Efficacy and safety of eco-friendly inhalers: focus on combination ipratropium bromide and albuterol in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and its treatment is critical to improve quality of life, reduce symptoms, and diminish the frequency of COPD exacerbations. Due to the harmful environmental effects of pressurized metered-dose inhalers (pMDIs) containing chlorofluorocarbons (CFCs), newer systems for delivering respiratory medications have been developed. A search of the literature in the PubMed database was undertaken using the keywords "COPD," "albuterol," "ipratropium bromide," and "Respimat® Soft Mist Inhaler™"; pertinent references within the identified citations were included. The environmental effect of CFC-pMDIs, the invention of the Respimat® Soft Mist Inhaler™ (SMI) (Boehringer Ingelheim, Ingelheim, Germany), and its use to deliver the combination of albuterol and ipratropium bromide for the treatment of COPD were reviewed. The adverse environmental effects of CFC-pMDIs stimulated the invention of novel delivery systems including the Respimat SMI. This review presents its development, internal mechanism, and use to deliver the combination of albuterol and ipratropium bromide. CFC-pMDIs contributed to the depletion of the ozone layer and the surge in disorders caused by harmful ultraviolet B radiation. The banning of CFCs spurred the development of novel delivery systems for respiratory medications. The Respimat SMI is an innovative device that produces a vapor of inhalable droplets with reduced velocity and prolonged aerosol duration that enhance deposition within the lower airway and is associated with improved patient satisfaction. Clinical trials have demonstrated that the Respimat SMI can achieve effects equivalent to pMDIs but with lower medication doses. The long-term safety and efficacy remain to be determined. The Respimat SMI delivery device is a novel, efficient, and well-received system for the delivery of aerosolized albuterol and ipratropium bromide to patients with COPD; however, the presence of longer-acting, less frequently dosed respiratory medications provide patients and providers with other therapeutic options.


Cancer insights from magnetic resonance spectroscopy of cells and excised tumors.
Multinuclear ex vivo magnetic resonance spectroscopy (MRS) of cancer cells, xenografts, human cancer tissue, and biofluids is a rapidly expanding field that is providing unique insights into cancer. Starting from the 1970s, the field has continued to evolve as a stand-alone technology or as a complement to in vivo MRS to characterize the metabolome of cancer cells, cancer-associated stromal cells, immune cells, tumors, biofluids and, more recently, changes in the metabolome of organs induced by cancers. Here, we review some of the insights into cancer obtained with ex vivo MRS and provide a perspective of future directions. Ex vivo MRS of cells and tumors provides opportunities to understand the role of metabolism in cancer immune surveillance and immunotherapy. With advances in computational capabilities, the integration of artificial intelligence to identify differences in multinuclear spectral patterns, especially in easily accessible biofluids, is providing exciting advances in detection and monitoring response to treatment. Metabolotheranostics to target cancers and to normalize metabolic changes in organs induced by cancers to prevent cancer-induced morbidity are other areas of future development.


Electroconvulsive therapy for depressive episodes: A brief review.
A representative case is presented to provide a forum for a brief review of electroconvulsive therapy (ECT), a treatment that remains safe and effective in treating several psychiatric and neuropsychiatric conditions. The history, indications, efficacy, adverse events, treatment course, and aftercare are discussed in order to provide the reader a general introduction to this useful procedure.


Cytologic features of pheochromocytoma and retroperitoneal paraganglioma: a morphologic and immunohistochemical study of 13 cases.
To review the cytologic features and potential pitfalls of pheochromocytoma and retroperitoneal paraganglioma and to evaluate complications of the aspiration procedure and the diagnostic utility of immunocytochemistry. We reviewed 15 cytologic specimens from 12 patients with 13 tumors (1 bilateral case). Ten were adrenal (pheochromocytomas) and 3 extraadrenal paragangliomas. Eleven specimens were from fine needle aspiration (FNA) procedures that were performed in collaboration with radiologists using 23-25-gauge needles. In 3 patients the cytologic material was obtained during intraoperative diagnosis. Immunocytochemistry was performed on alcohol-fixed smears. Two aspirates were hypocellular, while the remainder were cellular. Cells were distributed singly or formed discohesive groups. When present, cytoplasm was abundant and ill defined. Most cells had an eccentric nucleus and plasmacytoid morphology. Nuclear pleomorphism, binucleation and multinucletaion, naked nuclei and intranuclear preudoinclusions were common findings. In 2 cases a lipid background was seen focally. Evident cytoplasmic immunoexpression of synaptophysin or chromogranin was detected in the 10 cases analyzed. One patient developed a hypertensive episode during the FNA procedure. It was controlled medically without complications. When adequate cytologic material is present, the recognition of pheochromocytoma and extraadrenal paraganglioma is possible. Together with morphology, immunocytochemical studies allow a specific preoperative diagnosis. Scarce material can be a source of diagnostic errors. FNA of pheochromocytomas is not necessarily contraindicated. When analytic data are not diagnostic, FNA may follow. Aspiration must be performed in an area equipped with the therapeutic tools necessary to control a pheochromocytoma crisis.


Characterization of the effects of Bcl-2 and Bcl-xl deletion mutant expression in cell lines used for antibody production.
Strategies to maximize monoclonal antibody (MAb) yields by in vitro production methods entail that hybridoma cells be maintained at high density. Approaches to increase culture density and antibody yields from hybridomas by inhibiting apoptosis through over-expression of exogenous Bcl-2 family genes have produced variable results. In order to determine if expression of mutant forms of Bcl-2 and Bcl-xl could increase viable culture densities and batch MAb yields when compared to parental cell lines, recombinant delta loop deletion mutant of these apoptotic inhibitory genes were expressed in a myeloma and two hybridoma cell lines. Expression of either Bcl-2-delta or Bcl-xl-delta in P3x63Ag8.653 myeloma cells did not significantly increase viable cell densities in cultures over time. However, the rapid post-peak decline in viable cell density was significantly reduced in Bcl-xl-delta-expressing hybridoma cell lines 552 and 7.16.4 and in Bcl-2-expressing hybridoma 7.16.4. Significant increases in MAb yield were only observed in cultures of Bcl-xl-delta-expressing hybridoma 7.16.4. Annexin staining in hybridoma 7.16.4 confirmed that apoptosis was the primary means of cell death in this cell line, and expression of Bcl-2-delta and Bcl-xl-delta inhibited programmed cell death. These results suggest that cell viability in cultures can be improved by transfection and selection of hybridomas that express delta loop deletion mutant forms of Bcl-2 family genes; however, improvements in MAb yields are dependent upon the genetic background of each manipulated cell line.


[Antitumor effect of phlomio1 in vivo and in vitro].
To study the antitumor effect of phlomiol extracted from Phlomis younghusbandii in vivo and in vitro. The inhibitory effect of phlomiol on two kinds of human tumor cells proliferation was assayed by MTT method. Transplant tumor models of S180 and H22 were used. After transplantation, different doses of phlomiol were given to the mice for 14 days. The inhibitory rates were calculated. MTT method was used to assess the proliferation of T spleen lymphocyte cells and the activity of NK cells in tumor-bearing mice with S180. Phlomiol (50-100 mg x L(-1)) inhibited the proliferation of three kinds of tumor cells in vitro, antitumor effect of phlomiol was in a dose-dependent manner (r = 0.989, P < 0.05). The inhibitory rates of phlomiol (2.5, 5, 10 mg x kg(-1)) were 28.5%-65.0% and 35.0%-74.5% in tumor-bearing mice with S180 and H22 respectively, It could stimulate the spleen T-cells in tumor-bearing mice with S180 and increase the activity of the NK cells. Phlomiol could inhibit the proliferation of three kinds of tumor cells in vitro, present antitumor effect on the tumor-bearing mice, and improve the immunological function.


Antisense oligonucleotides suppress cell-volume-induced activation of chloride channels.
Cell volume regulation is an essential feature of most cells. After swelling in hypotonic media, the simultaneous activation of potassium and chloride channels is believed to be the initial, time-determining step in cell volume regulation. The activation of both pathways is functionally linked and enables the cells to lose ions and water, subsequently leading to cell shrinkage and readjustment of the initial volume. NIH 3T3 fibroblasts efficiently regulate their volume after swelling and bear chloride channels that are activated by decreasing extracellular osmolarity. The chloride current elicited in these cells after swelling is reminiscent of the current found in oocytes expressing an outwardly rectifying chloride current termed ICln. Introduction of antisense oligodeoxynucleotides complementary to the first 30 nucleotides of the coding region of the ICln channel into NIH 3T3 fibroblasts suppresses the activation of the swelling-induced chloride current. The experiments directly demonstrate an unambiguous link between a volume-activated chloride current and a cloned protein involved in chloride transport.


ex vivo-in vivo comparison of drug penetration analysis by confocal Raman microspectroscopy and tape stripping.
When it comes to skin penetration analysis of a topically applied formulation, the number of suitable methods is limited, and they often lack in spatial resolution. In vivo studies are pivotal, especially in the approval of a new product, but high costs and ethical difficulties are limiting factors. For that reason, good ex vivo models for testing skin penetration are crucial. In this study, caffeine was used as a hydrophilic model drug, applied as a 2% (w/w) hydrogel, to compare different techniques for skin penetration analysis. Confocal Raman microspectroscopy (CRM) and tape stripping with subsequent HPLC analysis were used to quantify caffeine. Experiments were performed ex vivo and in vivo. Furthermore, the effect of 5% (w/w) 1,2-pentanediol on caffeine skin penetration was tested, to compare those methods regarding their effectiveness in detecting differences between both formulations.


Successful treatment of keratoderma hereditaria mutilans with an aromatic retinoid.
Clinical features and treatment of keratoderma hereditaria mutilans (Vohwinkel's syndrome) are described in an 11-year-old boy. The disease, in particular the mutilating complications (pseudo-ainhum), responded satisfactorily to the oral administration of etretinate, an aromatic retinoid.


