our results demonstrated that the absorption permeability of isoalantolactone and alantolactone was good in the Caco-2 cell model. The isoalantolactone and alantolactone absorption elucidated in this study provides useful information for further pharmacokinetics studies. Since low intestinal absorption can now be ruled out as a cause, further studies are needed to explain the low oral bioavailability of the two sesquiterpene lactones.


Genetically predicted thyroid function and risk of colorectal cancer: a bidirectional Mendelian randomization study.
Observational studies have reported an association between thyroid function and colorectal cancer (CRC), with conflicting results. Elucidating the causal relationship between thyroid function and CRC facilitates the development of new preventive strategies to reduce CRC incidence. We applied a two-sample Mendelian randomization (MR) method to evaluate the causal relationship between five thyroid-related indexes, including hyperthyroidism, hypothyroidism, thyroid stimulating hormone (TSH), free thyroxine (FT4) and basal metabolic rate (BMR), and CRC. Genome-wide association study statistics for thyroid-related phenotypes were obtained from the ThyroidOmics consortium, and summary statistics for genetic associations with CRC were obtained from the FinnGen consortium. We set a series of criteria to screen single nucleotide polymorphisms (SNPs) as instrumental variables and then performed bidirectional MR analysis, stratified analysis and extensive sensitivity analysis. Multiplicative random-effects inverse variance weighted was the primary analysis method, supplemented by weighted median and MR-Egger. We identified 12 SNPs for hyperthyroidism, 10 SNPs for hypothyroidism, 41 SNPs for TSH, 18 SNPs for FT4, and 556 SNPs for BMR. Genetically predicted hyperthyroidism, hypothyroidism, TSH, and FT4 were not associated with CRC risk (all P > 0.05). Sensitivity analysis revealed no heterogeneity or pleiotropy. Genetically predicted BMR was significantly associated with increased CRC risk after removing outlier (OR = 1.30, P = 0.0029). Stratified analysis showed that BMR was significantly associated with colon cancer (OR = 1.33, P = 0.0074) but not rectal cancer. In the reverse analysis, there was no evidence of an effect of CRC on thyroid function (all P > 0.05). Our bidirectional MR analysis provides new insights into the relationship between thyroid function and CRC. CRC prevention may benefit from enhanced screening of high BMR populations.


ZNF451 favors triple-negative breast cancer progression by enhancing SLUG-mediated CCL5 transcriptional expression.
Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC.


Reliability and validity of the visual analogue scale for disability in patients with chronic musculoskeletal pain.
To determine the reliability and concurrent validity of a visual analogue scale (VAS) for disability as a single-item instrument measuring disability in chronic pain patients was the objective of the study. For the reliability study a test-retest design and for the validity study a cross-sectional design was used. A general rehabilitation centre and a university rehabilitation centre was the setting for the study. The study population consisted of patients over 18 years of age, suffering from chronic musculoskeletal pain; 52 patients in the reliability study, 344 patients in the validity study. Main outcome measures were as follows. Reliability study: Spearman's correlation coefficients (rho values) of the test and retest data of the VAS for disability; validity study: rho values of the VAS disability scores with the scores on four domains of the Short-Form Health Survey (SF-36) and VAS pain scores, and with Roland-Morris Disability Questionnaire scores in chronic low back pain patients. Results were as follows: in the reliability study rho values varied from 0.60 to 0.77; and in the validity study rho values of VAS disability scores with SF-36 domain scores varied from 0.16 to 0.51, with Roland-Morris Disability Questionnaire scores from 0.38 to 0.43 and with VAS pain scores from 0.76 to 0.84. The conclusion of the study was that the reliability of the VAS for disability is moderate to good. Because of a weak correlation with other disability instruments and a strong correlation with the VAS for pain, however, its validity is questionable.


Anatomic evaluation of the vertical face-lift in cadavers.
This study investigates how different orientations of tension vectors affect the amount of soft-tissue lift in specific cervicofacial regions. To compare differences in cosmetic neck and face changes generated by 3 different face-lift techniques, to quantify the amount of lift across different points on the face, and to quantify changes in platysmal dehiscence in each of 3 standard superficial musculoaponeurotic system plication face-lift techniques applied to fresh-frozen cadaver heads. Ten cadaver heads in an academic tertiary care center. Three different superficial musculoaponeurotic system plication rhytidectomy procedures were conducted in the following sequence: (1) vertical tension vector plication (vertical lift), (2) superolateral tension vector plication (superolateral lift), and (3) superolateral tension vector plication combined with midline platysmal plication (superolateral lift with platysmal plication). After completion of each technique, the amount of lift at 4 standard key points was measured and recorded, and differences in lift at the key points were analyzed. Vertical lift was associated with greater total lift than superolateral lift alone or superolateral lift with platysmal plication (P < .001 for both). Platysmal dehiscence increased from baseline measurements after superolateral lift and decreased after vertical lift (P = .002 for both). Our findings establish how different orientations of tension vectors applied during face-lift surgery achieve different structural changes to various key points across the face. This study helps the face-lift surgeon and student understand the underlying structural anatomic changes associated with different face-lift techniques, which ultimately result in different cosmetic outcomes. NA.


Trapped Pre-Macular Bubble of Octafluoropropane Gas Masquerading as Retained Submacular Perfluorocarbon Liquid.
To demonstrate, with the aid of retinal imaging, an abnormal post-operative macular appearance caused by the presence of a "fragmented" pre-retinal bubble of octafluoropropane (C3F8) masquerading as retained subretinal perfluorocarbon liquid (PFCL). This is an interventional case presentation. Colour fundus photography high-resolution spectral domain-optical coherence tomography (SD-OCT) and clinical progress demonstrate that the abnormal reflex was caused by the presence of a small fragment of C3F8 becoming lodged at the pre-foveal area. Submacular entrapment of various substances used during vitrectomy has been described in a number of case reports and case series. To our knowledge, this is the first described case of a retained fragment of fluorocarbon gas trapped at the macula following successful retinal detachment repair and highlights a previously unreported cause of an abnormal foveal appearance. However, clinical examination together with the use of SD-OCT is helpful in differentiating the appearance from that seen in other retained vitrectomy adjuncts.


A colorimetric fluorescent probe for the detection of carboxylesterase and carbamate pesticides.
A colorimetric fluorescent probe (BTCNA) was developed for the determination of carboxylesterase and carbamate pesticides. The probe used naphthalene-benzothiazole as the fluorescent group and naphthyl acetate as the recognition group. The recognition mechanism of BTCNA for carboxylesterase was based on the enzymatic hydrolysis of naphthyl acetate by carboxylesterase (CES). The test paper of the BTCNA gradually changed from light blue to bright yellow with the increase of CES activity. The probe solution gradually changed from light blue to earth-yellow as the carbaryl concentration increased. There was a linear functional relationship between the R*G (red, green) value of the photo and the CES activity. And a linear functional relationship between the carbaryl concentration and the R*G value of the photo was found. Additionally, BTCNA was successfully used to detect the concentration of carbaryl in actual samples. BTCNA is a rapid detection tool for CES activity and carbamate pesticides using a smartphone.