Pupillary response indexes the metrical hierarchy of unattended rhythmic violations.
The perception of music is a complex interaction between what we hear and our interpretation. This is reflected in beat perception, in which a listener infers a regular pulse from a musical rhythm. Although beat perception is a fundamental human ability, it is still unknown whether attention to the music is necessary to establish the perception of stronger and weaker beats, or meter. In addition, to what extent beat perception is dependent on musical expertise is still a matter of debate. Here, we address these questions by measuring the pupillary response to omissions at different metrical positions in drum rhythms, while participants attended to another task. We found that the omission of the salient first beat elicited a larger pupil dilation than the omission of the less-salient second beat. This result shows that participants not only detected the beat without explicit attention to the music, but also perceived a metrical hierarchy of stronger and weaker beats. This suggests that hierarchical beat perception is an automatic process that requires no or minimal attentional resources. In addition, we found no evidence for the hypothesis that hierarchical beat perception is affected by musical expertise, suggesting that elementary beat perception might be independent from musical expertise. Finally, our results show that pupil dilation reflects surprise without explicit attention, demonstrating that the pupil is an accessible index to signatures of unattentive processing.


Cortical interaction of bilateral inputs is similar for noxious and innocuous stimuli but leads to different perceptual effects.
The cerebral integration of somatosensory inputs from multiple sources is essential to produce adapted behaviors. Previous studies suggest that bilateral somatosensory inputs interact differently depending on stimulus characteristics, including their noxious nature. The aim of this study was to clarify how bilateral inputs evoked by noxious laser stimuli, noxious shocks, and innocuous shocks interact in terms of perception and brain responses. The experiment comprised two conditions (right-hand stimulation and concurrent stimulation of both hands) in which painful laser stimuli, painful shocks and non-painful shocks were delivered. Perception, somatosensory-evoked potentials (P45, N100, P260), laser-evoked potentials (N1, N2 and P2) and event-related spectral perturbations (delta to gamma oscillation power) were compared between conditions and stimulus modalities. The amplitude of negative vertex potentials (N2 or N100) and the power of delta/theta oscillations were increased in the bilateral compared with unilateral condition, regardless of the stimulus type (P < 0.01). However, gamma oscillation power increased for painful and non-painful shocks (P < 0.01), but not for painful laser stimuli (P = 0.08). Despite the similarities in terms of brain activity, bilateral inputs interacted differently for painful stimuli, for which perception remained unchanged, and non-painful stimuli, for which perception increased. This may reflect a ceiling effect for the attentional capture by noxious stimuli and warrants further investigations to examine the regulation of such interactions by bottom-up and top-down processes.


Role of medical therapy in the management of nasal polyps.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the nasal and paranasal sinus mucosa that, despite differing hypotheses regarding its cause, remains poorly understood. Major symptoms are nasal congestion or blockage, loss of smell, rhinorrhea, postnasal drip, and facial pain or pressure. Among the objectives of CRSwNP management are to eradicate nasal polyps from nasal and sinusal cavities, eliminate symptoms, and prevent recurrences. Corticosteroids are the mainstay of treatment and are the most effective drugs for treating CRSwNP. Other potential treatments are nasal saline irrigation and antihistamines (in allergic conditions). Endoscopic sinus surgery is recommended when medical treatment fails. After surgery, medical treatment, including nasal and oral corticosteroids, is recommended.


Prospective comparison of MR lung perfusion and lung scintigraphy.
This study attempted to assess the accuracy and potential of lung magnetic resonance (MR) perfusion imaging compared with perfusion scintigraphy in the evaluation of patients with suspected lung perfusion defects. The technique, which uses an inversion recovery turbo-FLASH sequence with ultra-short TE (1.4 msec), was tested in 24 patients suspected clinically of having acute pulmonary embolism (n = 19) and in patients with severe pulmonary emphysema (n = 5). Perfusion lung scintigraphy was performed within 48 hours prior to the MRI examination in both groups of patients. The dynamic study was acquired in the coronal plane and consisted of 10 images of 6 slices (a total of 60 images per series). Gadopentetate dimeglumine (0.1 mmol/kg) was manually injected as a compact bolus during the acquisition of the first image. Three senior radiologists reviewed all unprocessed two-dimensional coronal sections. They were blinded to clinical data and other imaging modalities. For the three observers, the average sensitivity and specificity of MR were 69% and 91%, respectively. The overall agreement between MR and scintigraphy appears to be good, with a good correlation between the two modalities (kappa = 0.63). However, the data showed variability depending on the location of the perfusion defect, with higher accuracy in the upper lobes. The agreement between MR perfusion and scintigraphy appears to be moderate in the left inferior lobe (kappa = 0.48). The data showed an overall good interobserver agreement (kappa = 0.66). MR perfusion of the lung is a promising technique in detecting lung perfusion defects.


Pathogenicity island-dependent activation of Rho GTPases Rac1 and Cdc42 in Helicobacter pylori infection.
Helicobacter pylori has been identified as the major aetiological agent in the development of chronic gastritis and duodenal ulcer, and it plays a role in the development of gastric carcinoma. Attachment of H. pylori to gastric epithelial cells leads to nuclear and cytoskeletal responses in host cells. Here, we show that Rho GTPases Rac1 and Cdc42 were activated during infection of gastric epithelial cells with either the wild-type H. pylori or the mutant strain cagA. In contrast, no activation of Rho GTPases was observed when H. pylori mutant strains (virB7 and PAI) were used that lack functional type IV secretion apparatus. We demonstrated that H. pylori-induced activation of Rac1 and Cdc42 led to the activation of p21-activated kinase 1 (PAK1) mediating nuclear responses, whereas the mutant strain PAI had no effect on PAK1 activity. Activation of Rac1, Cdc42 and PAK1 represented a very early event in colonization of gastric epithelial cells by H. pylori. Rac1 and Cdc42 were recruited to the sites of bacterial attachment and are therefore probably involved in the regulation of local and overall cytoskeleton rearrangement in host cells. Finally, actin rearrangement and epithelial cell motility in H. pylori infection depended on the presence of a functional type IV secretion system encoded by the cag pathogenicity island (PAI).


Procurement and preparation of human isolated small intestinal grafts for transplantation.
We have developed a donor operation that incorporates en bloc removal of the liver and intestine with a limited surgical resection in vivo. Over the past 18 months, we have used the following technique for the retrieval and preparation of seven isolated small intestinal allografts. The donor operation and bench preparation can be divided into three phases. During the first phase, the small intestine is removed with the liver, pancreas, and an aortic segment. In the second phase performed ex vivo, the donor liver can be separated from the specimen. The third phase involves additional bench dissection to yield an isolated intestinal allograft. The principle advantage of this technique is that it reduces potential liver injury by minimizing the surgical dissection required in vivo. Also, dividing the liver from the intestine ex vivo allows the organs to be separated in a bloodless field under controlled conditions that may be especially important when two different surgical teams are involved.


[Modern technics of irradiation of brain tumors in children].
Radiotherapy still represents with surgery the cornerstone in the management of pediatric brain tumors. Techniques of irradiation have benefited greatly from modern imaging, CT scan and MRI for tumor-volume delineation, as well as megavoltage equipment, mainly linear accelerators delivering both high-energy X-Rays and electrons, widely used in cranial-spinal irradiations. Furthermore, new modalities of doses and volumes have been tested in various tumors (medulloblastomas, germ cell tumors...), in studies frequently combining chemotherapy with conventional therapies. Nevertheless, local control remains a major concern in tumors such as brain stem and high grade supratentorial gliomas. Concerning iatrogenic neurological sequelae, particularly harmful in children, limited data suggest an improvement in recent years. This improvement is partly due to the reduced prophylactic doses for the treatment of medulloblastomas, but further long-term observations are necessary. For these reasons, multiple technical innovations have been investigated. Some of them concern irradiation selectivity: stereotactic pencil beams, interstitial brachytherapy, heavy charged particles, 3-dimensional treatment planning. Others aim to increase the irradiation "efficacy": multifractionation, high LET particles, radiation-sensitizers.


Effect of polyvalencies of glycotopes on the binding of a lectin from the edible mushroom, Agaricus bisporus.
Agaricus bisporus agglutinin (ABA) isolated from edible mushroom has a potent anti-proliferative effect on malignant colon cells with considerable therapeutic potential as an anti-neoplastic agent. Since previous studies on the structural requirement for binding were limited to molecular or submolecular levels of Galbeta1-3GalNAc (T; Thomsen-Friedenreich disaccharide glycotope; where Gal represents D-galactopyranose and GalNAc represents 2-acetamido-2-deoxy-D-galactopyranose) and its derivatives, the binding properties of ABA were further investigated using our collection of glycans by enzyme-linked lectinosorbent assay and lectin-glycan inhibition assay. The results indicate that polyvalent Galbeta1-related glycotopes, GalNAcalpha1-Ser/Thr (Tn), and their cryptoforms, are the most potent factor for ABA binding. They were up to 5.5x10(5) and 4.7x10(6) times more active than monomeric T and GalNAc respectively. The affinity of ABA for ligands can be ranked as: multivalent T (alpha) (Galbeta1-3GalNAcalpha1-), Tn and I / II (Galbeta1-3GlcNac/Galbeta1-4GlcNAc, where GlcNAc represents 2-acetamido-2-deoxy-D-glucopyranose)>>>>monomeric T (alpha) and Tn > I >>GalNAc>>> II, L (Galbeta1-4Glc, where Glc represents D-glucopyranose) and Gal (inactive). These specific binding features of ABA establish the importance of affinity enhancement by high-density polyvalent (versus multiantennary I / II) glycotopes and facilitate our understanding of the lectin receptor recognition events relevant to its biological activities.


Meibomian gland dysfunction and dry eye in keratoconus.
The objective of this report is to describe a case of meibomian gland dysfunction associated with keratoconus and to examine the importance of treatment for evaporative dry eye in cases of corneal ectasia. A 45-year-old man diagnosed as having keratoconus complained of burning, tearing, itching, and red eye. He had a history of penetrating corneal transplantation and wearing rigid contact lenses. The meibography revealed a severe meibomian gland dropout and normal tear meniscus height in both eyes. Objective propaedeutic tests are important tools for dry eye diagnosis and proper evaluation of ocular surface and tear film. In older patients, the classic signs of atopic conjunctivitis are not always present, and the causes of chronic rubbing must be further investigated. Treatment of underlying chronic inflammation such as dry eye, meibomian gland dysfunction, and blepharitis might be important to prevent keratoconus progression and guarantee symptom relief.


Ipsilateral retinopetal projection of the nucleus olfactoretinalis (NOR) during development and regeneration: a DiI study in a cichlid fish.
The development and regeneration of the ipsilateral retinopetal projection of the nucleus olfactoretinalis (NOR) in the cichlid fish Haplochromis burtoni was studied with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI) in fixed tissue. Throughout development most NOR cells projected to the contralateral retina. Only an insignificant, transient elevation of a projection to the ipsilateral retina was found in a few animals; however, after severing the contralateral processes of NOR cells by either enucleation or nerve crush, many animals had significantly more NOR cells with a regenerated process to the ipsilateral retina. Nevertheless, within a few weeks of surgery, the number of animals with ipsilaterally projecting cells were reduced to control values. The transiently enhanced ipsilateral projections to the retina imply changes in the guiding mechanism after these operations and the existence of control mechanisms against unusual connections to the retina in this bony fish.


Proteomics annotation of lipid rafts modified by virus infection.
Lipid rafts are sphingolipid- and cholesterol-enriched membrane microdomains, which are involved in entry, assembly and budding of various types of viruses. Identification of rafts associated proteins modified by virus infection could therefore provide novel insights into the mechanisms of virus infection as well as the development of new biomarkers for diagnosis and drug development. Proteomic approaches, such as LC-ESI-MS/MS, two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), two-dimensional difference gel electrophoresis (2D-DIGE), isotope-coded affinity tags (ICAT), Proteolytic ¹⁸O Labeling, isotope Tags for Relative and Absolute Quantification (iTRAQ), Stable Isotope Labeling with Amino acids in Cell culture (SILAC) and Multidimensional Protein Identification Technology (MudPIT), provide the large scale and unbiased platform to determine the dynamic profiles of the lipid rafts proteome. In this review, we summarized the research advance regarding modern proteomics analysis of host lipid rafts alterations in response to diverse virus infection.


[Perineo-transpubic approach to the management of posterior urethral post-traumatic rupture].
To study the place of the perineal-trans-pubic approach in the treatment of the posterior urethral post-traumatic rupture operated late, and to evaluate its results. Twenty-four patients whose had a total posterior urethral post-traumatic rupture were treated in our department in a stage of urethral strictures. All patients underwent perineal transpubic urethroplasty. In this study we detailed a technique description of the approach and a clinical evaluation of our results. This technique allows having a direct approach of the posterior urethra, to perform a tension free end to end urethral suture. The backward is about 3 years. We assessed 3 cases of recurrent urethral strictures. The cases of erectile dysfunction assessed were mainly related to the initial pelvic trauma. Finally this approach had not orthopaedic squall in all cases. Comparing to others, the perineal transpubic approach is the best one to manage the posterior urethral injuries treated with late. It gives a satisfactory results with a few disadvantages.


A meta-analytic review of the effectiveness of mood inductions in eliciting emotion-based behavioral risk-taking and craving in the laboratory.
Urgency research supports the role of emotions in risk-taking and craving. However, much of this work is based in self-report. It is not yet known whether existing experimental methods can effectively induce emotion-based risk-taking and craving. The present meta-analysis quantified the effectiveness of mood inductions in inducing risk-taking and craving in the laboratory. We also examined potential moderators, including participant factors, changes in emotional arousal, and study design factors. For negative mood inductions, the degree of changes in risk-taking, k = 35, Hedge's g (SE) = .12 (.04), 95% CI [.04, .21], and craving, k = 37, Hedge's g (SE) = .30 (.06), 95% CI [.19, .40] were small. Increases in emotional arousal were significantly related to increases in craving (B* = .26). For positive mood inductions, there was no significant change in risk-taking, k = 18, Hedge's g (SE) = .17 (.11), 95% CI [-.04, .38] nor craving, k = 8, Hedge's g (SE) = -.10 (.10), 95% CI [-.31, .10]; however, false positive feedback produced the largest increase in risk-taking. Study samples using guided imagery produced a moderate decrease in risk-taking. Overall, existing negative mood inductions increased risk-taking and craving in the laboratory to a small degree. Existing positive mood inductions failed to elicit risk-taking or craving, although the literature in this domain was sparser. We suggest that there is a great need to develop and optimize mood induction methods to better study emotion-based risk-taking and craving in the laboratory. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Locus of control and pre-pandemic depressive symptoms relate to psychological adjustment of college students to the COVID-19 pandemic.
The current study examines the relationships between change in depressive symptoms and locus of control orientations among college students during the COVID-19 pandemic. Participants: A sample of 341 undergraduate students were recruited from a large Midwestern United States university.Methods: Participants completed an online cross-sectional survey with self-report measures of current depressive symptoms, retrospective pre-pandemic depressive symptoms, and locus of control.Results: Depressive symptoms changed significantly during the COVID-19 pandemic (t(340) = 7.49, p < 0.01). Pre-pandemic depressive symptoms predicted symptom change with the greatest changes among students who had fewer pre-pandemic symptoms (b = -0.58, p < 0.01) and higher external locus of control orientation (b = 0.24, p < 0.01).Conclusions: An increased presence of mental health resources is needed on college campuses and external locus of control should be targeted through clinical intervention as a risk factor for adverse depressive responses to stressors among college students.


Effects of Partially Hydrolyzed Guar Gum Supplementation on the Fecal Microbiotas of Piglets.
Probiotics and prebiotics have become viable alternatives of growth-promoting antimicrobials in animal production. Here, we tested partially hydrolyzed guar gum (PHGG) as a possible prebiotic for piglets in the commercial farm. Five hundred and ninety-four piglets were used for the experiments, with 293 given a normal pig feed (control), while the rest the feed plus 0.06% (w/w) of PHGG (PHGG). One and three months post-PHGG supplementation, fecal samples were collected from randomly selected 20 piglets in each group and analyzed for microbiota and organic acid concentrations. Notably, the abundance of Streptococcus, and unclassified Ruminococcaceae were lower (p < 0.05) in PHGG than in control, one-month post-supplementation. Lactobacillus and Prevotella were higher (p < 0.05), while Streptococcus was lower (p < 0.05), in PHGG than in control, three months post-supplementation. The concentrations of acetate, propionate, and butyrate were greater in PHGG than in control, three months post-supplementation. Finally, PHGG grew faster and had fewer deaths until slaughter time (p < 0.05), than control. We concluded that PHGG not only was an effective prebiotic to alter gut microbiota of weanling piglets but also can possibly promote body weight accretion and health.


Development and reversal of fatigue in human tibialis anterior.
The lack of easily measurable, objective physiologic indices of muscle fatigue in humans has hampered the evaluation of interventions that putatively inhibit muscle fatigue. In 6 healthy subjects, isometric fatigue of right and left tibialis anterior (TA) was produced using 180 s of intermittent electrical stimulation to the motor point (40 Hz, 650-ms or 250-ms trains, 1 train/s). The time course, magnitude, and reproducibility of fatigue and recovery from fatigue was established, and the effect of duty cycle measured. During fatigue, force fell rapidly in all subjects over the first 70 s, then fell more slowly. Recovery was also biphasic--force increased rapidly over the initial 30 s then slowly--and was incomplete at 300 s. Comparing duty cycles of 0.65 versus 0.25, the longer duty cycle caused a greater fall in force (-65% versus -29%; P < 0.001) and lower recovery (P < 0.02). In all subjects, left leg muscles fatigued more than right. We conclude that this noninvasive fatigue and recovery protocol is highly reproducible and that it may prove useful for evaluating the effects of pharmacologic or restorative interventions on human muscle fatigue.


Relations between Mattering to Step- and Non-Residential Fathers and Adolescent Mental Health.
This study examined the relations between perceptions of 133 early adolescents in stepfamilies concerning how much they mattered to their stepfathers and nonresidential biological fathers and adolescents' mental health problems. Mattering to nonresidential biological fathers significantly negatively predicted mother-, teacher-, and youth-reported internalizing problems. Mattering to stepfathers significantly negatively predicted youth-reported internalizing and stepfather- and youth- reported externalizing problems. For teacher-reported externalizing problems, mattering to stepfathers and nonresidential biological fathers significantly interacted. Mattering to either father predicted low externalizing problems; perceptions of mattering to the second father did not predict a further reduction in problems. Results suggest that mattering is an important aspect of father-adolescent relationships, and highlight the importance of considering adolescents' relationships with both nonresidential fathers and stepfathers.


Cross-Linguistic Trends in Speech Errors: An Analysis of Sub-Lexical Errors in Cantonese.
Though past research on the sound structure of speech errors has contributed greatly to our understanding of phonological encoding, most of this research comes from a small set of majority languages with similar linguistic structures. To increase the linguistic diversity of relevant evidence, a large collection of speech errors was investigated in Cantonese, an under-studied language with unique phonological structures. In particular, the Cantonese data were examined for nine psycholinguistic effects commonly used as a lens on word-form encoding. Detailed quantitative analysis found that Cantonese has eight of these effects, providing broader cross-linguistic support for models based on these patterns. Yet Cantonese also exhibited differences with well-known Indo-European languages by having a higher rate of errors involving whole syllables and sub-constituents inside the syllable rime. These differences can be accounted for by recognizing the primacy of the syllable and mora in encoding Cantonese words, following proposals that have been made for Mandarin Chinese and Japanese.


Attachment-informed therapy for adults: Towards a unifying perspective on practice.
We aimed to provide an integrated overview of the key goals and strategies of an attachment-informed psychotherapy by summarizing the literature describing the clinical implications of attachment theory for psychological therapy for adults. We carried out a narrative thematic review of 58 texts from a diverse range of therapeutic schools, until we agreed that we had reached a saturation of themes. We identified six key themes: Changing internal working models; the therapeutic relationship and creating a secure base; formulating and processing relationship experiences; countertransference; separation, termination and boundary issues; and working with different attachment styles or patterns. We discuss empirical evidence in relation to each theme and highlight areas for research. Attachment theory provides a useful framework to inform psychological therapy with adults, but there is a pressing need for further research to empirically demonstrate the 'added value' of an attachment perspective. Attachment theory should be used to inform individual psychological therapy in adulthood. From the outset of their careers, therapists should receive training and supervision to enhance their awareness of their own and their clients' attachment experiences and how these play out during therapy. There is a need for greater empirical research to investigate whether the degree to which therapists formulate and meet clients' attachment needs influences outcomes.