Electrochemical flow injection approach for routine screening of lipase activity in pancreatic preparations.
A state-of-the-art strategy for the determination of lipase activity in pancreatic preparations using flow injection analysis (FIA) with electrochemical detection (FIA-ED) is described. The procedure is based on the enzymatic reaction of a specific substrate (1,3-dilinoleoyl-glycerol) with lipase from porcine pancreas and determination of enzymatically formed linoleic acid (LA) at +0.4 V by applying a cobalt (II) phthalocyanine-multiwalled carbon-nanotubes modified carbon paste electrode (Co(II)PC/MWCNT/CPE). In order to get a high-performance analytical method, sample preparation, flow system, and electrochemical conditions were optimized. Under optimized conditions the lipase activity of porcine pancreatic lipase was calculated to be 0.47 units per mg lipase protein based on the definition that 1 unit hydrolyses 1 microequivalent linoleic acid from 1,3-dilinoleoyl-glycerol per 1 min at pH 9 and 20 °C (kinetic measurement: 0-25 min). Moreover, the developed procedure was shown to be easily adaptable for the fixed-time assay (incubation time 25 min) as well. In this case, linear correlation between flow signal and lipase activity was found in the range from 0.8 to 18 U L-1. LOD and LOQ were determined to be 0.3 U L-1 and 1 U L-1, respectively. The kinetic assay was further preferred for the determination of lipase activity in commercially available pancreatic preparations. The lipase activities of all preparations obtained by the present method were found to be in good correlation with those obtained by the titrimetric method and declared by manufacturers.


Design, synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine derivatives as c-Met inhibitors.
Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC50 of 22.8nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC50 of 329nM and EBC-1 IC50 of 479nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization.


Growth hormone can regulate functions of porcine ovarian granulosa cells through the cAMP/protein kinase A system.
The action of growth hormone (GH) on the production of hormones, growth factors, growth factor binding protein and the occurrence of apoptosis in porcine ovarian granulosa cells, as well as the role of cAMP-stimulated protein kinase A (PKA) in the mediation of these effects, were studied. For this purpose, the effects of exogenous pGH (1-10,000 ng/ml), PKA blockers KT5720 (100 ng/ml) and Rp-cAMPS (1micromol), alone and in combination, on insulin-like growth factor type I (IGF-I), insulin-like binding protein 3 (IGFBP-3), oxytocin (OT) and prostaglandin F alpha (PGF) secretion, PKA and cAMP response element binding transcription factor (CREB) content and the occurrence of apoptosis were investigated. It was found (using RIA/IRMA) that GH addition to culture medium significantly stimulated IGF-I and PGF release and inhibited IGFBP-3 and OT secretion. GH significantly decreased the incidence of apoptosis (TUNEL method) in cultured cells. Immunocytochemical study and Western immunoblotting showed, that addition of GH caused a dramatic increase in the accumulation of immunoreactive PKA within the cells, whilst Western blotting did not reveal marked influence of GH on content of CREB in cell lysates. PKA blockers, given alone, were able to decrease IGFBP-3 output (Rp-cAMPS, but not KT5720), reduce basal OT release (either Rp-cAMPS and KT5720) and increase PGF accumulation (KT5720, but not Rp-cAMPS). Furthermore, PKA blockers were able to prevent stimulatory effects of GH on IGF-I and PGF release, and inhibitory effect of GH on IGFBP-3, OT output and on apoptosis. These observations suggest the involvement of GH and a PKA-dependent intracellular mechanism in the control of IGF-I, IGFBP-3, OT, PGF, cAMP and apoptosis in porcine ovarian granulosa cells. Stimulation of PKA by GH and the prevention of GH-induced effects by PKA blockers suggest that both stimulatory and inhibitory effects of GH on porcine ovarian cells are probably mediated by the cAMP/PKA system.


Subacute exogenous Rhizoctonia solani endophthalmitis following cataract extraction with intraocular lens implantation.
Seven weeks after uneventful cataract extraction with intraocular lens (IOL) implantation, a 64-year-old man presented to his cataract surgeon with decreased vision and photophobia. The subacute presentation with anterior uveitis prompted initial therapy with topical and periocular glucocorticoids. One month later, the patient presented to the vitreoretinal service with counting fingers visual acuity, prominent anterior chamber reaction, a 2.5 mm hypopyon, and inflammatory deposits over the IOL. Cultures grew Rhizoctonia solani. The inflammation was successfully treated with pars plana vitrectomy, IOL explantation, and intravitreal voriconazole. Rhizoctonia should be included in the differential diagnosis of subacute exogenous endophthalmitis, especially in the context of fibrillar white IOL plaques. No author has a financial or proprietary interest in any material or method mentioned.


Incorporating Natural Helpers to Address Service Disparities for Young Children with Conduct Problems.
In response to the high levels of unmet need among historically underserved young children with conduct problems, this paper outlines some of the key issues involved in incorporating natural helpers into the delivery of parenting interventions for the treatment of conduct problems among historically underserved children. Strategies for the selection and training of natural helpers are discussed along with challenges that might be encountered in these processes. Directions for future research are also highlighted. With appropriate selection and training procedures in place, natural helpers may increase the accessibility of services for children and families and foster the reduction of service disparities.


Analysis of the Xist RNA isoforms suggests two distinctly different forms of regulation.
The noncoding RNA Xist has been shown to direct the mammalian dosage compensation pathway. Expression of the Xist RNA is regulated through an uncharacterized post-transcriptional mechanism, thought to involve Xist RNA stability. We have previously demonstrated that Xist RNA isoforms contain different 3' ends. In this report we analyze the expression patterns of Xist RNA isoforms and show the Xist RNA long form (L-isoform) is the predominant form in early development. Significant amounts of both the short form (S-isoform) and the L-isoform were found in the female soma. We also define the precise sequence structure of the Xist RNA isoforms 3' ends and show the S-isoform and the L-isoform are structurally dissimilar. Our data show both the S-isoform and L-isoform are cleaved from the same primary transcript. However, the S-isoform is subsequently post-transcriptionally polyadenylated, while the L-isoform is not post-transcriptionally polyadenylated. Sequence organization of the L-isoform shows that there are at least five different nonadenylated L-isoforms in the female soma and only one in embryonic stem (ES) cells. This stem cell-and somatic cell-specific processing may suggest a role for Xist RNA processing in the regulation of Xist RNA expression.


DNA clastogenic activity of diethylstilbestrol.
Incubation of human leukocytes with the synthetic estrogen and known human carcinogen, diethylstilbestrol (DES), for 40 min caused extensive DNA strand breakage (clastogenesis), as measured by a fluorometric assay. The level of DNA clastogenesis was dose dependent above an apparent threshold of 10 microM. Clastogenesis was increased by addition of cysteamine, a reducing agent and hydroxyl radical scavenger, and was blocked by low concentrations of plasma. DES epoxide, a weakly estrogenic derivative, was about one-tenth as potent as a DNA clastogen. Unexpected and paradoxical findings were observed when cells were treated with DES in the presence of a hydrogen peroxide-generating system plus a peroxidase. At the subthreshold concentration of 10 microM DES, the oxidizing system increased DNA clastogenicity, yet at 30 microM DES the oxidizing system decreased clastogenicity. The addition of superoxide dismutase to the oxidizing system increased clastogenicity at both concentrations of DES. DNA damage was largely blocked by arsenite, N-ethylmaleimide, iodoacetamide and bromophenacyl bromide. These experiments provide further indication of the complex nature of reactions involving DES which can lead to DNA damage and which may be relevant to DES-induced carcinogenesis.