A monoclonal antibody to cellular transglutaminase.
A cellular enzyme-linked immunosorbent assay was developed for estimating cellular transglutaminase in situ using a monoclonal antibody produced to tissue transglutaminase. The minimum level of detection of TGase was 2-5 ng. The enzyme was present in greater amounts in WI-38 and IMR90 cells than in their simian virus-transformed counterparts. The levels of TGase in the virus-transformed cells increased significantly when the cells were grown in the presence of sodium butyrate to induce enzyme activity. Staining of confluent WI-38 cells by indirect immunofluorescence using the monoclonal antibody showed microscopic fibers suggesting that the enzyme may be associated with detergent-insoluble components.


Lateral inversions and introversion in Ingres.
The famous French nineteenth-century painter Jean-Auguste-Dominique Ingres (17801867) produced in the course of his career several left to right inversions of his own figural compositions. Because according to the narrative imagery conventions of directional viewing both the original and the reversed scenes should be looked at from left to right, the mirror-like reversion results in a dramatic alteration of the scenes' meaning. Considering that the literary topics that Ingres chose for his pictures often had an affective meaning for him, the lateral inversions may have been motivated by a subconscious wish to exorcise traumatic memories.


Bisphosphonates in periodontal treatment: a review.
Periodontitis is a multifactorial disease involving bacterial biofilms and the generation of an inflammatory response. The latter causes the major part of the periodontal tissue breakdown. Alveolar bone resorption is a major component of the periodontal destruction observed in periodontitis. Novel treatment modalities of periodontitis intend to control and modulate the host response to bacterial aggression. Drugs such as bisphosphonates (BPs) are proven antiresorptive agents that can potentially inhibit the alveolar bone resorption. This review describes the potential use of BPs in periodontal treatment and could be said that BPs have an in vitro and in vivo capability of reducing bone resorption. Only a few studies have been carried out on the improvement of clinical periodontal parameters after the administration of BPs. Therefore, the published data are not sufficient to establish an evidence-based relevance for the use of these drugs in the treatment of periodontal diseases.


What is the minimal vestibular function required for compensation?
Living with an uncompensated, abnormal vestibular system requires oppressive modification of life style and often prevents return to work and activities of daily living. Patients with vestibular abnormalities were studied to determine the minimal residual vestibular function required to achieve compensation. Three groups of patients with (a) complete unilateral loss of vestibular function with normal horizontal canal-vestibulo-ocular (HCVOR) function in the opposite ear, (b) complete unilateral loss with abnormal HCVOR function in the opposite ear, and (c) bilateral reduction of vestibular function from aminoglycoside toxicity underwent vestibuloocular (VOR), optokinetic (OKN), visual-VOR (VVOR), and computerized dynamic posturography (CDP) tests before and after therapeutic procedures. Results suggest that a minimal VOR response amplitude must be present for compensation of VVOR function to occur. The roles of VOR and OKN phase shifts in vestibular compensation are more complicated and require further study. Compensation of vestibulospinal function does not necessarily accompany VOR or VVOR compensation. Ascending and descending vestibular compensatory mechanisms may involve different spatial sensory inputs. Results of these studies have important implications for the diagnosis and treatment of patients with vestibular disorders, including selection and monitoring of patients for therapeutic regimens such as vestibular nerve section and streptomycin therapy.


Comparison of the use of LigaSure versus a standard technique for tonsillectomy in dogs.
The principal aim of this study was to document the effectiveness of tonsillectomy in dogs using a vessel-sealing device compared with a standard technique with tonsillectomy forceps. A secondary aim of the study was to document histopathological changes of the excised tonsillar tissue in dogs with brachycephalic obstructive airway syndrome. 20 dogs were studied. The time taken to remove a tonsil using LigaSure was a mean of 44.8 seconds (sd 15 seconds, 95 per cent CI 40 to 57 seconds) and with the standard technique a mean of 305.9 seconds (sd 67 seconds, 95 per cent CI 272 to 349 seconds). Significantly less haemorrhage occurred using LigaSure compared with the standard technique. Histopathology of the tonsils was characterised by multifocal neutrophilic and lymphocytic inflammation, and 1-2 mm of heat-induced coagulation necrosis at the cut edge of LigaSure tonsils. This study shows that LigaSure is significantly faster and resulted in less bleeding than the standard technique.


Risk factors and outcomes of fungal ventricular-assist device infections.
Infection is a common complication of ventricular-assist devices (VADs) and is associated with rehospitalization, thromboembolic events, VAD malfunction, delay in heart transplantation, and a high mortality rate. The objectives of this study were to investigate the frequency of fungal VAD infections and assess various risk factors and their effects on mortality as compared with bacterial VAD infections. We conducted a retrospective chart review of patients with infected VADs at a single tertiary care center. The frequency, risk factors, and outcomes of fungal versus bacterial VAD infections were compared. Of the 300 patients who received a VAD, 108 (36%) developed VAD infection, including 85 bacterial and 23 fungal infections. Most common bacterial causes of infection were Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and Pseudomonas aeuruginosa. The most common fungal etiologic agent was Candida albicans. Only the use of total parenteral nutrition was associated with the development of a fungal VAD infection in multivariate analysis (odds ratio, 6.95; 95% confidence interval, 1.71-28.16; P=.007). Patients who experienced fungal VAD infection were less likely to be cured (17.4% vs 56.3%; P=.001) and had greater mortality (91% vs 61%; P=.006), compared with those who experienced bacterial VAD infection. Fungi were responsible for approximately one-fifth of VAD infections and were associated with a mortality rate of 91%. Restriction of total parenteral nutrition use is essential in decreasing the rate of fungal VAD infection. Trials are needed for investigating the use of echinocandins or lipid formulations of amphotericin B for prevention and/or treatment of fungal VAD infection.


The "Spatial Equilibrium" Evolution of the Tourism Ecosystem and Theoretical Construction from a Multidisciplinary Perspective.
The evolution of the tourism ecosystem is characterized by its complexity, imbalance, and spatial heterogeneity. As a result, it has been the focus of academic attention across a wide range of disciplines, including geography, ecology, economics, management, sociology, and philosophy. Firstly, this article explores the connotations and characteristics of the spatial evolution of tourism ecosystems, subsequently proposing that the spatial evolution of tourism ecosystems is essentially different and "mutually inclusive." To do so, it searches through the relevant research results on "spatial equilibrium" in ecosystems from the perspectives of different disciplines and analyzes their different core concepts, theoretical systems, and research methods. Second, the coupling force acts as a key character and exerts an influence on "spatial equilibrium" in ecosystems as a dynamic mechanism, internal stability mechanism, and dynamic mechanism. Third, nonlinear, dynamic, evolutionary, systematic thinking, and axiomatic theories are combined to construct an internal stable evolution mechanism and abstract tourism ecosystem model to form an explanatory theoretical system. The results of the research show that the construction of the "spatial equilibrium" of the tourism ecosystem model should pertain to the initial state of the comprehensive environmental carrying capacity of the tourism ecosystem as it evolves to form a tourism ecosystem based on the coupling relationship between the internal and external elements of the "spatial equilibrium" state. Finally, the future research approaches in this field are summarized and assessed. The methodology and theoretical exploration discussed in this article will contribute to a better understanding of how to sustainably develop tourism destinations.


Renal disease in cats infected with feline immunodeficiency virus.
Feline immunodeficiency virus (FIV) and human immunodeficiency virus (HIV) infection cause similar clinical syndromes of immune dysregulation, opportunistic infections, inflammatory diseases, and neoplasia. Renal disease is the 4th most common cause of death associated with HIV infection. To investigate the association between FIV infection and renal disease in cats. Client-owned cats (153 FIV-infected, 306 FIV-noninfected) and specific-pathogen-free (SPF) research colony cats (95 FIV-infected, 98 FIV-noninfected). A mixed retrospective/prospective cross-sectional study. Blood urea nitrogen (BUN), serum creatinine, urine specific gravity (USG), and urine protein:creatinine ratio (UPC) data were compared between FIV-infected and FIV-noninfected cats. In FIV-infected cats, total CD4+ and CD8+ T lymphocytes were measured using flow cytometry, and CD4+:CD8+ T lymphocyte ratio was calculated. Renal azotemia was defined as a serum creatinine ≥ 1.9 mg/dL with USG ≤ 1.035. Proteinuria was defined as a UPC > 0.4 with an inactive urine sediment. Among the client-owned cats, no association was detected between FIV infection and renal azotemia (P = .24); however, a greater proportion of FIV-infected cats were proteinuric (25.0%, 16 of 64 cats) compared to FIV-noninfected cats (10.3%, 20 of 195 cats) (P < .01). Neither neuter status nor health status were risk factors for proteinuria in FIV-infected cats, but UPC was positively correlated with the CD4+:CD8+ T lymphocyte ratio (Spearman's rho = 0.37, P = .01). Among the SPF research colony cats, no association was detected between FIV infection and renal azotemia (P = .21) or proteinuria (P = .25). Proteinuria but not azotemia was associated with natural FIV infection.


An estimate of the proportion of the resting membrane conductance of the smooth muscle of guinea-pog taenia coli attributable to chloride.
1. The contribution of Cl and K to the steady-state membrane conductance of the smooth muscle of the guinea-pig taenia coli has been investigated by measuring the increase in membrane resistance in Cl-deficient and K-deficient solutions. A large external electrode was used for passing current and the voltage change was recorded with an intracellular electrode. The experiments were carried out in hypertonic solution in order to suppress spontaneous activity.2. When the tissue was exposed to K-deficient solution, the amplitude and time course of the electrotonic potential was increased and the membrane was hyperpolarized.3. When the tissue was exposed to Cl-deficient solutions in which Cl was replaced with an impermeant anion, benzene sulphonate, the size and time course of the electrotonic potential was increased whereas the membrane potential, after 20-30 min equilibration, was unchanged. The magnitude of the increase of the electrotonic potential depended on the substituted amount of Cl.4. When the tissue was exposed to low K the relation between the membrane conductance and the remaining external K concentration was the same in the presence of the normal Cl concentration and in Cl-deficient solution (7 mM-Cl). It was therefore concluded that any effect of benzene sulphonate on the K conductance is negligible.5. The effects of Cl or K deficiency on the electrotonic potential indicate that Cl and K ions account for most of the membrane conductance and that the contribution by Cl is about 40%.6. The ratio of P(Cl)/P(K) was calculated from the constant field theory on the assumption that the contribution of ions other than K and Cl to the membrane conductance is negligibly small. The mean value was 0.40.


Fractional radiofrequency treatment in acne scars: Systematic review of current evidence.
Fractional radiofrequency (FRF) is renowned for its use in cosmetic dermatology, with regard to the treatment of rhytides, striae, scarring and cellulite. We have systemically analysed its evidence for the use of FRF in acne scars. Our search identified 15 articles, one single-blinded randomised controlled trial, two split-face trials and thirteen prospective clinical studies, mostly single-centred. Case reports were excluded. In total 362 patients were treated. The longest follow-up was for 210 days, and on average the follow-up was for three months, varying between one and seven months. This review has found that there are many small studies showing promising results for the use of FRF in acne scars, either as an adjunct or more importantly as the sole treatment. There is however a need for larger trials against ablative and non-ablative lasers, in order to affirm the evidence present already. This is the first systematic review on the use of FRF in acne scars.


Hip and Core Muscle Injuries in Soccer.
Soccer is the most popular sport in the world and has the fourth highest number of sports injuries. Hip and groin injuries account for 14% of soccer injuries and can be difficult to recognize and treat as they often require a high level of suspicion and advanced imaging. Groin pain can be separated into 3 categories: (1) defined clinical entities for groin pain (adductor-related, iliopsoas-related, inguinal-related [sports hernias/athletic pubalgia], and pubic-related groin pain), (2) hip-related groin pain (hip morphologic abnormalities, labral tears, and chondral injuries), and (3) other causes of groin pain. Conservative approaches are typically the first line of treatment, but operative intervention has been reported to result in higher rates of return to sport in athletes with hip-related and inguinal-related groin pain injuries. In patients with concurrent hip-related and inguinal-related groin pain, the failure to recognize the relationship and treat both conditions may result in lower rates of return to sport. Preseason screening programs can identify high-risk athletes, who may benefit from a targeted prevention program. Further study on exercise therapy, early surgical intervention, and potential biologic intervention are needed to determine the most effective methods of preventing groin injuries in athletes.


Exploratory syntheses and structures of SrAu(4.3)In(1.7) and CaAg(3.5)In(1.9): electron-poor intermetallics with diversified polyanionic frameworks that are derived from the CaAu4In2 approximant.
The phase regions around quasicrystals and approximants (QC/ACs) are rich pools for electron-poor intermetallics with novel, complex structures, and bonding patterns. The present SrAu(4.30(1))In(1.70(1)) (1) and CaAg(3.54(1))In(1.88(1)) (2) were synthesized through chemical tunings of the model CaAu(4)In(2) (YCd(6)-Type) AC. Single crystal X-ray diffraction analyses reveals that crystal 1 has Pnma (CeCu(6)-type) symmetry, with a = 9.102(1) Å, b = 5.6379(9) Å, and c = 11.515(2) Å. The building block in 1 is a 19-vertex cluster Sr@Au(9)In(4)M(6) (M = Au/In), which vividly mimics Ca@(Au,In)(18) in Ca(3)Au(12.4)In(6.1) (YCd(6)-type) in geometry. These clusters aggregate into one-dimensional columns extending along the b axis. Crystal 2 (P6/mmm, a = 20.660(3) Å, c = 9.410(2) Å) is closely related to Na(26)Cd(141) (hP167) and Y(13)Pd(40)Sn(31) (hP168), which are differentiated by the selective occupation of Wyckoff 1a (0 0 0) or 2d (1/3 2/3 1/2) sites by Cd or Pd. Crystal 2 adopts the Na(26)Cd(141) structure, but the 1a site is split into two partially occupied sites. The synergistic disorder in the hexagonal tunnels along c is a major property. The valence electron count per atom (e/a) values for 1 and 2 are 1.63 and 1.74, respectively, the lowest among any other ternary phases in each system. These values are close to those of ACs in the Ca-Au-M (M = Ga, In) systems. Electronic structures for both are discussed in terms of the results of TB-LMTO-ASA calculations.


Migration of an embolized deployed stent from the left main with subsequent crushing: a new use for the IVUS catheter?
Coronary stent dislodgement and loss carries significant morbidity and risk of infarction and thrombosis if left untreated. There have been multiple previous techniques for stent retrieval or deployment after stent loss including wire braiding, distal small balloon retrieval technique, snare use, forceps in large vessels and the stent crush technique. We report an unusual case of a largely deployed stent which was iatrogenically embolized retrogradely to the left main and its migration using an IVUS catheter with successful stent crushing in the proximal circumflex with good angiographic and medium term clinical outcome.


A critical ethnographic perspective on risk and dangerousness in forensic psychiatry.
In the Canadian forensic psychiatric context, the concepts of risk and dangerousness interact, intersect, and morph into the notion of significant threat to the safety of the public. Stemming from the results of a critical ethnography of the Ontario Review Board, this article unpacks the central role of forensic psychiatric nursing, as an example of a 'psych' discipline (e.g., psychiatry and psychology), in a system that is built to produce risky persons and to legitimize their detention and supervision. By using excerpt of interviews conducted with nurses, ethnographic observations of Review Board hearings, and other documentary artifacts, the findings illustrate how rationalizations of risk and dangerousness are contingent on space, time, and observer. Depending on the time of the assessment or on the health-care professional who performs it, different elements including, but not limited to, mental illness, interpersonal relationships, financial instability, and sexual vulnerability, are relied upon in very fluid, interchangeable, and discretionary ways to justify findings of dangerousness. Such a dynamic expands the reach of psychiatry's legitimacy at identifying risky conduct and controlling risky persons to domains very loosely associated with the notion of dangerousness. The work of Foucault and Castel provides the theoretical backdrop on which rests the discussion and the implications for nursing.


Reticulocyte Hemoglobin vis-a-vis Serum Ferritin as a Marker of Bone Marrow Iron Store in Iron Deficiency Anemia.
To evaluate reticulocyte hemoglobin (RET-He) vis-a-vis serum ferritin as a marker of bone marrow iron store in iron deficiency anemia (IDA). A hospital based analytic study was conducted among patients (age group 15-65 years) with newly diagnosed and untreated IDA admitted in medicine ward and not suffering from any inflammatory disorders (excluded by C-reactive protein). Patient having other forms of anemia/ hemoglobinopathies/ malignancy, MCV > 80 fL and pregnant female were excluded. All patients were subjected to automated CBC, RET-He, iron studies and iron staining of bone marrow aspirates. Total 142 patients were included. Of these, 42 patients were excluded due to aparticulate bone marrow aspirate. Remaining 102 patients were classified in to Group A (grade 0 and 1-depleted iron stores) and Group B (grade 2 and 3 - functional iron deficiency). There were significant difference in means of RET-He (Group A 17.84 ± 2.39 vs. Group B 25.08 ± 4.42; P< 0.0001) and serum ferritin (Group A 8.68 ± 2.80 vs. Group B 15.61 ± 4.68; P < 0.0001). We observed significant positive correlation of ferritin with RET-He in total patients (r = 0.7860, p 0.0000), Group A (r = 0.7089, p 0.00) and Group B (r = 0.4675, p < 0.05) patients. RET-He was the only significant predictor of bone marrow iron stores (at P < 0.05). On ROC curve analysis, the AUC for RET-He was found to be 0.894 (P value < 0.01) and best cut off value for predicting IDA was 22.4 pg (sensitivity 98.88%, specificity 84.21%). The AUC for serum ferritin was 0.891 (P value < 0.01) and best cut off value for predicting IDA was 11.6 ng/ml (sensitivity 86.75%, specificity 89.47 %). RET-He correlated significantly with serum ferritin and is also a better predictor of bone marrow iron stores than the latter.


Start-up time and walking speed in older adults under loaded conditions during simulated road crossing.
BACKGROUND/STUDY CONTEXT: The safety of older pedestrians in road crossing has received considerable attention but previous studies measure gait characteristics only under unloaded conditions. The aim of this study was to investigate the start-up time and walking speed under loaded conditions that reflect daily activities of older adults in Singapore. Thirty-two older adults (age (SD) = 69.4 (7.0) years) and 20 young controls (age (SD) = 23.1 (2.0) years) walked under four conditions: (1) unloaded, (2) pushing a stroller loaded with 10 kg, (3) pulling a shopping cart loaded with 15 kg, and (4) carrying two shopping bags each loaded with 2 kg. Start-up time was determined from video recordings and walking speed measured using timing gates. A mixed-model analysis of variance (ANOVA; age by walking condition) with repeated measures was applied. Start-up times were slower in the stroller and shopping cart conditions compared with the unloaded and shopping bags conditions. Loading reduced walking speed, with the shopping cart being the slowest, followed by the stroller and then the shopping bags. A significant interaction was found, with young controls reducing their speeds more substantially while handling the stroller/cart than older participants. Loading caused a compromise in start-up time and walking speed. The start-up time was slower when pushing a stroller or pulling a shopping cart but remained unaffected by carrying shopping bags. Speed was reduced under all loaded conditions, with a greater effect in young than older participants when handling a stroller or shopping cart.


Women Bound to be Active: one year follow-up to an innovative pilot intervention to increase physical activity and self-worth in women.
The purpose of this investigation was to assess the effectiveness of a lifestyle intervention (a women's book club; Women Bound to be Active) in promoting long-term physical activity. Thirty-five women (26-70 years; mean age 50.6 years) completed the 8-month intervention and participated in the one-year follow-up. At follow-up, physical activity returned to baseline levels; however, self-worth and body mass index significantly improved. Women were more knowledgeable about physical activity at follow-up; however, they failed to maintain physical activity after the intervention. Components of the intervention were effective in improving self-worth and lowering BMI at one-year follow-up. To enhance long-term physical activity adherence, continued research and intervention modifications are needed.