Aerosolized sodium hypochlorite inhibits viability and allergenicity of mold on building materials.
Commercial and residential buildings can become contaminated with molds, which may trigger allergic disorders. Mold remediation efforts may require costly replacement of mold-contaminated building materials. Disinfectants that contain dilute sodium hypochlorite can kill mold and are practical to use. Whether they also inhibit mold allergy symptoms is unknown. We tested the hypothesis that sodium hypochlorite-containing spray products kill Aspergillus fumigatus and inhibit A fumigatus allergens. A fumigatus was grown on 3 common building construction materials, as well as in solution by conventional laboratory methods. Two sodium hypochlorite-containing household products (diluted bleach and Tilex) were sprayed on the mold-contaminated materials or added to mold in solution and compared with untreated controls. Surface mold and associated debris were mechanically removed from treated and untreated boards. Conidia in the extracted board materials were quantified by light microscopy, examined for morphologic changes by scanning electron microscopy, and cultured for viable mold. Extracts were tested for A fumigatus antigen by ELISA, and for A fumigatus allergen by skin prick testing using extracts prepared from both the boards and the cultured solutions. Both sodium hypochlorite disinfectants killed A fumigatus in solution and on mold-contaminated building materials. Light microscopy and scanning electron microscopy demonstrated changes to the conidial surface. Both dilute bleach and Tilex inhibited A fumigatus recognition by ELISA. Skin testing supported the results of the ELISAs and demonstrated loss of skin test reactivity to the sodium hypochlorite-treated mold solutions in most of the subjects. Of the 4 individuals who had a positive skin test result to mold grown on oriented strand board building material, 3 no longer reacted to extracts from bleach-treated boards. Spray application of sodium hypochlorite-containing disinfectants onto mold-contaminated building material kills A fumigatus, modifies the surface characteristics of A fumigatus conidia, reduces recognition of A fumigatus mold by ELISA, and results in loss of skin test reactivity to the treated mold in individuals allergic to A fumigatus.


Diatom biosilica: Source, physical-chemical characterization, modification, and application.
Growing research interest in the use of diatomaceous biosilica results from its unique properties such as chemical inertness, biocompatibility, high mechanical and thermal stability, low thermal conductivity, and homogeneous porous structure with a large specific surface. Unlike the production of synthetic silica materials with a micro- or nanoscale structure in an expensive conventional manufacturing process, diatomaceous biosilica can be produced in huge quantities without significant expenditure of energy and materials. This fact makes it an unlimited, easily accessible, natural, inexpensive, and renewable material. Moreover, the production of biosilica is extremely environmental friendly, as there is essentially no toxic waste and the process does not require more energy compared to the production of synthetic silica-based materials. For all these reasons, diatoms are an intriguing alternative to synthetic materials in developing cheap biomaterials used in a different branches of industry. In this review, the state-of-art of biosilica materials, their characteristics approaches, and possible ways of application have been reported.


Clinical effectiveness and safety of amlodipine/losartan-based single-pill combination therapy in patients with hypertension: Findings from real-world, multicenter observational databases.
Various single-pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real-world evidence regarding the effectiveness of these SPCs for hypertension. This study evaluated the real-world clinical efficacy and safety of amlodipine/losartan-based SPC therapies in patients with hypertension in a real-world setting. A total of 15 538 patients treated with amlodipine/losartan-based SPCs [amlodipine + losartan (AL), amlodipine + losartan + rosuvastatin (ALR), and amlodipine + losartan + chlorthalidone (ALC)] were selected from the database of three tertiary hospitals in Korea. The efficacy endpoints were target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) achievement rates. Safety was evaluated based on laboratory parameters. Drug adherence was defined as the proportion of medication days covered (PDC). The target BP attainment rate was above 90% and was similar among the three groups. Although many patients in the AL and ALC groups took statins, the target LDL-C attainment rate was significantly higher in the ALR group than in the AL and ALC groups. Safety endpoints were not significantly different among the groups, except serum uric acid level and incidence rate of new-onset hyperuricemia, which were significantly lower in the AL and ALR groups than in the ALC group. The PDC was > 90% in all groups. In the real-world hypertensive patients, amlodipine/losartan-based SPC therapy demonstrated good target BP achievement rates. Especially, rosuvastatin-combination SPC showed better target LDL-C goal achievement rate compared to the other SPCs. All three amlodipine/losartan-based SPC had excellent drug adherence.


Switching patterns of immediate-release forms of generic mixed amphetamine salts products among privately and publicly insured individuals aged 15-64 years in the United States, 2013-2019.
Immediate-release forms of generic mixed amphetamine salts (MAS) have been the subject of passive surveillance reports signaling lack of effectiveness. We examined switching patterns that might suggest whether long-term users of specific MAS are more likely to switch away or switch back after use of the MAS of interest in the FDA's Sentinel Distributed Database. We required at least 60-day continuous supply of selected MAS grouped by Abbreviated New Drug Application (ANDA) to describe patterns of switching away from and to generics approved under the ANDAs of interest among individuals ages 15-64 years with attention deficit hyperactivity disorder or narcolepsy during 2013-2019. We observed the greatest number of treatment episodes for ANDA 040422 (n = 525 771), followed by ANDA 202424 (n = 181 693), ANDA 040439 (n = 62 363), ANDA 040440 (n = 21 143), and ANDA 040480 (n = 8792). Of those with switches away from their original ANDA, episodes initiated on generic products under ANDA 040422 (48.6%) and ANDA 202424 (43.0%) were most likely to switch back, while those initiated on generic product under ANDA 040480 were least likely (24.1%). Of those episodes with switches to a generic under an ANDA of interest, about one-third (range 27.1% to 37.0%) switched back to the same product. These switches back had a median time to switch of about 30 days. These descriptive analyses, although subject to limitations, did not suggest increased switching away or switching back after use of the generics of interest. Continued post-marketing surveillance is warranted.


Mild cognitive deficits in patients with primary adrenal insufficiency.
The brain is a major target organ for cortisol considering its high density of glucocorticoid receptors. Several states of hypothalamus-pituitary-adrenal dysregulation point towards impairments in cognitive functioning. However, there is a very limited body of research on the effects of hypocortisolism on cognitive functioning. To evaluate cognitive functioning in patients with hypocortisolism (i.e., primary adrenal insufficiency (PAI)) and to examine the possible effect of postponing early-morning hydrocortisone intake on cognitive functioning. Thirty-one patients with PAI on regular morning hydrocortisone intake and 31 healthy matched controls underwent nine neuropsychological tests, evaluating memory and executive functioning. In addition, the effect of normal timing and postponement of morning hydrocortisone intake on neuropsychological tests were assessed in an additional 29 patients with PAI. Compared to controls, patients with PAI performed worse on auditory and visual memory tasks (all P ≤ 0.024) and executive functioning tasks (all P ≤ 0.012). In contrast, patients performed better on a concentration and an attention task (both P<0.05). Postponement of hydrocortisone intake in the morning did not affect the outcomes of neuropsychological tests. Patients on long-term hydrocortisone replacement for PAI show mild cognitive deficits compared to controls. There was no effect of postponement of regular hydrocortisone intake on cognition.


Preliminary support for the role of reward relevant effort and chronotype in the depression/insomnia comorbidity.
The presence of insomnia in the context of depression is linked to a number of poor outcomes including reduced treatment response, increased likelihood of relapse, and greater functional impairment. Given the frequent co-occurrence of depression and insomnia, research into systems and processes relevant to both disorders, specifically reward processing and circadian rhythm disruption, may help parse this complex comorbidity. A pilot study was conducted on a sample of 10 veterans with clinically significant depression and insomnia symptoms. Participants completed objective (actigraphy) and subjective (sleep diary) assessments of sleep, self-reports of chronotype, and behavioral tasks assessing reward relevant effort before and after 6 sessions of Cognitive Behavioral Therapy for Insomnia. Insomnia and depression significantly improved following CBT-I. Subjective sleep parameters significantly improved with large effect sizes. Actigraphy results were nonsignificant, but effect sizes for sleep efficiency and onset latency were in the medium range. Chronotype shifted significantly toward morningness following CBT-I, and an earlier chronotype at baseline was associated with increased reward effort following treatment. Changes in chronotype, depression and insomnia were not associated with changes in effort. Findings are limited by small sample size and lack of randomized control group. Findings should be interpreted as hypothesis generating in the service of furthering research aimed at uncovering potential mechanisms underlying the depression/insomnia comorbidity. Analyses of sleep data in extant datasets of reward processing impairments in depression as well as original projects aimed at exploring potential sleep, circadian rhythm, and reward interactions in depression are encouraged.


[The sigmoid vagina: experiences in the treatment of congenital absence or later loss of the vagina].
Construction of a neovagina by means of a pedicled sigmoid transplant is considered a successful and for the patient satisfactory method in congenital vaginal aplasia or loss of the vagina after radical cancer surgery in the pelvis. The operative procedure and the anatomical and functional results obtained in 23 patients treated by the author are reported and discussed.


cDNA structure and expression of bombyxin, an insulin-like brain secretory peptide of the silkmoth Bombyx mori.
Bombyxin, previously referred to as 4K-prothoracicotropic hormone, is a brain peptide of the silkmoth Bombyx mori, the amino acid sequence of which shows considerable homology with vertebrate insulin family peptides. Two independent clones have been isolated from a Bombyx larval brain cDNA library by using a synthetic oligonucleotide probe, one with the complete coding region for preprobombyxin (lambda Bb360) and the other covering the coding region, possibly for bombyxin, only partially (lambda Bb204). lambda Bb360 encodes preprobombyxin in the order of prepeptide/B-chain/proteolytic cleavage signal/C-peptide/proteolytic cleavage signal/A-chain. This domain organization of preprobombyxin is the same as that of preproinsulins, suggesting that the tertiary structure and posttranslational modification mechanism are conserved through the evolution of bombyxin and insulin. Genomic Southern hybridization analyses using this cDNA as probe suggest that the Bombyx genome contains multiple copies of bombyxin gene. Northern hybridization analyses indicate that the concentration of lambda Bb360-type bombyxin mRNA in the bombyxin-producing cells is remarkably high (2.8 x 10(9) molecules/micrograms of total RNA), without undergoing appreciable change during larval-pupal development.


Chronic omeprazole use in the elderly is associated with decreased risk of dementia and cognitive decline.
The association between proton pump inhibitor (PPI) use and increased risk of dementia is controversial. Investigating this issue in a large population of community-dwelling elders. Our database was retrospectively searched for all community-dwelling patients aged ≥65 years who newly diagnosed with dementia/cognitive decline (DCD) between January 2002 - December 2012. Receiving ≥11 prescriptions of PPIs/year was categorized as PPI users. Clinical data were collected from the medical files. Risk of DCD in PPI users was analyzed by Cox regression models. Included 48,632 elders of whom 8,848 were diagnosed with DCD (18.2%). PPI use was documented in 10,507, of whom 1,959 were subsequently diagnosed with DCD (18.6%). Among 38,125 non-PPI users, 6,889 (18.1%) were diagnosed with DCD. The hazard ratio for occurrence of DCD in PPI users compared to non-users was 0.85 (95% CI: 0.81-0.89, P <0.001) in an un-adjusted Cox regression model and 0.83 in a Cox regression model adjusted for age and sex (95% CI: 0.79-0.87, P <0.001). Multivariate Cox regression accounting for background diseases, marital status, and socioeconomic state yielded a hazard ratio of 0.77 (95% CI: 0.73-0.81, P <0.001). PPI use wasn't associated with DCD development in chronic PPI users.


NADPH-dependent microsomal metabolism of 14,15-epoxyeicosatrienoic acid to diepoxides and epoxyalcohols.
The arachidonic acid epoxygenase metabolite 14,15-epoxyeicosatrienoic acid is further metabolized by rat liver microsomal fractions to regioisomeric diepoxides and epoxyalcohols. Diepoxides result from epoxidation at the 5,6-, 8,9-, or 11,12-olefins. Hydroxylation leading to epoxyalcohols with a cis, trans-conjugated dienol occurs at carbons 5, 8, 9, or 12. Structural assignments were established by chromatographic and mass spectral comparisons with synthetic standards. The reaction requires NADPH and is inhibited by typical cytochrome P-450 inhibitors. Analysis of the time course of product formation during arachidonic acid oxidation by rat liver microsomal fractions indicated that all four regioisomeric epoxyeicosatrienoic acids can be further metabolized by the enzyme system.


Characterization of spatio-temporal epidural event-related potentials for mouse models of psychiatric disorders.
Distinctive features in sensory event-related potentials (ERPs) are endophenotypic biomarkers of psychiatric disorders, widely studied using electroencephalographic (EEG) methods in humans and model animals. Despite the popularity and unique significance of the mouse as a model species in basic research, existing EEG methods applicable to mice are far less powerful than those available for humans and large animals. We developed a new method for multi-channel epidural ERP characterization in behaving mice with high precision, reliability and convenience and report an application to time-domain ERP feature characterization of the Sp4 hypomorphic mouse model for schizophrenia. Compared to previous methods, our spatio-temporal ERP measurement robustly improved the resolving power of key signatures characteristic of the disease model. The high performance and low cost of this technique makes it suitable for high-throughput behavioral and pharmacological studies.


Place-Based Philanthropy and Measuring Community Well Being in the Age of COVID-19.
Place-based philanthropic organizations have long defined their value in terms of ability to improve well-being in the communities they serve. Desire to quantify and prove this impact has led such charities to be interested in and even invest in measures of community well-being. In this paper I explore how the onset of the COVID-19 pandemic has affected local philanthropy's relationship with data and information by increasing public awareness of community data as a tool for describing rapidly changing community needs, raising expectations for an expedited connection between data analysis and action, and compelling civic leaders to engage in scenario planning. I draw on the case of Syracuse, NY to illustrate how the presence of a real time collaborative data infrastructure presents promising opportunities to address the data needs of place-based philanthropy when it comes to monitoring and acting to improve community well-being in the COVID era.