Sequence of rat surfactant protein A gene and functional mapping of its upstream region.
Surfactant protein A (SP-A) is the major pulmonary surfactant protein. We have isolated a rat SP-A genomic clone and determined the sequence from 2.9 kilobases upstream of the transcriptional start through the termination of translation. The exon-intron structure of the rat gene has been determined and compared with the mouse, rabbit, and human genes. We have localized the major transcriptional start site in adult rat lung to nucleotide 30 downstream from the start of the TATA box. Functional mapping indicates that a DNA fragment containing 163 nucleotides upstream of the transcriptional start (-163) can function as a promoter of transcription of a reporter gene in both lung and nonlung derived cell lines. However, the function of this element is weaker in cells of nonlung origin. DNA elements located between -2902 and -163 silence the promoter activity in both lung and nonlung cells. Because the SP-A gene promoter region exhibits limited tissue specificity, the results suggest the existence of other DNA elements which overcome the silencer and confer further lung specificity.


Ectopic expression of carpel-specific MADS box genes from lily and lisianthus causes similar homeotic conversion of sepal and petal in Arabidopsis.
Two MADS box genes, Lily MADS Box Gene 2 (LMADS2) and Eustoma grandiflorum MADS Box Gene 1 (EgMADS1), with an extensive similarity to the petunia (Petunia hybrida) FLORAL BINDING PROTEIN 7/11 and Arabidopsis AGL11, were characterized from the lily (Lilium longiflorum) and lisianthus (Eustoma grandiflorum). The expression of LMADS2 and EgMADS1 mRNA was restricted to the carpel and was absent in the other flower organs or vegetative leaves. LMADS2 mRNA was detected mainly in ovules and weakly in style tissues of the carpel, whereas EgMADS1 mRNA was only expressed in the ovules. Transgenic Arabidopsis plants ectopically expressing LMADS2 or EgMADS1 showed similar novel phenotypes resembling 35S::AGAMOUS plants by significantly reducing plant size, flowering early, and losing inflorescence indeterminacy. Ectopic expression of these two genes also generated similar ap2-like flowers by inducing homeotic conversion of the sepals into carpel-like structures in which stigmatic papillae and ovules were observed. In addition, the petals were converted into stamen-like structures in the second whorl of 35S::LMADS2 and 35S::EgMADS1 transgenic Arabidopsis. Our data indicated that LMADS2 and EgMADS1 are putative D functional MADS box genes in lily and lisianthus with a function similar to C functional genes once ectopically expressed in Arabidopsis.


Diversity Training Goals, Limitations, and Promise: A Review of the Multidisciplinary Literature.
In this review, we utilize a narrative approach to synthesize the multidisciplinary literature on diversity training. In examining hundreds of articles on the topic, we discovered that the literature is amorphous and complex and does not allow us to reach decisive conclusions regarding best practices in diversity training. We note that scholars of diversity training, when testing the efficacy of their approaches, too often use proxy measures for success that are far removed from the types of consequential outcomes that reflect the purported goals of such trainings. We suggest that the enthusiasm for, and monetary investment in, diversity training has outpaced the available evidence that such programs are effective in achieving their goals. We recommend that researchers and practitioners work together for future investigations to propel the science of diversity training forward. We conclude with a roadmap for how to create a more rigorous and relevant science of diversity training.


Transcriptional coactivator complexes.
The last two decades have witnessed a tremendous expansion in our knowledge of the mechanisms employed by eukaryotic cells to control gene activity. A critical insight to transcriptional control mechanisms was provided by the discovery of coactivators, a diverse array of cellular factors that connect sequence-specific DNA binding activators to the general transcriptional machinery, or that help activators and the transcriptional apparatus to navigate through the constraints of chromatin. A number of coactivators have been isolated as large multifunctional complexes, and biochemical, genetic, molecular, and cellular strategies have all contributed to uncovering many of their components, activities, and modes of action. Coactivator functions can be broadly divide into two classes: (a) adaptors that direct activator recruitment of the transcriptional apparatus, (b) chromatin-remodeling or -modifying enzymes. Strikingly, several distinct coactivator complexes nonetheless share many subunits and appear to be assembled in a modular fashion. Such structural and functional modularity could provide the cell with building blocks from which to construct a versatile array of coactivator complexes according to its needs. The extent of functional interplay between these different activities in gene-specific transcriptional regulation is only now becoming apparent, and will remain an active area of research for years to come.


Comparison of Subjective and Objective Methods of Corneoscleral Limbus Identification from Anterior Segment Optical Coherence Tomography Images.
This study evaluates the reliability and validity of an automatic method of the external and internal limbal points identification from anterior segment optical coherence tomography (OCT) images in comparison with manual delineation. The purpose of this work was to evaluate the repeatability and precision of a previously proposed automatic method of external and internal limbal points identification and to compare them with the manual delineation by experienced clinicians in terms of limbus diameter. Optical coherence tomography tomograms obtained for 12 healthy volunteers without a history of eye diseases were analyzed. Fifteen OCT tomograms were captured for each patient. For all the images, the external and internal limbal points were determined using both the automatic and manual methods. The external and internal limbus diameters were used as the comparative parameter between the methods under consideration. The statistical analysis included mean, standard deviation, the Passing-Bablok regression, and the Pearson correlation coefficient. A strong linear dependence between the automatic and manual methods was identified. While compared with the subjective estimates from clinicians, the automatic technique overestimated the external limbus diameter (bias equals 0.21 mm for optometrist and 0.23 mm for ophthalmologist) and slightly underestimated the internal limbus diameter (bias equals 0.13 mm for optometrist and 0.04 mm for ophthalmologist). The automatic method showed significantly better repeatability than the manual method in the case of external limbal points identification and comparably high repeatability for internal limbal points recognition. Because of high precision and excellent repeatability, the automatic method of limbal points identification may be successfully used for estimation of the dynamic changes in the geometry of the anterior segment of the eye, where the large number of captured OCT images needs to be processed automatically with high precision.


Characterization of transposable elements in the genome of rice (Oryza sativa L.) using Representational Difference Analysis (RDA).
Representational Difference Analysis was applied to characterize genomic differentiations between rice ( Oryza sativa) and foxtail millet ( Setaria italica) and subsequently to identify rice transposable elements. Rice was used as the tester and millet as the driver. A total of eleven, non-redundant, positive clones were isolated from the library. Their analysis revealed that they all represent dispersed repetitive DNA sequences. In addition, homology searches using the BLAST procedure showed that they correspond to seven distinct rice transposable elements. Three had been previously identified as gypsy-like retroelements ( Retrosat1, RIRE3 and RIRE8). The remaining four are novel: we named them hipa (a CACTA-like transposon), houba (a copia-like retroelement), hopi and dagul (two gypsy-like retroelements). The RDA clones were used as probes in Southern hybridization experiments with genomic DNAs of several species from the family Poaceae. The results suggest that the genomic differentiations associated with the activity of these transposable elements are of relatively recent origin. In addition, comparison of the hybridization patterns obtained for several Oryza species suggests that several independent amplifications of these transposable elements might have occurred within the genus.


Prognostic and predictive biomarkers post curative intent therapy.
Large-scale screening trials have demonstrated that early diagnosis of lung cancer results in a significant reduction in lung cancer mortality. Despite improvements in detecting more lung cancers at early stages, the 5-year survival rates of lung cancers diagnosed before widespread disease is only 30-50%. High rates of recurrence, despite early diagnosis, suggest the need to improve treatment strategies based on the likelihood of recurrence in patient subsets, as well as explore the role of predictive markers for therapy selection in the adjuvant setting. In the era of personalized medicine, there have been a wide array of molecular alterations and signatures studied for their potential prognostic and predictive utility, however most have failed to translate into clinical tools. This review will discuss progress made in clinical management of lung cancer, and recent progress in the development of patient selection tools for the refinement of early stage lung cancers.


Histone synthesis in Trypanosoma cruzi.
Trypanosoma cruzi is an ancient, parasitic eukaryote which does not undergo chromatin condensation during cell division. This behavior may be explained if one considers the strong amino acid sequence divergence of Trypanosoma histones compared to higher eukaryotes. In the latter organisms histone synthesis is coupled to DNA replication. Considering the nonconserved amino acid sequence of T. cruzi histones, as well as the absence of chromatin condensation in this organism, we have studied histone synthesis in relation to DNA replication in this parasite. We have found that core histones and a fraction of histone H1 are synthesized concomitantly to DNA replication. However, another fraction of histone H1 is constitutively synthesized.


[Radiotherapy of prostate cancer].
With the development of modern radiation techniques, such as intensity-modulated radiotherapy (IMRT), a dose escalation in the definitive radiotherapy of prostate cancer and a consecutive improvement in biochemical recurrence-free survival (BFS) could be achieved. Among others, investigators at the Memorial Sloan-Kettering Cancer Center (MSKCC) saw 5-year BFS rates of up to 98%. A further gain in effectiveness and safety is expected of hypofractionation schedules, as suggested by data published by Kupelian et al., who saw a low 5-year rate of grade ≥2 rectal side-effects of 4.5%. However, randomized studies are just beginning to mature. Patients with intermediate or high-risk tumors should receive neoadjuvant (NHT) and adjuvant (AHT) androgen deprivation. Bolla et al. could show an increase in 5-year overall survival from 62-78%. The inclusion of the whole pelvis in the treatment field (WPRT) is still controversial. The RTOG 94-13 study showed a significant advantage in disease-free survival after 60 months but long-term data did not yield significant differences between WPRT and irradiation of the prostate alone.The German Society of Urology strongly recommends adjuvant radiotherapy of the prostate bed for pT3 N0 tumors with positive margins. In a pT3 N0 R0 or pT2 N0 R+ situation, adjuvant radiotherapy should at least be considered. So far, no randomized data on NHT and AHT have been published, so androgen deprivation remains an individual decision in the postoperative setting. In a retrospective analysis Spiotto et al. reported a positive effect for adjuvant WPRT and biochemical control.This article summarizes the essential publications on definitive and adjuvant radiotherapy and discusses the additional use of androgen deprivation and WPRT.