An in-silico study to understand the effect of lineage diversity on cold shock response: unveiling protein-RNA interactions among paralogous CSPs of E. coli.
Cold shock proteins (CSPs) are small, cytoplasmic, ubiquitous and acidic proteins. They have a single nucleic acid-binding domain and pose as "RNA chaperones" by binding to ssRNA in a low sequence specificity and cooperative manner. They are found in a family of nine homologous CSPs in E. coli. CspA, CspB, CspG and CspI are immensely cold inducible, CspE and CspC are consistently released at usual physiological temperatures and CspD is also induced under nutrient stress. The paralogous protein pairs CSPA/CSPB, CSPC/CSPE, CSPG/CSPI and CSPF/CSPH were first identified. The eight proteins were subjected to molecular modelling and simulation to obtain the most stable conformation in correspondence to their equilibrated RMSD and RMSF graph. The results were compared and it was observed that CSPB, CSPE, CSPF and CSPI were more stable than their paralogous partner conforming to their near equilibrated RMSD curve and low fluctuating RMSF graph. The paralogous proteins were docked with ssRNA and simultaneously binding affinity, interaction types, electrostatic surface potential, hydrophobicity, conformational analysis and SASA were calculated to minutely study and understand the molecular mechanism initiated by these proteins. It was found that CSPB, CSPC, CSPH and CSPI displayed higher affinity towards ssRNA than their paralogous partner. The results further corroborated with ΔGmmgbsa and ΔGfold energy. Between the paralogous pairs CSPC, CSPH and CSPI exhibited higher binding free energy than their partner. Further, CSPB, CSPC and CSPI exhibited higher folding free energy than their paralogous pair. CSPH exhibited highest ΔGmmgbsa of - 522.2 kcal/mol and lowest was displayed by CSPG of around - 309.3 kcal/mol. Highest number of mutations were recognised in CSPF/CSPH and CSPG/CSPI pair. Difference in interaction pattern was maximum in CSPF/CSPH owing to their high number of non-synonymous substitutions. Maximum difference in surface electrostatic potential was observed in case of CSPA, CSPG and CSPF. This research work emphasizes on discerning the molecular mechanism initiated by these proteins with a structural, mutational and functional approach. The online version contains supplementary material available at 10.1007/s13205-023-03656-2.


Development of molecular tools for the mulundocandin producer Aspergillus sydowii: DNA-mediated transformation and reporter gene expression.
The echinocandin-type antimycotic mulundocandin and its derivatives are produced by the filamentous fungus Aspergillus sydowii (strain FH2551). These agents have been considered as a potential drug to treat immunocompromised patients who suffer from severe opportunistic fungal infections. In order to generate strains with a modified mulundocandin biosynthesis, we developed molecular tools for genetic engineering of A. sydowii as an alternative to conventional strain improvement procedures. For our experiments, we used strain FH2551, which was discriminated from other Aspergillus strains by determining the sequence of the two internal transcribed spacers (ITS1 and ITS2) of the rDNA locus. In addition, the electrophoretic karyotype of A. sydowii was established using pulsed-field gel electrophoresis (PFGE), leading to a calculated genomic size of about 40 Mb. For gene mapping, chromosomes were subjected to PFGE either unrestricted or after incubation with rare cutting enzymes and probed with heterologous genes. Using the bacterial hygromycin B phosphotransferase gene as a selectable marker for transformation of A. sydowii, we generated transformants with single and multiple copies of plasmid DNA. Subsequently, the heterologous lacZ and gfp genes were efficiently transferred and expressed in A. sydowii. The majority of lacZ-transformants showed more than 6 pkat beta-galactosidase activity/mg protein, while the control strains had no significant background activity. Fluorescence microscopy of gfp-transformants demonstrated that the green-fluorescent protein is present in a stable and active form in the cytoplasm of vegetative hyphae and conidiospores.


A preliminary evaluation of the circulating leptin/adiponectin ratio in dogs with pituitary-dependent hyperadrenocorticism and concurrent diabetes mellitus.
Leptin and adiponectin are thought to modulate insulin sensitivity and pancreatic β-cell function, but there is limited information regarding the adipokine status of hyperglycemic dogs with hyperadrenocorticism. This study aimed to determine whether alterations in the leptin/adiponectin ratio, insulin sensitivity, and/or pancreatic β-cell function are associated with diabetes mellitus (DM) in dogs with pituitary-dependent hyperadrenocorticism (PDH). A total of 48 client-owned dogs were included in this prospective observational study: 20 dogs with PDH (10 normoglycemic and 10 with DM), 15 dogs with DM, and 13 healthy dogs. The serum concentrations of leptin, adiponectin, resistin, interleukin (IL)-1β, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF)-α were measured, and homeostatic model assessment indices (HOMAs) were calculated and compared among the groups. Serum leptin was significantly higher in PDH dogs with and without DM than in healthy and DM dogs, and it was lower in DM dogs than in PDH dogs without DM. Serum adiponectin was significantly lower in PDH dogs with DM than in healthy and PDH dogs, and it was significantly lower in DM dogs than in healthy dogs. Serum IL-10 was significantly higher in PDH dogs with DM than in healthy and PDH dogs without DM. The leptin/adiponectin ratio was significantly higher in PDH dogs with DM than in normoglycemic PDH dogs. Serum IL-6 concentrations were significantly higher in DM dogs than in healthy dogs. Serum IL-1β concentration was significantly higher in DM dogs than in healthy dogs and PDH dogs with DM and without DM. Serum TNF-α and IL-18 concentrations were not different among groups. The HOMAβ-cell function was significantly lower in PDH dogs with DM than in normoglycemic PDH dogs, while HOMAinsulin sensitivity was significantly lower in PDH dogs with DM than in healthy dogs. These results suggest that adipokine dysregulation, a reduction in insulin sensitivity, and a further impairment in pancreatic β-cell function might predispose PDH dogs to DM. Further longitudinal study will be necessary to confirm this result.


Sustained delivery of therapeutic concentrations of human clotting factor IX--a comparison of adenoviral and AAV vectors administered in utero.
Prenatal somatic gene therapy has been considered for genetic disorders presenting with morbidity at birth. Haemophilia is associated with an increased risk of catastrophic perinatal bleeding complications such as intracranial haemorrhage, which could be prevented by gene transfer in utero. Prenatal gene therapy may be more promising than postnatal treatment, as the fetus may be more amenable to uptake and integration of therapeutic DNA and the immaturity of its immune system may permit life-long immune tolerance of the transgenic protein, thus avoiding the dominant problem in haemophilia treatment, the formation of inhibitory antibodies. Adenovirus serotype 5-derived or AAV serotype 2-derived vectors carrying human clotting factor IX (hfIX) cDNA or a reporter gene were administered intramuscularly, intraperitoneally or intravascularly to late-gestation mouse fetuses. Both vector types were evaluated with respect to the kinetics of hfIX delivery to the systemic circulation and possible immune responses against the vector or the transgene product. Mice treated in utero by intramuscular injection of an adenoviral vector carrying hfIX cDNA exhibited high-level gene expression at birth and therapeutic--albeit continuously decreasing--plasma concentrations of hfIX over the entire 6 months of the study. Adenoviral vector spread to multiple organs was detected by polymerase chain reaction (PCR). Intramuscular, intraperitoneal or intravascular application of AAV vectors carrying hfIX cDNA led to much lower plasma concentrations of hfIX shortly after birth, which appeared to decline during the first month of life but stabilized in some of the mice at detectable levels. No signs of immune responses were found, either against the different viral vectors or against hfIX. This study demonstrates for the first time that sustained systemic delivery of a therapeutic protein can be achieved by prenatal gene transfer. It thus shows the feasibility of gene therapy in utero and provides a basis for considering this concept as a preventive therapeutic strategy for haemophilia and perhaps also for other plasma protein deficiencies.


Conventional and future diagnostics for avian influenza.
The significant and continued transboundary spread of Asian avian influenza H5N1 since 2003, paired with documented transmission from avian species to humans and other mammals, has focused global attention on avian influenza virus detection and diagnostic strategies. While the historic and conventional laboratory methods used for isolation and identification of the virus and for detection of specific antibodies continued to be widely applied, new and emerging technologies are rapidly being adapted to support avian influenza virus surveillance and diagnosis worldwide. Molecular tools in particular are advancing toward lab-on-chip and fully integrated technologies that are capable of same day detection, pathotyping, and phylogenetic characterization of influenza A viruses obtained from clinical specimens. The future of avian influenza diagnostics, rather than moving toward a single approach, is wisely adopting a strategy that takes advantage of the range of conventional and advancing technologies to be used in "fit-for-purpose" testing.


4D phase-contrast flow cardiovascular magnetic resonance: comprehensive quantification and visualization of flow dynamics in atrial septal defect and partial anomalous pulmonary venous return.
The case of an 8-year-old girl with atrial septal defect and associated anomalous pulmonary venous return is presented to illustrate the advantages of four dimensional flow (4D flow) over the current two dimensional flow (2D flow) in terms of time efficiency, easy planning, accurate and individual quantification of the blood sources contributing to the left-to-right shunting from one single acquisition, internal validation of flow measurement accuracy, possibility of reanalysis without rescanning in case of unexpected findings during the postprocessing, and comprehensive understanding of flow insight by use of particle tracing visualization.


Prevalence of chronic diseases among physicians in Taiwan: a population-based cross-sectional study.
The health of physicians is an important topic which needs to be addressed in order to provide the best quality of patient care. However, there are few studies on the prevalence of chronic diseases among physicians. In this study, we explored the prevalence of chronic diseases among physicians and compared the probability of chronic diseases between physicians and the general population using a population-based data set in Taiwan. A cross-sectional study. Taiwan. Our study consisted of 1426 practising physicians and 5704 general participants. We chose 22 chronic diseases from the Elixhauser Comorbidity index and nine highly prevalent medical conditions in an Asian population for analysis. We used conditional logistic regression analyses to investigate the OR and its corresponding 95% CI of chronic diseases between these two groups. The conditional logistic regression analyses showed that physicians had lower odds of peripheral vascular disorders (OR=0.41, 95% CI=0.19 to 0.90), uncomplicated diabetes (OR=0.76, 95% CI=0.60 to 0.97), complicated diabetes (OR=0.53, 95% CI=0.34 to 0.83), renal failure (OR=0.41, 95% CI=0.19 to 0.90), liver diseases (OR=0.78, 95% CI=0.66 to 0.94), and hepatitis B or C (OR=0.62, 95% CI=0.49 to 0.77) and higher odds of hypertension (OR=1.21, 95% CI=1.03 to 1.41), hyperlipidaemia (OR=1.43, 95% CI=1.23 to 1.67) and asthma (OR=1.59, 95% CI=1.16 to 2.18) than the general population. We concluded that although physicians had decreased prevalence of some chronic diseases, they had a significantly increased prevalence of hypertension, hyperlipidaemia and asthma.


Needs and Attitudes Related to the Adoption of Evidence-Based Practices Among Latinx Mental Health Professionals.
Empirically supported interventions are warranted to achieve desired clinical outcomes and improve service delivery. Thus, efforts to identify, adopt, and implement Evidence-Based Practices (EBPs) are underway across various Latinx communities, including Puerto Ricans, where there is a growing recognition and prevalence of mental health and substance use disorders. This study investigated the needs and attitudes toward EBPs among an interdisciplinary sample of mental health professionals in Puerto Rico. An anonymous survey was distributed to social workers, psychologists, and professional counselors (N = 237). Using structural equation modeling, four dimensions of attitudes towards EBPs (openness, divergence, appeal, and requirement) were regressed on various individual and organizational factors. Some socio-demographic characteristics, educational opportunities, and organizational factors significantly contributed to specific attitudes related to the adoption of EBPs. Female participants and those working in rural settings scored higher in the openness to innovation dimension. Greater organizational support and graduating from a private institution were associated with more divergence from research, while married individuals and those trained on EBPs scored lower on this dimension. The lack of exposure to EBPs in college and younger age predicted greater interest in the appeal of adopting an EBP intervention (i.e., would adopt an EBP if it made sense). No differences in attitudes toward EBPs were found by professional discipline or work setting (i.e., clinical, community, and schools). Recommendations to increase openness and interest in the appeal of EBPs among Spanish-speaking professional communities in Latin America are highlighted.


The interaction of cephaloridine with model membrane systems and rat kidney lysosomes.
The antibiotic cephaloridine has been shown to interact with phospholipid structures, using the techniques of ultraviolet difference spectroscopy, surface pressure measurements and liposome models. The results indicate that this interaction is at least partly hydrophobic in nature and help explain the disruptive effects of high concentrations of cephaloridine on both artificial and natural phospholipid structures (lysosomes). Low concentrations of cephaloridine were shown to inhibit a lysosomal membrane-bound phospholipase 2 and it is suggested that such an inhibition may explain the cephaloridine-induced stabilization of rat-kidney lysosomes.


Evaluation of learning and exposure in the undergraduate interventional radiology curriculum (ELIXIR).
To gauge current final year medical students' exposure to interventional radiology (IR)and assess their perceptions of IR as a prospective career option. An online questionnaire comprising of questions that gauge final-year medical students' understanding of and exposure to IR based on the recommendations set out by the British Society of Interventional Radiology (BSIR), was sent out to final-year students across 34 UK medical schools. Five hundred and ten responses were collected from 33 out of 34 eligible medical schools. Sixty-four per cent of respondents rated their own IR knowledge as inadequate. On average, only 50% of all subtopics proposed in the BSIR undergraduate curriculum was covered during medical school and 32.7% of respondents were not exposed to any fundamental IR principles and techniques recommended by the BSIR during medical school. Regarding careers, 2.7% of respondents reported a definite interest in pursuing a career in IR. Most respondents (89.8%) felt that there was insufficient undergraduate teaching on IR and that they lacked information to consider pursuing a career in IR (87.5%). Insufficient exposure and teaching on IR throughout medical schools have led to a lack of awareness and consideration of IR as a future career choice amongst UK medical students. The re-evaluation of IR teaching in the medical school curricula is needed. In the long-term, such recommendations could provide the much-needed solution to the workforce shortages seen in IR.


Inhibitory effects of cultured Dendrobium tosaense on atopic dermatitis murine model.
Dendrobium tosaense is one of the most valuable Chinese medicines and well developed health food. Atopic dermatitis (AD) is a chronic skin disease that occurs mainly in childhood. The pathogenesis of atopic dermatitis had been studied in BALB/c mice modeling by skin-inoculated ovalbumin (OVA) with 2,4,6-trinitro-1-chrolobenzene (TNCB). These mice exhibit features of chronic dermatitis, including skin rash, mast cells infiltration, and elevated serum anti-OVA specific IgE and cytokines modulation. In this study, a standardized ethyl acetate extract of D. tosaense (DtE) was used to protect these mice from the OVA/TNCB-induced skin lesions of atopic dermatitis. The results indicated an increased population of natural T regulatory cell was accompanied by immunosuppression in cytokine profiles and anti-OVA IgE level to significantly reduce Th2 polarization. Finally, toluidine blue staining indicated mast cell infiltration and degranulation was reduced in skin lesion. Our results were shed light on the usage of D. tosaense in AD.