End-label, free-solution capillary electrophoresis of highly charged oligosaccharides.
The effect of fluorescent tags on the separation of negatively charged oligosaccharides, derived from a partially hydrolyzed kappa-carrageenan, was studied. When the charge-to-friction ratio of oligosaccharides is increased by the end-label, the migration order is from smaller to larger oligomers, and the resolution of larger oligomers could be improved by using a sieving medium. The migration order can be entirely reversed when the charge-to-friction ratio of the solute is decreased by the end-label. The experimental electrophoretic mobilities obtained in this work are in excellent agreement with the recently reported theoretical model (Mayer, P.; Slater, G. W.; Drouin, G. Anal. Chem. 1994, 66, 1777-1780). The maximum number of separated oligomers (Mmax) as a function of applied voltage and injection time was also studied, but no strong dependencies were found. Resolution between small oligomers could be significantly improved by following this separation principle.


The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?
Mitochondria are well known as 'the powerhouses of the cell'. Indeed, their major role is cellular energy production driven by both mitochondrial and nuclear DNA. Such a feature makes these organelles essential for successful fertilisation and proper embryo implantation and development. Generally, mitochondrial DNA is exclusively maternally inherited; oocyte's mitochondrial DNA level is crucial to provide sufficient ATP content for the developing embryo until the blastocyst stage of development. Additionally, human fertility and early embryogenesis may be affected by either point mutations or deletions in mitochondrial DNA. It was suggested that their accumulation may be associated with ovarian ageing. If so, is mitochondrial dysfunction the cause or consequence of ovarian ageing? Moreover, such an obvious relationship of mitochondria and mitochondrial genome with human fertility and early embryo development gives the field of mitochondrial research a great potential to be of use in clinical application. However, even now, the area of assessing and improving DNA quantity and function in reproductive medicine drives many questions and uncertainties. This review summarises the role of mitochondria and mitochondrial DNA in human reproduction and gives an insight into the utility of their clinical use.


Ant larvae regulate worker foraging behavior and ovarian activity in a dose-dependent manner.
Division of labor in insect societies relies on simple behavioral rules, whereby individual colony members respond to dynamic signals indicating the need for certain tasks to be performed. This in turn gives rise to colony-level phenotypes. However, empirical studies quantifying colony-level signal-response dynamics are lacking. Here, we make use of the unusual biology and experimental amenability of the queenless clonal raider ant Cerapachys biroi, to jointly quantify the behavioral and physiological responses of workers to a social signal emitted by larvae. Using automated behavioral quantification and oocyte size measurements in colonies of different sizes and with different worker to larvae ratios, we show that the workers in a colony respond to larvae by increasing foraging activity and inhibiting ovarian activation in a progressive manner, and that these responses are stronger in smaller colonies. This work adds to our knowledge of the processes that link plastic individual behavioral/physiological responses to colony-level phenotypes in social insect colonies.


High-frequency ultrasound-responsive block copolymer micelle.
Micelles of a diblock copolymer composed of poly(ethylene oxide) and poly(2-tetrahydropyranyl methacrylate) (PEO-b-PTHPMA) in aqueous solution could be disrupted by high-frequency ultrasound (1.1 MHz). It was found that, upon exposure to a high-intensity focused ultrasound (HIFU) beam at room temperature, the pH value of the micellar solution decreased over irradiation time. The infrared spectroscopic analysis of solid block copolymer samples collected from the ultrasound irradiated micellar solution revealed the formation of carboxylic acid dimers and hydroxyl groups. These characterization results suggest that the high-frequency HIFU beam could induce the hydrolysis reaction of THPMA at room temperature resulting in the cleavage of THP groups. The disruption of PEO-b-PTHPMA micelles by ultrasound was investigated by using dynamic light scattering, atomic force microscopy, and fluorescence spectroscopy. On the basis of the pH change, it was found that the disruption process was determined by a number of factors such as the ultrasound power, the micellar solution volume and the location of the focal spot of the ultrasound beam. This study shows the potential to develop ultrasound-sensitive block copolymer micelles by having labile chemical bonds in the polymer structure, and to use the high-frequency HIFU to trigger a chemical reaction for the disruption of micelles.


On the mechanism of action of H2O2 in the cellular stress.
We propose a hypothesis according to which the reactive and reduced species of oxygen could be the intracellular inducers of the stress (or "heat-shock") response. This hypothesis is based on the following observations on Drosophila cells: a) the return to normoxia after 24 h anaerobiosis is sufficient to induce the synthesis of the "heat shock" proteins without elevation of temperature together with a rapid increase of O2 consumption; b) hydrogen peroxide introduced in the culture medium induces the early transcriptional activation of the "heat shock" genes (maximal after 5 minutes); c) hydrogen peroxide added to cellular extracts in vitro (thus acting as an intracellular metabolite) activates instantaneously the binding capacity of a "heat shock" factor to a DNA "heat shock" regulatory element. Thus, hydrogen peroxide, and possibly other reactive reduced species of oxygen, could trigger the onset of the stress (or "heat shock") response.


Effects of adenosine in combination with calcium channel blockers in patients with primary pulmonary hypertension.
The purpose of this study was to evaluate the effects of vasodilator combination therapy in patients with primary pulmonary hypertension. Calcium channel blockers and adenosine have each been shown to be effective in reducing pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension. However, the effects of combining these vasodilators have not been studied. To test the combination, 12 patients were placed on oral nifedipine and 3 on diltiazem therapy, using a dose titrated to maximal effect (mean nifedipine dose 103 +/- 24 mg, mean diltiazem dose 300 +/- 49 mg). Patients were then given maintenance doses of the calcium channel blocker at half the cumulative loading dose at 6-h intervals. One hour after the maintenance dose of calcium blocker, all patients received an infusion of adenosine, starting with 50 micrograms/kg per min and increasing by 50 micrograms/kg per min at 2-min intervals to a maximally tolerated dose (180 +/- 63 micrograms/kg per min). Ten patients responded to calcium channel blockers (defined as a > or = 20% decrease in pulmonary vascular resistance), with a 16% decrease in mean pulmonary artery pressure (p = 0.057), a 39% decrease in pulmonary vascular resistance (p = 0.002) and a 24% increase in stroke volume (p = 0.007). Five patients were nonresponders, with no significant changes in pulmonary artery pressure, pulmonary vascular resistance, cardiac index or stroke volume. In the calcium channel blocker responders, the combination of adenosine and calcium blocker reduced pulmonary vascular resistance by 49%, increased stroke volume by 33% and decreased mean pulmonary artery pressure by 14% compared with drug-free baseline values. In nonresponders, combination therapy resulted in nonsignificant changes in pulmonary artery pressure and pulmonary vascular resistance. Adenosine has the ability to further decrease pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension who respond to calcium channel blockers. Those who fail to respond to these agents have little added effect from adenosine.


Glycine neurotransmitter transporters: an update.
Glycine accomplishes several functions as a transmitter in the central nervous system (CNS). As an inhibitory neurotransmitter, it participates in the processing of motor and sensory information that permits movement, vision, and audition. This action of glycine is mediated by the strychnine-sensitive glycine receptor, whose activation produces inhibitory post-synaptic potentials. In some areas of the CNS, glycine seems to be co-released with GABA, the main inhibitory amino acid neurotransmitter. In addition, glycine modulates excitatory neurotransmission by potentiating the action of glutamate at N-methyl-D-aspartate (NMDA) receptors. It is believed that the termination of the different synaptic actions of glycine is produced by rapid re-uptake through two sodium-and-chloride-coupled transporters, GLYT1 and GLYT2, located in the plasma membrane of glial cells or pre-synaptic terminals, respectively. Glycine transporters may become major targets for therapeutic of pathological alterations in synaptic function. This article reviews recent progress on the study of the molecular heterogeneity, localization, function, structure, regulation and pharmacology of the glycine transporter proteins.


Does language influence the accuracy of judgments of stuttering in children?
To determine whether stuttering judgment accuracy is influenced by familiarity with the stuttering speaker's language. Audiovisual 7-min speech samples from nine 3- to 5-year-olds were used. Icelandic children who stutter (CWS), preselected for different levels of stuttering, were subdivided into 5-s intervals. Ten experienced Icelandic speech-language pathologists (ICE-SLPs) and 10 experienced U.S. speech-language pathologists (US-SLPs), the latter being unfamiliar with the Icelandic language, independently judged each 5-s interval (n = 756) as stuttered or nonstuttered on 2 separate occasions. As in previous studies, intervals judged to contain stuttering showed wide variability within the ICE-SLP and US-SLP groups. However, both SLP groups (a) displayed satisfactory mean intrajudge agreement, (b) met an independent stuttering judgment accuracy criterion test using English-speaking CWS samples, and (c) met an agreement criterion on approximately 90% of their stuttering and nonstuttering judgments on the Icelandic-speaking CWS samples. Experienced SLPs were shown to be highly accurate in recognizing stuttering and nonstuttering exemplars from young CWS speaking in an unfamiliar language. The findings suggest that judgments of occurrences of stuttering in CWS are not generally language dependent, although some exceptions were noted.


Spinal microglia-derived TNF promotes the astrocytic JNK/CXCL1 pathway activation in a mouse model of burn pain.
Burn injury-induced pain (BIP) is an extremely complicated condition usually resistant to analgesic drugs, while its pathogenesis remains unknown. Considerable attention has been attracted to elucidate the glial mechanisms in chronic pain. In this study, we initiatively used a mouse model of second-degree BIP to investigate the underlying non-neuronal mechanisms at the spinal cord level. Our behavioral results showed that hind-paw burn injury caused persistent allodynia and hyperalgesia for 2 weeks in mice. Further studies revealed that both microglia and astrocytes activated in a spatially- and temporally-dependent manner in spinal cord after burn injury. In addition, the phosphorylated p38 mitogen-activated protein kinase (MAPK)-mediated tumor necrosis factor (TNF) release in spinal microglia is essentially attributed to the early stage of BIP, while the c-Jun N-terminal kinase (JNK) MAPK-dependent chemokine CXCL1 expression is mainly involved in the maintenance of pain hypersensitivity. Most strikingly, burn injury-induced pain symptoms and the activation of astrocytes were significantly suppressed by TNF inhibitor Thalidomide. On the contrary, intrathecal injection of TNF caused apparent pain hypersensitivity, accompanied by the activation of astrocytes and the upregulation of CXCL1 via the JNK MAPK signaling pathway, indicating that TNF is the key cytokine in the interaction between microglia and astrocytes at the spinal level. Moreover, treatment with the CXCR2 receptor antagonist SB225002 to block the biological activities of CXCL1 significantly attenuated the mechanical allodynia and thermal hyperalgesia in this BIP model. Taken together, this study indicates that intervention of glial pathways provides a new perspective in the management of BIP.