Control of proton translocation induced by ATPase activity in chloroplasts.
1. Proton uptake was induced by ATP in the dark following light triggering of ATPase activity in chloroplasts. The accumulated protons were released when ATPase activity was inhibited by the energy transfer inhibitor DIO-9. 2. Approximately two protons were taken up for each ATP hydrolyzed at pH 8. A drop in H+/ATP ratio was caused by uncouplers such as NH4Cl and carbonyl cyanide p-trifluoromethoxyphenylhydrazone. These uncouplers caused an increase in the rate of ATP hydrolysis without a corresponding increase in proton uptake. 3. The energy transfer inhibitor dicyclocarbodiimide inhibited both ATPase activity and the rate of proton uptake without changing the H+/ATP ratio. 4. The antibiotic valinomycin caused an increase in the rate of both proton uptake and ATP hydrolysis without altering the ratio of H+/ATP. The H+/ATP ratio varied with changes in the external pH. The results were discussed in view of the chemiosmotic theory of oxidative and photosynthetic phosphorylation.


Cardiovascular stents: overview, evolution, and next generation.
Compared to bare-metal stents (BMSs), drug-eluting stents (DESs) have been regarded as a revolutionary change in coronary artery diseases (CADs). Releasing pharmaceutical agents from the stent surface was a promising progress in the realm of cardiovascular stents. Despite supreme advantages over BMSs, in-stent restenosis (ISR) and long-term safety of DESs are still deemed ongoing concerns over clinically application of DESs. The failure of DESs for long-term clinical use is associated with following factors including permanent polymeric coating materials, metallic stent platforms, non-optimal drug releasing condition, and factors that have recently been supposed as contributory factors such as degradation products of polymers, metal ions due to erosion and degradation of metals and their alloys utilizing in some stents as metal frameworks. Discovering the direct relation between stent materials and associating adverse effects is a complicated process, and yet it has not been resolved. For clinical success it is of significant importance to optimize DES design and explore novel strategies to overcome all problems including inflammatory response, delay endothelialization, and sub-acute stent thrombosis (ST) simultaneously. In this work, scientific reports are reviewed particularly focusing on recent advancements in DES design which covers both potential improvements of existing and recently novel prototype stent fabrications. Covering a wide range of information from the BMSs to recent advancement, this study mostly sheds light on DES's concepts, namely stent composition, drug release mechanism, and coating techniques. This review further reports different forms of DES including fully biodegradable DESs, shape-memory ones, and polymer-free DESs.


A three-dimensional model of the human immunodeficiency virus type 1 integration complex.
While the general features of HIV-1 integrase function are understood, there is still uncertainty about the composition of the integration complex and how integrase interacts with viral and host DNA. We propose an improved model of the integration complex based on current experimental evidence including a comparison with the homologous Tn5 transposase containing bound DNA and an analysis of DNA binding sites using Goodford's GRID. Our model comprises a pair of integrase dimers, two strands of DNA to represent the viral DNA ends and a strand of bent DNA representing the host chromosome. In our model, the terminal four base pairs of each of the viral DNA strands interact with the integrase dimer providing the active site, while bases one turn away interact with a flexible loop (residues 186-194) on the second integrase dimer. We propose that residues E152, Q148 and K156 are involved in the specific recognition of the conserved CA dinucleotide and that the active site mobile loop (residues 140-149) stabilises the integration complex by acting as a barrier to separate the two viral DNA ends. In addition, the residues responsible for DNA binding in our model show a high level of amino acid conservation.


Chronic dihydroergotoxine administration increases muscarinic cholinergic receptor binding in aged-rat brain.
Changes in the distribution and densities of muscarinic cholinergic receptors (mCh-R) and the effects of dihydroergotoxine (DHET) administration on these changes were studied in the aged-rat brain by in vitro autoradiography. mCh-R binding in the brain was markedly reduced in aged rats as compared with young adult rats, but chronic administration of DHET specifically recovered mCh-R binding in the temporal cortex and hippocampus.


In vitro toxicological evaluation of domestic effluent treated by formulated synthetic autochthonous bacterial consortium.
Supplementation of consortium comprising of aboriginal bacterial species with high degradation capacity can significantly enhance the biodegradation process of the domestic wastewater. The present study examined the bioremediation of domestic wastewater using a novel bacterial consortium comprising of five autochthonous bacterial strains with high potential for reduction in BOD, COD and protein content to 89%, 55% and 86%, respectively after 24 h of incubation. HPLC and GC-MS analyses revealed that the chosen consortium had successfully degraded wide-ranging complex organic compounds, which is crucial in the decontamination of wastewater. Phytotoxicity assay of the effluent exhibited that the seeds of Vigna radiata showed better growth and germination when subjected to wastewater treated by novel bacterial consortium as compared to the seeds exposed to untreated wastewater. Further, raw and treated wastewater were assessed for their genotoxicity with comet assay which displayed the intensity of DNA damage in the Allium cepa root tip cells before and after exposure to treated effluent. It is evident from the demonstrated results that the formulated bacterial consortium can be used successfully in a small-scale wastewater treatment plant.


Effect of inducers of DT-diaphorase on the haemolytic activity and nephrotoxicity of 2-amino-1,4-naphthoquinone in rats.
Reduction of naphthoquinones by DT-diaphorase is often described as a detoxification reaction. This is true for some naphthoquinone derivatives, such as alkyl and di-alkyl naphthoquinones, but the situation with other substances, such as 2-hydroxy-1,4-naphthoquinone, is more complex. In the present study, the effect of several substances that are known to increase tissue activities of DT-diaphorase on the toxicity of 2-amino-1,4-naphthoquinone has been investigated. Like 2-hydroxy-1,4-naphthoquinone, the 2-amino-derivative was found to cause both haemolytic anaemia and renal tubular necrosis in rats. Again like 2-hydroxy-1,4-naphthoquinone, the severity of the haemolysis induced by the 2-amino derivative was increased in animals pre-treated with inducers of DT-diaphorase, but the degree of nephrotoxicity was decreased. With these substances, therefore, DT-diaphorase both activates and detoxifies the quinone, depending on the target organ. It is not possible to generalize with regard to the effects of modulation of tissue levels of DT-diaphorase on naphthoquinone toxicity in vivo, since this may change not only the severity of the toxic effects, but also the target organ specificity. In evaluating the possible therapeutic applications of such compounds, the possibility of toxic effects upon the blood and kidney must be borne in mind. In man, renal damage by compounds such as 2-hydroxy- and 2-amino-1,4-naphthoquinone may be a particular problem, because of the low level of DT-diaphorase in human liver.


Morbidity and healthcare use among mothers of children with cancer: A population-based study.
The impact of a child's cancer diagnosis on subsequent maternal physical health is unclear. We identified all Ontario children diagnosed less than 18 years with cancer between 1992 and 2017. Linkage to administrative databases identified mothers who were matched to population controls. We identified physical health conditions, acute healthcare use, and preventive healthcare use through validated algorithms using healthcare data, and compared them between exposed (child with cancer) and unexposed mothers. Predictors of health outcomes were assessed among exposed mothers. We identified 5311 exposed mothers and 19,516 matched unexposed mothers. For exposed mothers, median age at last follow-up was 48 years, (interquartile range: 42-53). Exposed mothers had an increased risk of cancer (hazard ratio [HR] 1.2, 95% confidence interval [95% CI]: 1.0-1.5, p = .03), but not of any other adverse physical outcomes or of increased acute healthcare use. Exposed mothers were more likely to receive influenza vaccinations (odds ratio 1.4, 95% CI: 1.3-1.5, p < .0001), and underwent cancer screening at the same rate as unexposed mothers. Among exposed mothers, bereavement was associated with a subsequent increased risk of cancer (HR 1.7, 95% CI: 1.2-2.5, p = .004) and death (HR 2.2, 95% CI: 1.2-4.1, p = .01). Mothers of children with cancer are at increased risk of developing cancer, but not of other adverse physical health outcomes, and were equally or more likely to be adherent to preventive healthcare practices. Bereaved mothers were at increased risk of subsequent cancer and death. Interventions targeting specific subpopulations of mothers of children with cancer or focused on screening for specific cancers may be warranted.


Chemically modified tetracyclines induce apoptosis in cultured mast cells.
Chemically modified tetracyclines are a group of non-antimicrobial tetracycline derivatives, which possess antiinflammatory, anticollagenolytic and antiproliferative properties. Here we studied the effects of four different chemically modified tetracyclines (CMT-1, CMT-3, CMT-8 and CMT-308) on proliferation and viability of cultured mouse and human mast cells. All studied CMTs (25 microM) effectively inhibited the viability and proliferation of human mast cell line (HMC-1) cells and mouse bone marrow derived mast cells (mBMMCs), as judged by trypan blue exclusion and by incorporation of [(3)H]thymidine. The antiproliferative effect of CMTs was not dependent on the stimulating growth factor, i.e. CMTs inhibited both IL-3 and c-kit ligand-induced proliferation of mBMMCs. The reduced viability of mast cells was due to induction of apoptosis, as indicated by the increased amount of apoptotic nucleosomes and the appearance of TUNEL positive cells in the presence of CMTs. The induction of apoptosis was further confirmed by showing that CMT-3 induces activation of caspase-3 and caspase-9 in HMC-1 cells. Additionally, CMT-3 induced downregulation of the expression of antiapoptotic Bcl-2 protein in HMC-1 cells. Compared to doxycycline, the antiproliferative and proapoptotic effects of different CMTs were clearly more pronounced. Of the studied CMTs, CMT-3 and CMT-8 appeared to be the most potent inhibitors of mast cell proliferation and survival. The present results show that CMTs have an antiproliferative and proapoptotic effect on both malignant and non-malignant mast cells. In conclusion, CMTs could offer a novel means to treat disorders with inappropriate expansion of mast cells, such as rheumatoid arthritis and systemic mast cell diseases.


Paracortical immunoregulatory subpopulations in lymph nodes from homosexual men with persistent generalized lymphadenopathy.
Homosexual patients with persistent generalized lymphadenopathy usually show an abnormal expansion of paracortical T8+ lymphocytes relative to T4+ cells in lymph nodes with reactive follicular hyperplasia (RFH). This study was designed to characterize further the paracortical lymphocyte population in homosexual men with reactive follicular hyperplasia, because T8+ lymphocytes are antigenically and functionally heterogeneous. Frozen lymph node tissue from 10 patients was evaluated. Monoclonal antibodies to T8, Leu-15, NKH-1, Leu-7, and HLA-DR antigens were employed in the avidin-biotin complex immunoperoxidase technique. With digitized morphometry, positively stained cells for each marker were counted in five 0.145-mm2 microscopic fields. Four tonsils with RFH were used as controls. Most paracortical cells were T8+ (median, 4182 T8+ cells/five fields), and values were significantly higher than those for controls (median, 1518 T8+ cells p less than 0.006). In every case there were markedly fewer Leu 15-, NKH-1, Leu 7-, and HLA-DR-positive cells than T8+ cells (median values per five fields: Leu-15, 144; NKH-1, 12; Leu-7, 3; HLA-DR, 195). Moreover, these values were not significantly different from control values. Our findings suggest that the expanded paracortical T8+ population comprises cells with the immunophenotype of cytotoxic Leu-15-, T8+ lymphocytes, rather than natural killer or Leu-15+, T8+ suppressor cells.


Using ecological models in research on health disparities.
Ecological models of human interaction can be used to study complex community problems that affect health disparities. These models allow researchers to study the components of a problem and understand how the problem can be ameliorated with nursing interventions. This article describes four research studies in which ecological models were used to either understand a phenomenon or design and test an intervention. The methods used were ethnography, descriptive/correlational, and quasi-experimental. All subjects were low-income women and children, largely of Hispanic ethnicity, residing in South Texas. The ecological models were derived from Bronfenbrenner's ecology of human development theory, epidemiology, Rubin's theory of developmental tasks of pregnancy, and Barnard's model of mother-child interaction. Heuristic models that represent reality allow researchers to divide a complex problem, such as health disparities, into manageable components. The influence of families, neighborhoods, and communities can be considered without losing sight of individuals.


Liposomal remdesivir inhalation solution for targeted lung delivery as a novel therapeutic approach for COVID-19.
Strong infectivity enables coronavirus disease 2019 (COVID-19) to rage throughout the world. Moreover, the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic. Remdesivir is one of the most promising anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs. However, the limited clinical effects make its therapeutic effect controversial, which may result from the poor accumulation and activation of remdesivir in the lung. Therefore, we developed lyophilized remdesivir liposomes (Rdv-lips) which can be reconstituted as liposomal aerosol for pulmonary delivery to improve the in vivo behavior of existing remdesivir cyclodextrin conclusion compound (Rdv-cyc) injections. Liposome encapsulation endowed remdesivir with much higher solubility and better biocompatibility. The in vitro liposomal aerosol characterization demonstrated that Rdv-lips possessed a mass median aerodynamic diameter of 4.118 µm and fine particle fraction (<5 µm) higher than 50%, indicating good pulmonary delivery properties. Compared to the Rdv-cyc intravenous injection group, the Rdv-lips inhalation group displayed a nearly 100-fold increase in the remdesivir-active metabolite nucleotide triphosphate (NTP) concentration and better NTP accumulation in the lung than the Rdv-cyc inhalation group. A faster transition from remdesivir to NTP of Rdv-lips (inhalation) could also be observed due to better cell uptake. Compared to other preparations, the superiority of Rdv-lips was further evidenced by the results of an in vivo safety study, with little possibility of inducing inflammation. In conclusion, Rdv-lips for pulmonary delivery will be a potent formulation to improve the in vivo behavior of remdesivir and exert better therapeutic effects in COVID-19 treatment.


Impaired coronary flow reserve in obstructive sleep apnea and its improvement after continuous positive airway pressure therapy: a transthoracic Doppler echocardiographic study.
It is reported that patients with obstructive sleep apnea syndrome (OSAS) show endothelial dysfunction and that treatment of OSAS by continuous positive airway pressure (CPAP) therapy improves it. In this study we evaluated coronary flow reserve (CFR), which is considered to be affected by coronary microvascular dysfunction, and the change in CFR during treatment of OSAS by CPAP. Eleven patients who were diagnosed as having OSAS by polysomnography (PSG) were studied. Phasic coronary flow velocity was obtained in the left anterior descending coronary artery at baseline and during hyperemic conditions with transthoracic 2D echocardiography. CFR was defined as the ratio of hyperemic to basal mean diastolic velocity. CFR was obtained before and after the initiation of CPAP therapy. Coronary flow reserve was decreased (<2.5) in 8 of 11 (73%) patients at baseline. After CPAP therapy, CFR of these 8 patients increased significantly. Coronary flow reserve was decreased in 73% of the patients with OSAS and was significantly improved after CPAP therapy.