The implications of hearing loss on a medical student: A personal view and learning points for medical educators.
Due to the widening access to medicine scheme, students with disabilities are entering medicine. Hearing-impaired students are an important subcategory of medical students, whose specific learning challenges with respect to medicine are poorly explored in the literature. We feel that this topic is particularly important and relevant given the current covid-19 pandemic, which has led to the widespread use of surgical masks, thereby posing a barrier to hearing, communication and education for hearing-impaired medical students. Therefore, the medical education of these students is of even more paramount importance as the pandemic continues. This personal view details the experiences of a current hearing-impaired medical student in the United Kingdom, with key learning points for medical educators who may require insight into hearing loss and how to tailor their teaching techniques accordingly.


The mental health of healthcare workers in the COVID-19 pandemic: A systematic review.
The novel coronavirus 2019 (COVID-19) is widely spreading all over the world, causing mental health problems for most people. The medical staff is also under considerable psychological pressure. This study aimed to review all research carried out on the mental health status of health care workers (HCWs) to bring policymakers and managers' attention. A literature search conducted through e-databases, including PubMed, EMBASE, Scopus, and Web of Science (WoS) from December 2019 up to April 12th 2020. All cross- sectional studies published in English which assessed the health workers' psychological well-being during the SARS-CoV-2 pandemic included. Study quality was analyzed using NHLBI Study Quality assessment tools. One hundred relevant articles were identified through systematic search; of which eleven studies were eligible for this review. Their quality score was acceptable. The lowest reported prevalence of anxiety, depression, and stress among HCWs was 24.1%, 12.1%, and 29.8%, respectively. In addition, the highest reported values for the aforementioned parameters were 67.55%, 55.89%, and 62.99%, respectively. Nurses, female workers, front-line health care workers, younger medical staff, and workers in areas with higher infection rates reported more severe degrees of all psychological symptoms than other health care workers. Moreover, vicarious traumatization in non-front-line nurses and the general public was higher than that of the front-line nurses. During SARS-CoV-2 outbreak, the health care workers face aggravated psychological pressure and even mental illness. It would be recommended to the policymakers and managers to adopt the supportive, encouragement & motivational, protective, and training & educational interventions, especially through information and communication platform.


Mitigation strategies to safely conduct HIV treatment research in the context of COVID-19.
The International AIDS Society convened a multidisciplinary committee of experts in December 2020 to provide guidance and key considerations for the safe and ethical management of clinical trials involving people living with HIV (PLWH) during the SARS-CoV-2 pandemic. This consultation did not discuss guidance for the design of prevention studies for people at risk of HIV acquisition, nor for the programmatic delivery of antiretroviral therapy (ART). There is strong ambition to continue with HIV research from both PLWH and the research community despite the ongoing SARS-CoV-2 pandemic. How to do this safely and justly remains a critical debate. The SARS-CoV-2 pandemic continues to be highly dynamic. It is expected that with the emergence of effective SARS-CoV-2 prevention and treatment strategies, the risk to PLWH in clinical trials will decline over time. However, with the emergence of more contagious and potentially pathogenic SARS-CoV-2 variants, the effectiveness of current prevention and treatment strategies may be compromised. Uncertainty exists about how equally SARS-CoV-2 prevention and treatment strategies will be available globally, particularly for marginalized populations, many of whom are at high risk of reduced access to ART and/or HIV disease progression. All of these factors must be taken into account when deciding on the feasibility and safety of developing and implementing HIV research. It can be assumed for the foreseeable future that SARS-CoV-2 will persist and continue to pose challenges to conducting clinical research in PLWH. Guidelines regarding how best to implement HIV treatment studies will evolve accordingly. The risks and benefits of performing an HIV clinical trial must be carefully evaluated in the local context on an ongoing basis. With this document, we hope to provide a broad guidance that should remain viable and relevant even as the nature of the pandemic continues to develop.


CDCR with buccal mucosal graft: comparative and histopathological study.
Conjunctivodacryocystorhinostomy (CDCR) is a procedure with a high functional success rate, on the other hand post-operative complications are frequent and tube replacement is often required. Therefore, new investigations were undertaken in order to relieve the undesired effects of the tube. Implantation of the Jones tube circumscribed with a buccal mucosal graft and subsequent removal of the tube when an epithelium lined track was formed has been reported in the literature in recent years. In this study efficacy and safety of this alternative technique was evaluated. CDCR with insertion of Jones tube surrounded with a buccal mucosal graft was performed on 14 patients (14 eyes) between September 1995 and March 1997 and results were evaluated. Results were compared with our previous series of traditional CDCR, involving 22 patients (22 eyes). Functional success was obtained in all cases with relief of epiphora after a mean follow-up of 13.7+/-5.7 months. In 11 cases, tubes were removed at the sixth post-operative month and passage was blocked in 9 cases. Subsequent surgical tube reinsertion was performed in those patients. Biopsy specimens were obtained in two cases during tube replacement and were examined histologically. Disarrangement of the basal epithelial cells and infiltration of the surrounding connective tissue with round cells were observed. These histopathological findings suggested a significant graft degeneration threatening the continuity of the passage. Tube displacement existed in two patients, and partial mucosal graft extrusion was apparent in one case during the period with the tube still inserted. Surgical tube replacement was required in only two cases to correct lateral migration of the tube. Incidence of complications and need for surgical tube replacement were found to be less than our previous series of 22 CDCR patients without buccal mucosa grafting. These findings suggest that CDCR with buccal mucosal graft is a promising new method for the treatment of epiphora because of its low incidence of complications during the period with the tube. However, tube removal at the sixth post-operative month is probably not indicated. Therefore, studies with larger series and longer follow-up should be undertaken to confirm the advantages of the technique.


Histamine type 1 receptor deficiency reduces airway inflammation in a murine asthma model.
Histamine plays an important role in immediate and late immune responses. The histamine type 1 (H1) receptor is expressed on several immune cell populations, but its role in a murine model of asthma remains unclear. The present study evaluated the role of histamine H1 receptors in airway allergic inflammation by comparing the development of bronchial asthma in histamine H1 receptor gene knockout (H1RKO) and wild-type mice. H1RKO and wild-type mice were sensitized by intraperitoneal injection of ovalbumin (OVA) or saline, and then challenged with aerosolized OVA or saline. Ventilatory timing in response to inhaled methacholine was measured, and samples of blood, bronchoalveolar lavage, and lung tissues were taken 24 h after the last OVA challenge. OVA-treatedwild-type mice showed significantly increased airway eosinophilic infiltration, and airway response to methacholine compared to OVA-treated H1RKO mice. The serum level of immunoglobulin E and levels of interleukin (IL)-4, IL-5, IL-13, and TGF-beta1 in bronchoalveolar lavage fluid were lower in OVA-treated H1RKO mice than in OVA-treated wild-type mice, but there was no significant difference in interferon-gamma expression. Overall, deletion of histamine H1 receptors reduced allergic responses in a murine model of bronchial asthma. Histamine plays an important role via H1 receptors in the development of T helper type 2 responses to enhance airway inflammation.


An interferon-gamma-binding protein of novel structure encoded by the fowlpox virus.
Poxviruses have evolved various strategies to counteract the host immune response, one of which is based on the expression of soluble cytokine receptors. Using various biological assays, we detected a chicken interferon-gamma (chIFN-gamma)-neutralizing activity in supernatants of fowlpox virus (FPV)-infected cells that could be destroyed by trypsin treatment. Secreted viral proteins were purified by affinity chromatography using matrix-immobilized chIFN-gamma, followed by two-dimensional gel electrophoresis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis indicated that the viral IFN-gamma-binding protein in question was encoded by the FPV gene 016. The chicken IFN-gamma binding and neutralizing activity of the recombinant FPV016 protein was confirmed using supernatants of cells infected with a recombinant vaccinia virus that lacked its own IFN-gamma-binding protein but instead expressed the FPV016 gene. The FPV016 gene product also neutralized the activity of duck and human IFN-gamma but failed to neutralize the activity of mouse and rat IFN-gamma. Unlike previously known cellular and poxviral IFN-gamma receptors, which all contain fibronectin type III domains, the IFN-gamma-binding protein of FPV contains an immunoglobulin domain. Remarkably, it exhibits no significant homology to any known viral or cellular protein. Because IFN-gamma receptors of birds have not yet been characterized at the molecular level, the possibility remains that FPV016 represents a hijacked chicken gene and that avian and mammalian IFN-gamma receptors have fundamentally different primary structures.


Conformational Changes in Two Inter-Helical Loops of Mhp1 Membrane Transporter.
Mhp1 is a bacterial secondary transporter with high-resolution crystal structures available for both the outward- and inward-facing conformations. Through molecular dynamics simulations of the ligand-free Mhp1 as well as analysis of its crystal structures, here we show that two inter-helical loops, respectively located at the extra- and intracellular ends of the "hash motif" in the protein, play important roles in the conformational transition. In the outward- and inward-facing states of the protein, the loops adopt different secondary structures, either wrapped to the end of an alpha-helix, or unwrapped to extended conformations. In equilibrium simulations of 100 ns with Mhp1 in explicit lipids and water, the loop conformations remain largely stable. In targeted molecular dynamics simulations with the protein structure driven from one state to the other, the loops exhibit resistance and only undergo abrupt changes when other parts of the protein already approach the target conformation. Free energy calculations on the isolated loops further confirm that the wrapping/unwrapping transitions are associated with substantial energetic barriers, and consist of multiple sequential steps involving the rotation of certain backbone torsion angles. Furthermore, in simulations with the loops driven from one state to the other, a large part of the protein follows the loops to the target conformation. Taken together, our simulations suggest that changes of the loop secondary structures would be among the slow degrees of freedom in the conformational transition of the entire protein. Incorporation of detailed loop structures into the reaction coordinate, therefore, should improve the convergence and relevance of the resulting conformational free energy.


Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury.
Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.